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.

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.

• Authors: George D Demetri, Axel Le Cesne, Sant P Chawla, Thomas Brodowicz, Robert G Maki, Bruce A Bach, Dominic P Smethurst, Sarah Bray, Yong-jiang Hei, Jean-Yves Blay
• Journal: European journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 48 Issue 4 Pg. 547-63 (Mar 2012) ISSN: 1879-0852 [Electronic] England
• PMID: 22240283 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• Antibodies, Monoclonal
• Placebos
• conatumumab
• Doxorubicin

Topics

• 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