title: 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.
abstract: OBJECTIVE
  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/m(2) IV) and cisplatin (75 mg/m(2) IV) q3w up to 6 cycles.
  
  
  RESULTS
  Sunitinib 37.5 mg/pemetrexed 400 mg/m(2)/cisplatin 75 mg/m(2) 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/m(2)/cisplatin 75 mg/m(2), 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.
authors.affiliation: University of Colorado Cancer Center, Mail Stop F704, 1665 Aurora Court, ACP Room 2256, Aurora, CO 80045, USA. ross.camidge@ucdenver.edu
authors.forename: D Ross
authors.initials: DR
authors.lastname: Camidge
authors.forename: Normand
authors.initials: N
authors.lastname: Blais
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Jonker
authors.forename: Denis
authors.initials: D
authors.lastname: Soulières
authors.forename: Robert C
authors.initials: RC
authors.lastname: Doebele
authors.forename: Ana
authors.initials: A
authors.lastname: Ruiz-Garcia
authors.forename: Aron
authors.initials: A
authors.lastname: Thall
authors.forename: Ke
authors.initials: K
authors.lastname: Zhang
authors.forename: Scott A
authors.initials: SA
authors.lastname: Laurie
authors.forename: Richard C
authors.initials: RC
authors.lastname: Chao
authors.forename: Laura Q
authors.initials: LQ
authors.lastname: Chow
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D015331:Cohort Studies; D005260:Female; D005971:Glutamates / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D006147:Guanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy*; D008875:Middle Aged; D000068437:Pemetrexed; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000077210:Sunitinib
chemical_list: D005971:Glutamates; D007211:Indoles; D011758:Pyrroles; D000068437:Pemetrexed; D006147:Guanine; D002945:Cisplatin; D000077210:Sunitinib