Abstract
10024 Background: TH-302 is a 2-nitroimidazole prodrug of the DNA alkylator, bromo-isophosphoramide mustard. TH-302 is designed for activation in severe hypoxia, releasing Br-IPM. The MTD of TH-302 in combination with doxorubicin (Dox) was established at 300 mg/m2. A Phase II expansion at the MTD investigated the activity and safety 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), no prior chemotherapies (neoadjuvant permitted), evaluable by RECIST and acceptable hematologic, liver, renal and cardiac function. TH-302 (300 mg/m2) was administered IV over 30-60 minutes on Days 1 and 8, full dose Dox (75 mg/m2) as IV bolus 2 hours after TH-302 on Day 1 of a 21-day cycle and G-CSF was administered on Day 8. Results: 60 pts with STS (18 leiomyosarcoma, 16 MFH, 12 liposarcoma, 4 unclassified/undifferentiated, 3 angiosarcoma, 2 synovial, 2 high grade fibrosarcoma, 3 other) were treated between August 2009 and December 2010. Median age: 59 (range 23-78); 25 M/35 F. 14 pts are ongoing, 37 completed 6 cycles (27 received extra cycles TH-302 alone), 18 discontinued prior to Cycle 6 (PD-9, AE-4, clinical deterioration-2, pt decision-2, investigator decision-1). TH-302 related skin toxicities were reported in 35% of pts (two Grd 3: pruritus, pruritus/urticaria); mucosal toxicities were reported in 54% of pts (no Grd 3/4). Non-hematologic AEs: fatigue (61%), nausea (58%), alopecia (44%), stomatitis (40%). Gr3/4 hematologic toxicity: neutropenia (23%), thrombocytopenia (23%) and anemia (19%). Best response assessments in 58 pts: 17 (29%) PRs (15 confirmed, 2 unconfirmed), 34 (59%) SDs and 7 (12%) PDs. 6 mo progression-free rate is 56%. The median progression-free survival was 6.7 mo (95% CI: 5.6 to 8.1 mo). Median overall survival has not been reached (95% CI: 10.4 mo to not reached). Conclusions: TH-302 dosed at 300 mg/m2 in combination with full dose Dox in STS is well tolerated with a predictable safety profile including acceptable hematologic, skin and mucosal toxicity. The response rate and progression-free survival exceed that expected with doxorubicin alone and a randomized controlled study is planned.
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