Journal
ONCOLOGY
Volume 80, Issue 1-2, Pages 50-56Publisher
KARGER
DOI: 10.1159/000327739
Keywords
Hypoxia-activated prodrug; TH-302; Phase I clinical trial; Soft tissue sarcoma
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Funding
- Threshold Pharmaceuticals Inc.
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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/m(2) on day 1 (2 h after TH-302) of every 3-week cycle. TH-302 starting dose was 240 mg/m(2) 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/m(2). DLTs at 340 mg/m(2) 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. Copyright (C) 2011 S. Karger AG, Basel
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