A phase I pharmacokinetic and pharmacodynamic study of intravenous calcitriol in combination with oral gefitinib in patients with advanced solid tumors

Marwan G. Fakih, Donald L. Trump, Josephia R. Muindi, Jennifer D. Black, Ronald J. Bernardi, Patrick J. Creaven, James Schwartz, Michael G. Brattain, Alan Hutson, Renee French, Candace S. Johnson

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

Abstract

Purpose: In preclinical models, calcitriol and the tyrosine kinase inhibitor gefitinib are synergistic and modulate extracellular signal-regulated kinase (Erk) and Akt pathways. Therefore, we conducted a phase I study of calcitriol and gefitinib to determine the maximum tolerated dose (MTD) of this combination. Experimental Design: Calcitriol was given i.v. over 1 h on weeks 1, 3, and weekly thereafter. Gefitinib was given at a fixed oral daily dose of 250 mg starting at week 2 (day 8). Escalation occurred in cohorts of three patients until the MTD was defined. Pharmacokinetic studies were done for calcitriol and gefitinib. Serial skin biopsies were done to investigate epidermal growth factor receptor (EGFR) pathway pharmacodynamic interactions. Results: Thirty-two patients were treated. Dose-limiting hypercalcemia was noted in two of four patients receiving 96 μg/wk of calcitriol. One of seven patients developed dose-limiting hypercalcemia at the MTD 74 μg/wk calcitriol dose level. The relationship between calcitriol dose and peak serum calcitriol (Cmax) and systemic exposure (AUC) was linear. Mean (±SD) serum calcitriol Cmax at the MTD was 6.68 ± 1.42 ng/mL. Gefitinib treatment inhibited EGFR, Akt, and Erk phosphorylation in the skin. Calcitriol did not have consistent effects on skin EGFR or its downstream elements. The combination of gefitinib and calcitriol did not modulate tumor EGFR pathway in patients with serial tumor biopsies. Conclusions: High doses of weekly i.v. calcitriol can be administered safely in combination with gefitinib. Calcitriol concentrations achieved at the MTD 74 μg calcitriol exceed in vivo concentrations associated with antitumor activity in preclinical models.

Original languageEnglish (US)
Pages (from-to)1216-1223
Number of pages8
JournalClinical Cancer Research
Volume13
Issue number4
DOIs
StatePublished - Feb 15 2007

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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