Rationally designed treatment for solid tumors with MAPK pathway activation: a phase I study of paclitaxel and bortezomib using an adaptive dose-finding approach

Mol Cancer Ther. 2011 Aug;10(8):1509-19. doi: 10.1158/1535-7163.MCT-10-0944. Epub 2011 Jun 16.

Abstract

In the preclinical setting, phosphorylation and subsequent proteosomal degradation of the proapoptotic protein BIM confers resistance to paclitaxel in solid tumors with RAS/RAF/MAPK pathway activation. Concurrent administration of the proteasome inhibitor bortezomib enables paclitaxel-induced BIM accumulation, restoring cancer cell apoptosis in vitro and producing tumor regression in mice in vivo. A phase I study was conducted to determine the maximum tolerated dose (MTD) of paclitaxel and bortezomib combinatorial treatment. Sixteen patients with refractory solid tumors commonly exhibiting mitogen-activated protein kinase (MAPK) pathway activation were treated weekly with paclitaxel and bortezomib. Starting doses were 40 mg/m(2) for paclitaxel and 0.7 mg/m(2) for bortezomib. A modified continual reassessment method adapted for 2-drug escalation was used for MTD determination with 3-patient cohorts treated at each dose level. MTD was reached at 60 mg/m(2) paclitaxel and 1.0 mg/m(2) bortezomib, the recommended phase II dose. Therapy was overall well tolerated. Most frequently observed toxicities included anemia (in 43.75% of patients, one grade 3 event), fatigue (in 43.75% of patients, one grade 3 event beyond cycle 1), and neuropathy (in 31.25% of patients, one grade 3 event after cycle 1). Of 15 evaluable patients, one non-small-cell lung carcinoma (NSCLC) patient with paclitaxel exposure at the adjuvant setting had a partial response and five patients had stable disease (SD); median disease stabilization was 143.5 days; three NSCLC patients had SD lasting 165 days or longer. Thus, rationally designed weekly treatment with paclitaxel and bortezomib in solid tumors with MAPK pathway activation, including previously taxane-treated malignancies, is a tolerable regimen with preliminary signals of antitumor activity worthy of further investigation.

Publication types

  • Clinical Trial, Phase I
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Boronic Acids / administration & dosage*
  • Bortezomib
  • Female
  • Humans
  • MAP Kinase Signaling System / drug effects*
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Mitogen-Activated Protein Kinases / metabolism
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Paclitaxel / administration & dosage*
  • Pyrazines / administration & dosage*
  • Treatment Outcome

Substances

  • Boronic Acids
  • Pyrazines
  • Bortezomib
  • Mitogen-Activated Protein Kinases
  • Paclitaxel