Tirapazamine Plus Carboplatin and Paclitaxel in Advanced Malignant Solid Tumors: a California Cancer Consortium Phase I and Molecular Correlative Study
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4356 Vol. 9, 4356–4362, October 1, 2003 Clinical Cancer Research Tirapazamine Plus Carboplatin and Paclitaxel in Advanced Malignant Solid Tumors: A California Cancer Consortium Phase I and Molecular Correlative Study Primo N. Lara, Jr.,1 Paul Frankel, stable disease in at least one evaluation; 10 quickly pro- Philip C. Mack, Paul H. Gumerlock, Irina Galvin, gressed. One complete responder had normalization of vas- Cynthia L. Martel, Jeff Longmate, cular endothelial growth factor and plasminogen activator inhibitor-1 levels. James H. Doroshow, Heinz Josef Lenz, Conclusion: Dose levels 3 (carboplatin AUC of 6, 225 Derick H. M. Lau, and David R. Gandara mg/m2 paclitaxel, and 330 mg/m2 tirapazamine) and 2 (car- California Cancer Consortium at the University of California Davis boplatin AUC 6, 225 mg/m2 paclitaxel, and 260 mg/m2 tira- Cancer Center, Sacramento, California 95817 [P. N. L., P. C. M., pazamine) are the maximum tolerated doses for chemother- P. H. G., I. G., C. L. M., D. H. M. L., D. R. G.]; City of Hope apy naive and patients treated previously, respectively. Dose Comprehensive Cancer Center, Duarte, CA [P. F., J. L., J. H. D.]; and the University of Southern California Norris Comprehensive Cancer level 3 is the experimental arm of a Phase III Southwest Center, Los Angeles, CA [H. J. L.] 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 ABSTRACT being prospectively investigated in S0003. Purpose: Tumor hypoxia confers chemotherapy resist- ance. Tirapazamine is a cytotoxin that selectively targets INTRODUCTION hypoxic cells and has supra-additive toxicity with platinums Hypoxia affects Յ50% of human tumor cells and nega- and taxanes in preclinical studies. We conducted a Phase I tively influences the response to both radiation and standard study of tirapazamine, carboplatin, and paclitaxel and as- chemotherapeutic agents (1–6). For example, cisplatin had little sessed potential plasma markers of hypoxia as surrogates or no cytotoxic activity against hypoxic tumor cells in a pre- for response. clinical model despite killing a large proportion of nonhypoxic Experimental Design: Forty-two patients with advanced cells (7). Therefore, therapies that potentiate cytotoxicity against solid tumors were treated at four dose levels; parallel dose hypoxic cancer cells should theoretically increase the efficacy of escalations were carried out in chemotherapy-naive and platinum-based chemotherapy (8, 9). previously treated subjects. Pre and post-therapy plasma Hypoxic conditions alter cellular homeostasis, e.g., malig- levels of the hypoxia-induced proteins plasminogen activator nant cells subjected to hypoxia are induced to transcribe a inhibitor-1 and vascular endothelial growth factor were discrete set of genes (10), including the genes coding for PAI-1 measured. and VEGF2 (11). Hypoxia may then exert selection pressure on Results: Three of four chemotherapy-naı¨ve patients de- tumor populations by promoting angiogenesis, p53 mutations, veloped dose-limiting toxicities at dose level 4 (grade 3 sto- and resistance to apoptosis (12). Furthermore, tumor hypoxia matitis/infection, grade 3 emesis, and grade 4 febrile neu- has been shown to increase the metastatic potential of cancer tropenia). Four of seven previously treated patients cells, leading to the conclusion that hypoxia influences tumor developed dose-limiting toxicities at dose level 3, including phenotype as well as clinical outcome (13). This notion is one death [grade 3 myalgia, grade 3 infection/grade 4 neu- supported by the observation that tumor hypoxia (as measured tropenia, grade 3 infection/grade 4 neutropenia, and grade 5 by Eppendorf oxygen electrodes) is correlated with an increased infection (death)/grade 4 neutropenia]. Of 38 patients assess- incidence of distant metastases and treatment failure in a variety able for response, 3 had a complete response, 1 a partial of tumors, including soft tissue sarcomas, cervical cancer, and response, 1 an unconfirmed partial response, and 23 had head and neck carcinomas (14–16). Tirapazamine, the prototype for a novel class of anticancer compounds called “hypoxic cytotoxins,” is a benzotriazine com- pound that exhibits substantial differential toxicity for hypoxic Received 3/4/03; revised 6/3/03; accepted 6/9/03. cells. At equivalent tirapazamine concentrations, hypoxic mu- The costs of publication of this article were defrayed in part by the rine and/or human tumor cells were found to be Յ200 times payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. This work was supported in part by CA62505, CA63265, Bristol Myers Squibb (P. N. L.), the Hope Foundation (P. N. L.), and the American Cancer Society CRTG 0019701CCE (P. N. L.). 2 The abbreviations used are: VEGF, vascular endothelial growth factor; 1 To whom requests for reprints should be addressed, at University of AUC, area under the curve; NCI, National Cancer Institute; DLT, California Davis Cancer Center, 4501 X Street, Sacramento, CA 95817. dose-limiting toxicity; NSCLC, non-small cell lung cancer; IGFBP, Phone:(916) 734-3771;Fax:(916) 734-7946;E-mail:primo.lara@ucdmc. insulin-like growth factor-binding protein-3; MTD, maximum tolerated ucdavis.edu. dose. Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2003 American Association for Cancer Research. Clinical Cancer Research 4357 Table 1 Dose escalation scheme pate. Patients who had previously received carboplatin and Dose Tirapazamine Carboplatin Paclitaxel paclitaxel concurrently were excluded. Patients who were preg- level (mg/m2) (AUC) (mg/m2) nant or who had unstable medical conditions (such as uncon- 1 260 6 200 trolled congestive heart failure) or other uncontrolled intercur- 2 260 6 225 rent illnesses precluding investigational therapy were also 3 330 6 225 excluded. Patients were required to use a medically acceptable 4 390 6 225 contraceptive throughout the treatment period and for 3 months after cessation of treatment with tirapazamine. This study was approved by the NCI-Cancer Therapy Evaluation Program and the institutional review boards of each California Cancer Con- more sensitive than aerobic cells to killing by tirapazamine (17). sortium site. All patients gave written informed consent to Preclinical studies have also tested the combination of tira- participate. pazamine with platinum-containing compounds in hypoxic tu- Baseline Evaluation. Before study entry, all patients un- mor models. Combinations of tirapazamine with either cisplatin derwent a complete history and physical examination. Baseline or carboplatin show enhanced antitumor activity in a number of imaging studies of all known sites of disease were obtained in vivo and in vitro models. In some models, the cytotoxicity of within 4 weeks of initial therapy. An audiometric evaluation was tirapazamine plus a platinum or a taxane is substantially greater required for all patients because of potential ototoxic effects of than the additive effects of both drugs. Studies in mice have tirapazamine. Laboratory studies included a complete blood demonstrated enhanced antitumor activity for the three-drug count with differential and platelet count, comprehensive met- regimen of tirapazamine, carboplatin, and paclitaxel versus car- abolic panel (which includes electrolytes, serum creatinine, total boplatin/paclitaxel in the MV-522 human lung carcinoma xe- bilirubin, and aspartate aminotransferase). Patient plasma was nograft model, forming the basis for this clinical study (18). collected before cycles 1 and 2 for molecular correlative studies The combination of carboplatin-paclitaxel has shown en- (see below). couraging activity in a number of different tumor types, includ- DLT. DLT was defined as any Grade 3 or 4 nonhema- ing NSCLC, and its toxicity profile has been well characterized. tological toxicity (including nausea/vomiting with maximal an- A recent Phase III trial (S9509) showed that paclitaxel-carbo- tiemetic prophylaxis), Grade 3/4 thrombocytopenia, and Grade platin has increased tolerability compared with vinorelbine- 4 neutropenia with fever (defined as a temperature of 38.3°C or cisplatin, prospectively defined as the ability to complete ther- 101°F) or a documented infection, occurring during the first apy and the percentage of patients taken off study attributable to course of treatment. Toxicity was graded according to the NCI toxicity (19). Furthermore, a recent Phase III trial in NSCLC of common toxicity criteria version 2.0. cisplatin with or without tirapazamine demonstrated improved MTD. The MTD was defined as the highest dose level at response and survival in patients treated with the combination which not Ͼ1 patient experienced a DLT, when Ն6 patients (20). Finally, a recently concluded Phase I trial demonstrated the were treated at that dose and were evaluable for toxicity. The feasibility of delivering a 3-h infusion of paclitaxel at 225 MTD was one dose level below the DLT level. Separate MTDs 2 2 2 mg/m with tirapazamine (390 mg/m ) and cisplatin (75 mg/m ) were determined for each stratified group (i.e., treated previ- every 3 weeks (21). In view of these preclinical and clinical ously and untreated previously). observations, we conducted a Phase I trial of tirapazamine plus Study Design and Treatment Plan. The dose escalation paclitaxel and carboplatin, administered on a single