title: Sunitinib in combination with paclitaxel plus carboplatin in patients with advanced solid tumors: phase I study results.
abstract: OBJECTIVE
  To evaluate the maximum tolerated dose (MTD), safety, and antitumor activity of sunitinib combined with paclitaxel and carboplatin.
  
  
  METHODS
  Successive cohorts of patients with advanced solid tumors received oral sunitinib (25, 37.5, or 50 mg) for 2 consecutive weeks of a 3-week cycle (Schedule 2/1) or as a continuous daily dose for 3-week cycles (CDD schedule) in combination with paclitaxel (175-200 mg/m(2)) plus carboplatin (AUC 6 mg min/ml) on day one of each of 4 cycles. Dose-limiting toxicities (DLTs) and adverse events (AEs) were evaluated to determine the MTD. Efficacy parameters were analyzed in patients with measurable disease.
  
  
  RESULTS
  Forty-three patients were enrolled (n = 25 Schedule 2/1; n = 18 CDD schedule). Across all doses, 6 DLTs were observed [grade 4 papilledema, grade 5 GI hemorrhage, grade 3 neutropenic infection, and grade 4 thrombocytopenia (n = 3)]. The MTD for Schedule 2/1 was sunitinib 25 mg plus paclitaxel 175 mg/m(2) and carboplatin AUC 6 mg min/ml. The MTD was not determined for the CDD schedule. Treatment-related AEs included neutropenia (77%), thrombocytopenia (56%), and fatigue (47%). Of 38 evaluable patients, 4 (11%) had partial responses and 12 (32%) had stable disease. PK data indicated an increase in maximum and total plasma exposures to sunitinib and its active metabolite when given with paclitaxel and carboplatin compared with sunitinib monotherapy.
  
  
  CONCLUSIONS
  Myelosuppression resulting in prolonged dose delays and frequent interruptions was observed, suggesting that this treatment combination is not feasible in the general cancer population.
authors.affiliation: Karmanos Cancer Institute, Detroit, MI 48201, USA. heathe@karmanos.org
authors.forename: Elisabeth I
authors.initials: EI
authors.lastname: Heath
authors.forename: George R
authors.initials: GR
authors.lastname: Blumenschein
authors.forename: Roger B
authors.initials: RB
authors.lastname: Cohen
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Lorusso
authors.forename: Noelle K
authors.initials: NK
authors.lastname: Loconte
authors.forename: Sindy T
authors.initials: ST
authors.lastname: Kim
authors.forename: Ana
authors.initials: A
authors.lastname: Ruiz-Garcia
authors.forename: Richard C
authors.initials: RC
authors.lastname: Chao
authors.forename: George
authors.initials: G
authors.lastname: Wilding
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D016190:Carboplatin / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D023381:Endpoint Determination; D005260:Female; D006207:Half-Life; D006402:Hematologic Diseases / Q000139:chemically induced / Q000453:epidemiology; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage; D011758:Pyrroles / Q000008:administration & dosage; D000077210:Sunitinib; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D007211:Indoles; D011758:Pyrroles; D016190:Carboplatin; D017239:Paclitaxel; D000077210:Sunitinib