Phase I/II study of TH-302 combined with doxorubicin in soft tissue sarcoma.

Abstract

10036 Background: TH-302 is a 2-nitroimidazole prodrug of the DNA alkylator, bromo-isophosphoramide mustard. TH-302 is activated in severe hypoxia, releasing Br-IPM. In preclinical sarcoma models, TH-302 was active alone and enhanced the activity of doxorubicin (Dox). A phase I/II study was performed to investigate the safety and activity of TH-302 in combination with Dox in soft tissue sarcoma (STS). Methods: Eligible patients (pts) had ECOG ≤1, advanced or metastatic STS (AJCC grade 3 or 4), ≤2 prior chemotherapies, evaluable by RECIST, and acceptable hematologic, liver, renal and cardiac function. TH-302 was administered IV over 30-60 minutes on Day 1 and 8 and full dose Dox (75 mg/m2) as IV bolus 2 hours later on Day 1 of a 21-day cycle. A standard 3+3 design was used with phase II expansion in first-line pts at the combination MTD. TH-302 starting dose was 240 mg/m2. Results: 22 pts with STS (6 liposarcoma, 6 leiomyosarcoma, 5 pleomorphic NOS, 2 synovial, 3 other) were treated at TH-302 doses of 240 (6 pts), 300 (12) or 340 (4). 18 pts were first-line; 4 pts had received prior chemo. Median age: 58 (range 19-85); 10 M/12 F. 8 pts are ongoing, 6 completed study (4 received extra cycles TH-302 alone), 8 discontinued prior to Cycle 6 (AE/QOL-4, PD-3, pt decision-1). After Gr4 neutropenia at 240 mg/m2, all later pts received growth factor (GCSF) on Day 8. DLTs were Gr4 thrombocytopenia and Gr3 infection with Gr4 neutropenia at 340 mg/m2. The combination MTD of TH-302 is 300 mg/m2. 12 pts were treated at MTD with 1 DLT (Gr3 febrile neutropenia). Skin toxicities were reported in 11 pts (one Gr 3 cellulitis); mucosal toxicities were reported in 12 pts (one Gr 3 vaginitis). Nonhematologic AEs are Gr 1/2: fatigue (59%), nausea (45%), alopecia (41%). Gr3/4 hematologic toxicity: neutropenia (45%), thrombocytopenia (23%) and anemia (32%). There was no PK interaction between TH-302 and Dox. Best response assessments in 20 pts: 5 PRs (25%), 12 SDs (60%) and 3 PDs; excluding pt with post cycle 6 pathology confirmed enlarging necrotic tumor, 6 month progression-free rate is 56%. Conclusions: TH-302 may be administered in combination with full dose Dox in STS. Myelosuppression is dose limiting with the effects partially obviated by use of GCSF. Antitumor activity is encouraging. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Threshold Pharmaceuticals Threshold Pharmaceuticals Threshold Pharmaceuticals Threshold Pharmaceuticals