title: A phase I pharmacokinetic and pharmacodynamic study of intravenous calcitriol in combination with oral gefitinib in patients with advanced solid tumors.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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 mug/wk of calcitriol. One of seven patients developed dose-limiting hypercalcemia at the MTD 74 mug/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 mug calcitriol exceed in vivo concentrations associated with antitumor activity in preclinical models.
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute and the University at Buffalo, NY 14263, USA. marwan.fakih@roswellpark.org
authors.forename: Marwan G
authors.initials: MG
authors.lastname: Fakih
authors.forename: Donald L
authors.initials: DL
authors.lastname: Trump
authors.forename: Josephia R
authors.initials: JR
authors.lastname: Muindi
authors.forename: Jennifer D
authors.initials: JD
authors.lastname: Black
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Bernardi
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Creaven
authors.forename: James
authors.initials: J
authors.lastname: Schwartz
authors.forename: Michael G
authors.initials: MG
authors.lastname: Brattain
authors.forename: Alan
authors.initials: A
authors.lastname: Hutson
authors.forename: Renee
authors.initials: R
authors.lastname: French
authors.forename: Candace S
authors.initials: CS
authors.lastname: Johnson
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002117:Calcitriol / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D004357:Drug Synergism; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D006801:Humans; D007150:Immunohistochemistry; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D010766:Phosphorylation; D011799:Quinazolines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D011799:Quinazolines; D066246:ErbB Receptors; D002117:Calcitriol; D000077156:Gefitinib