The trifunctional antibody catumaxomab for the treatment of malignant ascites due to epithelial cancer: Results of a prospective randomized phase II/III trial

Abstract

Malignant ascites is a common manifestation of advanced cancers, and treatment options are limited. The trifunctional antibody catumaxomab (anti‐epithelial cell‐adhesion molecule x anti‐CD3) represents a targeted immunotherapy for the intraperitoneal (i.p.) treatment of malignant ascites secondary to epithelial cancers. In this phase II/III trial (EudraCT 2004‐000723‐15; NCT00836654), cancer patients ( n = 258) with recurrent symptomatic malignant ascites resistant to conventional chemotherapy were randomized to paracentesis plus catumaxomab (catumaxomab) or paracentesis alone (control) and stratified by cancer type (129 ovarian and 129 nonovarian). Catumaxomab was administered as an i.p. infusion on Days 0, 3, 7 and 10 at doses of 10, 20, 50 and 150 μg, respectively. The primary efficacy endpoint was puncture‐free survival. Secondary efficacy parameters included time to next paracentesis, ascites signs and symptoms and overall survival (OS). Puncture‐free survival was significantly longer in the catumaxomab group (median 46 days) than the control group (median 11 days) (hazard ratio = 0.254: p < 0.0001) as was median time to next paracentesis (77 versus 13 days; p < 0.0001). In addition, catumaxomab patients had fewer signs and symptoms of ascites than control patients. OS showed a positive trend for the catumaxomab group and, in a prospectively planned analysis, was significantly prolonged in patients with gastric cancer ( n = 66; 71 versus 44 days; p = 0.0313). Although adverse events associated with catumaxomab were frequent, they were manageable, generally reversible and mainly related to its immunologic mode of action. Catumaxomab showed a clear clinical benefit in patients with malignant ascites secondary to epithelial cancers, especially gastric cancer, with an acceptable safety profile.

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References 40

1. 1.

   Parsons SL, Watson SA, Steele RJC. Malignant ascites. Br J Surg. 1996;83:6-14.

   Not in our library10.1002/bjs.1800830104

2. 2.

   Muir JC, Von Roenn J, Smith TJ, Loprinzi CL, Von Gunten CF. Ascites. ASCO curriculum: optimizing cancer care. The importance of symptom management. 2001;1:1-31.

   Not in our library

3. 3.

   Ayantunde AA, Parsons S. Pattern and prognostic factors in patients with malignant ascites: a retrospective study. Ann Oncol. 2007;18:945-9.

   Not in our library10.1093/annonc/mdl499

4. 4.

   Tamsma J. The pathogenesis of malignant ascites. Cancer Treat Res. 2007;134:109-18.

   Not in our library10.1007/978-0-387-48993-3_6

5. 5.

   Preston N. New strategies for the management of malignant ascites. Eur J Cancer Care. 1995;4:178-83.

   Not in our library10.1111/j.1365-2354.1995.tb00090.x

6. 6.

   Hostetter RB, Marincola FM, Schwarzentruber DJ, deVita VT, Hellman S, Rosenberg SA. Malignant ascites. Cancer: principles and practice of oncology. 2005;2392-8.

   Not in our library

7. 7.

   Becker G, Galandi D, Blum HE. Malignant ascites: systematic review and guideline for treatment. Eur J Cancer. 2006;42:589-97.

   Not in our library10.1016/j.ejca.2005.11.018

8. 8.

   Garrison RN, Kaelin LD, Galloway RH, Heuser LS. Malignant ascites. Clinical and experimental observations. Ann Surg. 1986;203:644-51.

   Not in our library10.1097/00000658-198606000-00009

9. 9.

   Ayhan A, Gultekin M, Taskiran C, Dursun P, Firat P, Bozdag G, Celik NY, Yuce K. Ascites and epithelial ovarian cancers: a reappraisal with respect to different aspects. Int J Gynecol Cancer. 2007;17:68-75.

   Not in our library10.1111/j.1525-1438.2006.00777.x

10. 10.

    Lee CW, Bociek G, Faught W. A survey of practice in the management of malignant ascites. J Pain Symptom Manage. 1998;16:96-101.

    Not in our library10.1016/s0885-3924(98)00037-2

11. 11.

    Smith EM, Jayson GC. The current and future management of malignant ascites. Clin Oncol (R Coll Radiol). 2003;15:59-72.

    Not in our library10.1053/clon.2002.0135

12. 12.

    Ruf P, Lindhofer H. Induction of a long-lasting antitumor immunity by a trifunctional bispecific antibody. Blood. 2001;98:2526-34.

    Not in our library10.1182/blood.v98.8.2526

13. 13.
    The Fc-region of a new class of intact bispecific antibody mediates activation of accessory cells and NK cells and induces direct phagocytosis of tumour cells · 2000

    No notice
14. 14.

    Ruf P, Gires O, Jäger M, Fellinger K, Atz J, Lindhofer H. Characterisation of the new EpCAM-specific antibody HO-3: implications for trifunctional antibody immunotherapy of cancer. Br J Cancer. 2007;97:315-21.

    Not in our library10.1038/sj.bjc.6603881

15. 15.

    Went PT, Lugli A, Meier S, Bundi M, Mirlacher M, Sauter G, Dirnhofer S. Frequent EpCAM protein expression in human carcinomas. Hum Pathol. 2004;35:122-8.

    Not in our library10.1016/j.humpath.2003.08.026

16. 16.

    Passebosc-Faure K, Li G, Lambert C, Cottier M, Gentil-Perret A, Fournel P, Pérol M, Genin C. Evaluation of a panel of molecular markers for the diagnosis of malignant serous effusions. Clin Cancer Res. 2005;11:6862-7.

    Not in our library10.1158/1078-0432.ccr-05-0043

17. 17.

    De Angelis M, Buley ID, Heryet A, Gray W. Immunocytochemical staining of serous effusions with the monoclonal antibody Ber-EP4. Cytopathology. 1992;3:111-7.

    Not in our library10.1111/j.1365-2303.1992.tb00033.x

18. 18.

    Diaz-Arias AA, Loy TS, Bickel JT, Chapman RK. Utility of BER-EP4 in the diagnosis of adenocarcinoma in effusions: an immunocytochemical study of 232 cases. Diagn Cytopathol. 1993;9:516-21.

    Not in our library10.1002/dc.2840090509

19. 19.

    McLaughlin PM, Harmsen MC, Dokter WH, Kroesen BJ, van der Molen H, Brinker MG, Hollema H, Ruiters MH, Buys CH, de Leij LF. The epithelial glycoprotein 2 (EGP-2) promoter-driven epithelial-specific expression of EGP-2 in transgenic mice: a new model to study carcinoma-directed immunotherapy. Cancer Res. 2001;61:4105-11.

    Not in our library

20. 20.

    Okamoto S, Ito K, Sasano H, Moriya T, Niikura H, Terada Y, Sato S, Okamura K, Yaegashi N. Ber-EP4 and anti-calretinin antibodies: a useful combination for differential diagnosis of various histological types of ovarian cancer cells and mesothelial cells. Tohoku J Exp Med. 2005;206:31-40.

    Not in our library10.1620/tjem.206.31

21. 21.

    Heiss MM, Ströhlein MA, Jäger M, Kimmig R, Burges A, Schoberth A, Jauch KW, Schildberg FW, Lindhofer H. Immunotherapy of malignant ascites with trifunctional antibodies. Int J Cancer. 2005;117:435-43.

    Not in our library10.1002/ijc.21165

22. 22.

    Burges A, Wimberger P, Kümper C, Gorbounova V, Sommer H, Schmalfeldt B, Pfisterer J, Lichinitser M, Makhson A, Moiseyenko V, Lahr A, Schulze E, et al. Effective relief of malignant ascites in patients with advanced ovarian cancer by a trifunctional anti-EpCAM x anti-CD3 antibody: a phase I/II study. Clin Cancer Res. 2007;13:3899-905.

    Not in our library10.1158/1078-0432.ccr-06-2769

23. 23.

    Likert R. A technique for the measurement of attitudes. Arch Psychol. 1932;140:1-55.

    Not in our library

24. 24.

    Sartori S, Nielsen I, Tassinari D, Trevisani L, Abbasciano V, Malacarne P. Evaluation of a standardized protocol of intracavitary recombinant interferon alpha-2b in the palliative treatment of malignant peritoneal effusions. A prospective pilot study. Oncology. 2001;61:192-6.

    Not in our library10.1159/000055374

25. 25.

    Stuart GC, Nation JG, Snider DD, Thunberg P. Intraperitoneal interferon in the management of malignant ascites. Cancer. 1993;71:2027-30.

    Not in our library10.1002/1097-0142(19930315)71:6<2027::aid-cncr2820710617>3.0.co;2-c

26. 26.

    Hirte HW, Miller D, Tonkin K, Findlay B, Capstick V, Murphy J, Buckman R, Carmichael J, Levine M, Hill W. A randomized trial of paracentesis plus intraperitoneal tumor necrosis factor-alpha versus paracentesis alone in patients with symptomatic ascites from recurrent ovarian carcinoma. Gynecol Oncol. 1997;64:80-7.

    Not in our library10.1006/gyno.1996.4529

27. 27.

    Räth U, Kaufmann M, Schmid H, Hofmann J, Wiedenmann B, Kist A, Kempeni J, Schlick E, Bastert G, Kommerell B, Männel D. Effect of intraperitoneal recombinant human tumour necrosis factor alpha on malignant ascites. Eur J Cancer. 1991;27:121-5.

    Not in our library10.1016/0277-5379(91)90467-r

28. 28.

    Parsons SL, Watson SA, Steele RJ. Phase I/II trial of batimastat, a matrix metalloproteinase inhibitor, in patients with malignant ascites. Eur J Surg Oncol. 1997;23:526-31.

    Not in our library10.1016/s0748-7983(97)93077-8

29. 29.

    Katano M, Morisaki T. The past, the present and future of the OK-432 therapy for patients with malignant effusions. Anticancer Res. 1998;18:3917-25.

    Not in our library

30. 30.

    Hamilton CA, Maxwell GL, Chernofsky MR, Bernstein SA, Farley JH, Rose GS. Intraperitoneal bevacizumab for the palliation of malignant ascites in refractory ovarian cancer. Gynecol Oncol. 2008;111:530-2.

    Not in our library10.1016/j.ygyno.2008.04.028

31. 31.

    Kesterson JP, Mhawech-Fauceglia P, Lele S. The use of bevacizumab in refractory ovarian granulosa-cell carcinoma with symptomatic relief of ascites: a case report. Gynecol Oncol. 2008;111:527-9.

    Not in our library10.1016/j.ygyno.2008.07.015

32. 32.

    Marmé A, Strauss G, Bastert G, Grischke EM, Moldenhauer G. Intraperitoneal bispecific antibody (HEA125xOKT3) therapy inhibits malignant ascites production in advanced ovarian carcinoma. Int J Cancer. 2002;101:183-9.

    Not in our library10.1002/ijc.10562

33. 33.

    Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen R, Lele S, Copeland LJ, Walker JL, Burger RA, Gynecologic OncologyGroup. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006;354:34-43.

    Not in our library10.1056/nejmoa052985

34. 34.

    Jeyarajah DR, Thistlethwaite JR. General aspects of cytokine-release syndrome: timing and incidence of symptoms. Transplant Proc. 1993;25:16-20.

    Not in our library

35. 35.

    Winkler U, Jensen M, Manzke O, Schulz H, Diehl V, Engert A. Cytokine-release syndrome in patients with B-cell chronic lymphocytic leukemia and high lymphocyte counts after treatment with an anti-CD20 monoclonal antibody (rituximab. IDEC-C2B8). Blood. 1999;94:2217-24.

    Not in our library

36. 36.

    Bokemeyer C, Heiss M, Gamperl H, Linke R, Schulze E, Friccius-Quecke H, Lindhofer H, Parsons S. Safety of catumaxomab: cytokine-release-related symptoms as a possible predictive factor for efficacy in a pivotal phase II/III trial in malignant ascites. J Clin Oncol. 2009;27(Suppl).

    Not in our library

37. 37.

    Prandota J. Important role of proinflammatory cytokines/other endogenous substances in drug-induced hepatotoxicity: depression of drug metabolism during infections/inflammation states, and genetic polymorphisms of drug-metabolizing enzymes/cytokines may markedly contribute to this pathology. Am J Ther. 2005;12:254-61.

    Not in our library

38. 38.

    Molema G, Cohen-Tervaer JW, Kroesen BJ, Helfrich W, Meijer DK, de Leij LF. CD3 directed bispecific antibodies induce increased lymphocyte-endothelia l cell interactions in vitro. Br J Cancer. 2000;82:472-9.

    Not in our library10.1054/bjoc.1999.0945

39. 39.

    DeNardo GL, Mirick GR, Kroger LA, Bradt BM, Lamborn KR, DeNardo SJ. Characterization of human IgG antimouse antibody in patients with B-cell malignancies. Clin Cancer Res. 2003;9:4013-4021S.

    Not in our library

40. 40.

    Miotti S, Negri DR, Valota O, Calabrese M, Bolhuis RL, Gratama JW, Colnaghi MI, Canevari S. Level of anti-mouse-antibody response induced by bi-specific monoclonal antibody OC/TR in ovarian-carcinoma patients is associated with longer survival. Int J Cancer. 1999;84:62-8.

    Not in our library10.1002/(sici)1097-0215(19990219)84:1<62::aid-ijc12>3.0.co;2-t

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