title: Final safety and efficacy analysis of a phase I/II trial with imatinib and vinorelbine for patients with metastatic breast cancer.
abstract: BACKGROUND
  Imatinib is a tyrosine kinase inhibitor of BCR-ABL, ABL, PDGFR-α and -β, KIT, and DDR. In solid tumors, it inhibits proliferation and invasiveness and facilitates higher intratumoral cytotoxic drug concentrations. Vinorelbine has good tolerability and efficacy in metastatic breast cancer (MBC). This study evaluates the safety and efficacy of imatinib and vinorelbine in combination.
  
  
  METHODS
  In a prospective, open-label, phase I/II trial, 400 mg imatinib p.o. daily (corrected from 600 mg) was combined with an escalating dose of vinorelbine i.v. weekly in four dose levels of 10, 15, 20, and 25 mg/m(2) (each n ≥ 5) to treat patients with MBC (expressing PDGFR-α and/or -β, and/or KIT). The last patient of each level was treated for >28 days, before enrolment for the next dose level started. Study endpoints were feasibility and tolerability, incidence of hematological and nonhematological toxicity, and clinical efficacy (data cutoff: November 18, 2011). A total of 33 patients have been enrolled, and all dose levels have been fully recruited. One patient is still on study medication. A translational subprotocol is ongoing.
  
  
  RESULTS
  All 33 included patients are evaluable for safety (32 within the ITT population). Eleven patients were excluded early from the study (progressive disease, toxicity, and withdrawal of consent). Twenty-two patients participated in the study for >28 days ('ITT >28'). Within the ITT population, the response rate [complete response (CR) and partial response (PR)] was 9.4% (n = 3), the clinical benefit rate (CBR; CR+PR+stable disease) 50% (n = 16), and the median time to progression (TTP) 155 days. A total of 21.3% of the patients were on study medication for >6 months, and 15.2% for >12 months (mean 140 days, range 15-643). Within 'ITT >28', the response rate was 13.6%, CBR 72.7%, and median TTP 176 days. The response was independent of the receptor status (PDGFR-α, -β, and KIT). Toxicities were as follows (safety population): 21.6% severe leukopenia, 9.1% severe neutropenia (with 1 febrile neutropenia), 1 case of bowel perforation, 36% diarrhea (3% severe), 84.8% nausea (severe 15.2%), 48.5% vomiting (severe 9.1%), 27.3% infections (severe 6.1%), 12.1% peripheral neuropathy (severe 9.1%), and 36.4% dyspnea (3% severe). Four patients on trial died (nondrug-related).
  
  
  CONCLUSIONS
  The combination of imatinib and vinorelbine in MBC appeared to be feasible and tolerable. A CBR of 50% (ITT) in pretreated patients suggests that this combination may be active. Although toxicities were frequent, they appeared to be manageable.
authors.affiliation: OB/GYN, Breast Unit, University Hospital of Schleswig-Holstein, University of Kiel, Kiel, Germany.
authors.forename: Nicolai
authors.initials: N
authors.lastname: Maass
authors.forename: Christian
authors.initials: C
authors.lastname: Schem
authors.forename: Dirk O
authors.initials: DO
authors.lastname: Bauerschlag
authors.forename: Katharina
authors.initials: K
authors.lastname: Tiemann
authors.forename: Fritz W
authors.initials: FW
authors.lastname: Schaefer
authors.forename: Sven
authors.initials: S
authors.lastname: Hanson
authors.forename: Mathias
authors.initials: M
authors.lastname: Muth
authors.forename: Monika
authors.initials: M
authors.lastname: Baier
authors.forename: Marion T
authors.initials: MT
authors.lastname: Weigel
authors.forename: Antonia S
authors.initials: AS
authors.lastname: Wenners
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Alkatout
authors.forename: Maret
authors.initials: M
authors.lastname: Bauer
authors.forename: Walter
authors.initials: W
authors.lastname: Jonat
authors.forename: Christoph
authors.initials: C
authors.lastname: Mundhenke
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001549:Benzamides / Q000008:administration & dosage / Q000009:adverse effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects; D011446:Prospective Studies; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects; D014747:Vinblastine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D000077235:Vinorelbine
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D014747:Vinblastine; D000068877:Imatinib Mesylate; D000077235:Vinorelbine