First-line treatment of metastatic or locally advanced unresectable soft tissue sarcomas with conatumumab in combination with doxorubicin or doxorubicin alone: A Phase I/II open-label and double-blind study

• Published in: European journal of cancer (1990) 2012-03, Vol.48 (4), p.547-563
• Main Authors: Demetri, George D, Le Cesne, Axel, Chawla, Sant P, Brodowicz, Thomas, Maki, Robert G, Bach, Bruce A, Smethurst, Dominic P, Bray, Sarah, Hei, Yong-jiang, Blay, Jean-Yves
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Algorithms; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - adverse effects; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Conatumumab; Death receptor 5; Disease Progression; Double-Blind Method; Doxorubicin; Doxorubicin - administration & dosage; Doxorubicin - adverse effects; Female; Hematology, Oncology and Palliative Medicine; Humans; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Placebos; Sarcoma - drug therapy; Sarcoma - mortality; Sarcoma - pathology; Soft Tissue Neoplasms - drug therapy; Soft Tissue Neoplasms - mortality; Soft Tissue Neoplasms - pathology; Soft tissue sarcomas; TRAIL; Treatment Outcome; Young Adult
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/j.ejca.2011.12.008

Abstract Background Conatumumab is a fully human monoclonal agonist antibody that binds to death receptor 5 and induces apoptosis in sensitive cells. This study evaluated the safety and efficacy of doxorubicin ± conatumumab as first-line systemic therapy for metastatic or locally advanced/unresectable soft-tissue sarcoma. Methods In Phase I, six patients received doxorubicin (75 mg/m2 ) with conatumumab (15 mg/kg) every 3 weeks. In Phase II, patients were randomised (2:1) to receive doxorubicin with either double-blind conatumumab 15 mg/kg (conatumumab–doxorubicin; n = 86) or placebo (placebo–doxorubicin; n = 42). Patients who progressed on placebo–doxorubicin could receive open-label conatumumab monotherapy post-chemotherapy ( n = 21). Findings The expected histopathologic subtypes (e.g. leiomyosarcoma, liposarcoma, others) were represented in this trial. No unexpected adverse events were noted in either Phase I or II. Median progression-free survival in Phase II was 5.6 and 6.4 months in the conatumumab–doxorubicin and placebo–doxorubicin arms, respectively (stratified HR: 1.00; p = 0.973), with more early progressions noted in the first 3.5 months in the conatumumab–doxorubicin arm. Median overall survival was not reached after 8.6 months median follow-up in either arm. Common adverse events were nausea (conatumumab–doxorubicin: 66%; placebo–doxorubicin: 80%), alopecia (55%; 63%), fatigue (60%; 38%) and neutropenia (32%; 50%). Post-chemotherapy results were not notably improved by conatumumab dosing. Interpretation Addition of conatumumab to doxorubicin appeared to be safe but did not improve disease control in a heterogeneous unselected group of patients with soft tissue sarcomas. The results of this trial are very useful for estimating the outcomes of first-line therapy of sarcoma patients treated with standard doxorubicin. Funding This study was supported by Amgen Inc.