title: 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).
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.affiliation: Harvard Cancer Center, Boston, MA, USA. gdemetri@partners.org
authors.forename: George D
authors.initials: GD
authors.lastname: Demetri
authors.forename: Axel
authors.initials: A
authors.lastname: Le Cesne
authors.forename: Sant P
authors.initials: SP
authors.lastname: Chawla
authors.forename: Thomas
authors.initials: T
authors.lastname: Brodowicz
authors.forename: Robert G
authors.initials: RG
authors.lastname: Maki
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Bach
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Smethurst
authors.forename: Sarah
authors.initials: S
authors.lastname: Bray
authors.forename: Yong-jiang
authors.initials: YJ
authors.lastname: Hei
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Blay
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D018450:Disease Progression; D004311:Double-Blind Method; D004317:Doxorubicin / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009362:Neoplasm Metastasis; D010919:Placebos; D012509:Sarcoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D012983:Soft Tissue Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D010919:Placebos; C554537:conatumumab; D004317:Doxorubicin