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PI3K Inhibitors in Cancer: Clinical Implications and Adverse Effects

Rosalin Mishra, Hima Patel, Samar Alanazi and 2 more

International Journal of Molecular Sciences · 2021 · Review · CC BY

doi:10.3390/ijms22073464

Abstract

The phospatidylinositol-3 kinase (PI3K) pathway is a crucial intracellular signaling pathway which is mutated or amplified in a wide variety of cancers including breast, gastric, ovarian, colorectal, prostate, glioblastoma and endometrial cancers. PI3K signaling plays an important role in cancer cell survival, angiogenesis and metastasis, making it a promising therapeutic target. There are several ongoing and completed clinical trials involving PI3K inhibitors (pan, isoform-specific and dual PI3K/mTOR) with the goal to find efficient PI3K inhibitors that could overcome resistance to current therapies. This review focuses on the current landscape of various PI3K inhibitors either as monotherapy or in combination therapies and the treatment outcomes involved in various phases of clinical trials in different cancer types. There is a discussion of the drug-related toxicities, challenges associated with these PI3K inhibitors and the adverse events leading to treatment failure. In addition, novel PI3K drugs that have potential to be translated in the clinic are highlighted.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 19, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

PI3K/AKT signaling is involved in important physiological and pathophysiological functions that drive tumor progression such as metabolism, cell growth, proliferation, angiogenesis and metastasis. Pharmacological or genetic suppression of this signaling causes cancer cell death and regression of tumor growth. The PI3K pathway is activated via point mutation of the PIK3CA gene or inactivation of the phosphatase and tensin homolog (PTEN) gene. Activation of this pathway occurs in approximately 30–50% human cancers and results in resistance to various anti-cancer therapies.

PI3K proteins are classified into three main classes (I, II and III) based on the substrate specificities and structural characteristics. Class I PI3Ks are categorized into two subtypes (A and B) based on the mode of regulation. Class IA PI3Ks form dimers containing a regulatory (p85α, p85β, p55α, p55γ, p50α) and a catalytic (p110α, p110β, p110δ) subunit. Class I PI3Ks act downstream of both G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs). In addition, these regulatory subunits play an important role in stabilization of the p110 catalytic subunits and in suppression of the basal lipid kinase activity. Class IB PI3Ks which are activated downstream of GPCRs form heterodimers consisting of p110γ as catalytic subunit with other regulatory subunits such as p101, p87 or p84. This class consists of three isoforms (PI3K-C2α, PI3K-C2ß and PI3K-C2γ). These isoforms have a RAS-binding domain (RBD), a helical domain, and a catalytic domain but lack a regulatory domain. The class III PI3Ks also known as vacuolar protein sorting 34 (VPS34) heterodimerize with membrane-associated VPS15 regulatory subunit. This VPS34-VPS15 complex is ubiquitously expressed in mammals regulating several functions such as phagocytosis, autophagy, endocytosis and intracellular trafficking. Some reports have considered mTOR as class IV PI3K-related kinase whose catalytic domain is associated with ataxia-telangiectasia (ATM), fluorescence recovery after photo bleaching (FRAP) and transformation/transcription domain-associated protein (TRRAP) and FK506-binding protein 12 (FKBP12)/rapamycin (FRB)-binding domain and a C-terminal FAT domain (FATC). There are two Huntington elongation factor 3, PR65/A subunit of protein phosphatase 2A, TOR (HEAT) repeats in the N-terminal region which modulate the protein–protein interactions in mTOR signaling.

Small-molecule inhibitors targeting PI3K consist of pan, isoform-specific and dual PI3K/mTOR inhibitors. Wortmanin and LY294002 were the first-generation PI3K inhibitors that belong to the non-isoform-specific category. Wortmanin with irreversible inhibition, lack of selectivity and adverse effects resulted in termination of its clinical trials. Poor solubility, bioavailability and rapid degradation of LY294002 prevented its further biological evaluation and clinical studies. To date, five PI3K inhibitors (Copanlisib, Idelalisib, Umbralisib, Duvelisib and Alpelisib) have been approved by the United States Food and Drug Administration (FDA). This has encouraged clinicians and researchers to test other PI3K inhibitors in both preclinical and clinical settings with the goal to identify a potent PI3K inhibitor with significant clinical efficacy, low toxicities and optimum bioavailability. In this review, we discuss the challenges associated with successful development of PI3K inhibitors including the aberrant mutations/amplification of genes such as PI3K and/or PI3K-driven molecules, the role of these mutations and other molecules in PI3K-mediated drug sensitivity, and compensatory signaling mechanisms resulting in PI3K inhibitor resistance causing treatment failure in the clinic. In addition, we have summarized active, not-recruiting and completed trials along with detailed clinical outcomes for PI3K inhibitors in a wide variety of cancers along with the adverse events.

2. Signaling Molecules and Factors Contributing to PI3K Inhibitor Resistance

PI3K signaling is deregulated in a variety of cancers. There are several factors that ultimately result in resistance to PI3K inhibitors including (1) inactivation or loss of PTEN activity, (2) mutations and amplification of PI3K, (3) drug-related toxicities, (4) feedback upregulation leading to compensatory mechanisms, (5) non-coding RNA in regulating PI3K signaling, (6) enhanced insulin production upon PI3K inhibition, (7) selection of patient population in clinical trials and (8) miscellaneous resistance mechanisms, as summarized below.

2.1. Inactivation or Loss of PTEN Activity

PTEN is a well-characterized tumor suppressor which is a negative modulator of the PI3K pathway. PTEN regulates PI3K via dephosphorylating phosphatidylinositol-3, 4, 5-trisphosphate (PIP3). The loss of or gain in function is seen in several cancers including breast, brain and prostate. Increased PI3K signaling and tumorigenesis is observed in PTEN knock-in mice with PTEN mutations. Loss of PTEN lipid phosphatase activity causes the activation of AKT in PTEN-null cancers. A study by Juric et al. indicates that loss of PTEN can lead to clinical resistance to a PI3K inhibitor, Alpelisib in breast cancer. These studies indicate the possible role of PTEN in modulating response to PI3K inhibitors in different cancers.

2.2. Mutations and Amplification of PI3K

The p110α subunit of PIK3CA is frequently mutated and amplified (~30%) in a variety of cancers. There are hotspot mutations such as PIK3CAE545K in exon 9 in the helical PI3K homology domain that suppresses inhibition of p110α by p85 regulatory subunit. Another mutation is PIK3CAH1047 present in the catalytic subunit in exon 20 which enhances the interaction of p110α with the lipid membrane. E542K is another crucial PI3K mutation with significant oncogenic potential associated with elevated in vitro catalytic activity.The helical and kinase mutations in p110α domain induce oncogenic activity based on different interaction between the PI3K regulatory subunit, p85 with RAS-GTP. The oncogenic activity induced by helical domain mutations is independent of binding to p85 subunit. However, requires interaction with RAS-GTP. However, the kinase domain mutations are active without RAS-GTP binding but dependent on their interaction with p85. In addition, co-existence of both the domain mutations increases the p110 function and tumorigenic activity synergistically. A recent study has shown that C2 domain deletions in PIK3CA activate PI3K signaling significantly and also enhance the sensitivity to PI3Kα inhibitors. The deregulation of PI3K signaling leads to several oncogenic activities such as cancer cell proliferation, invasion, migration, glucose transport and angiogenesis that regulate tumor progression.

Genetically engineered mouse models (GEMMs) using PIK3CA mutations demonstrate important tumorigenic potential associated with PI3K signaling. For example, the PIK3CAH1047R knock-in mouse model promoted conditional activation of the PI3K pathway and induced breast tumorigenesis. Another study indicated that PIK3CA H1047R mutation with PTEN deletion led to the development of ovarian adenocarcinoma and granulosa cell tumor in a mouse model. Further, overexpression of wild-type catalytic subunits (p110ß, p110δ and p110γ) is known to induce an oncogenic phenotype. The role of p110ß is well established in cancers including breast and prostate. Although the mechanism of action of this subunit is not well known, some reports still indicate that it works via GPCR signaling. E633K is a p110ß helical mutation first reported in HER2+ breast cancer. PIK3CAD1067V is another recurrent somatic mutation in the p110β subunit which induced in vitro and in vivo cancer cell growth via the activated PI3K signaling pathway. Pharmacologic inhibition using a specific p110β inhibitor (TGX-221) inhibited growth in patient-derived renal cell carcinoma cells with endogenous PIK3CAD1067V and epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells as well as in NIH-3T3 cells engineered to express this mutation. In addition, expression of this mutation is known to promote Erlotinib resistance in EGFR-mutant lung adenocarcinoma cells. PI3Kδ plays a crucial role in myeloid cell activities such as inflammation-driven cell infiltration, neutrophil oxidative burst, immune complex-mediated macrophage activation, mast cell maturation and degranulation. It also plays an important role in inducing cancer cell proliferation and AKT activation in myeloid leukemia. PI3Kδ point mutations have been identified in a panel of diffuse B-cell lymphomas. It is known to regulate in vitro chemotactic migration in response to EGF and share similar biological function in breast cancer cells and macrophages.

PI3Kγ is expressed in immune cells of myeloid origin that regulates innate immunity in both cancer and inflammatory cells. PI3Kγ regulates solid tumor neovascularization, contributes to chemotactic response and reactive oxygen species (ROS) production in neutrophils. All these studies indicate the key role of PI3K and PI3K isoform-mediated signaling along with site-specific driver mutations that leads to oncogenic transformation of cancer cells which could ultimately lead to drug resistance.

2.3. Drug-Related Toxicities Affect Sustained Target Suppression

One major hurdle in the development PI3K inhibitors is the inability to achieve optimal drug-target blockade in tumors due to drug-related toxicities in patients. Toxicities from small-molecule PI3K inhibitors depend on their PI3K isozyme specificity. For example, the adverse effects associated with PI3Kα inhibitors are mostly rash and hyperglycemia, and the side effects associated with δ subunits are mostly gastrointestinal, transaminitis and myelosuppression. The pan-PI3K inhibitors share common dose-dependent toxicities such as fatigue, diarrhea, rash and hyperglycemia. Dual PI3K inhibitors have a broader toxicity profile compared to isoform or pan-PI3K inhibitors. Isoform-specific PI3Kδ inhibitors have a better effect in B-cell malignancy compared to pan or dual PI3K inhibitors because of the toxicity profile. Several studies have indicated that intermittent dosing schedules of PI3K drugs have a better safety profile over a continuous dosing pattern. A study by Hudson et al. showed that when administrated intermittently PI3Kα/δ inhibitor AZD8835 showed better anti-tumor efficacy in breast cancer xenograft models as a monotherapy and in combination with an ER inhibitor (Fulvestrant) and CDK4/6 inhibitor (Palbociclib) that suppressed AKT activation and induced cell death. Another study demonstrated that intermittent administration of mitogen-activated protein kinase kinase (MEK) inhibitor, GDC-0973 with a PI3K inhibitor (GDC-0941) triggered cell death and tumor growth inhibition. However, dosing schedules, suboptimal dose selection and on-target toxicities of several PI3K inhibitors failed to cause the complete and sustained inhibition of PI3K signaling, challenging the efficacy of these PI3K inhibitors in the clinic.

2.4. Feedback Upregulation Leading to Compensatory Mechanism

Drug resistance associated with pharmacological inhibition of PI3K inhibitors is caused due to feedback upregulation of the PI3K/AKT/mTOR pathway involving RTKs, growth factors and downstream transcription factors. One such transcription factor is forkhead box (FOXO), which represses RTKs or other adaptors that activate the PI3K pathway, such as human epidermal growth factor receptor 3 (HER3), insulin-like growth factor 1 receptor (IGF1R), EGFR, fibroblast growth factor receptor (FGFR) and insulin receptor (InsR). Therefore, inhibiting PI3K/AKT signaling suppresses the FOXO phosphorylation, causing FOXO-dependent repression of RTKs leading to derepression of molecules downstream of AKT such as S6K and growth factor receptor-bound protein 10 (GRB10), ultimately resulting in activation of multiple RTKs and partial maintenance of PIP3. Partial maintenance of PIP3 is also mediated by PI3K isoform p110ß in luminal breast cancer cells where PI3K is hyperactivated due to HER2-HER3 dimers. Another study showed the key role of FOXO-mediated adaptive resistance in matrix-attached cancer cells in response to inhibition of PI3K/mTOR signaling. Another FOXO-dependent adaptive response is via upregulation of Rictor, resulting in enhanced AKT activation in renal cancer cells.

Another transcription factor, signal transducer and activator of transcription 5 (STAT5) plays a crucial role in mediating resistance to PI3K inhibitors in vitro. A study by Britschgi et al. showed that STAT5 is activated by Janus kinase 2 (JAK2) that evoked a positive feedback loop to dampen the efficacy of PI3K/mTOR inhibition via secretion of interleukin-8 (IL-8) in several cell lines and primary breast tumors. The data also showed that pharmacological and genetic inhibition of JAK2 combined with PI3K/mTOR inhibition abrogated this feedback loop. Treatment with the AKT inhibitor AZD5363 activates several RTKs, estrogen receptor 1 (ESR1) mRNA, and ERα-mediated transcription of insulin-like growth factor 1 (IGF1) and IGF2 ligands. In another study, expression of ESR1 mRNA and ER-related proteins are increased upon PI3K inhibition using Alpelisib. These drug-related transcriptional alterations were abrogated via anti-ER drugs. Treatment with Alpelisib in ER+ breast cancer cells or patients with primary tumors resulted in activation of ERα via lysine methyltransferase 2D (KMT2D)-dependent FOXA1-PBX1 complex. All these data highlight the role of ERα-mediated feedback upregulation in response to PI3K inhibition that might result in drug insensitivity in PIK3CA-driven cancers.

2.5. Non-Coding RNA in Regulating PI3K Signaling

Non-coding RNAs (ncRNAs) are commonly employed for RNAs that do not encode proteins which are involved in cancer drug resistance. These ncRNAs include siRNA, piRNA, miRNA and lncRNA. In general, ncRNAs function to regulate gene expression at the transcriptional and post-transcriptional level. Several lncRNAs are known to interact with PI3K to activate signaling. For example, lncRNA CRNDE is overexpressed in several cancers to activate cell proliferation and growth via PI3K-dependent pathways. lncRNA OIP5-AS1 is another ncRNA that activates PI3K signaling and cause Cisplatin resistance in osteosarcoma. OIP5-AS1 loss causes miR-410 accumulation that facilitates cell cycle progression, proliferation and apoptosis inhibition by targeting Krüppel-Like Factor-10 (KLF10) via activating the PI3K/AKT/mTOR pathway in multiple myeloma. lncRNA CCAT1 regulates thyroid and squamous cancer cell migration via activation of the PI3K/AKT pathway. lncRNA H19 inhibits melanoma cell migration and invasion via inactivating PI3K/AKT/NFĸB signaling. lncRNA HOTAIR promotes Cisplatin resistance in gastric cancer by targeting miR-126/miR-34a through activation of the PI3K/AKT pathway. It is also involved in multidrug resistance to Imatinib in a PI3K/AKT-dependent signaling in myeloid leukemia cells. It also regulates cancer cell growth, metastasis and apoptosis via PI3K/AKT-dependent pathway in melanoma, adenocarcinoma and glioma. lncRNA NEAT1 plays a key role in PI3K/AKT-mediated tumorigenesis in several cancer types. HULC is another lncRNA that is involved in bladder cancer cell proliferation via regulation of ZIC2 and PI3K/AKT signaling. It induces leukemia cell proliferation and suppresses angiogenesis in gliomas via an AKT-dependent pathway. AB073614 and PTTG3P are known to promote cancer cell proliferation, migration and invasion via PI3K/AKT-dependent signaling in colorectal and hepatocellular carcinoma, respectively. MALAT1 is another crucial lncRNA which is upregulated in several cancers and induces tumorigenic phenomenon via miRNA-mediated PI3K/AKT-dependent signaling. lncRNA ATB induces bladder cancer cell proliferation, migration, and invasion via AKT/mTOR-mediated signaling. lncRNA BC087858 induces acquired resistance to EGFR-TKIs by activating PI3K/AKT and epithelial–mesenchymal transition (EMT)-dependent signaling in lung cancer.

Linc00659 and Linc00152 induce cancer cell growth and inhibit apoptosis in colorectal and lung cancer, respectively, via PI3K/AKT-mediated pathway activation. In similar lines, Linc00462 and Linc01296 regulate different hallmarks in tumor progression via AKT signaling. There are several other lncRNAs including UCA1, ecCEBPA, Ftx, RMEL3, lncARSR, BDLNR, ANRIL, ROR, MYD88, RNA-422 and PlncRNA-1 that are upregulated and mediate PI3K-dependent signaling in different cancers. Other lncRNAs which are downregulated yet known to mediate tumorigenesis via PI3K/AKT-dependent signaling include linc003121 in thyroid cancer, RP4 in colorectal cancer, MEG3 in endometrial cancer, GAS5 in various cancers. In summary, there is a long list of ncRNAs including those discussed above which are promising candidates to be targeted to overcome PI3K inhibitor resistance in clinic.

2.6. Enhanced Insulin Production upon PI3K Inhibition

The p110α subunit of PI3K is known to mediate cellular responses to insulin signaling in different diseases including cancer. Targeting this subunit via specific PI3K inhibitors inhibits the insulin-dependent signaling, which in turn promotes glycogen breakdown in liver and inhibits glucose uptake in skeletal muscle and adipose tissues, resulting in hyperglycemia. However, this effect is compensated via the insulin feedback pathway that activates PI3K/AKT/mTOR signaling in tumor cells compromising the therapeutic response to PI3K inhibitors. It has been shown that use of dietary and pharmaceutical approaches can also target this insulin feedback, resulting in enhanced efficacy and reduced toxicities due to PI3K inhibitors. Molinaro et al. have shown that insulin-mediated PI3K/AKT signaling is dependent on redundant PI3Kα/β activities and is mediated by RAS. In another study in acute leukemia patients, the effects of PI3K/AKT/mTOR inhibitors and insulin varied among the patient subsets, and it was noted that the variations in insulin responsiveness are associated with differential susceptibility to metabolic targeting. An increase in the plasma levels of insulin that is associated with hyperglycemia is also observed in patients treated with PI3K inhibitors and hence enhanced insulin level serves as a pharmacodynamics surrogate marker for such patients.

2.7. Selection of Patient Population in Clinical Trials

Selection of accurate patient population with active PIK3CA mutations determines the efficacy of PI3K inhibitors. For example, in a phase I study, the clinical benefit rate (CBR) to a PI3K inhibitor, Alpelisib was 44% in tumors with PIK3CA hotspot mutations versus 20% in those patients with WT PIK3CA. In another study, patients with PIK3CA H1047R mutation had a better survival rate (36%) over subjects with WT tumors. In addition, significant improvement in the progression-free survival (PFS) was seen for patients with PIK3CA mutant-specific ctDNA treated with Alpelisib, indicating that the efficacy of PI3Kα inhibitors is dependent on PIK3CA-mutant tumors. However, patients with other concurrent alterations in TP53, FGFR1 and KRAS did not benefit from Alpelisib, indicating that exclusion of these additional resistance biomarkers could enhance the efficacy of PI3K inhibitors in cancers. There is evidence suggesting that PIK3CA hotspot mutations do not always capture all PI3K-dependent tumor genotypes that potentially respond to PI3K inhibitors. Hence, selection of the optimal patient population with activating PIK3CA mutations and identification of other genotypes conferring PI3K pathway dependence including PIK3CA mutations or amplifications must be included in PI3K inhibitor-based trials.

2.8. Miscellaneous Resistance Mechanisms

In addition to those mentioned above, there are other factors and mechanisms of resistance and/or compensatory pathways derived from both clinical and in vitro lab studies, which affect PI3K signaling. These include (a) HRAS and KRAS mutations which reduce susceptibility to PI3K inhibitors while knockdown of these has shown to improve sensitivity to PI3K inhibitors. (b) NOTCH-MYC pathway/MYC amplification: NOTCH pathway and downstream induction of c-MYC confer resistance to PI3K inhibitors whereas knocking down MYC reverses resistance to PI3K/mTOR dual inhibitors. Another report indicated that MYC amplification is associated with eIF4E-mediated resistance to dual PI3K inhibitors. (c) Other factors that confer resistance to PI3K inhibitors include ribosomal S6 kinases 3/4 (RSK3/4), p21-activated kinase1 (PAK1), mitogen- and stress-activated kinase 1 (MSK1), lysine demethylase 6B (KDM6B), insulin-like growth factor-binding protein 5 (IGFBP5) and cyclin-dependent kinase 4/6 (CDK4/6). (d) FGFR1amplifications. Overexpression and/or amplification of AXL, serum/glucocorticoid regulated kinase family member 3 (SGK3), PIM1, S-phase kinase-associated protein 2 (SKP2), phosphoinositide-dependent kinase-1-serine/threonine-protein kinase1 (PDK1-SGK1). In addition, there are other factors leading to resistance mechanisms such as a high level of purine-related metabolites, elevated glycolysis with dysregulated mitochondrial signaling leading to loss of PTEN and PPP2R2B expression in response to dual PI3K/mTOR inhibitors, macrophages in the tumor microenvironment contributing to PI3K inhibitor resistance via the NFĸB pathway, and lack of PI3K mutant-specific inhibitors currently available. These are other pathways which need to be explored and targeted in the development of successful PI3K inhibitors.

3. Recent Advances in PI3K Inhibitor-Based Therapies

There are several PI3K inhibitors including pan, isoform-specific and dual PI3K/mTOR inhibitors which are tested in various phases of human clinical trials. In this section, we describe the active not-recruiting and completed studies involving PI3K inhibitors. We have also briefly mentioned about novel pan-PI3K inhibitors yet to be tested in clinical trials including RIDR-PI-103 that is currently investigated in our laboratory. Figure 1 highlights various drugs targeting PI3K signaling.

3.1. Pan-PI3K Inhibitors

Pan-PI3K inhibitors target all four isoforms (α, ß, δ, and γ) of class I PI3K and are ATP-competitive inhibitors. These inhibitors are associated with several adverse effects due to unselective blockage of PI3K signaling. Herein, we have listed pan-PI3K inhibitors which are in different stages of human clinical trials. Out of all pan-PI3K inhibitors, only Copanlisib has been approved by the FDA.

3.1.1. Buparlisib/NVP-BKM120/BKM120

Buparlisib/NVP-BKM120/BKM120 is a potent oral reversible bioavailable pan-PI3K inhibitor targeting p110 -α,-ß, -δ, -γ isoforms with IC50 values of 52, 166, 116 and 262 nM, respectively. Few of the active not-recruiting and completed trials testing Buparlisib in phase I and phase II are mentioned below. Most of the clinical trials using Buparlisib are either sponsored or are in collaboration with Novartis Pharmaceuticals. For example, a phase I active trial is testing Buparlisib with Rituximab, a chimeric monoclonal antibody against CD20 in patients with relapsed or refractory (R/R) indolent B-cell lymphoma. The study was sponsored by the Ohio State University Comprehensive Cancer Center. The main aim of the trial was to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of this drug combination.

There are several completed studies with Buparlisib without any significant clinical outcomes as summarized below. The trials with specific clinical outcomes and adverse events are summarized in Table 1. An early phase I study aimed to determine the grade of inhibition of PI3K/mTOR signaling in a pre-surgery setting with Buparlisib along with potential biomarker assessment for a pathologic complete response in breast cancer patients. This was sponsored by Grupo Hospital de Madrid. A phase II trial sponsored by University Hospital, Essen investigated the efficacy and safety of Buparlisib with tamoxifen (an ER inhibitor) in ER/PR+, HER2- breast cancer patients with prior exposure to anti-hormonal therapy. A phase I multicenter, non-randomized open-label dose-escalation study aimed to investigate the MTD of Buparlisib in combination with LEE011 (a CDK4/6 inhibitor) and Letrozole (a non-steroidal aromatase inhibitor) in HR+, HER2- post-menopausal women with locally advanced or metastatic breast cancer (MBC) was completed without significant outcomes. A phase I study tested the efficacy of Buparlisib in Chinese patients with advanced solid tumors.

Another phase I study of Buparlisib was explored in combination with chemotherapeutics Cisplatin and Etoposide in patients with small-cell lung cancer (SCLC). The study was sponsored by University of California. The primary objective of the trial was to determine the safety and feasibility and the secondary objectives were to establish the MTD, DLT and pharmacokinetic parameters of this triple drug combination regimen. It was also investigated with LEE011 plus Fulvestrant along with another PI3K-α-specific class I inhibitor (BYL719) to explore the clinical utility of this drug combination in ER+/HER2- locally advanced or metastatic breast cancer patients. A phase I dose-escalation treatment regimen included Buparlisib administrated in a concurrent treatment arms with chemotherapy (Capecitabine) or anti-HER2 targeted therapy in patients with MBC. The first treatment arm tested Buparlisib plus Capecitabine, the second arm tested BYL719 plus Capecitabine, the third arm tested BKM120 with Capecitabine plus Trastuzumab (a monoclonal antibody targeting HER2) and the last arm tested the concurrent treatment of Buparlisib with Capecitabine plus Lapatinib (a HER2-specific inhibitor). The study was initiated by the UNC Lineberger Comprehensive Cancer Center in collaboration with Novartis Pharmaceuticals and aimed to achieve the tolerability, safety, and MTD of these regimens. A phase II study sponsored by US Oncology Research investigated the safety and efficacy of Buparlisib in combination with chemotherapy, Capecitabine in breast cancer patients with brain metastases. Another chemotherapy (Docetaxel) was tested with Buparlisib in an early phase I pilot study to identify the adverse effects and the recommended phase 2 dose (RP2D) of Buparlisib in patients with locally advanced metastatic solid tumors who cannot be treated with surgery. The study was sponsored by Roswell Park Cancer Institute in collaboration with NCI and Novartis Pharmaceuticals. A multicenter, open-label phase I study sponsored by the UNC Lineberger Comprehensive Cancer Center aimed to define the MTD of Buparlisib with a chemotherapy regimen folinic acid (leucovorin)-fluorouracil-oxaliplatin (mFOLFOX6) in advanced metastatic pancreatic cancer patients. A phase I trial aimed to evaluate the preliminary anti-tumor effect, the safety profile/tolerability of BKM120 or BEZ235 (another PI3K/mTOR inhibitor) with Letrozole (non-steroidal aromatase inhibitor) used as endocrine therapy in post-menopausal MBC patients. The study was sponsored by the Vanderbilt-Ingram Cancer Center. A phase I study sponsored by Washington University School of Medicine in collaboration with NCI aimed to determine the toxicity profile and the MTD of Buparlisib with Fulvestrant in estrogen receptor (ER)+ stage IV breast cancer patients.

A phase I study evaluating the best dose of Buparlisib in combination with chemotherapies (Carboplatin and Pemetrexed disodium) was completed in patients with stage IV lung cancer. The study was sponsored by City of Hope Medical Center with NCI and aimed to figure out the RP2D, DLTs of this combination regimen. Other chemotherapies were also tested in combination with Buparlisib. For example, in a phase Ib study sponsored by Fondazione Michelangelo, Buparlisib was tested with Cisplatin (in group 1) or with Carboplatin (in group 2) to identify the RP2D of these drug combinations for patients with advanced solid tumors. A phase I pilot study aimed to identify the clinical benefits, overall response rate (ORR) and toxicities associated with Buparlisib treatment in patients with non-hodgkin lymphoma (NHL). The trial was sponsored by Mayo Clinic with NCI. Two phase I/II trials tested the efficacy of Buparlisib in combination with either thoracic radiotherapy or with Erlotinib, an EGFR inhibitor in non-small-cell lung cancer (NSCLC) patients. An open-label, phase II trial evaluated Buparlisib to determine the PFS for patients with R/R primary central nervous lymphoma (PCNSL) and R/R secondary central nervous system lymphoma (SCNSL).

3.1.2. CH5132799/PA-79

CH5132799/PA-79 is a novel oral pan-class I PI3K inhibitor with a strong inhibitory activity against the PI3Kα isoform (IC50 = 0.014 μM). This drug has promising anti-tumor activity in PI3K mutation-driven cancers and xenograft mice models. To date, there is only one phase I study that has tested CH5132799 as described in Table 1.

3.1.3. Pilaralisib/XL147/SAR245408

Pilaralisib/XL147/SAR245408 is a reversible pan-class I PI3K inhibitor against the PI3Kα/δ/γ isoforms with respective IC50 values of 39 nM/36 nM/23 nM in cell-free assays although known to be less potent to PI3Kβ isoform. Most trials using Pilaralisib were sponsored by Sanofi. In an early phase I study sponsored by Sanofi in collaboration with Merrimack Pharmaceuticals, Pilaralisib was tested with MM-121/SAR256212, an anti-HER3 antibody with a goal to determine the MTD and RP2D of this drug combination in patients with advanced solid tumors. Another such phase I dose-escalation trial tested the clinical efficacy of Pilaralisib with MSC1936369B, an oral MEK inhibitor in locally advanced or metastatic solid tumors to evaluate the safety, tolerability and initial PK profile of this drug combination. Similar phase I and II studies sponsored by Sanofi, respectively, investigated Pilaralisib as monotherapy in patients with advanced solid tumors or recurrent endometrial cancer.

3.1.4. ZSTK474

ZSTK474 is an oral ATP-competitive pan-PI3K class I inhibitor with week effectiveness against mTOR. To date, Zenyaku Kogyo Co., Ltd., Tokyo, Japan has sponsored all the known clinical trials using this drug. ZSTK474 was tested as a monotherapy in open-label phase I studies in Japanese patients and other cancer patients with advanced solid tumors to evaluate the safety, tolerability, efficacy and initial PK profile.

3.1.5. Sonolisib/PX-866

Sonolisib/PX-866 is an improved semi-synthetic analog of Wortmannin, which is an oral, irreversible pan-PI3K inhibitor that had demonstrated significant anti-tumor effect in squamous cell carcinoma of head and neck (SCCHN) patients with PI3K mutation. It exhibits strong inhibitory activity against PI3K110 -α, -δ and -γ isoforms but poor activity against the ß isoform. A phase I/II study tested Sonolisib in combination with Docetaxel in patients with solid tumors. The study was sponsored by Cascadian Therapeutics which also evaluated Sonalisib as monotherapy in patients with advanced solid tumor in yet another early phase I trial. A phase I/II open-label study determined the safety and efficacy of Sonolisib with Cetuximab-based chemotherapy in a combination treatment regimen. In the phase I part of the trial, Sonolisib plus Cetuximab was administrated in patients with castration resistant colorectal (CRC) cancer or progressive, recurrent SCCHN. The phase II part of the study was a randomized evaluation of the anti-tumor activity and safety of Sonolisib plus Cetuximab versus Cetuximab alone in patients with either incurable metastatic CRC who had a prior history of progression or recurrence on chemotherapy-based treatment regimens including Irinotecan and Oxaliplatin, or were resistant to Irinotecan treatment (group 1) or in metastatic SCCHN (group 2).

3.1.6. Pictilisib/GDC-0941/RG7321

Pictilisib/GDC-0941/RG7321 is an oral bioavailable potent PI3Kα/δ inhibitor with an IC50 of 3 nM and has weak selectivity against the p110β (10-fold) and p110γ (25-fold) isoforms. It binds and competes with the ATP-binding pocket to inhibit PI3K signaling pathway. It also had a better tolerability and safety profile in Japanese patients with advanced NSCLC. Most of the trials using Pictilisib are sponsored by Genentech. In one such open-label, multicenter, phase Ib dose-escalation study, Pictilisib was administered with one of three chemotherapies regimens: Arm A: Paclitaxel plus Carboplatin in Bevacizumab-ineligible NSCLC patients, Arm B: Paclitaxel, Carboplatin plus Bevacizumab in Bevacizumab-eligible NSCLC patients and Arm C: Pemetrexed, Cisplatin with Bevacizumab in Bevacizumab-eligible NSCLC patients to assess the tolerability, safety and PK profile of pictilisib. Another phase II study tested Pictilisib with the above chemotherapy regimens in NSCLC patients. A phase Ib open-label, three arm and dose-escalation study investigated the safety, tolerability, PK and activity of oral Pictilisib administered with either intravenous (IV) infusion of humanized monoclonal antibody Trastuzumab covalently linked to the cytotoxic agent DM1 (T-DM1) or IV infusion of Trastuzumab in HER+ breast cancer progressed on Transtuzumab therapy. Another phase I study tested the safety and efficacy of Pictilisib in advanced or metastatic tumors.

3.1.7. Copanlisib/BAY 80-6946/Aliqopa

Copanlisib/BAY 80-6946/Aliqopa is an intravenous highly potent and reversible pan-class I PI3K inhibitor with significant activity against α and δ isoforms. Copanlisib was brought into market by Bayer and approved by the FDA for treatment of patients with relapsed follicular lymphoma (FL). In a phase I trial, Copanlisib was tested with Paclitaxel in patients with advanced cancer to determine its MTD and RP2D.

There are several active trials which are not currently enrolling patients for Copanlisib testing as summarized below. For example, a phase Ib/II active trial is investigating Copanlisib in Japanese patients with relapsed indolent B-cell NHL. In another phase I study (ROCOCO), Copanlisib is currently being explored with Rogaratinib (a FGFR inhibitor) to evaluate the safety, tolerability and the MTD of this drug combination in patients with locally advanced or metastatic solid tumors with a primary objective to find the RP2D. The secondary objective of the trial is to characterize the PK profile and anti-tumor efficacy. A phase I/II study is testing the safety and efficacy of Copanlisib with chemotherapy, Gemcitabine in patients with R/R peripheral T-cell or NK/T-cell lymphoma. The study is sponsored by Chonnam National University Hospital in collaboration with Consortium for improving survival of lymphoma and Bayer to determine the DLTs, MTD and RP2D. In a large-scale randomized phase III study (CHRONOS-2 and 3), Copanlisib is treated alone or in combination with Rituximab in Rituximab-refractory indolent NHL patients. In further extension of this phase III study (CHRONOS-4) Copanlisib is explored with standard immune-chemotherapy versus placebo or immunotherapy control to assess the PFS in the above patients. A phase Ib/II study (COPAN-ORL06) sponsored by UNICANCER is assessing the MTD, efficacy and RP2D of Copanlisib in combination with Cetuximab in patients with recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC) with a PIK3CA mutation/amplification and/or a PTEN loss. A phase I/II trial is investigating the best dose and side effects of Copanlisib when given with Letrozole and Palbociclib in HR+ and HER2- stage I–IV breast cancer patients. A phase II study is testing the safety and efficacy of Copanlisib plus Gemcitabine and Cisplatin in patients with advanced cholangiocarcinoma. The study is sponsored by the H. Lee Moffitt Cancer Center and Research Institute in collaboration with Bayer.

3.1.8. B591

B591, a dihydrobenzofuran-imidazolium salt is a novel pan-PI3K inhibitor with potent inhibitory activity against class I PI3K. This has shown significant inhibition of cellular PI3K/AKT signaling with robust anti-tumor activity in a set of cancer cell lines. However, it has not entered into clinical trials.

3.1.9. TG-100-115

TG-100-115 is a pan-PI3K inhibitor, developed by Sanofi, which has significant activity against γ/δ isoforms with IC50 values of 83 nM/235 nM in cell-free assay. However, TG-100–115 has less effect against α/β isoforms. This drug is in phase I and phase II trials in other diseases but not in cancer. However, Song et al. have shown that TG100-115 can be used as a potent TRPM7 kinase inhibitor and a potent suppressor of breast cancer cell migration.

3.1.10. RIDR-PI-103

The pyridinylfuranopyrimidine inhibitor, PI-103 is a pan-PI3K inhibitor which targets p110α/β/δ/γ isoforms with IC50 values of 2 nM/3 nM/3 nM/15 nM in cell-free assays and has a strong activity against PI3Kα isoform. However, it failed in clinical trials due to toxicity and poor bioavailability issues. Therefore, a bioisostere of PI-103 (RIDR-PI-103) was synthesized with a structural modification containing a boronate in place of a phenolic hydroxyl group which enhanced the bioavailability of PI-103. RIDR-PI-103 differs from the boron-containing compound as it releases PI-103 under oxidative stress in tumor microenvironment. This self-cyclizing prodrug has shown significant in vitro anti-cancer efficacy in acute myeloid leukemia. In addition, our laboratory has shown that RIDR-PI-103 in combination with the chemotherapeutic, doxorubicin impaired PI3K signaling, increased DNA damage response and suppressed in vitro breast cancer cell growth. Active not-recruiting and completed trials with specific clinical outcomes for pan-PI3K inhibitors are summarized in Table 1.

4. Isoform-Specific Inhibitors

Isoform-specific PI3K inhibitors cause selective inhibition of specific PI3K isoforms (α/β/γ or δ). Out of all the isoform-specific drugs, four drugs which included Alpelisib, Idelalisib, Umbralisib and Duvelisib are approved by the FDA. These inhibitors reduce off-target toxicities although these require narrow patient selection.

4.1. BYL719/Alpelisib/Piqray

Alpelisib/BYL719/Piqray is a potent oral selective PI3Kα inhibitor targeting PIK3CA-mutated cancers. The role of Alpelisib has also been identified outside cancer in PIK3CA-related overgrowth syndromes (PROS) which are caused by mosaic gain-of-function mutations in the PIK3CA gene. It is shown that daily oral administration of Alpelisib in the mouse model of PROS post-tamoxifen administration, effectively suppressed PIK3CA pathway activation, which prevented the PROS phenotype and enhanced survival. Alpelisib was approved by the FDA for PIK3CA-mutated, HR+, HER2- advanced breast cancer who had received endocrine therapy previously. Most of the studies using Alpelisib are sponsored by Novartis Pharmaceuticals. One such trial tested Alpelisib in a phase I study with a HSP90 inhibitor (AUY922) to determine the MTD and/or recommended dose of expansion (RDE) of this drug combination in patients with advanced gastric cancer. A dose-escalation phase Ib trial involved Alpelisib with Imatinib (a RTK inhibitor) in gastrointestinal stromal tumor (GIST) patients who had relapsed with Imatinib and Sunitinib (a RTK inhibitor). A phase Ib/II investigated Alpelisib with HER3 monoclonal antibody (LJM716) versus Taxane or Irinotecan with previously treated esophageal squamous cell carcinoma patients. The aim of the study was to evaluate the MTD and/or RP2D of this drug combination. A phase Ib/II study investigated Alpelisib with an oral pan-PIM kinase inhibitor (LGH447/PIM447) in relapsed myeloma patients. The study aimed to explore the MTD and RP2D of this combination. Another phase II trial tested Alpelisib in Chinese patients with NSCLC.

There are several active not-recruiting studies testing Alpelisib in various stages of clinical trials as mentioned below. A phase II study (SAFIR PI3K) is underway in patients with PIK3CA-mutated advanced breast cancer which compares Alpelisib and ER inhibitor (Fulvestrant) versus chemotherapy in these patients. The trial sponsored by UNICANCER aims to determine whether this drug combination could prolong the PFS versus maintenance chemotherapy in the above subjects. A phase I study is currently testing Alpelisib with a potent, oral bioavailable selective estrogen receptor degrader (SERD), LSZ102 in advanced or metastatic ER+ breast cancer patients progressed after endocrine therapy. The study aims to identify the safety, tolerability, PK and anti-tumor efficacy of this combined regimen. A phase I study is testing Alpelisib in locally advanced squamous cell carcinoma head and neck cancer (LA-SCCHN) patients in combination with standard radiation and chemotherapy, Cisplatin. The study is sponsored by University Health Network, Toronto in collaboration with Novartis.

4.2. Serabelisib/INK-117/MLN-117/TAK-117

Serabelisib/INK-1117/MLN-1117/TAK-117 is a potent oral PI3K inhibitor with an IC50 of 21 nmol/L against PI3Kα isoform. The first in human phase I study evaluated the safety and efficacy of Serabelisb in patients with advanced solid tumors. A phase II study is investigating Serabelisib with oral mTORC1/2 inhibitor Sapanisertib (TAK-228) in TNBC patients to target the DNA repair pathway. The study is sponsored by Baylor Research Institute in collaboration with Takeda. A phase II study evaluated the efficacy and safety of MLN0128 and the combination of MLN0128 plus Serabelisib versus Everolimus in the treatment of metastatic clear-cell renal cell carcinoma (mccRCC) patients who progressed on vascular endothelial growth factor (VEGF)-targeted therapy. A phase I study tested Serabelisib with mTORC1/2 inhibitor Sapanisertib (TAK-228) in patients with advanced non-hematological patients to determine the DLTs, MTD and/or RP2D of this drug combination.

4.3. GSK2636771

GSK2636771 is an orally bioavailable PI3Kβ inhibitor with >900-fold selectivity over the PI3Kα/γ isoforms and >10-fold selectivity over the PI3Kδ isoform. A phase I study tested GSK2636771 with Enzalutamide in male patients with CRPC. The study was sponsored by GlaxoSmithKline and aimed to evaluate the safety and clinical efficacy to help guide the selection of the RP2D. To date, there are few active non-recruiting trials using GSK2636771. For example, a phase Ib/IIa, open-label, dose-finding study is evaluating the safety, efficacy and clinical activity of GSK2636771 with Paclitaxel in patients with higher grade of gastric adenocarcinoma. NCI is currently testing GSK2636771 in cancer patients with a PTEN alteration.

4.4. Idelalisib/GS-1101/CAL-101/Zydelig

Idelalisib/GS-1101/CAL-101/Zydelig, an oral PI3Kδ inhibitor with an IC50 value of 2.5 nM in cell-free assays was the first FDA-approved PI3K inhibitor for the treatment of patients with R/R CLL or LL/FL who progressed on prior therapies. A phase Ib study sponsored by Novartis Pharmaceuticals tested Idelalisib in a dose-escalation trial with BCL201 (elective BH3-mimetic inhibitor of BCL-2) in patients with FL and MCL. The primary objective of the study was to determine the safety and tolerability of this drug combination. Other completed trials with published clinical outcomes and adverse events for Idelalisib treatment are summarized in Table 2.

There are several active not-recruiting trials using Idelalisib. For example, a pilot phase I study is investigating Idelalisib with ACY-1215/Ricolinostat (a histone deacetylase inhibitor) in patients with R/R CLL. The study was sponsored by Dana-Farber Cancer Institute in collaboration with Acetylon Pharmaceuticals. Idelalisib is currently being tested in combination therapies with either Rituximab plus TRU-016, mAb targeting CD37 (phase I) or with Tirabrutinib, an oral bruton’s tyrosine kinase (BTK) inhibitor (phase II) in such patients. Another phase II trial (ILIAD) is testing Idelalisib in patients with relapse DLBCL. A phase II (COSMO) is evaluating the safety and efficacy of MOR00208 with Idelalisib or Venetoclax in R/R CLL/SLL patients treated earlier with a BTK inhibitor.

4.5. Zandelisib/ME-401/PWT-143

Zandelisib/ME-401/PWT-143 is an oral, selective PI3Kδ inhibitor which is in early phase of clinical trials mostly in lymphoma patients. Zandelisib is being investigated in Japanese patients with B-cell NHL in a phase I study sponsored by Kyowa Kirin Co. Ltd., Tokyo, Japan.

4.6. AMG 319

AMG 319 is a PI3Kδ-specific inhibitor developed by Amgen. AMG 319 was tested in patients with R/R lymphoid malignancies to evaluate its tolerability, safety and PK profile.

4.7. YY-20394/Linperlisib

YY-20394/Linperlisib is an oral highly selective PI3Kδ inhibitor which is studied in patients with R/R B-cell malignancies. This drug was developed by Shanghai Ying Li Pharmaceutical Co. Ltd., Shanghai, China.

4.8. INCB050465/Parsaclisib/IBI-376

INCB050465/Parsaclisib/IBI-376 is a next-generation highly selective potent PI3Kδ inhibitor initially developed by Incyte Corporation, which sponsored a phase I study to evaluate the safety and tolerability of a pan-PIM inhibitor (INCB053914) in combination with Parsaclisib in R/R DLBCL patients.

There are two active non-recruiting phase I trials investigating Parsaclisib in B-cell lymphoma patients. Another phase I study is testing Parsaclisib with Pembrolizumab in higher-grade solid tumors including lung cancer. In addition, several phase II studies are exploring Parsaclisib as monotherapy in FL patients (CITADEL 203) and in MCL patients (CITADEL-204). Parsaclisib is being tested ± BTK inhibitor (CITADEL 205) and in combination with Bendamustine plus Obinutuzumab in patients with B-cell malignancies (CITADEL 102).

4.9. Umbralisib/TGR-1202/RP5264

Umbralisib/TGR-1202/RP5264 is a next-generation highly specific, oral inhibitor targeting the δ isoform of PI3K. There are many trials testing Umbralisib sponsored by TG Therapeutics. One such phase I trial evaluated the safety and efficacy of Umbralisib as a monotherapy or with nab-Paclitaxel plus Gemcitabine or FOLFOX in patients with R/R solid tumors. A phase I study evaluated the efficacy and safety of Umbralisib with Obinutuzumab (anti-CD20 monoclonal antibody) and Chlorambucil (chemotherapy) in CLL patients. Another phase I study tested the efficacy of Umbralisib with Brentuximab vedotin, an anti-body drug conjugate (ADC) against CD30 in patients with HL.

Phase II/III studies are actively testing Umbralisib as a monotherapy in patients with non-follicular iNHL and with Ublituximab, anti-CD20 monoclonal antibody in combinational therapy in previously untreated CLL patients. A phase I study sponsored by the Vanderbilt-Ingram Cancer Center is currently testing Umbralisib with Ruxolitinib in patients with myeloproliferative neoplasm. Umbralisib has been recently approved by the FDA for treatment of patients with R/R marginal zone lymphoma (MZL) who had at least one prior anti-CD20-based therapy and for adults with R/R follicular lymphoma (FL) relapsed on three prior lines of systemic therapy.

4.10. Tenalisib/RP6530

Tenalisib/RP6530 is a novel, potent PI3Kδ/γ inhibitor with activity more than 300-fold and 100-fold over α and β isoforms, respectively. It was developed by Rhizen Pharmaceuticals and mostly tested against B-cell malignancies. An open-label, phase I/II trial is assessing the safety and efficacy of Tenalisib with a histone deacetylase (HDAC) inhibitor, romidepsin in patients with R/R T-cell lymphoma.

4.11. Taselisib/GDC-0032/RG-7604

GDC-0032/Taselisib/RG-7604 is a potent class I PI3K inhibitor having strong activity against the PI3K α, δ and γ isoforms. It exhibits less potency to the ß isoform. There are several ongoing and completed trials using Taselisib in human subjects. Genentech has sponsored all the trials for Taselisib. A phase I study is investigating the safety and tolerability of Taselisib alone in patients with advanced solid tumors or NHL and with Fulvestrant in advanced HER2- and HR+ breast cancer patients. Taselisib is being tested in a phase II study in patients with different cancers (excluding breast) with PIK3CA mutation but without KRAS mutation or PTEN loss. The study is sponsored by the NCI.

4.12. AZD8186

AZD8186 is a specific ß/δ inhibitor, developed by AstraZeneca, which is currently in phase I/II clinical studies.

4.13. AZD8835

AZD8835 is a δ/α-specific PI3K inhibitor, developed by AstraZeneca, with one trial listed so far in patients with solid tumors.

4.14. IPI-145/Duvelisib/INK1197

Duvelisib/IPI-145/INK1197 is an oral highly selective PI3K δ/γ inhibitor with IC50 values of 243 pM and 50 nM, respectively, in cell-free assay. Duvelisib (September 2018, NDA 311155) was approved by the FDA for treatment of patients with R/R CLL/SLL. A multicenter open-label phase I study aimed to investigate the safety and PK of Duvelisib in Japanese subjects with R/R lymphoma was completed in 2017. The study was sponsored by AbbVie in collaboration with Infinity Pharmaceuticals. A phase II study evaluating the clinical activity, long-term safety, and overall survival rate of Duvelisib in patients with hematologic malignancies was recently completed without significant clinical outcomes.

4.15. Leniolisib/CDZ173

Leniolisib/CDZ173 is a potent and selective PI3Kδ inhibitor. Most of the studies using Leniolisib are sponsored by Novartis Pharmaceuticals. Although no studies are known in cancer but it is implicated in immunodeficiency disorders such as activated PI3Kδ syndrome/p110δ-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency (APDS/PASLI) where it has been tested in phase II/III trials. Rao et al. have shown that treatment with Leniolisib resulted in dose-dependent inhibition of PI3Kδ pathway hyperactivation in cells expressing APDS-causative p110δ variants and in T-cell blasts derived from patients. In addition it was shown that oral administration of Leniolisib in six APDS patients resulted in dose-dependent inhibition of the PI3K/AKT pathway evaluated via ex vivo assay and had enhanced immune dysregulation. Thus, Leniolisib is known to be well tolerated and has improved laboratory and clinical parameters in patients with APDS, supporting the specific inhibition of PI3Kδ as a promising new targeted therapy in patients with APDS and other diseases characterized by hyperactivation of the PI3Kδ pathway. Leniolisib is also tested in patients with primary sjögren’s syndrome (PSS) in phase II trials where its oral administration resulted in inhibition of phosphorylated AKT in ex vivo stimulated B cells, decreased the serum CXCL13 levels and reduced the frequency of circulating follicular T helper-like cells.

4.16. Eganelisib/IPI-549

Eganelisib/IPI-549 is a potent PI3K-γ inhibitor with >100-fold selectivity with an IC50 value of 16 nM. Eganelisib is the first-in-class, oral, selective PI3K-γ inhibitor identified in preclinical studies which reprogrammed macrophages from an immune-suppressive to an immune-activating phenotype and overcome resistance to checkpoint inhibitors. A phase I study is evaluating the safety, efficacy, PK and PD of Eganelisib in combination with Etrumadenant/AB928 (a selective dual adenosine receptor, A2aR/A2bR antagonist) plus pegylated liposomal doxorubicin (PLD) in patients with TNBC or gynecological tumors. Active not-recruiting and completed trials with specific clinical outcomes are summarized in Table 2.

5. Dual PI3K/mTOR Inhibitors

Dual PI3K/mTOR inhibitors target both PI3K and mTOR signaling. To date, none of these drugs have received FDA approval for treatment of any cancer. The detailed clinical outcomes of completed and active not-recruiting studies with adverse effects are summarized in Table 3.

5.1. Dactolisib/BEZ-235/NVP-BEZ235

Dactolisib/BEZ235/NVPBEZ235 is a dual pan-class I PI3K inhibitor targeting p110α/ß/γ/δ as well as mTOR kinase inhibitor with IC50 values of 4 nM/5 nM/7 nM/75 nM and 20.7 nM for p110α/γ/δ/β and mTOR, respectively. Dactolisib, developed by Novartis Pharmaceuticals, is known to inhibit both mTORC1 and mTORC2 activity. A phase Ib study sponsored by the Vanderbilt-Ingram Cancer Center investigated the safety and efficacy of Dactolisib with BKM120 in combination with endocrine therapy in post-menopausal patients with HR+ metastatic breast cancer. Another phase I/II study investigated Dactolisib in patients with advanced breast cancer. A phase I trial tested Dactolisib with RAD001/Everolimus in patients with advanced solid tumors without any significant outcomes. Another such phase Ib study evaluated the safety, pharmacokinetics, and pharmacodynamics of Dactolisib with MEK162 in patients with selected advanced solid tumors. A phase Ib/II study of Dactolisib with Trastuzumab versus Lapatinib and Capecitabine was completed in patients with HER2+ locally advanced or metastatic breast cancer who failed on prior Trastuzumab treatment. The trial aimed to find the MTD and the RP2D of this drug combination. Another phase I trial investigated the MTD and RDE of Abiraterone Acetate in combination with Dactolosib and Abiraterone Acetate with BKM120 in CRPC patients. However, despite all these studies, Dactolisib was removed from clinical trials in 2015.

5.2. Apitolisib/GDC-0980/RG7422

Apitolisib/GDC-0980/RG7422 is a potent, class I PI3K inhibitor targeting α/β/δ/γ isoforms with IC50 values of 5 nM/27 nM/7 nM/14 nM, respectively, in cell-free assays. Apitolisib also targets mTOR signaling. Genentech Inc. sponsored several phase I/II studies using Apitolisib. A phase Ib, dose-escalation study evaluated the safety, tolerability and PK properties of Apitolisib with Paclitaxel with or without Bevacizumab in patients with locally advanced breast cancer. A phase Ib study assessed the safety and PK properties of Apitolisib in combination with Fluoropyrimidine, Oxaliplatin, and Bevacizumab in patients with advanced solid tumors. A phase I study evaluated Apitolisib with either Paclitaxel and Carboplatin (with or without Bevacizumab) or Pemetrexed and Cisplatin in patients with locally advanced or metastatic solid tumors. Apitolisib was evaluated as a monotherapy in patients with R/R solid tumors or with NHL. The study was sponsored by Genentech Inc. and aimed to assess the safety, tolerability, and pharmacokinetics of escalating doses of Apitolisib.

5.3. Gedatolisib/PF-05212384/PKI-587

Gedatolisib/PF-05212384/PKI-587, developed by Pfizer, is a highly potent dual inhibitor of PI3Kα/γ and mTOR with IC50 values of 0.4 nM, 5.4 nM and 1.6 nM, respectively, in cell-free assays. Details of clinical studies with specific clinical outcomes are summarized in Table 3.

5.4. SF1126

SF1126, brought into market by SignalRx, is a small-molecule conjugate that selectively inhibits all PI3K class IA isoforms and other members of the PI3K superfamily, including DNA-PK and mTOR. It has been tested in a phase I study in patients with advanced solid tumors and B-cell malignancies. A phase II study sponsored by Semafore Pharmaceuticals in collaboration with SignalRX Pharmaceuticals, Inc. evaluated the safety and tolerability of SF1126 by assessing the DLTs, MTD, and RP2D in patients with advanced or metastatic tumors. A current non-recruiting phase I trial is studying SF1126 with immunotherapy (Nivolumab) in patients with advanced or metastatic hepatocellular carcinoma and Child-Pugh A-B7 cirrhosis.

5.5. Omipalisib/GSK458/GSK2126458

Omipalisib/GSK458/GSK2126458 is a reversible, selective, pan-PI3K ATP-competitive inhibitor with a Ki for the catalytic p110α subunit in the subnanomolar range that targets the mTOR pathway. The first-in-human phase I study tested Omipalisib in patients with advanced solid tumors. The study was sponsored by GlaxoSmithkline. A phase I open-label, dose-escalation study evaluated the safety, efficacy, and PK of Omipalisib in patients with solid tumors or lymphoma.

5.6. Samotolisib/LY3023414

Samotolisib/LY3023414 is a dual inhibitor of PI3Kα and mTOR with potential anti-neoplastic activity. A phase I trial evaluated the safety of Samotolisib in patients with advanced solid tumors. A phase II study is testing the effectiveness of Samotolisib in patients with endometrial cancer. Two phase I studies sponsored by Eli Lilly and Company evaluated Samotolisib in combination with chemotherapies or other targeted therapies in patients with advanced cancer or lung cancer. In addition, a phase II study tested Samotolisib as monotherapy or in combination with other agents versus standard of care (Gemcitabine or Capecitabine) in patients with metastatic pancreatic ductal adenocarcinoma (PDAC). A phase I study is currently exploring Samotolisib with a CDK4/6 inhibitor LY2835219 (Abemaciclib) in MBC patients. The study is also sponsored by Eli Lilly and Company and aims to investigate the safety of this drug combination.

5.7. Bimiralisib/PQR309

Bimiralisib/PQR309 is a potent, oral bioavailable, pan-class I PI3K inhibitor that also targets mTORC1 and mTORC2. A phase II study sponsored by PIQUR Therapeutics AG aimed to assess the safety, tolerability, and the RP2D of Bimiralisib in patients with R/R lymphoma. There are two other phase II studies that are completed in patients with R/R primary central nervous system lymphoma (PCNSL) and advanced lymphoma and HNSCC harboring NOTCH1 loss of function mutations. Another phase I/II study evaluated the safety and pharmacokentic properties of Bimiralisib in combination with chemotherapy, Eribulin in patients with locally advanced or metastatic HER2-negative cancer in the escalation part and in TNBC patients in the expansion part of the study.

5.8. Paxalisib/GDC-0084/RG7666

Paxalisib/GDC-0084/RG7666, developed by PIQUR therapeutics, is a potent dual inhibitor of PI3K and mTOR signaling. A phase I study is investigating Paxalisib in pediatric patients with newly diagnosed diffuse intrinsic pontine glioma or diffuse midline gliomas. The study is sponsored by St. Jude Children’s Research Hospital in collaboration with Kazia Therapeutics Ltd., Sydney, Australia which aims to determine the safety, MTD, RP2D, and the pharmacokinetic properties of Paxalisib in the pediatric population. A phase II study is also investigating the efficacy and the pharmacokinetic properties of Paxalisib in glioblastoma patients.

5.9. XL765/Voxtalisib/SAR245409

Voxtalisib/SAR245409/XL765 is a dual inhibitor of PI3K/mTOR which targets the PI3K p110γ, DNA-PK and mTOR pathways. This drug was introduced into market by Sanofi. Sanofi sponsored a phase I/II study testing the safety and tolerability of Voxtalisib as a monotherapy or in combination regimen in patients who were benefiting from this treatment. A phase II study evaluated the efficacy of Voxtalisib with MEK1/2 inhibitor, Pimasertib in patients with ovarian cancer. Most of the studies using this drug are completed and the details of the clinical outcomes with adverse effects are listed in Table 3.

6. Conclusions

Resistance to current PI3K therapies continues to push the need to expand our understanding of cancer treatment. Very few PI3K inhibitors are approved by the FDA as PI3K inhibitors suffer from many adverse effects, and poor solubility and permeability. However, these issues are addressed via improved PK techniques. Designing new PI3K inhibitors based on variable structural and binding sites (mutant selective inhibitors) could be used to increase selectivity and reduce toxicity for isoform-specific PI3K inhibitors. Targeting other pathways with ERK, EGFR, CDK4/6, SGLT2 inhibitors, anti-estrogen therapies or HDAC as a combinatorial therapy approach could increase the efficacy for PI3K inhibitors. The mechanism of action which includes the synergistic combination of PI3K with mTOR inhibitors must be explored for better targeting of the PI3K pathway. In this context, Yang et al. have already shown that addition of Dactolisib, a dual PI3K/mTOR inhibitor or ZSTK474, a pan-PI3K inhibitor, in combination with Temsirolimus, a mTORC1 inhibitor, synergistically inhibited cancer cell growth and overcame cellular resistance to Temsirolimus regardless of PTEN status. Emerging evidence in a study by Tang et al. suggested that a combinatorial approach using dual PI3K/mTOR inhibitors could achieve better anti-cancer outcomes. Other factors that could overcome the challenges to PI3K inhibitors in the clinic include selection of accurate patient population with activating PIK3CA mutations, optimizing the dosing schedules, etc. Another challenge in the clinic is a lack of selective PI3Kγ inhibitors. The biggest issue in developing small-molecule inhibitors against PI3Kγ (member of PI3K class IB) is to obtain inhibitors that have good selectivity for PI3Kγ against other PI3K isoforms as PI3Kγ show high sequence similarity in the conserved ATP-kinase-binding site with class I isoforms, leading to difficulties in developing specific γ inhibitors. Further research is needed to understand whether using a dual or multi-targeted approach inhibiting two or more PI3K enzymes or direct inhibition of PI3Kγ could help to achieve maximal efficacy against these inhibitors. In addition, there are several new P13K drugs such as RIDR-PI-103, B591 and TG-100–115 with limited in vitro and in vivo studies which need to be further explored using PK and PD models so that it could be translated to clinic.

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    Not in our library10.1042/bj20061489

  14. 14.

    Frazzetto M., Suphioglu C., Zhu J., Schmidt-Kittler O., Jennings I.G., Cranmer S.L., Jackson S.P., Kinzler K.W., Vogelstein B., Thompson P.E. Dissecting isoform selectivity of PI3K inhibitors: The role of non-conserved residues in the catalytic pocket. Biochem. J. 2008;414:383-390.

    Not in our library10.1042/bj20080512

  15. 15.

    Schultz R.M., Merriman R.L., Andis S.L., Bonjouklian R., Grindey G.B., Rutherford P.G., Gallegos A., Massey K., Powis G. In vitro and in vivo antitumor activity of the phosphatidylinositol-3-kinase inhibitor, wortmannin. Anticancer Res. 1995;15:1135-1139.

    Not in our library

  16. 16.

    Kong D., Yamori T. Phosphatidylinositol 3-kinase inhibitors: Promising drug candidates for cancer therapy. Cancer Sci. 2008;99:1734-1740.

    Not in our library10.1111/j.1349-7006.2008.00891.x

  17. 17.
    PTEN Alterations and Their Role in Cancer Management: Are We Making Headway on Precision Medicine? · 2020
    No notice
  18. 18.

    Papa A., Wan L., Bonora M., Salmena L., Song M.S., Hobbs R.M., Lunardi A., Webster K., Ng C., Newton R.H., et al. Cancer-associated PTEN mutants act in a dominant-negative manner to suppress PTEN protein function. Cell. 2014;157:595-610.

    Not in our library10.1016/j.cell.2014.03.027

  19. 19.
    PTEN/PTENP1: ‘Regulating the regulator of RTK-dependent PI3K/Akt signalling’, new targets for cancer therapy · 2018
    No notice
  20. 20.

    Juric D., Castel P., Griffith M., Griffith O.L., Won H.H., Ellis H., Ebbesen S.H., Ainscough B.J., Ramu A., Iyer C., et al. Convergent loss of PTEN leads to clinical resistance to a PI(3)Kalpha inhibitor. Nature. 2015;518:240-244.

    Not in our library10.1038/nature13948

  21. 21.

    Samuels Y., Wang Z., Bardelli A., Silliman N., Ptak J., Szabo S., Yan H., Gazdar A., Powell S.M., Riggins G.J., et al. High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004;304:554.

    Not in our library10.1126/science.1096502

  22. 22.

    Triscott J., Rubin M.A. Prostate Power Play: Does Pik3ca Accelerate Pten-Deficient Cancer Progression? Cancer Discov. 2018;8:682-685.

    Not in our library10.1158/2159-8290.cd-18-0369

  23. 23.

    Levine D.A., Bogomolniy F., Yee C.J., Lash A., Barakat R.R., Borgen P.I., Boyd J. Frequent mutation of the PIK3CA gene in ovarian and breast cancers. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2005;11:2875-2878.

    Not in our library10.1158/1078-0432.ccr-04-2142

  24. 24.

    Ikenoue T., Kanai F., Hikiba Y., Obata T., Tanaka Y., Imamura J., Ohta M., Jazag A., Guleng B., Tateishi K., et al. Functional analysis of PIK3CA gene mutations in human colorectal cancer. Cancer Res. 2005;65:4562-4567.

    Not in our library10.1158/0008-5472.can-04-4114

  25. 25.

    Jiang W., He T., Liu S., Zheng Y., Xiang L., Pei X., Wang Z., Yang H. The PIK3CA E542K and E545K mutations promote glycolysis and proliferation via induction of the beta-catenin/SIRT3 signaling pathway in cervical cancer. J. Hematol. Oncol. 2018;11:139.

    Not in our library10.1186/s13045-018-0674-5

  26. 26.
    Mutation of the PIK3CA oncogene in human cancers · 2006
    No notice
  27. 27.

    Zhao L., Vogt P.K. Helical domain and kinase domain mutations in p110alpha of phosphatidylinositol 3-kinase induce gain of function by different mechanisms. Proc. Natl. Acad. Sci. USA. 2008;105:2652-2657.

    Not in our library10.1073/pnas.0712169105

  28. 28.

    Croessmann S., Sheehan J.H., Lee K.M., Sliwoski G., He J., Nagy R., Riddle D., Mayer I.A., Balko J.M., Lanman R., et al. PIK3CA C2 Domain Deletions Hyperactivate Phosphoinositide 3-kinase (PI3K), Generate Oncogene Dependence, and Are Exquisitely Sensitive to PI3Kalpha Inhibitors. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2018;24:1426-1435.

    Not in our library10.1158/1078-0432.ccr-17-2141

  29. 29.

    Yuan W., Stawiski E., Janakiraman V., Chan E., Durinck S., Edgar K.A., Kljavin N.M., Rivers C.S., Gnad F., Roose-Girma M., et al. Conditional activation of Pik3ca(H1047R) in a knock-in mouse model promotes mammary tumorigenesis and emergence of mutations. Oncogene. 2013;32:318-326.

    Not in our library10.1038/onc.2012.53

  30. 30.

    Kinross K.M., Montgomery K.G., Kleinschmidt M., Waring P., Ivetac I., Tikoo A., Saad M., Hare L., Roh V., Mantamadiotis T., et al. An activating Pik3ca mutation coupled with Pten loss is sufficient to initiate ovarian tumorigenesis in mice. J. Clin. Investig. 2012;122:553-557.

    Not in our library10.1172/jci59309

  31. 31.

    Aoki M., Schetter C., Himly M., Batista O., Chang H.W., Vogt P.K. The catalytic subunit of phosphoinositide 3-kinase: Requirements for oncogenicity. J. Biol. Chem. 2000;275:6267-6275.

    Not in our library10.1074/jbc.275.9.6267

  32. 32.
    Characterization of a tumor-associated activating mutation of the p110β PI 3-kinase. · 2013
    Not checked
  33. 33.

    Hill K.M., Kalifa S., Das J.R., Bhatti T., Gay M., Williams D., Taliferro-Smith L., De Marzo A.M. The role of PI 3-kinase p110beta in AKT signally, cell survival, and proliferation in human prostate cancer cells. Prostate. 2010;70:755-764.

    Not in our library10.1002/pros.21108

  34. 34.

    Dbouk H.A., Vadas O., Shymanets A., Burke J.E., Salamon R.S., Khalil B.D., Barrett M.O., Waldo G.L., Surve C., Hsueh C., et al. G protein-coupled receptor-mediated activation of p110beta by Gbetagamma is required for cellular transformation and invasiveness. Sci. Signal. 2012;5:ra89.

    Not in our library10.1126/scisignal.2003264

  35. 35.

    Cook G.W., Benton M.G., Akerley W., Mayhew G.F., Moehlenkamp C., Raterman D., Burgess D.L., Rowell W.J., Lambert C., Eng K., et al. Structural variation and its potential impact on genome instability: Novel discoveries in the EGFR landscape by long-read sequencing. PLoS ONE. 2020;15:e0226340.

    Not in our library10.1371/journal.pone.0226340

  36. 36.

    Elwy F., Helwa R., El Leithy A.A., Shehab Z., Assem M.M., Hassan N.H. PIK3CA mutations in HER2-positive Breast Cancer Patients; Frequency and Clinicopathological Perspective in Egyptian Patients. Asian Pac. J. Cancer Prev. 2017;18:57-64.

    Not in our library10.22034/apjcp.2017.18.1.57

  37. 37.

    Pazarentzos E., Giannikopoulos P., Hrustanovic G., St John J., Olivas V.R., Gubens M.A., Balassanian R., Weissman J., Polkinghorn W., Bivona T.G. Oncogenic activation of the PI3-kinase p110beta isoform via the tumor-derived PIK3Cbeta(D1067V) kinase domain mutation. Oncogene. 2016;35:1198-1205.

    Not in our library10.1038/onc.2015.173

  38. 38.

    Fung-Leung W.P. Phosphoinositide 3-kinase delta (PI3Kdelta) in leukocyte signaling and function. Cell. Signal. 2011;23:603-608.

    Not in our library10.1016/j.cellsig.2010.10.002

  39. 39.

    Kaneda M.M., Messer K.S., Ralainirina N., Li H., Leem C.J., Gorjestani S., Woo G., Nguyen A.V., Figueiredo C.C., Foubert P., et al. PI3Kgamma is a molecular switch that controls immune suppression. Nature. 2016;539:437-442.

    Not in our library10.1038/nature19834

  40. 40.

    Sujobert P., Bardet V., Cornillet-Lefebvre P., Hayflick J.S., Prie N., Verdier F., Vanhaesebroeck B., Muller O., Pesce F., Ifrah N., et al. Essential role for the p110delta isoform in phosphoinositide 3-kinase activation and cell proliferation in acute myeloid leukemia. Blood. 2005;106:1063-1066.

    Not in our library10.1182/blood-2004-08-3225

  41. 41.

    Zhang J., Grubor V., Love C.L., Banerjee A., Richards K.L., Mieczkowski P.A., Dunphy C., Choi W., Au W.Y., Srivastava G., et al. Genetic heterogeneity of diffuse large B-cell lymphoma. Proc. Natl. Acad. Sci. USA. 2013;110:1398-1403.

    Not in our library10.1073/pnas.1205299110

  42. 42.

    Sawyer C., Sturge J., Bennett D.C., O’Hare M.J., Allen W.E., Bain J., Jones G.E., Vanhaesebroeck B. Regulation of breast cancer cell chemotaxis by the phosphoinositide 3-kinase p110delta. Cancer Res. 2003;63:1667-1675.

    Not in our library

  43. 43.

    Stockmann C., Doedens A., Weidemann A., Zhang N., Takeda N., Greenberg J.I., Cheresh D.A., Johnson R.S. Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis. Nature. 2008;456:814-818.

    Not in our library10.1038/nature07445

  44. 44.

    Hawkins P.T., Stephens L.R. PI3K signalling in inflammation. Biochim. Biophys. Acta. 2015;1851:882-897.

    Not in our library10.1016/j.bbalip.2014.12.006

  45. 45.

    Hanker A.B., Kaklamani V., Arteaga C.L. Challenges for the Clinical Development of PI3K Inhibitors: Strategies to Improve Their Impact in Solid Tumors. Cancer Discov. 2019;9:482-491.

    Not in our library10.1158/2159-8290.cd-18-1175

  46. 46.

    Hudson K., Hancox U.J., Trigwell C., McEwen R., Polanska U.M., Nikolaou M., Morentin Gutierrez P., Avivar-Valderas A., Delpuech O., Dudley P., et al. Intermittent High-Dose Scheduling of AZD8835, a Novel Selective Inhibitor of PI3Kalpha and PI3Kdelta, Demonstrates Treatment Strategies for PIK3CA-Dependent Breast Cancers. Mol. Cancer Ther. 2016;15:877-889.

    Not in our library10.1158/1535-7163.mct-15-0687

  47. 47.

    Hoeflich K.P., Merchant M., Orr C., Chan J., Den Otter D., Berry L., Kasman I., Koeppen H., Rice K., Yang N.Y., et al. Intermittent administration of MEK inhibitor GDC-0973 plus PI3K inhibitor GDC-0941 triggers robust apoptosis and tumor growth inhibition. Cancer Res. 2012;72:210-219.

    Not in our library10.1158/0008-5472.can-11-1515

  48. 48.

    Chandarlapaty S., Sawai A., Scaltriti M., Rodrik-Outmezguine V., Grbovic-Huezo O., Serra V., Majumder P.K., Baselga J., Rosen N. AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell. 2011;19:58-71.

    Not in our library10.1016/j.ccr.2010.10.031

  49. 49.

    Chakrabarty A., Sanchez V., Kuba M.G., Rinehart C., Arteaga C.L. Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors. Proc. Natl. Acad. Sci. USA. 2012;109:2718-2723.

    Not in our library10.1073/pnas.1018001108

  50. 50.

    Yu Y., Yoon S.O., Poulogiannis G., Yang Q., Ma X.M., Villen J., Kubica N., Hoffman G.R., Cantley L.C., Gygi S.P., et al. Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling. Science. 2011;332:1322-1326.

    Not in our library10.1126/science.1199484

  51. 51.

    Costa C., Ebi H., Martini M., Beausoleil S.A., Faber A.C., Jakubik C.T., Huang A., Wang Y., Nishtala M., Hall B., et al. Measurement of PIP3 levels reveals an unexpected role for p110beta in early adaptive responses to p110alpha-specific inhibitors in luminal breast cancer. Cancer Cell. 2015;27:97-108.

    Not in our library10.1016/j.ccell.2014.11.007

  52. 52.

    Muranen T., Selfors L.M., Worster D.T., Iwanicki M.P., Song L., Morales F.C., Gao S., Mills G.B., Brugge J.S. Inhibition of PI3K/mTOR leads to adaptive resistance in matrix-attached cancer cells. Cancer Cell. 2012;21:227-239.

    Not in our library10.1016/j.ccr.2011.12.024

  53. 53.

    Lin A., Piao H.L., Zhuang L., dos Sarbassov D., Ma L., Gan B. FoxO transcription factors promote AKT Ser473 phosphorylation and renal tumor growth in response to pharmacologic inhibition of the PI3K-AKT pathway. Cancer Res. 2014;74:1682-1693.

    Not in our library10.1158/0008-5472.can-13-1729

  54. 54.

    Britschgi A., Andraos R., Brinkhaus H., Klebba I., Romanet V., Muller U., Murakami M., Radimerski T., Bentires-Alj M. JAK2/STAT5 inhibition circumvents resistance to PI3K/mTOR blockade: A rationale for cotargeting these pathways in metastatic breast cancer. Cancer Cell. 2012;22:796-811.

    Not in our library10.1016/j.ccr.2012.10.023

  55. 55.

    Fox E.M., Kuba M.G., Miller T.W., Davies B.R., Arteaga C.L. Autocrine IGF-I/insulin receptor axis compensates for inhibition of AKT in ER-positive breast cancer cells with resistance to estrogen deprivation. Breast Cancer Res. 2013;15:R55.

    Not in our library10.1186/bcr3449

  56. 56.

    Bosch A., Li Z., Bergamaschi A., Ellis H., Toska E., Prat A., Tao J.J., Spratt D.E., Viola-Villegas N.T., Castel P., et al. PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer. Sci. Transl. Med. 2015;7:283ra251.

    Not in our library10.1126/scitranslmed.aaa4442

  57. 57.

    Toska E., Osmanbeyoglu H.U., Castel P., Chan C., Hendrickson R.C., Elkabets M., Dickler M.N., Scaltriti M., Leslie C.S., Armstrong S.A., et al. PI3K pathway regulates ER-dependent transcription in breast cancer through the epigenetic regulator KMT2D. Science. 2017;355:1324-1330.

    Not in our library10.1126/science.aah6893

  58. 58.

    Corra F., Agnoletto C., Minotti L., Baldassari F., Volinia S. The Network of Non-coding RNAs in Cancer Drug Resistance. Front. Oncol. 2018;8:327.

    Not in our library10.3389/fonc.2018.00327

  59. 59.
    Role of non-coding RNAs and RNA modifiers in cancer therapy resistance · 2020
    No notice
  60. 60.

    Shen S., Liu H., Wang Y., Wang J., Ni X., Ai Z., Pan H., Liu H., Shao Y. Long non-coding RNA CRNDE promotes gallbladder carcinoma carcinogenesis and as a scaffold of DMBT1 and C-IAP1 complexes to activating PI3K-AKT pathway. Oncotarget. 2016;7:72833-72844.

    Not in our library10.18632/oncotarget.12023

  61. 61.

    Liu X.X., Xiong H.P., Huang J.S., Qi K., Xu J.J. Highly expressed long non-coding RNA CRNDE promotes cell proliferation through PI3K/AKT signalling in non-small cell lung carcinoma. Clin. Exp. Pharmacol. Physiol. 2017;44:895-902.

    Not in our library10.1111/1440-1681.12780

  62. 62.

    Ellis B.C., Graham L.D., Molloy P.L. CRNDE, a long non-coding RNA responsive to insulin/IGF signaling, regulates genes involved in central metabolism. Biochim. Biophys. Acta. 2014;1843:372-386.

    Not in our library10.1016/j.bbamcr.2013.10.016

  63. 63.

    Song L., Zhou Z., Gan Y., Li P., Xu Y., Zhang Z., Luo F., Xu J., Zhou Q., Dai F. Long noncoding RNA OIP5-AS1 causes cisplatin resistance in osteosarcoma through inducing the LPAATbeta/PI3K/AKT/mTOR signaling pathway by sponging the miR-340-5p. J. Cell. Biochem. 2019;120:9656-9666.

    Not in our library10.1002/jcb.28244

  64. 64.
    LncRNA OIP5-AS1 loss-induced microRNA-410 accumulation regulates cell proliferation and apoptosis by targeting KLF10 via activating PTEN/PI3K/AKT pathway in multiple myeloma · 2017
    No notice
  65. 65.

    Yang T., Zhai H., Yan R., Zhou Z., Gao L., Wang L. lncRNA CCAT1 promotes cell proliferation, migration, and invasion by down-regulation of miR-143 in FTC-133 thyroid carcinoma cell line. Braz. J. Med Biol. Res. 2018;51:e7046.

    Not in our library10.1590/1414-431x20187046

  66. 66.
    Co-activation of super-enhancer-driven CCAT1 by TP63 and SOX2 promotes squamous cancer progression · 2018
    No notice
  67. 67.

    Liao Z., Zhao J., Yang Y. Downregulation of lncRNA H19 inhibits the migration and invasion of melanoma cells by inactivating the NFkappaB and PI3K/Akt signaling pathways. Mol. Med. Rep. 2018;17:7313-7318.

    Not in our library10.3892/mmr.2018.8782

  68. 68.

    Yan J., Dang Y., Liu S., Zhang Y., Zhang G. LncRNA HOTAIR promotes cisplatin resistance in gastric cancer by targeting miR-126 to activate the PI3K/AKT/MRP1 genes. Tumour Biol. 2016.

    Not in our library10.1007/s13277-016-5448-5

  69. 69.

    Cheng C., Qin Y., Zhi Q., Wang J., Qin C. Knockdown of long non-coding RNA HOTAIR inhibits cisplatin resistance of gastric cancer cells through inhibiting the PI3K/Akt and Wnt/beta-catenin signaling pathways by up-regulating miR-34a. Int. J. Biol. Macromol. 2018;107:2620-2629.

    Not in our library10.1016/j.ijbiomac.2017.10.154

  70. 70.

    Wang H., Li Q., Tang S., Li M., Feng A., Qin L., Liu Z., Wang X. The role of long noncoding RNA HOTAIR in the acquired multidrug resistance to imatinib in chronic myeloid leukemia cells. Hematology. 2017;22:208-216.

    Not in our library10.1080/10245332.2016.1258152

  71. 71.

    Luan W., Li R., Liu L., Ni X., Shi Y., Xia Y., Wang J., Lu F., Xu B. Long non-coding RNA HOTAIR acts as a competing endogenous RNA to promote malignant melanoma progression by sponging miR-152-3p. Oncotarget. 2017;8:85401-85414.

    Not in our library10.18632/oncotarget.19910

  72. 72.
    Association of HOTAIR expression with PI3K/Akt pathway activation in adenocarcinoma of esophagogastric junction · 2016
    Not checked
  73. 73.
    Knockdown of long non-coding RNA HOTAIR inhibits malignant biological behaviors of human glioma cells via modulation of miR-326 · 2015
    No notice
  74. 74.

    Xu H., Li J., Zhou Z.G. NEAT1 promotes cell proliferation in multiple myeloma by activating PI3K/AKT pathway. Eur. Rev. Med Pharmacol. Sci. 2018;22:6403-6411.

    Not in our library10.26355/eurrev_201810_16053

  75. 75.

    Guo H.M., Yang S.H., Zhao S.Z., Li L., Yan M.T., Fan M.C. LncRNA NEAT1 regulates cervical carcinoma proliferation and invasion by targeting AKT/PI3K. Eur. Rev. Med Pharmacol. Sci. 2018;22:4090-4097.

    Not in our library10.26355/eurrev_201807_15400

  76. 76.

    Wang J., Ma W., Liu Y. Long non-coding RNA HULC promotes bladder cancer cells proliferation but inhibits apoptosis via regulation of ZIC2 and PI3K/AKT signaling pathway. Cancer Biomark. 2017;20:425-434.

    Not in our library10.3233/cbm-170188

  77. 77.

    Lu Y., Li Y., Chai X., Kang Q., Zhao P., Xiong J., Wang J. Long noncoding RNA HULC promotes cell proliferation by regulating PI3K/AKT signaling pathway in chronic myeloid leukemia. Gene. 2017;607:41-46.

    Not in our library10.1016/j.gene.2017.01.004

  78. 78.
    HULC long noncoding RNA silencing suppresses angiogenesis by regulating ESM-1 via the PI3K/Akt/mTOR signaling pathway in human gliomas · 2016
    No notice
  79. 79.

    Wang Y., Kuang H., Xue J., Liao L., Yin F., Zhou X. LncRNA AB073614 regulates proliferation and metastasis of colorectal cancer cells via the PI3K/AKT signaling pathway. Biomed. Pharmacother. 2017;93:1230-1237.

    Not in our library10.1016/j.biopha.2017.07.024

  80. 80.
    The long non-coding RNA PTTG3P promotes cell growth and metastasis via up-regulating PTTG1 and activating PI3K/AKT signaling in hepatocellular carcinoma · 2018
    No notice
  81. 81.

    Wang N., Hou M.S., Zhan Y., Shen X.B., Xue H.Y. MALAT1 promotes cisplatin resistance in cervical cancer by activating the PI3K/AKT pathway. Eur. Rev. Med. Pharmacol. Sci. 2018;22:7653-7659.

    Not in our library10.26355/eurrev_201811_16382

  82. 82.

    Liu D., Zhu Y., Pang J., Weng X., Feng X., Guo Y. Knockdown of long non-coding RNA MALAT1 inhibits growth and motility of human hepatoma cells via modulation of miR-195. J. Cell. Biochem. 2018;119:1368-1380.

    Not in our library10.1002/jcb.26297

  83. 83.

    Chen Y., Huang W., Sun W., Zheng B., Wang C., Luo Z., Wang J., Yan W. LncRNA MALAT1 Promotes Cancer Metastasis in Osteosarcoma via Activation of the PI3K-Akt Signaling Pathway. Cell. Physiol. Biochem. 2018;51:1313-1326.

    Not in our library10.1159/000495550

  84. 84.

    Meseure D., Vacher S., Lallemand F., Alsibai K.D., Hatem R., Chemlali W., Nicolas A., De Koning L., Pasmant E., Callens C., et al. Prognostic value of a newly identified MALAT1 alternatively spliced transcript in breast cancer. Br. J. Cancer. 2016;114:1395-1404.

    Not in our library10.1038/bjc.2016.123

  85. 85.

    Zhang X., He X., Liu Y., Zhang H., Chen H., Guo S., Liang Y. MiR-101-3p inhibits the growth and metastasis of non-small cell lung cancer through blocking PI3K/AKT signal pathway by targeting MALAT-1. Biomed. Pharmacother. 2017;93:1065-1073.

    Not in our library10.1016/j.biopha.2017.07.005

  86. 86.

    Zhai X., Xu W. Long Noncoding RNA ATB Promotes Proliferation, Migration, and Invasion in Bladder Cancer by Suppressing MicroRNA-126. Oncol. Res. 2018;26:1063-1072.

    Not in our library10.3727/096504018x15152072098476

  87. 87.

    Pan H., Jiang T., Cheng N., Wang Q., Ren S., Li X., Zhao C., Zhang L., Cai W., Zhou C. Long non-coding RNA BC087858 induces non-T790M mutation acquired resistance to EGFR-TKIs by activating PI3K/AKT and MEK/ERK pathways and EMT in non-small-cell lung cancer. Oncotarget. 2016;7:49948-49960.

    Not in our library10.18632/oncotarget.10521

  88. 88.

    Tsai K.W., Lo Y.H., Liu H., Yeh C.Y., Chen Y.Z., Hsu C.W., Chen W.S., Wang J.H. Linc00659, a long noncoding RNA, acts as novel oncogene in regulating cancer cell growth in colorectal cancer. Mol. Cancer. 2018;17:72.

    Not in our library10.1186/s12943-018-0821-1

  89. 89.

    Zhang Y., Xiang C., Wang Y., Duan Y., Liu C., Jin Y., Zhang Y. lncRNA LINC00152 knockdown had effects to suppress biological activity of lung cancer via EGFR/PI3K/AKT pathway. Biomed. Pharmacother. 2017;94:644-651.

    Not in our library10.1016/j.biopha.2017.07.120

  90. 90.

    Gong J., Qi X., Zhang Y., Yu Y., Lin X., Li H., Hu Y. Long noncoding RNA linc00462 promotes hepatocellular carcinoma progression. Biomed. Pharmacother. 2017;93:40-47.

    Not in our library10.1016/j.biopha.2017.06.004

  91. 91.

    Wu J., Cheng G., Zhang C., Zheng Y., Xu H., Yang H., Hua L. Long noncoding RNA LINC01296 is associated with poor prognosis in prostate cancer and promotes cancer-cell proliferation and metastasis. Onco Targets Ther. 2017;10:1843-1852.

    Not in our library10.2147/ott.s129928

  92. 92.
    Targeting PI3K in cancer: mechanisms and advances in clinical trials · 2019
    No notice
  93. 93.

    Min X., Liu K., Zhu H., Zhang J. Long Noncoding RNA LINC003121 Inhibits Proliferation and Invasion of Thyroid Cancer Cells by Suppression of the Phosphatidylinositol-3-Kinase (PI3K)/Akt Signaling Pathway. Med. Sci. Monit. 2018;24:4592-4601.

    Not in our library10.12659/msm.908652

  94. 94.

    Liu M.L., Zhang Q., Yuan X., Jin L., Wang L.L., Fang T.T., Wang W.B. Long noncoding RNA RP4 functions as a competing endogenous RNA through miR-7-5p sponge activity in colorectal cancer. World J. Gastroenterol. 2018;24:1004-1012.

    Not in our library10.3748/wjg.v24.i9.1004

  95. 95.

    Sun K.X., Wu D.D., Chen S., Zhao Y., Zong Z.H. LncRNA MEG3 inhibit endometrial carcinoma tumorigenesis and progression through PI3K pathway. Apoptosis. 2017;22:1543-1552.

    Not in our library10.1007/s10495-017-1426-7

  96. 96.

    Pickard M.R., Williams G.T. Regulation of apoptosis by long non-coding RNA GAS5 in breast cancer cells: Implications for chemotherapy. Breast Cancer Res. Treat. 2014;145:359-370.

    Not in our library10.1007/s10549-014-2974-y

  97. 97.

    Yacqub-Usman K., Pickard M.R., Williams G.T. Reciprocal regulation of GAS5 lncRNA levels and mTOR inhibitor action in prostate cancer cells. Prostate. 2015;75:693-705.

    Not in our library10.1002/pros.22952

  98. 98.

    Hopkins B.D., Pauli C., Du X., Wang D.G., Li X., Wu D., Amadiume S.C., Goncalves M.D., Hodakoski C., Lundquist M.R., et al. Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature. 2018;560:499-503.

    Not in our library10.1038/s41586-018-0343-4

  99. 99.

    Molinaro A., Becattini B., Mazzoli A., Bleve A., Radici L., Maxvall I., Sopasakis V.R., Molinaro A., Backhed F., Solinas G. Insulin-Driven PI3K-AKT Signaling in the Hepatocyte Is Mediated by Redundant PI3Kalpha and PI3Kbeta Activities and Is Promoted by RAS. Cell Metab. 2019;29:1400-1409.

    Not in our library10.1016/j.cmet.2019.03.010

  100. 100.

    Nepstad I., Hatfield K.J., Gronningsaeter I.S., Aasebo E., Hernandez-Valladares M., Hagen K.M., Rye K.P., Berven F.S., Selheim F., Reikvam H., et al. Effects of insulin and pathway inhibitors on the PI3K-Akt-mTOR phosphorylation profile in acute myeloid leukemia cells. Signal Transduct. Target. Ther. 2019;4:20.

    Not in our library10.1038/s41392-019-0050-0

  101. 101.

    Juric D., Rodon J., Tabernero J., Janku F., Burris H.A., Schellens J.H.M., Middleton M.R., Berlin J., Schuler M., Gil-Martin M., et al. Phosphatidylinositol 3-Kinase alpha-Selective Inhibition With Alpelisib (BYL719) in PIK3CA-Altered Solid Tumors: Results From the First-in-Human Study. J. Clin. Oncol. 2018;36:1291-1299.

    Not in our library10.1200/jco.2017.72.7107

  102. 102.

    Mayer I.A., Abramson V.G., Isakoff S.J., Forero A., Balko J.M., Kuba M.G., Sanders M.E., Yap J.T., Van den Abbeele A.D., Li Y., et al. Stand up to cancer phase Ib study of pan-phosphoinositide-3-kinase inhibitor buparlisib with letrozole in estrogen receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. J. Clin. Oncol. 2014;32:1202-1209.

    Not in our library10.1200/jco.2013.54.0518

  103. 103.

    Juric D., Krop I., Ramanathan R.K., Wilson T.R., Ware J.A., Sanabria Bohorquez S.M., Savage H.M., Sampath D., Salphati L., Lin R.S., et al. Phase I Dose-Escalation Study of Taselisib, an Oral PI3K Inhibitor, in Patients with Advanced Solid Tumors. Cancer Discov. 2017;7:704-715.

    Not in our library10.1158/2159-8290.cd-16-1080

  104. 104.

    Andre F., Ciruelos E.M., Rubovszky G., Campone M., Loibl S., Rugo H.S., Iwata H., Conte P., Mayer I.A., Kaufman B., et al. Alpelisib (ALP) + fulvestrant (FUL) for advanced breast cancer (ABC): Results of the Phase 3 SOLAR-1 trial. Oncol. PRO EMSO. 2018;29.

    Not in our library10.1093/annonc/mdy424.010

  105. 105.

    Mayer I.A., Abramson V.G., Formisano L., Balko J.M., Estrada M.V., Sanders M.E., Juric D., Solit D., Berger M.F., Won H.H., et al. A Phase Ib Study of Alpelisib (BYL719), a PI3Kalpha-Specific Inhibitor, with Letrozole in ER+/HER2- Metastatic Breast Cancer. Clin. Cancer Res. 2017;23:26-34.

    Not in our library10.1158/1078-0432.ccr-16-0134

  106. 106.

    Ruicci K.M., Pinto N., Khan M.I., Yoo J., Fung K., MacNeil D., Mymryk J.S., Barrett J.W., Nichols A.C. ERK-TSC2 signalling in constitutively-active HRAS mutant HNSCC cells promotes resistance to PI3K inhibition. Oral. Oncol. 2018;84:95-103.

    Not in our library10.1016/j.oraloncology.2018.07.010

  107. 107.

    Engelman J.A., Chen L., Tan X., Crosby K., Guimaraes A.R., Upadhyay R., Maira M., McNamara K., Perera S.A., Song Y., et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat. Med. 2008;14:1351-1356.

    Not in our library10.1038/nm.1890

  108. 108.

    Dey N., Leyland-Jones B., De P. MYC-xing it up with PIK3CA mutation and resistance to PI3K inhibitors: Summit of two giants in breast cancers. Am. J. Cancer Res. 2015;5:1-19.

    Not in our library

  109. 109.

    Ilic N., Utermark T., Widlund H.R., Roberts T.M. PI3K-targeted therapy can be evaded by gene amplification along the MYC-eukaryotic translation initiation factor 4E (eIF4E) axis. Proc. Natl. Acad. Sci. USA. 2011;108:E699-E708.

    Not in our library10.1073/pnas.1108237108

  110. 110.

    Serra V., Eichhorn P.J., Garcia-Garcia C., Ibrahim Y.H., Prudkin L., Sanchez G., Rodriguez O., Anton P., Parra J.L., Marlow S., et al. RSK3/4 mediate resistance to PI3K pathway inhibitors in breast cancer. J. Clin. Investig. 2013;123:2551-2563.

    Not in our library10.1172/jci66343

  111. 111.

    Walsh K., McKinney M.S., Love C., Liu Q., Fan A., Patel A., Smith J., Beaven A., Jima D.D., Dave S.S. PAK1 mediates resistance to PI3K inhibition in lymphomas. Clin. Cancer Res. 2013;19:1106-1115.

    Not in our library10.1158/1078-0432.ccr-12-1060

  112. 112.

    Wu S., Wang S., Zheng S., Verhaak R., Koul D., Yung W.K. MSK1-Mediated beta-Catenin Phosphorylation Confers Resistance to PI3K/mTOR Inhibitors in Glioblastoma. Mol. Cancer Ther. 2016;15:1656-1668.

    Not in our library10.1158/1535-7163.mct-15-0857

  113. 113.

    Wang W., Lim K.G., Feng M., Bao Y., Lee P.L., Cai Y., Chen Y., Zhang H., Marzese D., Hoon D.S.B., et al. KDM6B Counteracts EZH2-Mediated Suppression of IGFBP5 to Confer Resistance to PI3K/AKT Inhibitor Treatment in Breast Cancer. Mol. Cancer Ther. 2018;17:1973-1983.

    Not in our library10.1158/1535-7163.mct-17-0802

  114. 114.

    Vora S.R., Juric D., Kim N., Mino-Kenudson M., Huynh T., Costa C., Lockerman E.L., Pollack S.F., Liu M., Li X., et al. CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors. Cancer Cell. 2014;26:136-149.

    Not in our library10.1016/j.ccr.2014.05.020

  115. 115.

    Wheler J.J., Atkins J.T., Janku F., Moulder S.L., Stephens P.J., Yelensky R., Valero V., Miller V., Kurzrock R., Meric-Bernstam F. Presence of both alterations in FGFR/FGF and PI3K/AKT/mTOR confer improved outcomes for patients with metastatic breast cancer treated with PI3K/AKT/mTOR inhibitors. Oncoscience. 2016;3:164-172.

    Not in our library10.18632/oncoscience.307

  116. 116.

    Elkabets M., Pazarentzos E., Juric D., Sheng Q., Pelossof R.A., Brook S., Benzaken A.O., Rodon J., Morse N., Yan J.J., et al. AXL mediates resistance to PI3Kalpha inhibition by activating the EGFR/PKC/mTOR axis in head and neck and esophageal squamous cell carcinomas. Cancer Cell. 2015;27:533-546.

    Not in our library10.1016/j.ccell.2015.03.010

  117. 117.

    Gasser J.A., Inuzuka H., Lau A.W., Wei W., Beroukhim R., Toker A. SGK3 mediates INPP4B-dependent PI3K signaling in breast cancer. Mol. Cell. 2014;56:595-607.

    Not in our library10.1016/j.molcel.2014.09.023

  118. 118.

    Song J.H., Singh N., Luevano L.A., Padi S.K.R., Okumura K., Olive V., Black S.M., Warfel N.A., Goodrich D.W., Kraft A.S. Mechanisms Behind Resistance to PI3K Inhibitor Treatment Induced by the PIM Kinase. Mol. Cancer Ther. 2018;17:2710-2721.

    Not in our library10.1158/1535-7163.mct-18-0374

  119. 119.

    Clement E., Inuzuka H., Nihira N.T., Wei W., Toker A. Skp2-dependent reactivation of AKT drives resistance to PI3K inhibitors. Sci. Signal. 2018;11.

    Not in our library10.1126/scisignal.aao3810

  120. 120.
    PDK1-SGK1 Signaling Sustains AKT-Independent mTORC1 Activation and Confers Resistance to PI3Kα Inhibition · 2016
    No notice
  121. 121.

    Makinoshima H., Umemura S., Suzuki A., Nakanishi H., Maruyama A., Udagawa H., Mimaki S., Matsumoto S., Niho S., Ishii G., et al. Metabolic Determinants of Sensitivity to Phosphatidylinositol 3-Kinase Pathway Inhibitor in Small-Cell Lung Carcinoma. Cancer Res. 2018;78:2179-2190.

    Not in our library10.1158/0008-5472.can-17-2109

  122. 122.

    Qian X.J., Li Y.T., Yu Y., Yang F., Deng R., Ji J., Jiao L., Li X., Wu R.Y., Chen W.D., et al. Inhibition of DNA methyltransferase as a novel therapeutic strategy to overcome acquired resistance to dual PI3K/mTOR inhibitors. Oncotarget. 2015;6:5134-5146.

    Not in our library10.18632/oncotarget.3016

  123. 123.

    Koh K.X., Tan G.H., Hui Low S.H., Mohd Omar M.F., Han M.J., Iacopetta B., Soo R., Beloueche-Babari M., Bhattacharya B., Soong R. Acquired resistance to PI3K/mTOR inhibition is associated with mitochondrial DNA mutation and glycolysis. Oncotarget. 2017;8:110133-110144.

    Not in our library10.18632/oncotarget.22655

  124. 124.

    Usman M.W., Gao J., Zheng T., Rui C., Li T., Bian X., Cheng H., Liu P., Luo F. Author Correction: Macrophages confer resistance to PI3K inhibitor GDC-0941 in breast cancer through the activation of NF-kappaB signaling. Cell Death Dis. 2019;10:501.

    Not in our library10.1038/s41419-019-1692-0

  125. 125.

    Maira S.M., Pecchi S., Huang A., Burger M., Knapp M., Sterker D., Schnell C., Guthy D., Nagel T., Wiesmann M., et al. Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor. Mol. Cancer Ther. 2012;11:317-328.

    Not in our library10.1158/1535-7163.mct-11-0474

  126. 126.

    Clinical Trials.gov. Study of BKM120 & Rituximab in Patients with Relapsed or Refractory Indolent B-cell Lymphoma.

    Not in our library

  127. 127.

    Clinical Trails.gov. Pharmacodynamic Study of BKM120 in Breast Cancer.

    Not in our library

  128. 128.

    Clinical Trials.gov. Trial of BKM120/Tamoxifen-Combination in Patients with HR-pos, HER2-neg Breast Cancer (PIKTAM).

    Not in our library

  129. 129.

    Clinical Trials.gov. Dose Escalation Study of LEE011 in Combination with Buparlisib and Letrozole in HR+, HER2-Negative Post-Menopausal Women with Advanced Breast Cancer.

    Not in our library

  130. 130.

    Clinical Trials.gov. A Phase I Study of BKM120 in Adult Chinese Patients with Advanced Solid Tumors.

    Not in our library

  131. 131.

    Clinical Trials.gov. Cisplatin, Etoposide and PI3K Inhibitor BKM120 in Treating Patients with Advanced Solid Tumors or Small Cell Lung Cancer.

    Not in our library

  132. 132.

    Clinical Trials.gov. Study of LEE011 with Fulvestrant and BYL719 or BKM120 in Advanced Breast Cancer.

    Not in our library

  133. 133.

    Clinical Trials.gov. Study of bkm120 or byl719 and Capecitabine in Patients with Metastatic Breast Cancer.

    Not in our library

  134. 134.

    Clinical Trials.gov. STAR Cape+BKM120 MBC with Brain Met.

    Not in our library

  135. 135.

    Clinical Trails.gov. PI3K Inhibitor BKM120 and Docetaxel in Treating Patients with Advanced Solid Tumor That Is Locally Advanced, Cannot Be Removed by Surgery, or Metastatic.

    Not in our library

  136. 136.

    Clinical Trials.gov. BKM120 + mFOLFOX6 in Advanced Solid Tumors with Expansion Cohort Pancreatic Cancer.

    Not in our library

  137. 137.

    Clinical Trials.gov. PhIb BKM120 or BEZ235+Endocrine Treatment in Post-Menopausal Patients with Hormone Receptor + Metastatic Breast Cancer.

    Not in our library

  138. 138.

    Clinical Trials.gov. BKM120 and Fulvestrant for Treating Postmenopausal Patients with Estrogen Receptor-Positive Stage IV Breast Cancer.

    Not in our library

  139. 139.

    Clinical Trials.gov. PI3K Inhibitor BKM120, Carboplatin, and Pemetrexed Disodium in Treating Patients with Stage IV Non-Small Cell Lung Cancer.

    Not in our library

  140. 140.

    Clinical Trails.gov. Study of the Combination of BKM120 and Cisplatin or Carboplatin in Patients with Advanced Solid Tumors.

    Not in our library

  141. 141.

    Clinical Trails.gov. Buparlisib in Treating Patients with Relapsed or Refractory Non-Hodgkin Lymphoma.

    Not in our library

  142. 142.

    Clinical Trails.gov. Palliative Thoracic Radiotherapy Plus BKM120.

    Not in our library

  143. 143.

    Clinical Trail.gov. Trial of Erlotinib and BKM120 in Patients with Advanced Non Small Cell Lung Cancer Previously Sensitive to Erlotinib.

    Not in our library

  144. 144.

    Clinical Trails.gov. Buparlisib (BKM120) in Patients with Recurrent/Refractory Primary Central Nervous System Lymphoma (PCNSl) and Recurrent/Refractory Secondary Central Nervous System Lymphoma (SCNSL).

    Not in our library

  145. 145.

    Tanaka H., Yoshida M., Tanimura H., Fujii T., Sakata K., Tachibana Y., Ohwada J., Ebiike H., Kuramoto S., Morita K., et al. The Selective Class I PI3K Inhibitor CH5132799 Targets Human Cancers Harboring Oncogenic PIK3CA Mutations. Clin. Cancer Res. 2011;17:3272-3281.

    Not in our library10.1158/1078-0432.ccr-10-2882

  146. 146.

    Ohwada J., Ebiike H., Kawada H., Tsukazaki M., Nakamura M., Miyazaki T., Morikami K., Yoshinari K., Yoshida M., Kondoh O., et al. Discovery and biological activity of a novel class I PI3K inhibitor, CH5132799. Bioorganic Med. Chem. Lett. 2011;21:1767-1772.

    Not in our library10.1016/j.bmcl.2011.01.065

  147. 147.

    Foster P., Yamaguchi K., Hsu P.P., Qian F., Du X., Wu J., Won K.-A., Yu P., Jaeger C.T., Zhang W., et al. The Selective PI3K Inhibitor XL147 (SAR245408) Inhibits Tumor Growth and Survival and Potentiates the Activity of Chemotherapeutic Agents in Preclinical Tumor Models. Mol. Cancer Ther. 2015;14:931-940.

    Not in our library10.1158/1535-7163.mct-14-0833

  148. 148.

    Elmenier F.M., Lasheen D.S., Abouzid K.A. Phosphatidylinositol 3 kinase (PI3K) inhibitors as new weapon to combat cancer. Eur. J. Med. Chem. 2019;183:111718.

    Not in our library10.1016/j.ejmech.2019.111718

  149. 149.

    Clinical Trials.gov. A Study of Investigational SAR256212 in Combination with SAR245408 in Patients with Solid Tumor Cancers.

    Not in our library

  150. 150.

    Clinical Trials.gov. Oral SAR245408 (XL147) and Oral MSC1936369B in Patients with Locally Advanced or Metastatic Solid Tumors.

    Not in our library

  151. 151.

    Clinical Trials.gov. Safety and Pharmacokinetics of SAR245408 Daily Oral in Patients with Solid Tumors.

    Not in our library

  152. 152.

    Clinical Trials.gov. Study of XL147 (SAR245408) in Advanced or Recurrent Endometrial Carcinoma.

    Not in our library

  153. 153.

    Kong D.X., Yamori T. ZSTK474, a novel phosphatidylinositol 3-kinase inhibitor identified using the JFCR39 drug discovery system. Acta Pharmacol. Sin. 2010;31:1189-1197.

    Not in our library10.1038/aps.2010.150

  154. 154.

    Clinical Trials.gov. A Study of ZSTK474 in Japanese Patients with Advanced Solid Malignancies.

    Not in our library

  155. 155.

    Clinical Trials.gov. A Safety Study of Oral ZSTK474 in Patients with Cancer.

    Not in our library

  156. 156.

    Simpson D.R., Mell L.K., Cohen E.E. Targeting the PI3K/AKT/mTOR pathway in squamous cell carcinoma of the head and neck. Oral Oncol. 2015;51:291-298.

    Not in our library10.1016/j.oraloncology.2014.11.012

  157. 157.
    Phosphatidylinositol 3-kinase (PI3K) inhibitors as cancer therapeutics · 2013
    No notice
  158. 158.

    Clinical Trials.gov. Study of PX-866 and Docetaxel in Solid Tumors.

    Not in our library

  159. 159.

    Clinical Trails.gov. Phase I Trial of Oral PX-866.

    Not in our library

  160. 160.

    Clinical Trails.gov. Phase 1 and 2 Study of PX-866 and Cetuximab.

    Not in our library

  161. 161.

    Folkes A.J., Ahmadi K., Alderton W.K., Alix S., Baker S.J., Box G., Chuckowree I.S., Clarke P.A., Depledge P., Eccles S.A., et al. The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-t hieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer. J. Med. Chem. 2008;51:5522-5532.

    Not in our library10.1021/jm800295d

  162. 162.

    Han N., Jiang Y., Gai Y., Liu Q., Yuan L., Wang Y., Li M., Zhang Y., Lan X. (11)C-Labeled Pictilisib (GDC-0941) as a Molecular Tracer Targeting Phosphatidylinositol 3-Kinase (PI3K) for Breast Cancer Imaging. Contrast Media Mol. Imaging. 2019;2019:1760184.

    Not in our library10.1155/2019/1760184

  163. 163.

    Yamamoto N., Fujiwara Y., Tamura K., Kondo S., Iwasa S., Tanabe Y., Horiike A., Yanagitani N., Kitazono S., Inatani M., et al. Phase Ia/Ib study of the pan-class I PI3K inhibitor pictilisib (GDC-0941) administered as a single agent in Japanese patients with solid tumors and in combination in Japanese patients with non-squamous non-small cell lung cancer. Investig. New Drugs. 2017;35:37-46.

    Not in our library10.1007/s10637-016-0382-3

  164. 164.

    Clinical Trails.gov. A Study of the Safety and Pharmacology of PI3-Kinase Inhibitor GDC-0941 in Combination with Either Paclitaxel and Carboplatin (with or without Bevacizumab) or Pemetrexed, Cisplatin, and Bevacizumab in Patients with Advanced Non-Small Cell Lung Cancer.

    Not in our library

  165. 165.

    Clinical Trials.gov. Safety and Efficacy of Carboplatin/Paclitaxel and Carboplatin/Paclitaxel/Bevacizumab with and without Pictilisib in Previously Untreated Advanced or Recurrent Non-Small Cell Lung Cancer.

    Not in our library

  166. 166.

    Clinical Trials.gov. Trastuzumab and Trastuzumab-MCC-DM1 Administered Intravenously and GDC-0941 Administered Orally to Patients with HER2-Positive Metastatic Breast Cancer Who Have Progressed on Previous Trastuzumab-Based Therapy.

    Not in our library

  167. 167.

    Clinical Trials.gov. A study of GDC-0941 in Participants with Locally Advanced or Metastatic Solid Tumors for Which Standard Therapy Either Does not Exist or Has Proven Ineffective or Intolerable.

    Not in our library

  168. 168.

    Liu N., Rowley B.R., Bull C.O., Schneider C., Haegebarth A., Schatz C.A., Fracasso P.R., Wilkie D.P., Hentemann M., Wilhelm S.M., et al. BAY 80-6946 is a highly selective intravenous PI3K inhibitor with potent p110alpha and p110delta activities in tumor cell lines and xenograft models. Mol. Cancer Ther. 2013;12:2319-2330.

    Not in our library10.1158/1535-7163.mct-12-0993-t

  169. 169.

    Markham A. Copanlisib: First Global Approval. Drugs. 2017;77:2057-2062.

    Not in our library10.1007/s40265-017-0838-6

  170. 170.

    Clinical Trails.gov. Phase I Study of PI3(Phosphoinositol 3)-Kinase Inhibitor BAY80-6946 with Paclitaxel in Patients with Advanced Cancer.

    Not in our library

  171. 171.

    Clinical Trails.gov. Japanese Phase Ib/II Copanlisib in Relapsed, Indolent B-cell NHL.

    Not in our library

  172. 172.

    Clinical Trials.gov. Phase 1 Study of the Combination of Rogaratinib with Copanlisib in Patients with Fibroblast Growth Factor Receptor (FGFR)-Positive, Locally Advanced or Metastatic Solid Tumors (ROCOCO).

    Not in our library

  173. 173.

    Clinical Trails.gov. Copanlisib and Gemcitabine in Relapsed/Refractory PTCL.

    Not in our library

  174. 174.

    Clinical Trials.gov. Phase III Copanlisib in Rituximab-Refractory iNHL (CHRONOS-2).

    Not in our library

  175. 175.

    Clinical Trails.gov. Copanlisib and Rituximab in Relapsed Indolent B-cell Non-Hodgkin’s Lymphoma (iNHL) (CHRONOS-3).

    Not in our library

  176. 176.

    Clinical Trials.gov. Study of Copanlisib in Combination with Standard Immunochemotherapy in Relapsed Indolent Non-Hodgkin’s Lymphoma (iNHL) (CHRONOS-4).

    Not in our library

  177. 177.

    Clinical Trails.gov. Copanlisib in Association with Cetuximab in Patients with Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinomas Harboring a PI3KCA Mutation/Amplification and/or a PTEN Loss (COPAN-ORL06).

    Not in our library

  178. 178.

    Clinical Trails.gov. Copanlisib, Letrozole, and Palbociclib in Treating Patients with Hormone Receptor Positive HER2 Negative Stage I-IV Breast Cancer.

    Not in our library

  179. 179.

    Clinical Trails.gov. Copanlisib (BAY 80-6946) in Combination with Gemcitabine and Cisplatin in Advanced Cholangiocarcinoma.

    Not in our library

  180. 180.

    Zhou H., Yu C., Kong L., Xu X., Yan J., Li Y., An T., Gong L., Gong Y., Zhu H., et al. B591, a novel specific pan-PI3K inhibitor, preferentially targets cancer stem cells. Oncogene. 2019;38:3371-3386.

    Not in our library10.1038/s41388-018-0674-5

  181. 181.

    Doukas J., Wrasidlo W., Noronha G., Dneprovskaia E., Fine R., Weis S., Hood J., Demaria A., Soll R., Cheresh D. Phosphoinositide 3-kinase gamma/delta inhibition limits infarct size after myocardial ischemia/reperfusion injury. Proc. Natl. Acad. Sci. USA. 2006;103:19866-19871.

    Not in our library10.1073/pnas.0606956103

  182. 182.

    Song C., Bae Y., Jun J., Lee H., Kim N.D., Lee K.-B., Hur W., Park J.-Y., Sim T. Identification of TG100-115 as a new and potent TRPM7 kinase inhibitor, which suppresses breast cancer cell migration and invasion. Biochim. Biophys. Acta. 2017;1861:947-957.

    Not in our library10.1016/j.bbagen.2017.01.034

  183. 183.

    Westhoff M.A., Kandenwein J.A., Karl S., Vellanki S.H., Braun V., Eramo A., Antoniadis G., Debatin K.M., Fulda S. The pyridinylfuranopyrimidine inhibitor, PI-103, chemosensitizes glioblastoma cells for apoptosis by inhibiting DNA repair. Oncogene. 2009;28:3586-3596.

    Not in our library10.1038/onc.2009.215

  184. 184.

    Luo L., Zhong Q., Guo S., Zhang C., Zhang Q., Zheng S., He L., Wang G. Development of a bioavailable boron-containing PI-103 Bioisostere, PI-103BE. Bioorganic Med. Chem. Lett. 2020;30:127258.

    Not in our library10.1016/j.bmcl.2020.127258

  185. 185.

    Zhu H., Mishra R., Yuan L., Abdul Salam S.F., Liu J., Gray G., Sterling A.D., Wunderlich M., Landero-Figueroa J., Garrett J.T., et al. Oxidative Cyclization-Induced Activation of a Phosphoinositide 3-Kinase Inhibitor for Enhanced Selectivity of Cancer Chemotherapeutics. ChemMedChem. 2019;14:1933-1939.

    Not in our library10.1002/cmdc.201900481

  186. 186.

    Mishra R., Yuan L., Patel H., Karve A., Zhu H., White A., Alanazi S., Desai P., Merino E., Garrett J. Phosphoinositide 3-Kinase (PI3K) Reactive Oxygen Species (ROS)-Activated Prodrug in Combination with Anthracycline Impairs PI3K Signaling, Increases DNA Damage Response and Reduces Breast Cancer Cell Growth. Int. J. Mol. Sci. 2021;22:2088.

    Not in our library10.3390/ijms22042088

  187. 187.

    Annals of Oncology 2012. Abstract 664Tip: A Phase I Trial of Irinotecan (iri) and BKM120 in Previously Treated Patients (pts) with Metastic Colorectal Cancer (MCRC).

    Not in our library

  188. 188.

    Owonikoko T.K., Harvey R.D., Carthon B., Chen Z., Lewis C., Collins H., Zhang C., Lawson D.H., Alese O.B., Bilen M.A., et al. A Phase I Study of Safety, Pharmacokinetics, and Pharmacodynamics of Concurrent Everolimus and Buparlisib Treatment in Advanced Solid Tumors. Clin. Cancer Res. 2020;26:2497-2505.

    Not in our library10.1158/1078-0432.ccr-19-2697

  189. 189.

    Ando Y., Inada-Inoue M., Mitsuma A., Yoshino T., Ohtsu A., Suenaga N., Sato M., Kakizume T., Robson M., Quadt C., et al. Phase I dose-escalation study of buparlisib (BKM120), an oral pan-class I PI3K inhibitor, in Japanese patients with advanced solid tumors. Cancer Sci. 2014;105:347-353.

    Not in our library10.1111/cas.12350

  190. 190.

    Bendell J.C., Rodon J., Burris H.A., de Jonge M., Verweij J., Birle D., Demanse D., De Buck S.S., Ru Q.C., Peters M., et al. Phase I, dose-escalation study of BKM120, an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors. J. Clin. Oncol. 2012;30:282-290.

    Not in our library10.1200/jco.2011.36.1360

  191. 191.

    Bardia A., Gounder M., Rodon J., Janku F., Lolkema M.P., Stephenson J.J., Bedard P.L., Schuler M., Sessa C., LoRusso P., et al. Phase Ib Study of Combination Therapy with MEK Inhibitor Binimetinib and Phosphatidylinositol 3-Kinase Inhibitor Buparlisib in Patients with Advanced Solid Tumors with RAS/RAF Alterations. Oncologist. 2020;25:e160-e169.

    Not in our library10.1634/theoncologist.2019-0297

  192. 192.

    Smyth L.M., Monson K.R., Jhaveri K., Drilon A., Li B.T., Abida W., Iyer G., Gerecitano J.F., Gounder M., Harding J.J., et al. A phase 1b dose expansion study of the pan-class I PI3K inhibitor buparlisib (BKM120) plus carboplatin and paclitaxel in PTEN deficient tumors and with dose intensified carboplatin and paclitaxel. Investig. New Drugs. 2017;35:742-750.

    Not in our library10.1007/s10637-017-0445-0

  193. 193.

    Bedard P.L., Tabernero J., Janku F., Wainberg Z.A., Paz-Ares L., Vansteenkiste J., Van Cutsem E., Perez-Garcia J., Stathis A., Britten C.D., et al. A phase Ib dose-escalation study of the oral pan-PI3K inhibitor buparlisib (BKM120) in combination with the oral MEK1/2 inhibitor trametinib (GSK1120212) in patients with selected advanced solid tumors. Clin. Cancer Res. 2015;21:730-738.

    Not in our library10.1158/1078-0432.ccr-14-1814

  194. 194.

    Chu Q., Mahipal A., Schuler M., De Braud F., Dirix L., Rampersad A., Zhou J., Wu Y., Kalambakas S., Wen P. Dose-Escalation Study of Sonidegib (Lde225) Plus Buparlisib (Bkm120) in Patients (Pts) with Advanced Solid Tumors. Ann. Oncol. 2014;25:iv147-iv148.

    Not in our library10.1093/annonc/mdu331.5

  195. 195.

    Zambrano C.C., Schuler M.H., Machiels J.-P.H., Hess D., Paz-Ares L., Awada A., Von Moos R., Steeghs N., Ahnert J.R., De Mesmaeker P., et al. Phase lb study of buparlisib (BKM120) plus either paclitaxel (PTX) in advanced solid tumors (aST) or PTX plus trastuzumab (TZ) in HER2+ breast cancer (BC). J. Clin. Oncol. 2014;32:627.

    Not in our library10.1200/jco.2014.32.15_suppl.627

  196. 196.

    McKay R.R. A phase I study of buparlisib (BKM120) with bevacizumab (BEV) in patients (pts) with metastatic renal cell carcinoma (mRCC) progressing on prior vascular endothelial growth factor (VEGF) therapies. J. Clin. Oncol. 2015;33:4559.

    Not in our library10.1200/jco.2015.33.15_suppl.4559

  197. 197.

    Ragon B.K., Kantarjian H., Jabbour E., Ravandi F., Cortes J., Borthakur G., DeBose L., Zeng Z., Schneider H., Pemmaraju N., et al. Buparlisib, a PI3K inhibitor, demonstrates acceptable tolerability and preliminary activity in a phase I trial of patients with advanced leukemias. Am. J. Hematol. 2017;92:7-11.

    Not in our library10.1002/ajh.24568

  198. 198.

    Wen P.Y., Rodon J.A., Mason W., Beck J.T., DeGroot J., Donnet V., Mills D., El-Hashimy M., Rosenthal M. Phase I, open-label, multicentre study of buparlisib in combination with temozolomide or with concomitant radiation therapy and temozolomide in patients with newly diagnosed glioblastoma. ESMO Open. 2020;5.

    Not in our library10.1136/esmoopen-2020-000673

  199. 199.

    Shih K.C., Chowdhary S.A., Becker K.P., Baehring J.M., Liggett W.H., Burris H.A., Hainsworth J.D. A phase II study of the combination of BKM120 (buparlisib) and bevacizumab in patients with relapsed/refractory glioblastoma multiforme (GBM). J. Clin. Oncol. 2015;33:2065.

    Not in our library10.1200/jco.2015.33.15_suppl.2065

  200. 200.

    Goodwin R., Jonker D., Chen E., Kennecke H., Cabanero M., Tsao M.S., Vickers M., Bohemier C., Lim H., Ritter H., et al. A phase Ib study of a PI3Kinase inhibitor BKM120 in combination with panitumumab in patients with KRAS wild-type advanced colorectal cancer. Investig. New Drugs. 2020;38:1077-1084.

    Not in our library10.1007/s10637-019-00814-3

  201. 201.

    Massard C., Chi K.N., Castellano D., de Bono J., Gravis G., Dirix L., Machiels J.P., Mita A., Mellado B., Turri S., et al. Phase Ib dose-finding study of abiraterone acetate plus buparlisib (BKM120) or dactolisib (BEZ235) in patients with castration-resistant prostate cancer. Eur. J. Cancer. 2017;76:36-44.

    Not in our library10.1016/j.ejca.2017.01.024

  202. 202.

    Rodon J. A Phase I dose escalation and expansion trial of BKM120, An oral pan-PI3K Inhibitor, in patients with advanced solid tumors: Analysis of pharmacodynamic biomarker data. Ann. Oncol. 2012;23:ix158-ix159.

    Not in our library10.1016/s0923-7534(20)33015-5

  203. 203.

    Gelderblom H., Jones R.L., George S., Valverde Morales C., Benson C., Jean-Yves B., Renouf D.J., Doi T., Le Cesne A., Leahy M., et al. Imatinib in combination with phosphoinositol kinase inhibitor buparlisib in patients with gastrointestinal stromal tumour who failed prior therapy with imatinib and sunitinib: A Phase 1b, multicentre study. Br. J. Cancer. 2020;122:1158-1165.

    Not in our library10.1038/s41416-020-0769-y

  204. 204.

    Algazi A.P., Rotow J., Posch C., Ortiz-Urda S., Pelayo A., Munster P.N., Daud A. A dual pathway inhibition strategy using BKM120 combined with vemurafenib is poorly tolerated in BRAF V600(E/K) mutant advanced melanoma. Pigment Cell Melanoma Res. 2019;32:603-606.

    Not in our library10.1111/pcmr.12777

  205. 205.

    Rosenthal M., Clement P.M., Campone M., Gil-Gil M.J., DeGroot J., Chinot O., Idbaih A., Gan H., Raizer J., Wen P.Y., et al. Buparlisib plus carboplatin or lomustine in patients with recurrent glioblastoma: A phase Ib/II, open-label, multicentre, randomised study. ESMO Open. 2020;5.

    Not in our library10.1136/esmoopen-2020-000672

  206. 206.

    Assouline S., Amrein L., Aloyz R., Banerji V., Caplan S., Owen C., Hasegawa W., Robinson S., Shivakumar S., Prica A., et al. IND.216: A phase II study of buparlisib and associated biomarkers, raptor and p70S6K, in patients with relapsed and refractory chronic lymphocytic leukemia. Leuk. Lymphoma. 2020;61:1653-1659.

    Not in our library10.1080/10428194.2020.1734594

  207. 207.

    Younes A., Salles G., Martinelli G., Bociek R.G., Barrigon D.C., Barca E.G., Turgut M., Gerecitano J., Kong O., Pisal C.B., et al. Pan-phosphatidylinositol 3-kinase inhibition with buparlisib in patients with relapsed or refractory non-Hodgkin lymphoma. Haematologica. 2017;102:2104-2112.

    Not in our library10.3324/haematol.2017.169656

  208. 208.

    Iyer G., Tully C.M., Garcia-Grossman I.R., Scott S.N., Boyd M.E., McCoy A.S., Berger M.F., Al-Ahmadie H., Solit D.B., Rosenberg J.E., et al. Phase 2 study of the pan-isoform PI3 kinase inhibitor BKM120 in metastatic urothelial carcinoma patients. J. Clin. Oncol. 2015;33:324.

    Not in our library10.1200/jco.2015.33.7_suppl.324

  209. 209.

    Wen P.Y., Touat M., Alexander B.M., Mellinghoff I.K., Ramkissoon S., McCluskey C.S., Pelton K., Haidar S., Basu S.S., Gaffey S.C., et al. Buparlisib in patients with recurrent glioblastoma harboring phosphatidylinositol 3-kinase pathway activation: An Open-Label, Multicenter, Multi-Arm, Phase II Trial. J. Clin. Oncol. 2019;37:741-750.

    Not in our library10.1200/jco.18.01207

  210. 210.

    Piha-Paul S.A., Taylor M.H., Spitz D., Schwartzberg L., Beck J.T., Bauer T.M., Meric-Bernstam F., Purkayastha D., Karpiak L., Szpakowski S., et al. Efficacy and safety of buparlisib, a PI3K inhibitor, in patients with malignancies harboring a PI3K pathway activation: A phase 2, open-label, single-arm study. Oncotarget. 2019;10:6526-6535.

    Not in our library10.18632/oncotarget.27251

  211. 211.

    Clinical Trails.gov. BKM120 as Second-Line Therapy for Advanced Endometrial Cancer.

    Not in our library

  212. 212.

    Vansteenkiste J.F., Canon J.L., De Braud F., Grossi F., De Pas T., Gray J.E., Su W.C., Felip E., Yoshioka H., Gridelli C., et al. Safety and Efficacy of Buparlisib (BKM120) in Patients with PI3K Pathway-Activated Non-Small Cell Lung Cancer: Results from the Phase II BASALT-1 Study. J. Thorac. Oncol. 2015;10:1319-1327.

    Not in our library10.1097/jto.0000000000000607

  213. 213.
    Phase 2 study of buparlisib (BKM120), a pan-class I PI3K inhibitor, in patients with metastatic triple-negative breast cancer · 2020
    No notice
  214. 214.

    Heudel P.E., Fabbro M., Roemer-Becuwe C., Kaminsky M.C., Arnaud A., Joly F., Roche-Forestier S., Meunier J., Foa C., You B., et al. Phase II study of the PI3K inhibitor BKM120 in patients with advanced or recurrent endometrial carcinoma: A stratified type I-type II study from the GINECO group. Br. J. Cancer. 2017;116:303-309.

    Not in our library10.1038/bjc.2016.430

  215. 215.

    Loibl S., de la Pena L., Nekljudova V., Zardavas D., Michiels S., Denkert C., Rezai M., Bermejo B., Untch M., Lee S.C., et al. Neoadjuvant buparlisib plus trastuzumab and paclitaxel for women with HER2+ primary breast cancer: A randomised, double-blind, placebo-controlled phase II trial (NeoPHOEBE). Eur. J. Cancer. 2017;85:133-145.

    Not in our library10.1016/j.ejca.2017.08.020

  216. 216.

    Grommes C., Pentsova E., Nolan C., Wolfe G., Mellinghoff I.K., Deangelis L. Phase II study of single agent buparlisib in recurrent/refractory primary (PCNSL) and secondary CNS lymphoma (SCNSL). Ann. Oncol. 2016;27:106.

    Not in our library10.1093/annonc/mdw367.13

  217. 217.

    Fayette J., Digue L., Ferlay C., Treilleux I., Garin G., Wang Q., Hebert C., Even C., Cupissol D., Couchon-Thaunat S., et al. PIK-ORL: A phase II, multicenter trial aiming to evaluate BKM120 in monotherapy in patients (pts) with metastatic/recurrent head and neck squamous cell carcinoma (HNSCC) after failure of platin and cetuximab or anti-EGFR-based therapy. Ann. Oncol. 2016;27:vi331.

    Not in our library10.1093/annonc/mdw376.11

  218. 218.

    Anantharaman A., Nguyen H.G., Cooperberg M.R., Meng M.V., Carroll P., Friedlander T.W., Zhang L., Thomas M., Febbo P.G., Feng F.Y.-C., et al. A pharmacodynamic study of pre-prostatectomy buparlisib in men with high-risk, localized prostate cancer. J. Clin. Oncol. 2016;34:e14110.

    Not in our library10.1200/jco.2016.34.15_suppl.e14110

  219. 219.

    Martin M., Chan A., Dirix L., O’Shaughnessy J., Hegg R., Manikhas A., Shtivelband M., Krivorotko P., Batista Lopez N., Campone M., et al. A randomized adaptive phase II/III study of buparlisib, a pan-class I PI3K inhibitor, combined with paclitaxel for the treatment of HER2- advanced breast cancer (BELLE-4). Ann. Oncol. 2017;28:313-320.

    Not in our library10.1093/annonc/mdw562

  220. 220.

    Baselga J., Im S.A., Iwata H., Cortes J., De Laurentiis M., Jiang Z., Arteaga C.L., Jonat W., Clemons M., Ito Y., et al. Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. Oncol. 2017;18:904-916.

    Not in our library10.1016/s1470-2045(17)30376-5

  221. 221.

    Jochen H.L. A phase I study of the PI3K inhibitor buplarlisib (B) with concurrent chemoradiotherapy (CRT) in patients with high risk locally advanced squamous cell cancer of the head and neck (LASCCHN). J. Clin. Oncol. 2018;36:6071.

    Not in our library

  222. 222.

    Batlevi C.L., Hamlin P.A., Matasar M.J., Horwitz S.M., Gerecitano J.F., Moskowitz C.H., Straus D.J., Zelenetz A.D., Drullinsky P., Copeland A., et al. Phase I dose escalation of ibrutinib and buparlisib in relapsed/refractory diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and follicular lymphoma (FL). J. Clin. Oncol. 2017;35:7544.

    Not in our library10.1200/jco.2017.35.15_suppl.7544

  223. 223.

    Dummer R., Sandhu S.K., Miller W.H., Butler M.O., Blank C.U., Muñoz-Couselo E., Iii H.A.B., Postow M.A., Chmielowski B., Middleton M.R., et al. A phase II, multicenter study of encorafenib/binimetinib followed by a rational triple-combination after progression in patients with advanced BRAF V600-mutated melanoma (LOGIC2). J. Clin. Oncol. 2020;38:10022.

    Not in our library10.1200/jco.2020.38.15_suppl.10022

  224. 224.

    Brisson R.J., Dekker A., De Souza J.A., Saloura V., Vokes E.E., Seiwert T.Y. A pilot study of the pan-class I PI3K inhibitor buparlisib in combination with cetuximab in patients with recurrent/metastatic head and neck cancer. J. Clin. Oncol. 2017;35:6039.

    Not in our library10.1200/jco.2017.35.15_suppl.6039

  225. 225.

    Blagden S., Omlin A., Josephs D., Stavraka C., Zivi A., Pinato D.J., Anthoney A., Decordova S., Swales K., Riisnaes R., et al. First-in-human study of CH5132799, an oral class I PI3K inhibitor, studying toxicity, pharmacokinetics, and pharmacodynamics, in patients with metastatic cancer. Clin. Cancer Res. 2014;20:5908-5917.

    Not in our library10.1158/1078-0432.ccr-14-1315

  226. 226.

    Soria J.C., LoRusso P., Bahleda R., Lager J., Liu L., Jiang J., Martini J.F., Mace S., Burris H. Phase I dose-escalation study of pilaralisib (SAR245408, XL147), a pan-class I PI3K inhibitor, in combination with erlotinib in patients with solid tumors. Oncologist. 2015;20:245-246.

    Not in our library10.1634/theoncologist.2014-0449

  227. 227.

    Shapiro G.I., Rodon J., Bedell C., Kwak E.L., Baselga J., Brana I., Pandya S.S., Scheffold C., Laird A.D., Nguyen L.T., et al. Phase I safety, pharmacokinetic, and pharmacodynamic study of SAR245408 (XL147), an oral pan-class I PI3K inhibitor, in patients with advanced solid tumors. Clin. Cancer Res. 2014;20:233-245.

    Not in our library10.1158/1078-0432.ccr-13-1777

  228. 228.

    Brown J.R., Davids M.S., Rodon J., Abrisqueta P., DeCillis A.P., Rockich K., Egile C., Kelly A., Xu Y., Lager J., et al. Phase I Trial of SAR245408 (S08), a Pan-Phosphatidylinositol 3 Kinase (PI3K) Inhibitor, in Patients with Chronic Lymphocytic Leukemia (CLL) and Lymphoma. Blood. 2011;118:2683.

    Not in our library10.1182/blood.v118.21.2683.2683

  229. 229.

    Wheler J., Mutch D., Lager J., Castell C., Liu L., Jiang J., Traynor A.M. Phase I Dose-Escalation Study of Pilaralisib (SAR245408, XL147) in Combination with Paclitaxel and Carboplatin in Patients with Solid Tumors. Oncologist. 2017;22:377.

    Not in our library10.1634/theoncologist.2016-0257

  230. 230.

    Tolaney S., Burris H., Gartner E., Mayer I.A., Saura C., Maurer M., Ciruelos E., Garcia A.A., Campana F., Wu B., et al. Phase I/II study of pilaralisib (SAR245408) in combination with trastuzumab or trastuzumab plus paclitaxel in trastuzumab-refractory HER2-positive metastatic breast cancer. Breast Cancer Res. Treat. 2015;149:151-161.

    Not in our library10.1007/s10549-014-3248-4

  231. 231.

    Blackwell K., Burris H., Gomez P., Lynn Henry N., Isakoff S., Campana F., Gao L., Jiang J., Mace S., Tolaney S.M. Phase I/II dose-escalation study of PI3K inhibitors pilaralisib or voxtalisib in combination with letrozole in patients with hormone-receptor-positive and HER2-negative metastatic breast cancer refractory to a non-steroidal aromatase inhibitor. Breast Cancer Res. Treat. 2015;154:287-297.

    Not in our library10.1007/s10549-015-3615-9

  232. 232.

    Bechter O.E., Dumez H., Costermans J., Punie K., Liu L., Jiang J., Dedieu J.-F., Schöffski P. Phase I safety and pharmacokinetic (PK) dose escalation study with SAR245408 (S) polymorph E, a PI3K inhibitor, in patients (pts) with solid tumors or lymphoma. J. Clin. Oncol. 2015;33:e13599.

    Not in our library10.1200/jco.2015.33.15_suppl.e13599

  233. 233.

    Hotte S.J., Chi K.N., Joshua A.M., Tu D., Macfarlane R.J., Gregg R.W., Ruether J.D., Basappa N.S., Finch D., Salim M., et al. A Phase II Study of PX-866 in Patients With Recurrent or Metastatic Castration-resistant Prostate Cancer: Canadian Cancer Trials Group Study IND205. Clin. Genitourin. Cancer. 2019;17:201-208.

    Not in our library10.1016/j.clgc.2019.03.005

  234. 234.

    Pitz M.W., Eisenhauer E.A., MacNeil M.V., Thiessen B., Easaw J.C., Macdonald D.R., Eisenstat D.D., Kakumanu A.S., Salim M., Chalchal H., et al. Phase II study of PX-866 in recurrent glioblastoma. Neurooncology. 2015;17:1270-1274.

    Not in our library10.1093/neuonc/nou365

  235. 235.

    Schoffski P., Cresta S., Mayer I.A., Wildiers H., Damian S., Gendreau S., Rooney I., Morrissey K.M., Spoerke J.M., Ng V.W., et al. A phase Ib study of pictilisib (GDC-0941) in combination with paclitaxel, with and without bevacizumab or trastuzumab, and with letrozole in advanced breast cancer. Breast Cancer Res. 2018;20:109.

    Not in our library10.1186/s13058-018-1015-x

  236. 236.

    Leong S., Moss R.A., Bowles D.W., Ware J.A., Zhou J., Spoerke J.M., Lackner M.R., Shankar G., Schutzman J.L., van der Noll R., et al. A Phase I Dose-Escalation Study of the Safety and Pharmacokinetics of Pictilisib in Combination with Erlotinib in Patients with Advanced Solid Tumors. Oncologist. 2017;22:1491-1499.

    Not in our library10.1634/theoncologist.2017-0090

  237. 237.

    Sarker D., Ang J.E., Baird R., Kristeleit R., Shah K., Moreno V., Clarke P.A., Raynaud F.I., Levy G., Ware J.A., et al. First-in-human phase I study of pictilisib (GDC-0941), a potent pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors. Clin. Cancer Res. 2015;21:77-86.

    Not in our library10.1158/1078-0432.ccr-14-0947

  238. 238.

    Vuylsteke P., Huizing M., Petrakova K., Roylance R., Laing R., Chan S., Abell F., Gendreau S., Rooney I., Apt D., et al. Pictilisib PI3Kinase inhibitor (a phosphatidylinositol 3-kinase [PI3K] inhibitor) plus paclitaxel for the treatment of hormone receptor-positive, HER2-negative, locally recurrent, or metastatic breast cancer: Interim analysis of the multicentre, placebo-controlled, phase II randomised PEGGY study. Ann. Oncol. 2016;27:2059-2066.

    Not in our library10.1093/annonc/mdw320

  239. 239.

    Krop I.E., Mayer I.A., Ganju V., Dickler M., Johnston S., Morales S., Yardley D.A., Melichar B., Forero-Torres A., Lee S.C., et al. Pictilisib for oestrogen receptor-positive, aromatase inhibitor-resistant, advanced or metastatic breast cancer (FERGI): A randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. Oncol. 2016;17:811-821.

    Not in our library10.1016/s1470-2045(16)00106-6

  240. 240.

    Schmid P., Pinder S.E., Wheatley D., Macaskill J., Zammit C., Hu J., Price R., Bundred N., Hadad S., Shia A., et al. Phase II Randomized Preoperative Window-of-Opportunity Study of the PI3K Inhibitor Pictilisib Plus Anastrozole Compared With Anastrozole Alone in Patients With Estrogen Receptor-Positive Breast Cancer. J. Clin. Oncol. 2016;34:1987-1994.

    Not in our library10.1200/jco.2015.63.9179

  241. 241.

    Patnaik A., Appleman L.J., Tolcher A.W., Papadopoulos K.P., Beeram M., Rasco D.W., Weiss G.J., Sachdev J.C., Chadha M., Fulk M., et al. First-in-human phase I study of copanlisib (BAY 80-6946), an intravenous pan-class I phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors and non-Hodgkin’s lymphomas. Ann. Oncol. 2016;27:1928-1940.

    Not in our library10.1093/annonc/mdw282

  242. 242.

    Doi T., Fuse N., Yoshino T., Kojima T., Bando H., Miyamoto H., Kaneko M., Osada M., Ohtsu A. A Phase I study of intravenous PI3K inhibitor copanlisib in Japanese patients with advanced or refractory solid tumors. Cancer Chemother. Pharmacol. 2017;79:89-98.

    Not in our library10.1007/s00280-016-3198-0

  243. 243.

    Ramanathan R.K., Von Hoff D.D., Eskens F., Blumenschein G., Richards D., Genvresse I., Reschke S., Granvil C., Skubala A., Pena C., et al. Phase Ib Trial of the PI3K Inhibitor Copanlisib Combined with the Allosteric MEK Inhibitor Refametinib in Patients with Advanced Cancer. Target. Oncol. 2020;15:163-174.

    Not in our library10.1007/s11523-020-00714-0

  244. 244.

    Morschhauser F., Machiels J.P., Salles G., Rottey S., Rule S.A.J., Cunningham D., Peyrade F., Fruchart C., Arkenau H.T., Genvresse I., et al. On-Target Pharmacodynamic Activity of the PI3K Inhibitor Copanlisib in Paired Biopsies from Patients with Malignant Lymphoma and Advanced Solid Tumors. Mol. Cancer Ther. 2020;19:468-478.

    Not in our library10.1158/1535-7163.mct-19-0466

  245. 245.

    Kim R.D., Alberts S.R., Pena C., Genvresse I., Ajavon-Hartmann A., Xia C., Kelly A., Grilley-Olson J.E. Phase I dose-escalation study of copanlisib in combination with gemcitabine or cisplatin plus gemcitabine in patients with advanced cancer. Br. J. Cancer. 2018;118:462-470.

    Not in our library10.1038/bjc.2017.428

  246. 246.

    Song Y., Liu W., Niu Y., Cisternas G., Huang F., Garcia-Vargas J., Childs B., Mehra A., Li T., Hiemeyer F., et al. 260P A phase I study of copanlisib, a pan-class I phosphatidylinositol 3-kinase (PI3K) inhibitor, in Chinese patients with relapsed indolent non-Hodgkin lymphoma (iNHL). Ann. Oncol. 2020;31:S1344.

    Not in our library10.1016/j.annonc.2020.10.254

  247. 247.

    Lenz H., Hawkes E., Verhoef G., Haioun C., Thye L.S., Heo D.S., Ardeshna K., Chong G., Christensen J.H., Shi V., et al. Phase II study of single-agent copanlisib in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). J. Clin. Oncol. 2017;35:7356.

    Not in our library10.1200/jco.2017.35.15_suppl.7536

  248. 248.

    Spreafico A., Sawyer M.B., Siu L.L., Huang F., Reschke S., Xia C., Yan Z., Genvresse I., Cisternas G., Kelly A., et al. Effects of rifampin on the pharmacokinetics of copanlisib, a novel pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor in cancer patients. J. Clin. Oncol. 2018;36:e14559.

    Not in our library10.1200/jco.2018.36.15_suppl.e14559

  249. 249.

    Dreyling M., Morschhauser F., Bouabdallah K., Bron D., Cunningham D., Assouline S.E., Verhoef G., Linton K., Thieblemont C., Vitolo U., et al. Phase II study of copanlisib, a PI3K inhibitor, in relapsed or refractory, indolent or aggressive lymphoma. Ann. Oncol. 2017;28:2169-2178.

    Not in our library10.1093/annonc/mdx289

  250. 250.

    Clinical Trails.gov. Copanlisib in Treating Patients with Persistent or Recurrent Endometrial Cancer.

    Not in our library

  251. 251.

    Fritsch C., Huang A., Chatenay-Rivauday C., Schnell C., Reddy A., Liu M., Kauffmann A., Guthy D., Erdmann D., De Pover A., et al. Characterization of the novel and specific PI3Kalpha inhibitor NVP-BYL719 and development of the patient stratification strategy for clinical trials. Mol. Cancer Ther. 2014;13:1117-1129.

    Not in our library10.1158/1535-7163.mct-13-0865

  252. 252.

    Elkabets M., Vora S., Juric D., Morse N., Mino-Kenudson M., Muranen T., Tao J., Campos A.B., Rodon J., Ibrahim Y.H., et al. mTORC1 inhibition is required for sensitivity to PI3K p110alpha inhibitors in PIK3CA-mutant breast cancer. Sci. Transl. Med. 2013;5:196ra199.

    Not in our library10.1126/scitranslmed.3005747

  253. 253.

    Crunkhorn S. Genetic disorders: PI3K inhibitor reverses overgrowth syndrome. Nat. Rev. Drug Discov. 2018;17:545.

    Not in our library10.1038/nrd.2018.120

  254. 254.

    Andre F., Ciruelos E., Rubovszky G., Campone M., Loibl S., Rugo H.S., Iwata H., Conte P., Mayer I.A., Kaufman B., et al. Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer. N. Engl. J. Med. 2019;380:1929-1940.

    Not in our library10.1056/nejmoa1813904

  255. 255.

    Markham A. Alpelisib: First Global Approval. Drugs. 2019;79:1249-1253.

    Not in our library10.1007/s40265-019-01161-6

  256. 256.

    Clinical Trials.gov. PI3K Inhibitor BYL719 in Combination with the HSP90 Inhibitor AUY922 in Patients with Advanced or Metastatic Gastric Cancer.

    Not in our library

  257. 257.

    Clinical Trails.gov. A Dose-Finding Study of a Combination of Imatinib and BYL719 in the Treatment of 3rd Line Gist Patients.

    Not in our library

  258. 258.

    Clinical Trails.gov. Study of Safety & Efficacy of the Combination of LJM716 & BYL719 in Patients with Previously Treated Esophageal Squamous Cell Carcinoma (ESCC).

    Not in our library

  259. 259.

    Clinical Trails.gov. Study of the Safety and Effectiveness of LGH447 and BYL719 in Patients with Relapsed and Refractory Multiple Myeloma.

    Not in our library

  260. 260.

    Clinical Trials.gov. A Phase II, Open Label, Multiple Arm Study of AUY922, BYL719, INC280, LDK378 and MEK162 in Chinese Patients with Advanced Non-Small Cell Lung Cancer.

    Not in our library

  261. 261.

    Clinical Trails.gov. SAFIR PI3K a Phase II Randomized Trial Comparing Alpelisib and Fulvestrant Versus Chemotherapy as Maintenance Therapy in Patients with PIK3CA Mutated Advanced Breast Cancer (SAFIR PI3K).

    Not in our library

  262. 262.

    Clinical Trails.gov. Phase I/Ib Trial of LSZ102 Single Agent or LSZ102 + LEE011 or LSZ102 + BYL719 in ER+ Breast Cancers.

    Not in our library

  263. 263.

    Clinical Trails.gov. Phase I Study of BYL719 in Combination with Cisplatin and Radiotherapy in Patients with Squamous Cell Head and Neck Cancer.

    Not in our library

  264. 264.

    Juric D., de Bono J.S., LoRusso P.M., Nemunaitis J., Heath E.I., Kwak E.L., Macarulla Mercade T., Geuna E., Jose de Miguel-Luken M., Patel C., et al. A First-in-Human, Phase I, Dose-Escalation Study of TAK-117, a Selective PI3Kalpha Isoform Inhibitor, in Patients with Advanced Solid Malignancies. Clin. Cancer Res. 2017;23:5015-5023.

    Not in our library10.1158/1078-0432.ccr-16-2888

  265. 265.

    Clinical Trails.gov. TAK-228 and TAK-117 Followed by Cisplatin and Nab Paclitaxel for Metastatic Triple Negative Breast Cancer.

    Not in our library

  266. 266.

    Clinical Trails.gov. MLN0128 and MLN0128 + MLN1117 Compared with Everolimus in the Treatment of Adults with Advanced or Metastatic Clear-Cell Renal Cell Carcinoma.

    Not in our library

  267. 267.

    Clinical Trails.gov. A Safety and Pharmacokinetic Study of TAK-228 in Combination with TAK-117 in Adult Participants with Advanced Nonhematologic Malignancies.

    Not in our library

  268. 268.

    Clinical Trails.gov. Dose-Finding Study of GSK2636771 When Administered in Combination with Enzalutamide in Male Subjects with Metastatic Castration-Resistant Prostate Cancer.

    Not in our library

  269. 269.

    Clinical Trails.gov. PI3Kβ Selective Inhibitor with Paclitaxel, Advanced Gastric Adenocarcinoma.

    Not in our library

  270. 270.

    Clinical Trails.gov. Testing GSK2636771 as a Potential Targeted Treatment in Cancers with PTEN Loss of Expression (MATCH-Subprotocol P).

    Not in our library

  271. 271.

    Clinical Trails.gov. Testing GSK2636771 as a Potential Targeted Treatment in Cancers with PTEN Genetic Changes (MATCH-Subprotocol N).

    Not in our library

  272. 272.

    Yang Q., Modi P., Newcomb T., Queva C., Gandhi V. Idelalisib: First-in-Class PI3K Delta Inhibitor for the Treatment of Chronic Lymphocytic Leukemia, Small Lymphocytic Leukemia, and Follicular Lymphoma. Clin. Cancer Res. 2015;21:1537-1542.

    Not in our library10.1158/1078-0432.ccr-14-2034

  273. 273.

    Clinical Trails.gov. Study of Safety and Efficacy of BCL201 and Idelalisib in Patients with FL and MCL.

    Not in our library

  274. 274.

    Clinical Trails.gov. ACY-1215 in Combination with BCR Pathway Inhibitors in Relapsed CLL.

    Not in our library

  275. 275.

    Clinical Trails.gov. Phase 1b Safety and Efficacy Study of TRU-016.

    Not in our library

  276. 276.

    Clinical Trails.gov. Safety and Efficacy of the Combination of Tirabrutinib and Idelalisib with and without Obinutuzumab in Adults with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL).

    Not in our library

  277. 277.

    Clinical Trails.Trial of Idelalisib in Patients with Relapsed Diffuse Large B-cell Lymphoma (ILIAD).

    Not in our library

  278. 278.

    Clinical Trails.gov. Study to Evaluate Safety and Preliminary Efficacy of Tafasitamab with Idelalisib or Venetoclax in R/R CLL/SLL Patients Pretreated with BTKi (COSMOS).

    Not in our library

  279. 279.

    Clinical Trails.gov. Study of ME-401 in Subjects with Relapsed or Refractory Indolent B-cell Non-Hodgkin’s Lymphoma.

    Not in our library

  280. 280.

    Clinical Trails.gov. AMG 319 Lymphoid Malignancy FIH.

    Not in our library

  281. 281.

    Clinical Trails.gov. A Study of YY-20394 in Participants with Relapsed/Refractory Follicular Non-Hodgkin’s Lymphoma.

    Not in our library

  282. 282.

    Clinical Trails.gov. A Safety and Tolerability Study of INCB053914 in Combination with INCB050465 in Diffuse Large B-Cell Lymphoma.

    Not in our library

  283. 283.

    Clinical Trails.gov. A Study of INCB050465 in Japanese Subjects with Previously Treated B-Cell Lymphoma (CITADEL-111).

    Not in our library

  284. 284.

    Clinical Trails.gov. INCB050465 in Combination with Rituximab, Bendamustine and Rituximab, or Ibrutinib in Participants with Previously Treated B-cell Lymphoma (CITADEL-112).

    Not in our library

  285. 285.

    Clinical Trails.gov. Pembrolizumab Combined with Itacitinib (INCB039110) and/or Pembrolizumab Combined with INCB050465 in Advanced Solid Tumors.

    Not in our library

  286. 286.

    Clinical Trails.gov. An Open-Label Study of INCB050465 in Relapsed or Refractory Follicular Lymphoma (CITADEL-203).

    Not in our library

  287. 287.

    A Study of INCB050465 in Subjects with Relapsed or Refractory Marginal Zone Lymphoma (CITADEL-204).

    Not in our library

  288. 288.

    Clinical Trails.gov. A Study of INCB050465 in Relapsed or Refractory Mantle Cell Lymphoma Previously Treated with or without a BTK INHIBITOR (CITADEL-205).

    Not in our library

  289. 289.

    Clinical Trails.gov. Study Evaluating Safety and Efficacy of INCB050465 Combined with Bendamustine and Obinutuzumab in Relapsed or Refractory Follicular Lymphoma (CITADEL-102).

    Not in our library

  290. 290.

    Clinical Trails.gov. TGR-1202 Alone and in Combination with Either Nab-Paclitaxel + Gemcitabine or with FOLFOX in Patients with Select Relapsed or Refractory Solid Tumors.

    Not in our library

  291. 291.

    Clinical Trails.gov. TGR-1202, a PI3K Delta Inhibitor, in Combination with Obinutuzumab and Chlorambucil in Patients with Chronic Lymphocytic Leukemia (CLL).

    Not in our library

  292. 292.

    Clinical Trails.gov. Novel PI3K Delta Inhibitor TGR-1202, in Combination with Brentuximab Vedotin for Hodgkin’s Lymphoma Patients.

    Not in our library

  293. 293.

    Clinical Trails.gov. Study to Assess the Efficacy and Safety of Umbralisib in Patients with Non-Follicular Indolent Non-Hodgkin’s Lymphoma.

    Not in our library

  294. 294.

    Clinical Trails.gov. Ublituximab + TGR-1202 Compared to Obinutuzumab + Chlorambucil in Patients with Untreated and Previously Treated Chronic Lymphocytic Leukemia (UNITY-CLL).

    Not in our library

  295. 295.

    Clinical Trails.gov. GR-1202 + Ruxolitinib PMF PPV-MF PET-MF MDS/MPN Polycythemia Vera Resistant to Hydroxyurea.

    Not in our library

  296. 296.

    U.S. FDA.

    Not in our library

  297. 297.

    Clinical Trails.gov. Safety and Efficacy Study of a Dual PI3K Delta/Gamma Inhibitor in Hematological Malignancies (PI3K).

    Not in our library

  298. 298.

    Clinical Trails.gov. Efficacy and Safety of Tenalisib (RP6530) in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL).

    Not in our library

  299. 299.

    Clinical Trails.gov. Efficacy and Safety Study of Tenalisib (RP6530), a Novel PI3K δ/γ Dual Inhibitor in Patients with Relapsed/Refractory Indolent Non-Hodgkin’s Lymphoma (iNHL).

    Not in our library

  300. 300.

    Safety and Efficacy of Tenalisib (RP6530) in Combination with Romidepsin in Patients with Relapsed/Refractory T-Cell Lymphoma.

    Not in our library

  301. 301.

    Clinical Trails.gov. A Dose Escalation Study Evaluating the Safety and Tolerability of GDC-0032 in Participants with Locally Advanced or Metastatic Solid Tumors or Non-Hodgkin’s Lymphoma (NHL) and in Combination with Endocrine Therapy in Locally Advanced or Metastatic Hormone Receptor-Positive Breast Cancer.

    Not in our library

  302. 302.

    Clinical Trails.gov. Testing GDC-0032 (taselisib) as a Potential Targeted Treatment in Cancers with PIK3CA Genetic Changes (MATCH-Subprotocol I).

    Not in our library

  303. 303.

    Clinical Trails.gov. AZD8186 First Time In Patient Ascending Dose Study.

    Not in our library

  304. 304.

    Clinical Trails.gov. Phase I, Dose Study to Look at the Safety and Pharmacokinetics of AZD8835 in Patients with Advanced Solid Tumours.

    Not in our library

  305. 305.

    Blair H.A. Duvelisib: First Global Approval. Drugs. 2018;78:1847-1853.

    Not in our library10.1007/s40265-018-1013-4

  306. 306.

    Rodrigues D.A., Sagrillo F.S., Fraga C.A.M. Duvelisib: A 2018 Novel FDA-Approved Small Molecule Inhibiting Phosphoinositide 3-Kinases. Pharmaceuticals. 2019;12:69.

    Not in our library10.3390/ph12020069

  307. 307.

    Clinical Trails.gov. Study Evaluating Duvelisib in Japanese Subjects with Relapsed or Refractory Lymphoma.

    Not in our library

  308. 308.

    Clinical Trails.gov. A Long-Term, Continued Treatment and Follow-Up Study in Subjects with Hematologic Malignancies Treated with Duvelisib (IPI-145).

    Not in our library

  309. 309.

    Rao V.K. Effective “activated PI3Kdelta syndrome”-targeted therapy with the PI3Kdelta inhibitor leniolisib. Blood. 2017;130:2307-2316.

    Not in our library10.1182/blood-2017-08-801191

  310. 310.

    Donner. T. A randomised, double-blind study to assess the safety, tolerability and preliminary efficacy of leniolisib (CDZ173) in patients with primary sjögren’s syndrome. Ann. Rheum. Dis. 2018;77:174.

    Not in our library

  311. 311.

    De Vera A.A., Gupta P., Lei Z., Liao D., Narayanan S., Teng Q., Reznik S.E., Chen Z.-S. Immuno-oncology agent IPI-549 is a modulator of P-glycoprotein (P-gp, MDR1, ABCB1)-mediated multidrug resistance (MDR) in cancer: In vitro and in vivo. Cancer Lett. 2019;442:91-103.

    Not in our library10.1016/j.canlet.2018.10.020

  312. 312.

    Clinical Trails.gov. A Study to Evaluate Safety/Tolerability of Immunotherapy Combinations in Participants with Triple-negative Breast Cancer or Gynecologic Malignancies.

    Not in our library

  313. 313.

    Rodon J., Curigliano G., Delord J.P., Harb W., Azaro A., Han Y., Wilke C., Donnet V., Sellami D., Beck T. A Phase Ib, open-label, dose-finding study of Alpelisib in combination with paclitaxel in patients with advanced solid tumors. Oncotarget. 2018;9:31709-31718.

    Not in our library10.18632/oncotarget.25854

  314. 314.

    Soares H.P., Al-Toubah T.E., Kim R.D., Kim J., Lewis N.K., Mahipal A. Final report: A phase I trial of BYL719 in combination with gemcitabine and nab-paclitaxel in locally advanced and metastatic pancreatic cancer. J. Clin. Oncol. 2018;36:398.

    Not in our library10.1200/jco.2018.36.4_suppl.398

  315. 315.

    Shah D.P. Phase I trial of daily PI3Kα inhibitor BYL719 plus letrozole (L) or exemestane (E) for patients (pts) with hormone receptor-positive (HR+) metastatic breast cancer (MBC). J. Clin. Oncol. 2014;32:2605.

    Not in our library10.1200/jco.2014.32.15_suppl.2605

  316. 316.

    Juric D., Janku F., Rodon J., Burris H.A., Mayer I.A., Schuler M., Seggewiss-Bernhardt R., Gil-Martin M., Middleton M.R., Baselga J., et al. Alpelisib Plus Fulvestrant in PIK3CA-Altered and PIK3CA-Wild-Type Estrogen Receptor-Positive Advanced Breast Cancer: A Phase 1b Clinical Trial. JAMA Oncol. 2019;5:e184475.

    Not in our library10.1001/jamaoncol.2018.4475

  317. 317.

    Ando Y., Iwasa S., Takahashi S., Saka H., Kakizume T., Natsume K., Suenaga N., Quadt C., Yamada Y. Phase I study of Alpelisib (BYL719), an alpha-specific PI3K inhibitor, in Japanese patients with advanced solid tumors. Cancer Sci. 2019;110:1021-1031.

    Not in our library10.1111/cas.13923

  318. 318.

    Hyman D.M., Tran B., Jaime J.C., Garralda E., Machiels J.-P.H., Schellens J.H.M., Bedard P., Campone M., Cassier P., Sarantopoulos J., et al. Phase Ib study of BGJ398 in combination with BYL719 in patients (pts) with select advanced solid tumors. J. Clin. Oncol. 2016;34:2500.

    Not in our library10.1200/jco.2016.34.15_suppl.2500

  319. 319.

    Jain S., Santa-Maria C.A., Rademaker A., Giles F.J., Cristofanilli M., Gradishar W.J. Phase I study of Alpelisib (BYL-719) and T-DM1 in HER2-positive metastatic breast cancer after trastuzumab and taxane therapy. J. Clin. Oncol. 2017;35:1026.

    Not in our library10.1200/jco.2017.35.15_suppl.1026

  320. 320.

    Baselga J., Curigliano G., Martín M., André F., Beck J.T., Tortora G., Wilke C., Charbonnier L., Blumenstein L., Donnet V., et al. Abstract CT061: A phase Ib study of Alpelisib (BYL719) + everolimus ± exemestane in patients with advanced solid tumors or HR+/HER2-breast cancer. Cancer Res. 2016;76:14.

    Not in our library

  321. 321.

    Juric D., Soria J.-C., Sharma S., Banerji U., Azaro A., Desai J., Ringeisen F.P., Kaag A., Radhakrishnan R., Hourcade-Potelleret F., et al. A phase 1b dose-escalation study of BYL719 plus binimetinib (MEK162) in patients with selected advanced solid tumors. J. Clin. Oncol. 2014;32:9051.

    Not in our library10.1200/jco.2014.32.15_suppl.9051

  322. 322.

    Tabernero J., Van Geel R., Guren T.K., Yaeger R.D., Spreafico A., Faris J.E., Yoshino T., Yamada Y., Kim T.W., Bendell J.C., et al. Phase 2 results: Encorafenib (ENCO) and cetuximab (CETUX) with or without Alpelisib (ALP) in patients with advanced BRAF-mutant colorectal cancer (BRAFm CRC). J. Clin. Oncol. 2016;34:3544.

    Not in our library10.1200/jco.2016.34.15_suppl.3544

  323. 323.

    Mayer I.A., Prat A., Egle D., Blau S., Fidalgo J.A.P., Gnant M., Fasching P.A., Colleoni M., Wolff A.C., Winer E.P., et al. A Phase II Randomized Study of Neoadjuvant Letrozole Plus Alpelisib for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer (NEO-ORB). Clin. Cancer Res. 2019;25:2975-2987.

    Not in our library10.1158/1078-0432.ccr-18-3160

  324. 324.

    Lu Y.S. Abstract P4-13-27: A phase Ib dose de-escalation study of combined tamoxifen and goserelin acetate with Alpelisib (BYL719) or buparlisib (BKM120) in premenopausal patients with HR+/HER2– locally advanced or metastatic breast cancer. Cancer Res. 2016;76:4-27.

    Not in our library

  325. 325.

    Shah D.P., Chandarlapaty S., Dickler M.N., Ulaner G., Zamora S.J., Sterlin V., Iasonos A., Coughlin C.M., Morozov A., Ero J., et al. Phase I study of LJM716, BYL719, and trastuzumab in patients (pts) with HER2-amplified (HER2+) metastatic breast cancer (MBC). J. Clin. Oncol. 2015;33:590.

    Not in our library10.1200/jco.2015.33.15_suppl.590

  326. 326.

    Munster P.N., Hamilton E.P., Estevez L.G., De Boer R.H., Mayer I.A., Campone M., Asano S., Bhansali S., Zhang V., Hewes B., et al. Ph IB study of LEE011 and BYL719 in combination with letrozole in ER+, HER2- breast cancer. J. Clin. Oncol. 2014;32:143.

    Not in our library10.1200/jco.2014.32.26_suppl.143

  327. 327.

    Dunn F., Riaz N., Baxi S.S., McBride S.M., Sherman E., Michel L., Haque S., Katabi N., Wong R.J., Xiao H., et al. Phase Ib study of cetuximab + BYL719 + IMRT in stage III-IVB head and neck squamous cell carcinoma (HNSCC). J. Clin. Oncol. 2017;35:6081.

    Not in our library10.1200/jco.2017.35.15_suppl.6081

  328. 328.

    Sharma P. Clinical and biomarker results from phase I/II study of PI3K inhibitor BYL 719 (Alpelisib) plus nab-paclitaxel in HER2-negative metastatic breast cancer. J. Clin. Oncol. 2018;36:1018.

    Not in our library10.1200/jco.2018.36.15_suppl.1018

  329. 329.

    Konstantinopoulos P.A., Barry W.T., Birrer M., Westin S.N., Cadoo K.A., Shapiro G.I., Mayer E.L., O’Cearbhaill R.E., Coleman R.L., Kochupurakkal B., et al. Olaparib and alpha-specific PI3K inhibitor Alpelisib for patients with epithelial ovarian cancer: A dose-escalation and dose-expansion phase 1b trial. Lancet Oncol. 2019;20:570-580.

    Not in our library10.1016/s1470-2045(18)30905-7

  330. 330.

    Clinical Trails.gov. A Study of Sapanisertib, Combination of Sapanisertib with MLN1117, Paclitaxel and Combination of Sapanisertib with Paclitaxel in Women with Endometrial Cancer.

    Not in our library

  331. 331.

    Arkenau H.-T., Mateo J., Lemech C.R., Infante J.R., Burris H.A., Bang Y.-J., Eder J.P., Herbst R.S., Sharma S., Chung H.C., et al. A phase I/II, first-in-human dose-escalation study of GSK2636771 in patients (pts) with PTEN-deficient advanced tumors. J. Clin. Oncol. 2014;32:2514.

    Not in our library10.1200/jco.2014.32.15_suppl.2514

  332. 332.

    Flinn I.W., Kahl B.S., Leonard J.P., Furman R.R., Brown J.R., Byrd J.C., Wagner-Johnston N.D., Coutre S.E., Benson D.M., Peterman S., et al. Idelalisib, a selective inhibitor of phosphatidylinositol 3-kinase-delta, as therapy for previously treated indolent non-Hodgkin lymphoma. Blood. 2014;123:3406-3413.

    Not in our library10.1182/blood-2013-11-538546

  333. 333.

    Brown J.R., Byrd J.C., Coutre S.E., Benson D.M., Flinn I.W., Wagner-Johnston N.D., Spurgeon S.E., Kahl B.S., Bello C., Webb H.K., et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110delta, for relapsed/refractory chronic lymphocytic leukemia. Blood. 2014;123:3390-3397.

    Not in our library10.1182/blood-2013-11-535047

  334. 334.

    Kahl B.S., Spurgeon S.E., Furman R.R., Flinn I.W., Coutre S.E., Brown J.R., Benson D.M., Byrd J.C., Peterman S., Cho Y., et al. A phase 1 study of the PI3Kdelta inhibitor idelalisib in patients with relapsed/refractory mantle cell lymphoma (MCL). Blood. 2014;123:3398-3405.

    Not in our library10.1182/blood-2013-11-537555

  335. 335.

    Fukuhara N., Kinoshita T., Yamamoto K., Nagai H., Izutsu K., Yamamoto G., Bhargava P., Rajakumaraswamy N., Humeniuk R., Mathias A., et al. Phase 1b study to investigate the safety and tolerability of idelalisib in Japanese patients with relapsed/refractory follicular lymphoma and chronic lymphocytic leukemia. Jpn. J. Clin. Oncol. 2020;50:1395-1402.

    Not in our library10.1093/jjco/hyaa153

  336. 336.

    Smith S.M., Pitcher B.N., Jung S.H., Bartlett N.L., Wagner-Johnston N., Park S.I., Richards K.L., Cashen A.F., Jaslowski A., Smith S.E., et al. Safety and tolerability of idelalisib, lenalidomide, and rituximab in relapsed and refractory lymphoma: The Alliance for Clinical Trials in Oncology A051201 and A051202 phase 1 trials. Lancet Haematol. 2017;4:e176-e182.

    Not in our library10.1016/s2352-3026(17)30028-5

  337. 337.

    Cheah C.Y., Nastoupil L.J., Neelapu S.S., Forbes S.G., Oki Y., Fowler N.H. Lenalidomide, idelalisib, and rituximab are unacceptably toxic in patients with relapsed/refractory indolent lymphoma. Blood. 2015;125:3357-3359.

    Not in our library10.1182/blood-2015-03-633156

  338. 338.

    Arita A., Hanlon K., Chkourko H., Lannutti B.J., Johnson D.M., Gabrilove J.L., Scigliano E., Parekh S.S., Brody J. Effect of phosphotidylinositol 3-kinase-delta inhibitor idelalisib (GS-1101) on signaling in primary non-Hodgkin lymphoma cells: Correlative studies from NCT01306643. J. Clin. Oncol. 2013;31:8579.

    Not in our library10.1200/jco.2013.31.15_suppl.8579

  339. 339.

    Gopal A.K., Fanale M.A., Moskowitz C.H., Shustov A.R., Mitra S., Ye W., Younes A., Moskowitz A.J. Phase II study of idelalisib, a selective inhibitor of PI3Kdelta, for relapsed/refractory classical Hodgkin lymphoma. Ann. Oncol. 2017;28:1057-1063.

    Not in our library10.1093/annonc/mdx028

  340. 340.

    Gopal A.K., Kahl B.S., de Vos S., Wagner-Johnston N.D., Schuster S.J., Jurczak W.J., Flinn I.W., Flowers C.R., Martin P., Viardot A., et al. PI3Kdelta inhibition by idelalisib in patients with relapsed indolent lymphoma. N. Engl. J. Med. 2014;370:1008-1018.

    Not in our library10.1056/nejmoa1314583

  341. 341.

    Zelenetz A.D., Barrientos J.C., Brown J.R., Coiffier B., Delgado J., Egyed M., Ghia P., Illes A., Jurczak W., Marlton P., et al. Idelalisib or placebo in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia: Interim results from a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2017;18:297-311.

    Not in our library10.1016/s1470-2045(16)30671-4

  342. 342.

    Furman R.R., Sharman J.P., Coutre S.E., Cheson B.D., Pagel J.M., Hillmen P., Barrientos J.C., Zelenetz A.D., Kipps T.J., Flinn I., et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N. Engl. J. Med. 2014;370:997-1007.

    Not in our library10.1056/nejmoa1315226

  343. 343.

    Eyre T.A., Preston G., Kagdi H.H., Islam A., Nicholson T., Fegan C., Smith H.W., Cursley A.P., Ramroth H., Rajakumaraswamy N. A Multicentre, Retrospective Observational Study to Evaluate the Clinical Outcomes of Patients with Chronic Lymphocytic Leukaemia (CLL) Treated with Idelalisib and Rituximab in the UK (RETRO-idel)—A Cohort of 110 Patients. Blood. 2019;134:1762.

    Not in our library10.1182/blood-2019-126845

  344. 344.

    Tomowiak C., Desseaux X., Poulain S., Herbaux C., Perrot A., Mahe B., Morel P., Tournilhac O., Lepretre S., Aurran T., et al. Open label non-randomized phase II Study Exploring «chemo-free» treatment association with idelalisib + obinutuzumab in patients with relapsed/refractory (R/R) waldenstrom’s macroglobulinemia (MW), a filo trial: Results of the intermediary analysis of the induction phase. Blood. 2019;134:346.

    Not in our library

  345. 345.

    Lampson B.L., Kasar S.N., Matos T.R., Morgan E.A., Rassenti L., Davids M.S., Fisher D.C., Freedman A.S., Jacobson C.A., Armand P., et al. Idelalisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity. Blood. 2016;128:195-203.

    Not in our library10.1182/blood-2016-03-707133

  346. 346.

    Ghia P. Acalabrutinib (Acala) versus idelalisib plus rituximab (IdR) or bendamustine plus rituximab (BR) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): ASCEND final results. J. Clin. Oncol. 2020;38:8015.

    Not in our library10.1200/jco.2020.38.15_suppl.8015

  347. 347.

    Danilov A.V., Herbaux C., Walter H.S., Hillmen P., Rule S.A., Kio E.A., Karlin L., Dyer M.J.S., Mitra S.S., Yi P.C., et al. Phase Ib Study of Tirabrutinib in Combination with Idelalisib or Entospletinib in Previously Treated Chronic Lymphocytic Leukemia. Clin. Cancer Res. 2020;26:2810-2818.

    Not in our library10.1158/1078-0432.ccr-19-3504

  348. 348.

    Qiu L., Qi J., Song Y., Jiang B., Tu M., Ping L., Li Z., Zhu J., Xu Y., Bao H., et al. A phase I study of a selective PI3Kδ inhibitor YY-20394 in patients with relapsed or refractory B-cell malignancies. J. Clin. Oncol. 2019;37:7563.

    Not in our library10.1200/jco.2019.37.15_suppl.7563

  349. 349.

    Ramchandren R., Phillips T.J., Wertheim M., Gutierrez M., Edenfield W.J., Akard L.P., Caimi P.F., Call J., Persky D.O., DeMarini D.J., et al. Ongoing phase 1/2 study of INCB050465 for relapsed/refractory (R/R) B-cell malignancies (CITADEL-101). J. Clin. Oncol. 2017;35:7530.

    Not in our library10.1200/jco.2017.35.15_suppl.7530

  350. 350.

    Coleman M., Belada D., Casasnovas R., Gressin R., Lee H., Mehta A., Munoz J., Verhoef G., Corrado C., James D., et al. Phase 2 study of parsaclisib (INCB050465) for relapsed or refractory diffuse large b-cell lymphoma (DLBCL) (CITADEL-202). J. Clin. Oncol. 2019;37:e19038.

    Not in our library10.1200/jco.2019.37.15_suppl.e19038

  351. 351.

    Clinical Trails.gov. TGR-1202 and Ibrutinib in Treating Patients with Relapsed or Refractory Diffuse Large B-cell Lymphoma.

    Not in our library

  352. 352.

    Burris H.A., Flinn I.W., Patel M.R., Fenske T.S., Deng C., Brander D.M., Gutierrez M., Essell J.H., Kuhn J.G., Miskin H.P., et al. Umbralisib, a novel PI3Kdelta and casein kinase-1epsilon inhibitor, in relapsed or refractory chronic lymphocytic leukaemia and lymphoma: An open-label, phase 1, dose-escalation, first-in-human study. Lancet Oncol. 2018;19:486-496.

    Not in our library10.1016/s1470-2045(18)30082-2

  353. 353.

    Nastoupil L.J., Lunning M.A., Vose J.M., Schreeder M.T., Siddiqi T., Flowers C.R., Cohen J.B., Burger J.A., Wierda W.G., O’Brien S., et al. Tolerability and activity of ublituximab, umbralisib, and ibrutinib in patients with chronic lymphocytic leukaemia and non-Hodgkin lymphoma: A phase 1 dose escalation and expansion trial. Lancet Haematol. 2019;6:e100-e109.

    Not in our library10.1016/s2352-3026(18)30216-3

  354. 354.

    Davids M.S., Kim H.T., Nicotra A., Savell A., Francoeur K., Hellman J.M., Bazemore J., Miskin H.P., Sportelli P., Stampleman L., et al. Umbralisib in combination with ibrutinib in patients with relapsed or refractory chronic lymphocytic leukaemia or mantle cell lymphoma: A multicentre phase 1-1b study. Lancet Haematol. 2019;6:e38-e47.

    Not in our library10.1016/s2352-3026(18)30196-0

  355. 355.

    Mato A.R., Schuster S.J., Lamanna N., Flinn I., Barrientos J.C., Kambhampati S., Cheson B.D., Barr P.M., Pagel J.M., Reeves J.A., et al. A phase 2 study to assess the safety and efficacy of umbralisib (TGR-1202) in pts with CLL who are intolerant to prior BTK or PI3Kδ inhibitor therapy. J. Clin. Oncol. 2018;36:7530.

    Not in our library10.1200/jco.2018.36.15_suppl.7530

  356. 356.

    Huen A., Haverkos B.M., Zain J., Radhakrishnan R., Lechowicz M.J., Devata S., Korman N.J., Pinter-Brown L., Oki Y., Barde P.J., et al. Phase I/Ib Study of Tenalisib (RP6530), a Dual PI3K delta/gamma Inhibitor in Patients with Relapsed/Refractory T-Cell Lymphoma. Cancers. 2020;12:2293.

    Not in our library10.3390/cancers12082293

  357. 357.

    Abramson V.G., Oliveira M., Cervantes A., Wildiers H., Patel M.R., Bauer T.M., Bedard P.L., Becerra C., Richey S., Wei M.C., et al. A phase Ib, open-label, dose-escalation study of the safety and pharmacology of taselisib (GDC-0032) in combination with either docetaxel or paclitaxel in patients with HER2-negative, locally advanced, or metastatic breast cancer. Breast Cancer Res. Treat. 2019;178:121-133.

    Not in our library10.1007/s10549-019-05360-3

  358. 358.

    Langer C.J., Redman M.W., Wade J.L., Aggarwal C., Bradley J.D., Crawford J., Stella P.J., Knapp M.H., Miao J., Minichiello K., et al. SWOG S1400B (NCT02785913), a Phase II Study of GDC-0032 (Taselisib) for Previously Treated PI3K-Positive Patients with Stage IV Squamous Cell Lung Cancer (Lung-MAP Sub-Study). J. Thorac. Oncol. 2019;14:1839-1846.

    Not in our library10.1016/j.jtho.2019.05.029

  359. 359.

    Saura C., Hlauschek D., Oliveira M., Zardavas D., Jallitsch-Halper A., de la Pena L., Nuciforo P., Ballestrero A., Dubsky P., Lombard J.M., et al. Neoadjuvant letrozole plus taselisib versus letrozole plus placebo in postmenopausal women with oestrogen receptor-positive, HER2-negative, early-stage breast cancer (LORELEI): A multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2019;20:1226-1238.

    Not in our library10.1016/s1470-2045(19)30334-1

  360. 360.

    Filho O.M., Goel S., Barry W.T., Hamilton E.P., Tolaney S.M., Yardley D.A., Rees R., DeMeo M., Mills C., Hafner M., et al. A mouse-human phase I co-clinical trial of taselisib in combination with TDM1 in advanced HER2-positive breast cancer (MBC). J. Clin. Oncol. 2017;35:1030.

    Not in our library10.1200/jco.2017.35.15_suppl.1030

  361. 361.

    Lopez J.S., SelviMiralles M., Ameratunga M., Minchom A., Pascual J., Banerji U., Bye H., Raynaud F.I., E Swales K., Malia J., et al. PIPA: A phase Ib study of selective ß-isoform sparing phosphatidylinositol 3-kinase (PI3K) inhibitor taselisib (T) plus palbociclib (P) in patients (pts) with advanced solid cancers—Safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) analysis of the doublet combination. J. Clin. Oncol. 2019;37:3087.

    Not in our library10.1200/jco.2019.37.15_suppl.3087

  362. 362.

    Lehmann B.D., Abramson V.G., Sanders M.E., Mayer E.L., Haddad T.C., Nanda R., Van Poznak C., Storniolo A.M., Nangia J.R., Gonzalez-Ericsson P.I., et al. TBCRC 032 IB/II Multicenter Study: Molecular Insights to AR Antagonist and PI3K Inhibitor Efficacy in Patients with AR(+) Metastatic Triple-Negative Breast Cancer. Clin. Cancer Res. 2020;26:2111-2123.

    Not in our library10.1158/1078-0432.ccr-19-2170

  363. 363.

    Baselga J., Dent S.F., Cortés J., Im Y.-H., Diéras V., Harbeck N., Krop I.E., Verma S., Wilson T.R., Jin H., et al. Phase III study of taselisib (GDC-0032) + fulvestrant (FULV) v FULV in patients (pts) with estrogen receptor (ER)-positive, PIK3CA-mutant (MUT), locally advanced or metastatic breast cancer (MBC): Primary analysis from SANDPIPER. J. Clin. Oncol. 2018;36:LBA1006.

    Not in our library10.1200/jco.2018.36.18_suppl.lba1006

  364. 364.

    De Bono J., Hansen A., Choudhury A., Cook N., Heath E., Higano C., Linch M., Martin-Liberal J., Rathkopf D., Wisinski K., et al. AZD8186, a potent and selective inhibitor of PI3Kβ/δ, as monotherapy and in combination with abiraterone acetate plus prednisone (AAP), in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC). Ann. Oncol. 2018;29:viii291-viii292.

    Not in our library10.1093/annonc/mdy284.042

  365. 365.

    Flinn I.W., Cherry M.A., Maris M.B., Matous J.V., Berdeja J.G., Patel M. Combination trial of duvelisib (IPI-145) with rituximab or bendamustine/rituximab in patients with non-Hodgkin lymphoma or chronic lymphocytic leukemia. Am. J. Hematol. 2019;94:1325-1334.

    Not in our library10.1002/ajh.25634

  366. 366.

    Clinical Trails.gov. A Phase 1b/2 Study of IPI-145 Plus FCR in Previously Untreated, Younger Patients with CLL.

    Not in our library

  367. 367.

    Flinn I.W., Miller C.B., Ardeshna K.M., Tetreault S., Assouline S.E., Mayer J., Merli M., Lunin S.D., Pettitt A.R., Nagy Z., et al. DYNAMO: A Phase II Study of Duvelisib (IPI-145) in Patients With Refractory Indolent Non-Hodgkin Lymphoma. J. Clin. Oncol. 2019;37:912-922.

    Not in our library10.1200/jco.18.00915

  368. 368.

    Flinn I.W., Hillmen P., Montillo M., Nagy Z., Illes A., Etienne G., Delgado J., Kuss B.J., Tam C.S., Gasztonyi Z., et al. The phase 3 DUO trial: Duvelisib vs ofatumumab in relapsed and refractory CLL/SLL. Blood. 2018;132:2446-2455.

    Not in our library10.1182/blood-2018-05-850461

  369. 369.

    Clinical Trails.gov. A Dose-Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of IPI-549.

    Not in our library

  370. 370.

    Shi F., Zhang J., Liu H., Wu L., Jiang H., Wu Q., Liu T., Lou M., Wu H. The dual PI3K/mTOR inhibitor dactolisib elicits anti-tumor activity in vitro and in vivo. Oncotarget. 2017;9:706-717.

    Not in our library10.18632/oncotarget.23091

  371. 371.

    Clinical Trails.gov. A Phase I/II Study of BEZ235 Inpatients Withadvanced Solid Malignancies Enriched by Patients with Advanced Breast Cancer.

    Not in our library

  372. 372.

    Clinical Trails.gov. Dose Finding Study of RAD001 (Everolimus, Afinitor®) in Combination with BEZ235 in Patients with Advanced Solid Tumors.

    Not in our library

  373. 373.

    Clinical Trails.gov. Safety, Pharmacokinetics and Pharmacodynamics of BEZ235 Plus MEK162 in Selected Advanced Solid Tumor Patients.

    Not in our library

  374. 374.

    Clinical Trails.gov. A Phase Ib/II Study of BEZ235 and Trastuzumab in Patients with HER2-Positive Breast Cancer Who Failed Prior to Trastuzumab.

    Not in our library

  375. 375.

    Clinical Trail.gov. Phase Ib of Abiraterone Acetate Plus BEZ235 or BKM120 in Castration-Resistant Prostate Cancer (CRPC) Patients.

    Not in our library

  376. 376.

    Clinical Trails.gov. Study of the Safety and Pharmacology of GDC-0980 in Combination with Paclitaxel with or without Bevacizumab in Patients with Locally Recurrent or Metastatic Breast Cancer.

    Not in our library

  377. 377.

    Clinical Trails.gov. GDC-0980 in Combination with a Fluoropyrimidine, Oxaliplatin, and Bevacizumab in Patients with Advanced Solid Tumors.

    Not in our library

  378. 378.

    Clinical Trails.gov. A Study of the Safety and Pharmacology of GDC-0980 in Combination with Either Paclitaxel and Carboplatin (with or without bevacizumab) or Pemetrexed and Cisplatin in Patients with Solid Tumors.

    Not in our library

  379. 379.

    Clinical Trails.gov. A Study Evaluating GDC-0980 Administered once Weekly in Patients with Refractory Solid Tumors or Non-Hodgkin’s Lymphoma.

    Not in our library

  380. 380.

    Venkatesan A.M., Dehnhardt C.M., Santos E.D., Chen Z., Dos Santos O., Ayral-Kaloustian S., Khafizova G., Brooijmans N., Mallon R., Hollander I., et al. Bis(morpholino-1,3,5-triazine) Derivatives: Potent Adenosine 5′-Triphosphate Competitive Phosphatidylinositol-3-kinase/Mammalian Target of Rapamycin Inhibitors: Discovery of Compound26(PKI-587), a Highly Efficacious Dual Inhibitor. J. Med. Chem. 2010;53:2636-2645.

    Not in our library10.1021/jm901830p

  381. 381.

    Mahadevan D., Chiorean E., Harris W., Von Hoff D., Stejskal-Barnett A., Qi W., Anthony S., Younger A., Rensvold D., Cordova F., et al. Phase I pharmacokinetic and pharmacodynamic study of the pan-PI3K/mTORC vascular targeted pro-drug SF1126 in patients with advanced solid tumours and B-cell malignancies. Eur. J. Cancer. 2012;48:3319-3327.

    Not in our library10.1016/j.ejca.2012.06.027

  382. 382.

    Clinical Trails.gov. A Dose Escalation Study of SF1126, a PI3 Kinase (PI3K) Inhibitor, Given by Intravenous (IV) Infusion in Patients with Solid Tumors (SF112600106).

    Not in our library

  383. 383.

    Clinical Trails.gov. Phase 1 Study of SF1126 in Combination with Nivolumab in Patients with Advanced Hepatocellular Carcinoma.

    Not in our library

  384. 384.

    Munster P.N., Aggarwal R., Hong D., Schellens J.H., Van Der Noll R., Specht J.M., Witteveen P.O., Werner T.L., Dees E.C., Bergsland E.K., et al. First-in-Human Phase I Study of GSK2126458, an Oral Pan-Class I Phosphatidylinositol-3-Kinase Inhibitor, in Patients with Advanced Solid Tumor Malignancies. Clin. Cancer Res. 2016;22:1932-1939.

    Not in our library10.1158/1078-0432.ccr-15-1665

  385. 385.

    Clinical Trails.gov. Dose-Escalation Study of GSK2126458 (FTIH).

    Not in our library

  386. 386.

    Wu C.-P., Hung C.-Y., Lusvarghi S., Huang Y.-H., Tseng P.-J., Hung T.-H., Yu J.-S., Ambudkar S.V. Overexpression of ABCB1 and ABCG2 contributes to reduced efficacy of the PI3K/mTOR inhibitor samotolisib (LY3023414) in cancer cell lines. Biochem. Pharmacol. 2020;180:114137.

    Not in our library10.1016/j.bcp.2020.114137

  387. 387.

    Clinical Trails.gov. A Study of LY3039478 in Participants with Advanced or Metastatic Solid Tumors.

    Not in our library

  388. 388.

    Clinical Trails.gov. Study of LY3023414 for the Treatment of Recurrent or Persistent Endometrial Cancer.

    Not in our library

  389. 389.

    Clinical Trails.gov. A Study of Prexasertib (LY2606368) with Chemotherapy or Targeted Agents in Participants with Advanced Cancer.

    Not in our library

  390. 390.

    Clinical Trails.gov. A Study of Abemaciclib (LY2835219) in Combination with Another Anti-Cancer Drug in Participants with Lung Cancer (NSCLC).

    Not in our library

  391. 391.

    Clinical Trails.gov. A Study of Abemaciclib (LY2835219) Alone or in Combination with Other Agents in Participants with Previously Treated Pancreatic Ductal Adenocarcinoma.

    Not in our library

  392. 392.

    Clinical Trails.gov. A Study of LY2835219 (Abemaciclib) in Combination with Therapies for Breast Cancer That Has Spread.

    Not in our library

  393. 393.

    Clinical Trails.gov. Phase 2 Study with PQR309 in Relapsed or Refractory Lymphoma Patients.

    Not in our library

  394. 394.

    Clinical Trails.gov. PQR309 in Patients with Relapsed or Refractory Primary Central Nervous System Lymphoma.

    Not in our library

  395. 395.

    Clinical Trails.gov. Open-Label, Non Randomized Phase 2 Study with Safety Run-in.

    Not in our library

  396. 396.

    Clinical Trails.gov. Single-Arm Study with Bimiralisib in Patients with HNSCC Harboring NOTCH1 Loss of Function Mutations (HNSCC).

    Not in our library

  397. 397.

    Clinical Trails.gov. PQR309 and Eribulin in Metastatic HER2 Negative and Triple-Negative Breast Cancer (PIQHASSO).

    Not in our library

  398. 398.

    Clinical Trails.gov. Study of GDC-0084 in Pediatric Patients with Newly Diagnosed Diffuse Intrinsic Pontine Glioma or Diffuse Midline Gliomas.

    Not in our library

  399. 399.

    Clinical Trails.gov. Safety, Pharmacokinetics and Efficacy of Paxalisib (GDC-0084) in Newly-Diagnosed Glioblastoma.

    Not in our library

  400. 400.

    Clinical Trails.gov. Open Label Treatment Extension Study with SAR245408 or SAR245409 as a Monotherapy or as a Combination Regimen.

    Not in our library

  401. 401.

    Clinical Trail.gov. Trial of Pimasertib with SAR245409 or Placebo in Ovarian Cancer.

    Not in our library

  402. 402.

    Bendell J.C., Kurkjian C., Infante J.R., Bauer T.M., Burris H.A., Greco F.A., Shih K.C., Thompson D.S., Lane C.M., Finney L.H., et al. A phase 1 study of the sachet formulation of the oral dual PI3K/mTOR inhibitor BEZ235 given twice daily (BID) in patients with advanced solid tumors. Investig. New Drugs. 2015;33:463-471.

    Not in our library10.1007/s10637-015-0218-6

  403. 403.

    Toyoda M., Watanabe K., Amagasaki T., Natsume K., Takeuchi H., Quadt C., Shirao K., Minami H. A phase I study of single-agent BEZ235 special delivery system sachet in Japanese patients with advanced solid tumors. Cancer Chemother. Pharmacol. 2019;83:289-299.

    Not in our library10.1007/s00280-018-3725-2

  404. 404.

    Fazio N., Buzzoni R., Baudin E., Antonuzzo L., Hubner R.A., Lahner H., WW D.E.H., Raderer M., Teule A., Capdevila J., et al. A Phase II Study of BEZ235 in Patients with Everolimus-resistant, Advanced Pancreatic Neuroendocrine Tumours. Anticancer Res. 2016;36:713-719.

    Not in our library

  405. 405.

    Dolly S.O., Wagner A.J., Bendell J.C., Kindler H.L., Krug L.M., Seiwert T.Y., Zauderer M.G., Lolkema M.P., Apt D., Yeh R.F., et al. Phase I Study of Apitolisib (GDC-0980), Dual Phosphatidylinositol-3-Kinase and Mammalian Target of Rapamycin Kinase Inhibitor, in Patients with Advanced Solid Tumors. Clin. Cancer Res. 2016;22:2874-2884.

    Not in our library10.1158/1078-0432.ccr-15-2225

  406. 406.

    Powles T., Lackner M.R., Oudard S., Escudier B., Ralph C., Brown J.E., Hawkins R.E., Castellano D., Rini B.I., Staehler M.D., et al. Randomized Open-Label Phase II Trial of Apitolisib (GDC-0980), a Novel Inhibitor of the PI3K/Mammalian Target of Rapamycin Pathway, Versus Everolimus in Patients With Metastatic Renal Cell Carcinoma. J. Clin. Oncol. 2016;34:1660-1668.

    Not in our library10.1200/jco.2015.64.8808

  407. 407.

    Makker V., Recio F.O., Ma L., Matulonis U.A., Lauchle J.O., Parmar H., Gilbert H.N., Ware J.A., Zhu R., Lu S., et al. A multicenter, single-arm, open-label, phase 2 study of apitolisib (GDC-0980) for the treatment of recurrent or persistent endometrial carcinoma (MAGGIE study). Cancer. 2016;122:3519-3528.

    Not in our library10.1002/cncr.30286

  408. 408.

    Wainberg Z.A., Shapiro G., Curigliano G., Leong S., Kristeleit R.S., Alsina M., Carolyn M., Britten D., Milella M., Middleton M.R., et al. Phase I study of the PI3K/mTOR inhibitor PF-05212384 in combination with other antitumor agents. J. Clin. Oncol. 2015;33:2590.

    Not in our library10.1200/jco.2015.33.15_suppl.2590

  409. 409.

    Colombo I. Abstract: 568P Phase I dose-escalation study of the dual PI3K/mTORC1/2 inhibitor Gedatolisib (PF-05212384) in combination with paclitaxel (P) and carboplatin (C) in patients (pts) with advanced solid tumours. Ann. Oncol. 2020;31:S487.

    Not in our library10.1016/j.annonc.2020.08.682

  410. 410.

    Shapiro G.I., Bell-McGuinn K.M., Molina J.R., Bendell J., Spicer J., Kwak E.L., Pandya S.S., Millham R., Borzillo G., Pierce K.J., et al. First-in-Human Study of PF-05212384 (PKI-587), a Small-Molecule, Intravenous, Dual Inhibitor of PI3K and mTOR in Patients with Advanced Cancer. Clin. Cancer Res. 2015;21:1888-1895.

    Not in our library10.1158/1078-0432.ccr-14-1306

  411. 411.

    Radovich M. Abstract OT3-06-02: An initial safety study of gedatolisib plus PTK7-ADC for metastatic triple-negative breast cancer. Cancer Res. 2019;79:4.

    Not in our library10.1158/1078-0432.ccr-21-3078

  412. 412.

    Kondo S., Tajimi M., Funai T., Inoue K., Asou H., Ranka V.K., Wacheck V., Doi T. Phase 1 dose-escalation study of a novel oral PI3K/mTOR dual inhibitor, LY3023414, in patients with cancer. Investig. New Drugs. 2020;38:1836-1845.

    Not in our library10.1007/s10637-020-00968-5

  413. 413.

    Sweeney C. Phase 1b/2 study of enzalutamide (ENZ) with LY3023414 (LY) or placebo (PL) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) after progression on abiraterone. J. Clin. Oncol. 2019;37:5009.

    Not in our library10.1200/jco.2019.37.15_suppl.5009

  414. 414.

    Zauderer M.G., Alley E.W., Bendell J., Capelletto E., Bauer T.M., Callies S., Szpurka A.M., Kang S., Willard M.D., Wacheck V., et al. Phase 1 cohort expansion study of LY3023414, a dual PI3K/mTOR inhibitor, in patients with advanced mesothelioma. Investig. New Drugs. 2021.

    Not in our library10.1007/s10637-021-01086-6

  415. 415.

    Machacek M. Abstract: Population pharmacokinetics of PQR309, a dual PI3K/mTOR inhibitor in adult patients with advanced solid tumors. J. Clin. Oncol. 2016;34:e14101.

    Not in our library10.1200/jco.2016.34.15_suppl.e14101

  416. 416.

    Wicki A., Brown N., Xyrafas A., Bize V., Hawle H., Berardi S., Cmiljanovic N., Cmiljanovic V., Stumm M., Dimitrijevic S., et al. First-in human, phase 1, dose-escalation pharmacokinetic and pharmacodynamic study of the oral dual PI3K and mTORC1/2 inhibitor PQR309 in patients with advanced solid tumors (SAKK 67/13). Eur. J. Cancer. 2018;96:6-16.

    Not in our library10.1016/j.ejca.2018.03.012

  417. 417.

    Wen P.Y. A first-in-human phase 1 study to evaluate the brain-penetrant PI3K/mTOR inhibitor GDC-0084 in patients with progressive or recurrent high-grade glioma. J. Clin. Oncol. 2016;34:2012.

    Not in our library10.1200/jco.2016.34.15_suppl.2012

  418. 418.

    Papadopoulos K.P., Tabernero J., Markman B., Patnaik A., Tolcher A.W., Baselga J., Shi W., Egile C., Ruiz-Soto R., Laird A.D., et al. Phase I safety, pharmacokinetic, and pharmacodynamic study of SAR245409 (XL765), a novel, orally administered PI3K/mTOR inhibitor in patients with advanced solid tumors. Clin. Cancer Res. 2014;20:2445-2456.

    Not in our library10.1158/1078-0432.ccr-13-2403

  419. 419.

    Janne P.A., Cohen R.B., Laird A.D., Mace S., Engelman J.A., Ruiz-Soto R., Rockich K., Xu J., Shapiro G.I., Martinez P., et al. Phase I safety and pharmacokinetic study of the PI3K/mTOR inhibitor SAR245409 (XL765) in combination with erlotinib in patients with advanced solid tumors. J. Thorac. Oncol. 2014;9:316-323.

    Not in our library10.1097/jto.0000000000000088

  420. 420.

    Mehnert J.M., Edelman G., Stein M., Camisa H., Lager J., Dedieu J.F., Ghuysen A.F., Sharma J., Liu L., LoRusso P.M. A phase I dose-escalation study of the safety and pharmacokinetics of a tablet formulation of voxtalisib, a phosphoinositide 3-kinase inhibitor, in patients with solid tumors. Investig. New Drugs. 2018;36:36-44.

    Not in our library10.1007/s10637-017-0467-7

  421. 421.

    Schram A.M., Gandhi L., Mita M.M., Damstrup L., Campana F., Hidalgo M., Grande E., Hyman D.M., Heist R.S. A phase Ib dose-escalation and expansion study of the oral MEK inhibitor pimasertib and PI3K/MTOR inhibitor voxtalisib in patients with advanced solid tumours. Br. J. Cancer. 2018;119:1471-1476.

    Not in our library10.1038/s41416-018-0322-4

  422. 422.

    Wen P.Y., Omuro A., Ahluwalia M.S., Fathallah-Shaykh H.M., Mohile N., Lager J.J., Laird A.D., Tang J., Jiang J., Egile C., et al. Phase I dose-escalation study of the PI3K/mTOR inhibitor voxtalisib (SAR245409, XL765) plus temozolomide with or without radiotherapy in patients with high-grade glioma. Neuro Oncol. 2015;17:1275-1283.

    Not in our library10.1093/neuonc/nov083

  423. 423.

    Cloughesy T.F., Mischel P.S., Omuro A.M.P., Prados M., Wen P.Y., Wu B., Rockich K., Xu Y., Lager J.J., Mellinghoff I.K. Tumor pharmacokinetics (PK) and pharmacodynamics (PD) of SAR245409 (XL765) and SAR245408 (XL147) administered as single agents to patients with recurrent glioblastoma (GBM): An Ivy Foundation early-phase clinical trials consortium study. J. Clin. Oncol. 2013;31:2012.

    Not in our library10.1200/jco.2013.31.15_suppl.2012

  424. 424.

    Awan F.T., Gore L., Gao L., Sharma J., Lager J., Costa L.J. Phase Ib trial of the PI3K/mTOR inhibitor voxtalisib (SAR245409) in combination with chemoimmunotherapy in patients with relapsed or refractory B-cell malignancies. Br. J. Haematol. 2016;175:55-65.

    Not in our library10.1111/bjh.14181

  425. 425.

    Brown J.R., Hamadani M., Hayslip J., Janssens A., Wagner-Johnston N., Ottmann O., Arnason J., Tilly H., Millenson M., Offner F., et al. Voxtalisib (XL765) in patients with relapsed or refractory non-Hodgkin lymphoma or chronic lymphocytic leukaemia: An open-label, phase 2 trial. Lancet Haematol. 2018;5:e170-e180.

    Not in our library10.1016/s2352-3026(18)30030-9

  426. 426.

    Yang S., Xiao X., Meng X., Leslie K.K. A mechanism for synergy with combined mTOR and PI3 kinase inhibitors. PLoS ONE. 2011;6:e26343.

    Not in our library10.1371/journal.pone.0026343

  427. 427.

    Tang K.D., Ling M.T. Targeting drug-resistant prostate cancer with dual PI3K/mTOR inhibition. Curr. Med. Chem. 2014;21:3048-3056.

    Not in our library10.2174/0929867321666140414100127

  428. 428.

    Ruckle T., Schwarz M.K., Rommel C. PI3Kgamma inhibition: Towards an ‘aspirin of the 21st century’? Nat. Rev. Drug Discov. 2006;5:903-918.

    Not in our library10.1038/nrd2145

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