title: A phase I trial of dasatinib, an SRC-family kinase inhibitor, in combination with paclitaxel and carboplatin in patients with advanced or recurrent ovarian cancer.
abstract: OBJECTIVE
  We conducted a phase I study of dasatinib, an oral SRC-family tyrosine kinase inhibitor, in combination with paclitaxel and carboplatin in the treatment of advanced and recurrent epithelial ovarian cancer.
  
  
  METHODS
  The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives included defining toxicity, response rate (RR), pharmacokinetics, and pharmacodynamics. Using a "3+3" design, cohorts of three to six patients received paclitaxel (175 mg/m(2)) and carboplatin (AUC 6) every 3 weeks with escalating doses of dasatinib (100, 120, and 150 mg daily), followed by an eight-patient expansion cohort.
  
  
  RESULTS
  Twenty patients were enrolled between June 2007 and December 2009. The median age was 61 years (range: 42-82) with a median of 2 prior regimens (range: 0-6), and 71% had platinum-sensitive disease. There were three to six patients in each cohort, and eight in the expansion cohort. Pharmacokinetics were observed over the first two cycles of therapy. One DLT was observed in the 100 mg dasatinib cohort (grade 3 myalgia). Other toxicities in all cycles included neutropenia (95% grade 3-4; 91% in the 150 mg dosing cohort), thrombocytopenia (35% grade 3-4), and fatigue (10% grade 3). The RR was 40% [three complete responses, (15%); five partial responses, (25%)],10 patients (50%) had stable disease, and two were not evaluable. The PFS(6-month) actuarial estimate was 86%. The median PFS and OS were 7.8 and 16.2 months, respectively.
  
  
  CONCLUSIONS
  Due to the high incidence of myelosuppression with subsequent cycles, the recommended phase II dose of dasatinib is 150 mg daily in combination with paclitaxel and carboplatin. The combination was safe with evidence of clinical activity.
authors: Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA. secor002@mc.duke.edu
authors: Angeles Alvarez
authors: AA
authors: Secord
authors: Deanna K
authors: DK
authors: Teoh
authors: William T
authors: WT
authors: Barry
authors: Miao
authors: M
authors: Yu
authors: Gloria
authors: G
authors: Broadwater
authors: Laura J
authors: LJ
authors: Havrilesky
authors: Paula S
authors: PS
authors: Lee
authors: Andrew
authors: A
authors: Berchuck
authors: Johnathan
authors: J
authors: Lancaster
authors: Robert M
authors: RM
authors: Wenham
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016190:Carboplatin / Q000008:administration & dosage; D000069439:Dasatinib; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D013844:Thiazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
chemical_list: D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D016190:Carboplatin; D019061:src-Family Kinases; D017239:Paclitaxel; D000069439:Dasatinib