title: A phase I/II pharmacokinetic and pharmacogenomic study of calcitriol in combination with cisplatin and docetaxel in advanced non-small-cell lung cancer.
abstract: BACKGROUND
  Preclinical studies demonstrated antiproliferative synergy of 1,25-D3 (calcitriol) with cisplatin. The goals of this phase I/II study were to determine the recommended phase II dose (RP2D) of 1,25-D3 with cisplatin and docetaxel and its efficacy in metastatic non-small-cell lung cancer.
  
  
  METHODS
  Patients were ≥18 years, PS 0-1 with normal organ function. In the phase I portion, patients received escalating doses of 1,25-D3 intravenously every 21 days prior to docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) using standard 3 + 3 design, targeting dose-limiting toxicity (DLT) rate <33 %. Dose levels of 1,25-D3 were 30, 45, 60, and 80 mcg/m(2). A two-stage design was employed for phase II portion. We correlated CYP24A1 tagSNPs with clinical outcome and 1,25-D3 pharmacokinetics (PK).
  
  
  RESULTS
  34 patients were enrolled. At 80 mcg/m(2), 2/4 patients had DLTs of grade 4 neutropenia. Hypercalcemia was not observed. The RP2D of 1,25-D3 was 60 mcg/m(2). Among 20 evaluable phase II patients, there were 2 confirmed, 4 unconfirmed partial responses (PR), and 9 stable disease (SD). Median time to progression was 5.8 months (95 % CI 3.4, 6.5), and median overall survival 8.7 months (95 % CI 7.6, 39.4). CYP24A1 SNP rs3787554 (C > T) correlated with disease progression (P = 0.03) and CYP24A1 SNP rs2762939 (C > G) trended toward PR/SD (P = 0.08). There was no association between 1,25-D3 PK and CYP24A1 SNPs.
  
  
  CONCLUSIONS
  The RP2D of 1,25-D3 with docetaxel and cisplatin was 60 mcg/m(2) every 21 days. Pre-specified endpoint of 50 % confirmed RR was not met in the phase II study. Functional SNPs in CYP24A1 may inform future studies individualizing 1,25-D3.
authors: Division of Medical Oncology, Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA. nithyar@umich.edu
authors: N
authors: N
authors: Ramnath
authors: S
authors: S
authors: Daignault-Newton
authors: G K
authors: GK
authors: Dy
authors: J R
authors: JR
authors: Muindi
authors: A
authors: A
authors: Adjei
authors: V L
authors: VL
authors: Elingrod
authors: G P
authors: GP
authors: Kalemkerian
authors: K B
authors: KB
authors: Cease
authors: P J
authors: PJ
authors: Stella
authors: D E
authors: DE
authors: Brenner
authors: S
authors: S
authors: Troeschel
authors: C S
authors: CS
authors: Johnson
authors: D L
authors: DL
authors: Trump
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D002117:Calcitriol / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage; D018450:Disease Progression; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D013250:Steroid Hydroxylases / Q000235:genetics*; D015996:Survival Rate; D043823:Taxoids / Q000008:administration & dosage; D016896:Treatment Outcome; D065668:Vitamin D3 24-Hydroxylase
chemical_list: D043823:Taxoids; D000077143:Docetaxel; D013250:Steroid Hydroxylases; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol; D002945:Cisplatin