Randomized phase 3, multicenter, open-label study comparing evofosfamide (Evo) in combination with doxorubicin (D) vs. D alone in patients (pts) with advanced soft tissue sarcoma (STS): Study TH-CR-406/SARC021

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.