Phase I, pharmacogenomic, drug interaction study of sorafenib and bevacizumab in combination with paclitaxel in patients with advanced refractory solid tumors

E. Gabriela Chiorean*, Susan M. Perkins, R. Matthew Strother, Anne Younger, Jennifer M. Funke, Safi G. Shahda, Noah M. Hahn, Kumar Sandrasegaran, David R. Jones, Todd C. Skaar, Bryan P. Schneider, Christopher J. Sweeney, Daniela E. Matei

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

VEGF blockade does not uniformly result in clinical benefit. We evaluated safety, dose-limiting toxicities (DLT), recommended phase II dose (RP2D), antitumor efficacy, and exploratory biomarkers including pharmacogenomics and pharmacokinetics with sorafenib, bevacizumab, and paclitaxel in patients with refractory cancers. The study had a “3 þ 3” design, using paclitaxel 80 mg/m2 every week for 3 weeks, in every 4 week cycles, bevacizumab 5 mg/kg every 2 weeks, and sorafenib 200 or 400 mg twice a day, 5 or 7 days/week (5/7, 7/7). The MTD cohort was expanded. Twenty-seven patients enrolled in 3 cohorts: sorafenib 200 mg twice a day 5/7, 200 mg twice a day 7/7, and 400 mg twice a day 5/7. DLTs were grade 3 neutropenia >7 days (cohort 1, 1), grade 3 hypertension (cohort 2, 1), grade 3 hand–foot skin reaction (HFSR; cohort 3, 2). MTD was sorafenib 200 mg twice a day 7/7. Six DLTs occurred in cohort 2 expansion: grade 3 HFSR (2), grade 2 HFSR with sorafenib delay >7 days (2), grade 4 cerebrovascular accident (1), grade 3 neutropenia >7 days (1). RP2D was sorafenib 200 mg twice a day 5/7. Most patients (62%) dose reduced sorafenib to 200 mg daily 5/7 after a median 3 (range, 2–17) cycles. Response rates were 48% overall (27) and 64% for ovarian cancers (14). VEGF-A-1154AA and -7TT recessive homozygous genotypes conferred worse overall survival versus alternative genotypes (7 vs. 22 months). Intermittent, low-dose sorafenib (200 mg twice a day 5/7) combined with bevacizumab and paclitaxel was tolerable and had high antitumor efficacy in patients with refractory cancer (NCT00572078).

Original languageEnglish (US)
Pages (from-to)2155-2162
Number of pages8
JournalMolecular cancer therapeutics
Volume19
Issue number10
DOIs
StatePublished - Oct 1 2020
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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