A phase i trial to determine the safety, pharmacokinetics, and pharmacodynamics of intercalated BMS-690514 with paclitaxel/carboplatin (PC) in advanced or metastatic solid malignancies

Laura Q.M. Chow, Derek I. Jonker, Grace K. Dy, Garth Nicholas, Catherine Fortin, Daniel Patricia, Alex A. Adjei, Chandra P. Belani, Ashok Gupta, Jong Soon Park, Steven Zhang, Eric I. Sbar, Scott A. Laurie

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Purpose: A phase I dose escalation study was performed to determine the maximum tolerated dose (MTD) of intercalated dosing of BMS-690514, a reversible oral panHER/VEGF receptor inhibitor, combined with paclitaxel/carboplatin (PC) in advanced solid tumors. Secondary endpoints included safety, pharmacokinetics (PK), exploratory pharmacodynamics (PD), and preliminary efficacy. Experimental design: Patients received fixed doses of P (200 mg/m2) and C (AUC 6 mg/mL min) q21 days with intercalated BMS-690514 (Days 4-19) starting at 100 mg/day and increasing by 50 mg/day using a 3 + 3 dose escalation design until the MTD was reached. Twenty additional patients were enrolled in the expansion cohort at the recommended phase II dose (RP2D). Results: The MTD was reached at 150 mg/day. DLTs included grade 3 thrombosis at 100 mg (1 patient) and grade 3 diarrhea at 150 mg (1 patient) and 200 mg (2 patients). Serious adverse events (AEs) occurring in 20/37 patients included neutropenia (n = 5), diarrhea (n = 4), pulmonary embolism (n = 3), and simultaneous dehydration, acute renal failure, and febrile neutropenia (n = 2). BMS-690514-related AEs included diarrhea (97 %), acneiform rash (60 %), fatigue (43 %), nausea (30 %), and anorexia (30 %). There were no treatment-related deaths. Sequential intermittent administration of PC did not affect the PK of BMS-690514. Of the 32 patients evaluable for efficacy, there were 12 partial responses including five patients with non-small-cell lung cancer and 12 patients with stable disease. Conclusions: The MTD of intercalated BMS-609514 combined with PC was 150 mg/day. This approach was tolerable with manageable toxicities and antitumor activity in a variety of solid tumor types.

Original languageEnglish (US)
Pages (from-to)1273-1285
Number of pages13
JournalCancer chemotherapy and pharmacology
Volume71
Issue number5
DOIs
StatePublished - May 2013

Keywords

  • BMS-690514
  • EGFR
  • Intercalated therapy
  • Paclitaxel/carboplatin
  • Phase I
  • Solid malignancies
  • Tyrosine kinase inhibitor
  • VEGFR

ASJC Scopus subject areas

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

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