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A Phase I Study of the Safety and Pharmacokinetics of the Hypoxia-Activated Prodrug TH-302 in Combination with Doxorubicin in Patients with Advanced Soft Tissue SarcomaGanjoo K.N.a · Cranmer L.D.b · Butrynski J.E.c · Rushing D.d · Adkins D.e · Okuno S.H.f · Lorente G.g · Kroll S.g · Langmuir V.K.g · Chawla S.P.h
aStanford University Medical Center, Stanford, Calif., bArizona Cancer Center, Tucson, Ariz., cDana-Farber Cancer Institute, Boston, Mass., dIndiana University Simon Cancer Center, Indianapolis, Ind., eWashington University, St. Louis, Mo., fMayo Clinic, Rochester, Minn., gThreshold Pharmaceuticals, Redwood City, Calif., and hSarcoma Oncology Center, Santa Monica, Calif., USA
Purpose: The purpose of this study was to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), safety, pharmacokinetics and preliminary activity of TH-302, a hypoxia-activated prodrug, in combination with doxorubicin in patients with advanced soft tissue sarcoma. Patients and Methods: TH-302 was administered intravenously on days 1 and 8 and doxorubicin 75 mg/m2 on day 1 (2 h after TH-302) of every 3-week cycle. TH-302 starting dose was 240 mg/m2 with a classic 3 + 3 dose escalation. Pharmacokinetics were assessed on days 1 and 8 of cycle 1. Tumor assessments were performed after every second cycle. Results: Sixteen patients enrolled. Prophylactic growth factor support was added due to grade 4 neutropenia. The MTD was 300 mg/m2. DLTs at 340 mg/m2 were neutropenia-associated infection and grade 4 thrombocytopenia. Common adverse events included fatigue, nausea and skin rash. There was no evidence of pharmacokinetic interaction between TH-302 and doxorubicin. Five of 15 (33%) evaluable patients had a partial response by RECIST (Response Evaluation Criteria in Solid Tumors) criteria. Conclusions: The hematologic toxicity of doxorubicin is increased when combined with TH-302. This can be mitigated by prophylactic growth factor support. Toxicities were manageable and there was evidence of antitumor activity.
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