1395O - Randomized phase 3, multicenter, open-label study comparing evofosfamide (Evo) in combination with doxorubicin (D) vs. D alone in patients (pts) wi...

Date 08 October 2016
Event ESMO 2016 Congress
Session Sarcoma
Topics Anticancer agents
Soft Tissue Sarcomas
Therapy
Biological Therapy
Presenter William Tap
Citation Annals of Oncology (2016) 27 (6): 483-492. 10.1093/annonc/mdw388
Authors W. Tap1, Z. Papai2, B. van Tine3, S. Attia4, K. Ganjoo5, R.L. Jones6, S. Schuetze7, D. Reed8, S.P. Chawla9, R. Riedel10, A. Krarup-Hansen11, A. Italiano12, P. Hohenberger13, G. Grignani14, L. Cranmer15, T. Alcindor16, A. Lopez-Pousa17, T. Pearce18, S. Kroll18, P. Schoffski19
  • 1Oncology, Memorial Sloan-Kettering Cancer Center, 10065 - New York/US
  • 2Oncology, Semmelweis University Kutvolgyi Clinical Center, Budapest/HU
  • 3Division Of Oncology, Washington University School of Medicine, St Louis/US
  • 4Hematology/oncology, Mayo Clinic, Jacksonville/US
  • 5Oncology, Stanford University Medical Center, Stanford/US
  • 6Medical Oncology, Royal Marsden Hospital, SW3 6JJ - London/GB
  • 7Oncology, University of Michigan, Ann Arbor/US
  • 8Pediatrics, H. Lee Moffitt Cancer Center University of South Florida, Tampa/US
  • 9Med. Oncology, Sarcoma Oncology Center, 90403 - Santa Monica/US
  • 10Oncology, Duke University Medical Center, Durham/US
  • 11Clinical Medicine, Herlev, Gentofte/DK
  • 12Medical Oncology, Institute Bergonié, 33076 - Bordeaux/FR
  • 13Dept. Of Surgery, Universitätsklinikum Mannheim, 68167 - Mannheim/DE
  • 14Oncology, Istituto di Candiolo-IRCCS-Fondazione Piemontese per la Ricerca sul Cancro-Onlus, Candiolo/IT
  • 15Oncology, Fred Hutchinson Cancer Research Center, Seattle/US
  • 16Oncology, McGill University Health Center The Montreal General Hospital, H3G 1A4 - Montreal/CA
  • 17Research, Hospital de la Santa Creu i Sant Pau, Barcelona/ES
  • 18Clinical Development, Threshold Pharmaceuticals, Inc., 94080 - South San Francisco/US
  • 19General Medical Oncology, University Hospitals Leuven - Campus Gasthuisberg, Leuven/BE

Abstract

Background

Evo is a hypoxia-activated prodrug preferentially activated under hypoxic conditions to release the DNA alkylator Br-IPM. A phase 2 study of Evo (300 mg/m2) with D (75 mg/m2) resulted in a 6 month progression free rate of 58%. A Phase 3 study, conducted through SARC, assessed the benefit of adding Evo to D as first-line therapy for advanced STS.

Methods

This was a multi-national, open-label, randomized (1:1) Phase 3 study of Evo (300 mg/m2) IV on Days 1 and 8 (21-day cycle) with D on Day 1 vs. D alone (75 mg/m2, bolus or continuous). Pts on Evo plus D could receive Evo alone after Cycle 6. Key eligibility: locally advanced unresectable or metastatic STS, intermediate or high grade, no prior chemotherapy for advanced disease, ECOG 0/1, measurable disease (RECIST 1.1). The primary endpoint was overall survival (OS). The study had 85% power and one-sided alpha of 2.5% to detect 33% improvement in OS. Secondary endpoints were PFS, response rate (RR) and safety.

Results

From Sept 2011 to Jan 2014, 640 pts were randomized (317 Evo + D, 323 D); 621 pts were treated. Baseline characteristics were balanced. Median age: 59 years (range 18-89); 54% female; 57% ECOG 0; 36% leiomyosarcoma, 17% liposarcoma, 12% undifferentiated pleomorphic sarcoma; 89% metastatic, 11% locally advanced disease. Median cycles were 6 and D dose intensity was >90% through 6 cycles, in both arms. Single agent Evo was continued in 46% of pts on Evo + D after Cycle 6. OS endpoint was not reached (HR = 1.06 [95% CI: 0.88-1.29]) with median OS of 18.4 months with Evo + D vs 19.0 months with D. RR was 28.4% on Evo + D vs 18.3% for D (odds ratio of 1.77 [95% CI: 1.20 – 2.58, p = 0.003]. Median PFS was 6.3 months on Evo + D vs 6.0 months on D, HR = 0.85 (95% CI: 0.70-1.03, p = 0.099). Most common grade 3/4/5 AEs were anemia (35%), neutropenia (33%) and leucopenia (18%). Febrile neutropenia was noted in 18% of pts on Evo + D and 11% on D. AEs leading to death were 2.6% on Evo + D and 1.0% on D. AEs leading to discontinuation were 8.3% on Evo + D and 6.2% on D.

Conclusions

The combination of Evo + D did not improve OS compared to D. The safety profile was consistent with that previously reported.

Clinical trial identification

NCT01440088 First Received: September 20, 2011

Legal entity responsible for the study

Threshold Pharmaceuticals

Funding

Threshold Pharmaceuticals

Disclosure

W. Tap: Receipt of grants/research supports: Sarcoma Foundation of America Receipt of honoraria or consultation fees: Novartis, EMD Serono, Eli Lilly, Daiichi Sankyo, Janssen. R.L. Jones: Consulting role with Eisai Pharmamar Merck Adaptimmune Immune design Immodulon Daiichi Lilly Pfizer. S.P. Chawla: Consulting and Advisory Board: Novartis, Threshold, Eisai, J & J, Amgen, CytRx, Lilly, EMD Serono,Tracon, Morphotek. Research Funding: Amgen,Cytrx, Threshold, Novartis, J&J, Eisai, Tracon, Morphotek. R. Riedel: Advisory board for EMD Serono/Threshold re: TH-302 and institutional clinical research support from Threshold. L. Cranmer: The institution has received funding from Threshold Pharmaceuticals and EMD Serono. T. Pearce: Employee for Threshold Pharmaceuticals. S. Kroll: Employee of Threshold Pharmaceuticals, who is company leading development of TH-302 and also stock ownership in Threshold Pharmaceuticals. All other authors have declared no conflicts of interest.