A phase I clinical, pharmacokinetic, and pharmacodynamic study of weekly or every three week ixabepilone and daily sunitinib in patients with advanced solid tumors

Alberto J. Montero, Deukwoo Kwon, Aurea Flores, Krisztina Kovacs, Jonathan Trent, Pasquale W Benedetto, Caio Rocha-Lima, Jaime R Merchan

Research output: Contribution to journalArticle

3 Citations (Scopus)

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/m2; schedule B: 20, 30, or 40 mg/m2), 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.

Original languageEnglish (US)
Pages (from-to)3209-3217
Number of pages9
JournalClinical Cancer Research
Volume22
Issue number13
DOIs
StatePublished - Jul 1 2016

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Appointments and Schedules
Pharmacokinetics
Neoplasms
Colorectal Neoplasms
sunitinib
ixabepilone
Leukopenia
Fatigue
Half-Life
Research Design
Safety

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

A phase I clinical, pharmacokinetic, and pharmacodynamic study of weekly or every three week ixabepilone and daily sunitinib in patients with advanced solid tumors. / Montero, Alberto J.; Kwon, Deukwoo; Flores, Aurea; Kovacs, Krisztina; Trent, Jonathan; Benedetto, Pasquale W; Rocha-Lima, Caio; Merchan, Jaime R.

In: Clinical Cancer Research, Vol. 22, No. 13, 01.07.2016, p. 3209-3217.

Research output: Contribution to journalArticle

Montero, Alberto J. ; Kwon, Deukwoo ; Flores, Aurea ; Kovacs, Krisztina ; Trent, Jonathan ; Benedetto, Pasquale W ; Rocha-Lima, Caio ; Merchan, Jaime R. / A phase I clinical, pharmacokinetic, and pharmacodynamic study of weekly or every three week ixabepilone and daily sunitinib in patients with advanced solid tumors. In: Clinical Cancer Research. 2016 ; Vol. 22, No. 13. pp. 3209-3217.
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AU - Kwon, Deukwoo

AU - Flores, Aurea

AU - Kovacs, Krisztina

AU - Trent, Jonathan

AU - Benedetto, Pasquale W

AU - Rocha-Lima, Caio

AU - Merchan, Jaime R

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AB - 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/m2; schedule B: 20, 30, or 40 mg/m2), 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.

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