Cited by 155Sarcoma Diagnosis and TreatmentBioactive Compounds and Antitumor AgentsPARP inhibition in cancer therapy

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Phase II Study of the Safety and Antitumor Activity of the Hypoxia-Activated Prodrug TH-302 in Combination With Doxorubicin in Patients With Advanced Soft Tissue Sarcoma

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Chawla, Sant P., Cranmer, Lee D., Van Tine, Brian A., Reed, Damon R., Okuno, Scott H., Butrynski, James E., Adkins, Douglas R., Hendifar, Andrew E., Kroll, Stew, Ganjoo, Kristen N.·2014·Journal of Clinical Oncology

DOI 10.1200/jco.2013.54.3660PMC PMC4588714

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Abstract

PURPOSE: TH-302, a prodrug of the cytotoxic alkylating agent bromo-isophosphoramide mustard, is preferentially activated in hypoxic conditions. This phase II study investigated TH-302 in combination with doxorubicin, followed by single-agent TH-302 maintenance therapy in patients with first-line advanced soft tissue sarcoma (STS) to assess progression-free survival (PFS), response rate, overall survival, safety, and tolerability. PATIENTS AND METHODS: In this open-label phase II study, TH-302 300 mg/m(2) was administered intravenously on days 1 and 8 with doxorubicin 75 mg/m(2) on day 1 of each 21-day cycle. After six cycles, patients with stable and/or responding disease could receive maintenance monotherapy with TH-302. RESULTS: Ninety-one patients initiated TH-302 plus doxorubicin induction treatment. The PFS rate at 6 months (primary efficacy measure) was 58% (95% CI, 46% to 68%). Median PFS was 6.5 months (95% CI, 5.8 to 7.7 months); median overall survival was 21.5 months (95% CI, 16.0 to 26.2 months). Best tumor responses were complete response (n = 2 [2%]) and partial response (n = 30 [34%]). During TH-302 maintenance (n = 48), five patients improved from stable disease to partial response, and one patient improved from partial to complete response. The most common adverse events during induction were fatigue, nausea, and skin and/or mucosal toxicities as well as anemia, thrombocytopenia, and neutropenia. These were less severe and less frequent during maintenance. There was no evidence of TH-302-related hepatic, renal, or cardiac toxicity. CONCLUSION: PFS, overall survival, and tumor response compared favorably with historical outcomes achieved with other first-line chemotherapies for advanced STS. A phase III study of TH-302 is ongoing (NCT01440088).

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Self-citation

Authors: Chawla, S. P., Cranmer, L. D., Van Tine, B. A., Reed, D. R., Okuno, S. H., Butrynski, J. E., Adkins, D. R., Hendifar, A. E., Kroll, S., & Ganjoo, K. N.
Affiliations: Cedars-Sinai Medical Center (US)
Sant P. Chawla, Sarcoma Oncology Center, Santa Monica; Andrew E. Hendifar, Cedars Sinai Medical Center, Los Angeles; Stew Kroll, Threshold Pharmaceuticals, South San Francisco; Kristen N. Ganjoo, Stanford University Medical Center, Stanford, CA; Lee D. Cranmer, University of Arizona Cancer Center, Tucson, AZ; Brian A. Van Tine and Douglas R. Adkins, Washington University in St Louis, St Louis, MO; Damon R. Reed, Moffitt Cancer Center and Research Institute, Tampa, FL; Scott H. Okuno, Mayo Clinic,...
ORCID: Chawla, Sant P.
Cranmer, Lee D.
Reed, Damon R.
Okuno, Scott H.
Adkins, Douglas R.
Hendifar, Andrew E.
Ganjoo, Kristen N.
Venue: Journal of Clinical Oncology
Publisher: American Society of Clinical Oncology (ASCO)
Published: 2014-10-10
Volume: 32
Issue: 29
Pages: 3299-3306
ISSN: 0732-183X (ISSN-L)
1527-7755
DOI: 10.1200/jco.2013.54.3660
PMC: PMC4588714
OpenAlex: W2162527266
Cited by: 155
References: 29
Citations by year: 2026: 3 · 2025: 6 · 2024: 3 · 2023: 7 · 2022: 11 · 2021: 20 · 2020: 10 · 2019: 12 · 2018: 14 · 2017: 17 · 2016: 33 · 2015: 19
FWCI: 18.46
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Oncology (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Amgen
GlaxoSmithKline
Merck KGaA
EMD Serono
National Cancer Institute (P30CA076292)
Topics: Health Sciences › Medicine › Oncology › Sarcoma Diagnosis and Treatment
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
Keywords: TH-302, doxorubicin, soft tissue sarcoma, hypoxia-activated prodrug, combination chemotherapy, maintenance monotherapy, progression-free survival, anticancer activity, drug safety and tolerability, first-line therapy
MeSH terms: Adult, Aged, Antineoplastic Combined Chemotherapy Protocols, Doxorubicin, Female, Humans, Male, Middle Aged, Nitroimidazoles, Phosphoramide Mustards, Prodrugs, Sarcoma, Survival Rate, Treatment Outcome

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Phase II Study of the Safety and Antitumor Activity of the Hypoxia-Activated Prodrug TH-302 in Combination With Doxorubicin in Patients With Advanced Soft Tissue Sarcoma

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