Demetri, G. D., Le Cesne, A., Chawla, S. P., Brodowicz, T., Maki, R. G., Bach, B. A., Smethurst, D. P., Bray, S., Hei, Y. J., Blay, J. Y. (March 2012) 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. Eur J Cancer, 48 (4). pp. 547-63. ISSN 1879-0852 (Electronic)0959-8049 (Linking)
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.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | Adult Aged Aged, 80 and over Algorithms Antibodies, Monoclonal/*administration & dosage/adverse effects Antineoplastic Combined Chemotherapy Protocols/adverse effects/*therapeutic use Disease Progression Double-Blind Method Doxorubicin/*administration & dosage/adverse effects Female Humans Male Middle Aged Neoadjuvant Therapy Neoplasm Metastasis Placebos Sarcoma/*drug therapy/mortality/pathology Soft Tissue Neoplasms/*drug therapy/mortality/pathology Treatment Outcome Young Adult |
| Subjects: | diseases & disorders > cancer > drugs and therapies diseases & disorders > cancer > cancer types > sarcoma |
| CSHL Authors: | |
| Communities: | CSHL labs > Maki lab |
| Depositing User: | Matt Covey |
| Date: | March 2012 |
| Date Deposited: | 20 Oct 2016 19:00 |
| Last Modified: | 20 Oct 2016 19:00 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/33730 |
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