Published in:
01-02-2013 | Original Article
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
Authors:
D. Ross Camidge, Normand Blais, Derek J. Jonker, Denis Soulières, Robert C. Doebele, Ana Ruiz-Garcia, Aron Thall, Ke Zhang, Scott A. Laurie, Richard C. Chao, Laura Q. Chow
Published in:
Cancer Chemotherapy and Pharmacology
|
Issue 2/2013
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Abstract
Purpose
To determine the maximum tolerated dose (MTD), safety and tolerability of sunitinib plus pemetrexed and cisplatin for advanced solid malignancies.
Methods
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.
Results
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.
Conclusions
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.