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

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)

URL: https://www.ncbi.nlm.nih.gov/pubmed/22240283
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.

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: http://repository.cshl.edu/id/eprint/33730

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