title: Sunitinib combined with pemetrexed and carboplatin in patients with advanced solid malignancies--results of a phase I dose-escalation study.
abstract: OBJECTIVE
  The maximum tolerated dose (MTD) and overall safety of sunitinib plus pemetrexed and carboplatin was determined in patients with advanced solid malignancies.
  
  
  METHODS
  In this phase I dose-escalation study, patients received oral sunitinib on a continuous daily dosing (CDD) schedule (37.5 mg/day) or Schedule 2/1 (2 weeks on treatment, 1 week off treatment; 37.5 or 50 mg/day). Pemetrexed (400-500 mg/m(2) IV) and carboplatin (AUC = 5 mg·min/ml IV) were administered q3w. At the MTD for the chosen schedule, a cohort of patients with non-small cell lung cancer (NSCLC) or mesothelioma was further evaluated.
  
  
  RESULTS
  Twenty-one patients were enrolled on Schedule 2/1 (expansion cohort included) and 3 patients on the CDD schedule. The MTD on Schedule 2/1 was sunitinib 37.5 mg/day with pemetrexed 500 mg/m(2) and carboplatin AUC = 5 mg·min/ml; MTD on the CDD schedule was not established. Dose-limiting toxicities included grade 3/4 neutropenia, grade 3 thrombocytopenia, and grade 3 hand-foot syndrome. The most common grade 3/4 drug-related non-hematologic adverse events at Schedule 2/1 MTD were fatigue/asthenia and diarrhea (both n = 4). Grade 3/4 hematologic abnormalities included neutropenia (83%) and leukopenia (83%). Pharmacokinetic data revealed no clinically significant drug-drug interactions. Best response at the Schedule 2/1 MTD was stable disease ≥8 weeks in 3/5 evaluable patients (60%).
  
  
  CONCLUSIONS
  With this combination, in patients with advanced solid malignancies, sunitinib MTD on Schedule 2/1 was 37.5 mg/day. Sunitinib plus pemetrexed and carboplatin were tolerable at the MTD, although sunitinib dose delays and reductions were often required due to myelosuppression.
authors: Centre de Lutte Contre le Cancer du CHUM - Hôpital Notre-Dame, 6ième étage (G6162), Pavillon Deschamps, 1560 Sherbrooke Est, Montréal, QC, H2L 4M1, Canada, normand.blais@geoq.com.
authors: Normand
authors: N
authors: Blais
authors: D Ross
authors: DR
authors: Camidge
authors: Derek J
authors: DJ
authors: Jonker
authors: Denis
authors: D
authors: Soulières
authors: Scott A
authors: SA
authors: Laurie
authors: Sami G
authors: SG
authors: Diab
authors: Ana
authors: A
authors: Ruiz-Garcia
authors: Aron
authors: A
authors: Thall
authors: Ke
authors: K
authors: Zhang
authors: Richard C
authors: RC
authors: Chao
authors: Laura Q
authors: LQ
authors: Chow
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D004334:Drug Administration Schedule; D005260:Female; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D007970:Leukopenia / Q000139:chemically induced; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D020714:Maximum Tolerated Dose; D008654:Mesothelioma / Q000188:drug therapy* / Q000378:metabolism; D008875:Middle Aged; D000068437:Pemetrexed; D011758:Pyrroles / Q000008:administration & dosage; D000077210:Sunitinib; D055815:Young Adult
chemical_list: D005971:Glutamates; D007211:Indoles; D011758:Pyrroles; D000068437:Pemetrexed; D006147:Guanine; D016190:Carboplatin; D000077210:Sunitinib
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