Tirapazamine plus carboplatin and paclitaxel in advanced malignant solid tumors: A California Cancer Consortium phase I and molecular correlative study

Primo N Lara, Paul Frankel, Philip Mack, Paul H. Gumerlock, Irina Galvin, Cynthia L. Martel, Jeff Longmate, James H. Doroshow, Heinz Josef Lenz, Derick H Lau, David R Gandara

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Purpose: Tumor hypoxia confers chemotherapy resistance. Tirapazamine is a cytotoxin that selectively targets hypoxic cells and has supra-additive toxicity with platinums and taxanes in preclinical studies. We conducted a Phase I study of tirapazamine, carboplatin, and paclitaxel and assessed potential plasma markers of hypoxia as surrogates for response. Experimental Design: Forty-two patients with advanced solid tumors were treated at four dose levels; parallel dose escalations were carried out in chemotherapy-naive and previously treated subjects. Pre and post-therapy plasma levels of the hypoxia-induced proteins plasminogen activator inhibitor-1 and vascular endothelial growth factor were measured. Results: Three of four chemotherapy-naïve patients developed dose-limiting toxicities at dose level 4 (grade 3 stomatitis/infection, grade 3 emesis, and grade 4 febrile neutropenia). Four of seven previously treated patients developed dose-limiting toxicities at dose level 3, including one death [grade 3 myalgia, grade 3 infection/grade 4 neutropenia, grade 3 infection/grade 4 neutropenia, and grade 5 infection (death)/grade 4 neutropenia]. Of 38 patients assessable for response, 3 had a complete response, 1 a partial response, 1 an unconfirmed partial response, and 23 had stable disease in at least one evaluation; 10 quickly progressed. One complete responder had normalization of vascular endothelial growth factor and plasminogen activator inhibitor-1 levels. Conclusion: Dose levels 3 (carboplatin AUC of 6, 225 mg/m2 paclitaxel, and 330 mg/m2 tirapazamine) and 2 (carboplatin AUC 6, 225 mg/m2 paclitaxel, and 260 mg/m2 tirapazamine) are the maximum tolerated doses for chemotherapy naive and patients treated previously, respectively. Dose level 3 is the experimental arm of a Phase III Southwest Oncology Group trial (S0003) in advanced non-small cell lung cancer. Potential markers of tumor hypoxia may be useful correlates in studies of hypoxic cytotoxins and are being prospectively investigated in S0003.

Original languageEnglish (US)
Pages (from-to)4356-4362
Number of pages7
JournalClinical Cancer Research
Volume9
Issue number12
StatePublished - Oct 1 2003

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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