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A Phase I Pharmacokinetic and Pharmacodynamic Study of Intravenous Calcitriol in Combination with Oral Gefitinib in Patients with Advanced Solid Tumors

Authors' Affiliations: Departments of ¹ Medicine and ² Biostatistics, Roswell Park Cancer Institute and the University at Buffalo; ³ Department of Pharmacology, Roswell Park Cancer Institute, Buffalo, New York; and ⁴ Department of Pediatrics, Baylor College of Medicine, Houston, Texas

Requests for reprints: Marwan G. Fakih, Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. Phone: 716-845-8189 or 716-845-3362; Fax: 716-845-8008; E-mail: marwan.fakih{at}roswellpark.org.

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 (C_max) and systemic exposure (AUC) was linear. Mean (±SD) serum calcitriol C_max 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.

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