A Phase i clinical trial of the combination of imatinib and paclitaxel in patients with advanced or metastatic solid tumors refractory to standard therapy

Michael J. Pishvaian, Rebecca Slack, Eunice Y. Koh, Jan H. Beumer, Marion L. Hartley, Ion Cotarla, John Deeken, Aiwu Ruth He, Jimmy Hwang, Shakun Malik, Kashif Firozvi, Minetta Liu, Beth Elston, Sandy Strychor, Merrill J. Egorin, John L. Marshall

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Purpose 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/m2 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 diseasespecific Phase II trials is warranted.

Original languageEnglish (US)
Pages (from-to)843-853
Number of pages11
JournalCancer chemotherapy and pharmacology
Volume70
Issue number6
DOIs
StatePublished - Dec 2012

Keywords

  • Imatinib
  • Paclitaxel
  • Phase I

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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    Pishvaian, M. J., Slack, R., Koh, E. Y., Beumer, J. H., Hartley, M. L., Cotarla, I., Deeken, J., He, A. R., Hwang, J., Malik, S., Firozvi, K., Liu, M., Elston, B., Strychor, S., Egorin, M. J., & Marshall, J. L. (2012). A Phase i clinical trial of the combination of imatinib and paclitaxel in patients with advanced or metastatic solid tumors refractory to standard therapy. Cancer chemotherapy and pharmacology, 70(6), 843-853. https://doi.org/10.1007/s00280-012-1969-9