title: A Phase I clinical trial of the combination of imatinib and paclitaxel in patients with advanced or metastatic solid tumors refractory to standard therapy.
abstract: OBJECTIVE
  Pre-clinical data suggest that combining imatinib with traditional cytotoxic chemotherapy may improve imatinib efficacy. We conducted a Phase I study of imatinib in combination with paclitaxel in patients with advanced or metastatic solid tumors.
  
  
  METHODS
  Patients were accrued to the study in a standard 3 + 3 design. Patients were restaged every two cycles, and those with stable disease (SD), or better, continued study treatment without interruption. Maximally tolerated doses (MTDs) and pharmacokinetic profiles of combination imatinib and paclitaxel were assessed.
  
  
  RESULTS
  Fifty-eight patients were enrolled, including 40 in the Phase I dose escalation portion. Alternating dose escalation of imatinib and paclitaxel on a 28-day cycle resulted in MTDs of 800 mg imatinib daily, on days 1-4, 8-11, 15-18, and 22-25, and 100 mg/m(2) paclitaxel weekly, on days 3, 10, and 17. Two expansion cohorts, comprising 10 breast cancer patients and 8 patients with soft-tissue sarcomas, were enrolled at the MTDs. The most common adverse events were flu-like symptoms (64 %) and nausea/vomiting (71 %). The most common Grade 3/4 toxicities were neutropenia (26 %), flu-like symptoms (12 %), and pain (12 %). There were no relevant differences in the pharmacokinetic profiles of either drug when given in combination compared with alone. Thirty-eight subjects were evaluable for response, 18 (47.4 %) of whom experienced clinical benefit. Five patients (13.2 %) had a partial response (PR) and 13 patients (34.2 %) had SD; the average time to progression in those with clinical benefit was 17 weeks (range: 7-28 weeks).
  
  
  CONCLUSIONS
  This combination of imatinib and paclitaxel was reasonably safe and tolerable, and demonstrated evidence of anti-tumor activity. Further exploration in disease-specific Phase II trials is warranted.
authors.affiliation: Lombardi Comprehensive Cancer Center, Developmental Therapeutics Program, Washington, DC 20007, USA. pishvaim@georgetown.edu
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Pishvaian
authors.forename: Rebecca
authors.initials: R
authors.lastname: Slack
authors.forename: Eunice Y
authors.initials: EY
authors.lastname: Koh
authors.forename: Jan H
authors.initials: JH
authors.lastname: Beumer
authors.forename: Marion L
authors.initials: ML
authors.lastname: Hartley
authors.forename: Ion
authors.initials: I
authors.lastname: Cotarla
authors.forename: John
authors.initials: J
authors.lastname: Deeken
authors.forename: Aiwu Ruth
authors.initials: AR
authors.lastname: He
authors.forename: Jimmy
authors.initials: J
authors.lastname: Hwang
authors.forename: Shakun
authors.initials: S
authors.lastname: Malik
authors.forename: Kashif
authors.initials: K
authors.lastname: Firozvi
authors.forename: Minetta
authors.initials: M
authors.lastname: Liu
authors.forename: Beth
authors.initials: B
authors.lastname: Elston
authors.forename: Sandy
authors.initials: S
authors.lastname: Strychor
authors.forename: Merrill J
authors.initials: MJ
authors.lastname: Egorin
authors.forename: John L
authors.initials: JL
authors.lastname: Marshall
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D001549:Benzamides; D017024:Chemotherapy, Adjuvant; D015331:Cohort Studies; D018450:Disease Progression; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology* / Q000532:radiotherapy / Q000601:surgery; D009503:Neutropenia / Q000139:chemically induced; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D018714:Radiotherapy, Adjuvant; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D017239:Paclitaxel