Sunitinib combined with pemetrexed and cisplatin: results of a phase I dose-escalation and pharmacokinetic study in patients with advanced solid malignancies, with an expanded cohort in non-small cell lung cancer and mesothelioma
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To determine the maximum tolerated dose (MTD), safety and tolerability of sunitinib plus pemetrexed and cisplatin for advanced solid malignancies.
Using a 3 + 3 dose-escalation design, patients received oral sunitinib (37.5 or 50 mg) qd on a continuous daily dosing (CDD) schedule or Schedule 2/1 (2 weeks on, 1 week off treatment) plus pemetrexed (400 or 500 mg/m2 IV) and cisplatin (75 mg/m2 IV) q3w up to 6 cycles.
Sunitinib 37.5 mg/pemetrexed 400 mg/m2/cisplatin 75 mg/m2 CDD (n = 5) was not tolerated. Lower doses on this schedule were not explored. The Schedule 2/1 MTD (n = 15) was sunitinib 37.5 mg/pemetrexed 500 mg/m2/cisplatin 75 mg/m2, based on one dose-limiting toxicity (myocardial infarction) out of six patients. The MTD was further studied in an expansion cohort of 10 non-small cell lung cancer (NSCLC) patients and one mesothelioma patient. There were no clinically significant drug–drug interactions. Cumulative myelosuppression was problematic: the median relative dose intensity (% actual/intended) across all cycles was 61 % for sunitinib, 78 % for pemetrexed, and 74 % for cisplatin. Four of eight NSCLC patients in the dose-escalation and expansion cohorts at the Schedule 2/1 MTD who were evaluable for efficacy had stable disease ≥8 weeks, and the one patient with mesothelioma had a partial response.
In patients with advanced solid malignancies, sunitinib was not tolerated at 37.5 mg CDD with standard pemetrexed and cisplatin doses. Dose reductions were often needed due to cumulative myelosuppression following cycle 1. The MTD showed modest antitumor activity.
KeywordsSolid tumors NSCLC Phase I Sunitinib Pemetrexed Cisplatin
We would like to thank all of the participating patients and their families, as well as the global network of investigators, research nurses, study coordinators, and operations staff. We would also like to acknowledge Tanya Boutros for coordination of PK assays, and Michelle McWilliam for data review. Medical writing support was provided by Susanne Gilbert at ACUMED (New York, NY) and was funded by Pfizer Inc. This study was sponsored by Pfizer Inc.
Conflict of interest
A Ruiz-Garcia, A Thall, K Zhang, and RC Chao are employees of Pfizer Inc. and hold stock in Pfizer Inc., the makers of SUTENT®. RC Doebele has research grants from ImClone Systems, Inc., Eli Lilly & Co., and Pfizer, Inc.
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