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Vol. 80, No. 1-2, 2011
Issue release date: June 2011
Section title: Clinical Study
Oncology 2011;80:50–56
(DOI:10.1159/000327739)

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 Sarcoma

Ganjoo 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

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Article / Publication Details

First-Page Preview
Abstract of Clinical Study

Received: 1/23/2011
Accepted: 2/23/2011
Published online: 5/31/2011
Issue release date: June 2011

Number of Print Pages: 7
Number of Figures: 1
Number of Tables: 4

ISSN: 0030-2414 (Print)
eISSN: 1423-0232 (Online)

For additional information: http://www.karger.com/OCL

Abstract

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.

© 2011 S. Karger AG, Basel


  

Author Contacts

Kristen N. Ganjoo, MD
Stanford University
875 Blake Wilbur Drive
Stanford, CA 94305 (USA)
E-Mail kganjoo@stanford.edu

  

Article Information

Presented in part at the 2009 Chemotherapy Foundation Symposium XXVII, 2009 Connective Tissue Oncology Society Annual Meeting and 2010 American Society of Clinical Oncology Annual Meeting.

Received: January 23, 2011
Accepted after revision: February 23, 2011
Published online: May 31, 2011
Number of Print Pages : 7
Number of Figures : 1, Number of Tables : 4, Number of References : 22

  

Publication Details

Oncology (International Journal for Cancer Research and Treatment)

Vol. 80, No. 1-2, Year 2011 (Cover Date: June 2011)

Journal Editor: Markman M. (Philadelphia, Pa.)
ISSN: 0030-2414 (Print), eISSN: 1423-0232 (Online)

For additional information: http://www.karger.com/OCL


Article / Publication Details

First-Page Preview
Abstract of Clinical Study

Received: 1/23/2011
Accepted: 2/23/2011
Published online: 5/31/2011
Issue release date: June 2011

Number of Print Pages: 7
Number of Figures: 1
Number of Tables: 4

ISSN: 0030-2414 (Print)
eISSN: 1423-0232 (Online)

For additional information: http://www.karger.com/OCL


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Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
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