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Tirapazamine Plus Carboplatin and Paclitaxel in Advanced Malignant Solid Tumors

A California Cancer Consortium Phase I and Molecular Correlative Study

California Cancer Consortium at the University of California Davis Cancer Center, Sacramento, California 95817 [P. N. L., P. C. M., P. H. G., I. G., C. L. M., D. H. M. L., D. R. G.]; City of Hope Comprehensive Cancer Center, Duarte, CA [P. F., J. L., J. H. D.]; and the University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA [H. J. L.]

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.

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				S. K. Williamson, J. J. Crowley, P. N. Lara Jr, J. McCoy, D. H.M. Lau, R. W. Tucker, G. M. Mills, and D. R. Gandara Phase III Trial of Paclitaxel Plus Carboplatin With or Without Tirapazamine in Advanced Non-Small-Cell Lung Cancer: Southwest Oncology Group Trial S0003 J. Clin. Oncol., December 20, 2005; 23(36): 9097 - 9104. [Abstract] [Full Text] [PDF]

				Q.-T. Le, J. McCoy, S. Williamson, J. Ryu, L. E. Gaspar, M. J. Edelman, S. R. Dakhil, S. D. Sides, J. J. Crowley, and D. R. Gandara Phase I Study of Tirapazamine Plus Cisplatin/Etoposide and Concurrent Thoracic Radiotherapy in Limited-Stage Small Cell Lung Cancer (S0004): A Southwest Oncology Group Study Clin. Cancer Res., August 15, 2004; 10(16): 5418 - 5424. [Abstract] [Full Text] [PDF]