A Phase I Clinical, Pharmacokinetic, and Pharmacodynamic Study of Weekly or Every Three Week Ixabepilone and Daily Sunitinib in Patients with Advanced Solid Tumors

Clin Cancer Res. 2016 Jul 1;22(13):3209-17. doi: 10.1158/1078-0432.CCR-15-2184. Epub 2016 Feb 10.

Abstract

Purpose: To evaluate the safety, MTD, pharmacokinetics/pharmacodynamics, and early clinical activity of ixabepilone given either weekly or every 3 weeks in combination with daily sunitinib in patients with advanced solid tumors.

Experimental design: Eligible patients received either weekly (schedule A) or every 3 weeks (schedule B) ixabepilone at escalating doses (schedule A: 7.5, 15, or 20 mg/m(2); schedule B: 20, 30, or 40 mg/m(2)), and oral sunitinib (37.5 mg daily), starting on day 8 of cycle 1. Dose-limiting toxicities (DLT) were assessed during cycle 1.

Results: The ixabepilone and sunitinib combination was fairly well tolerated. DLTs were observed in 3 subjects (1 in schedule 3A and 2 in schedule 3B). The most common grade 3-4 hematologic and nonhematologic adverse events were leukopenia and fatigue, respectively. Four patients (3 in schedule A) achieved a partial response, while 13 patients had stable disease. Nine of 17 heavily pretreated colorectal cancer patients had clinical benefit. Coadministration of sunitinib with ixabepilone on a weekly (but not every 3 week) schedule was associated with a significant increase in the half-life and a significant decrease in the clearance of ixabepilone. Correlative studies demonstrated a significant association between higher baseline plasma angiogenic activity (PAA) and clinical benefit in schedule A patients. Weekly, but not every 3 weeks, ixabepilone led to a significant decrease in PAA postbaseline.

Conclusions: Coadministration of ixabepilone with sunitinib has acceptable toxicity and encouraging clinical activity in heavily pretreated patients, particularly in patients with metastatic colorectal cancer. Clin Cancer Res; 22(13); 3209-17. ©2016 AACR.

Publication types

  • Clinical Trial, Phase I

MeSH terms

  • Adult
  • Aged
  • Angiogenesis Inhibitors / pharmacokinetics
  • Angiogenesis Inhibitors / therapeutic use*
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / therapeutic use*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacokinetics
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Biomarkers, Tumor / blood
  • Drug Administration Schedule
  • Epothilones / administration & dosage
  • Epothilones / pharmacokinetics*
  • Epothilones / therapeutic use*
  • Female
  • Humans
  • Indoles / administration & dosage
  • Indoles / pharmacokinetics*
  • Indoles / therapeutic use*
  • Male
  • Middle Aged
  • Neoplasms / drug therapy*
  • Neovascularization, Pathologic / drug therapy
  • Pyrroles / administration & dosage
  • Pyrroles / pharmacokinetics*
  • Pyrroles / therapeutic use*
  • Sunitinib
  • Tubulin Modulators / pharmacokinetics
  • Tubulin Modulators / therapeutic use*

Substances

  • Angiogenesis Inhibitors
  • Antineoplastic Agents
  • Biomarkers, Tumor
  • Epothilones
  • Indoles
  • Pyrroles
  • Tubulin Modulators
  • ixabepilone
  • Sunitinib