A phase I/II pharmacokinetic and pharmacogenomic study of calcitriol in combination with cisplatin and docetaxel in advanced non-small-cell lung cancer

N. Ramnath, S. Daignault-Newton, G. K. Dy, J. R. Muindi, A. Adjei, V. L. Elingrod, G. P. Kalemkerian, K. B. Cease, P. J. Stella, D. E. Brenner, S. Troeschel, C. S. Johnson, D. L. Trump

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

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-D 3 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/m2 and cisplatin 75 mg/m2 using standard 3 + 3 design, targeting dose-limiting toxicity (DLT) rate <33 %. Dose levels of 1,25-D 3 were 30, 45, 60, and 80 mcg/m2. 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/m2, 2/4 patients had DLTs of grade 4 neutropenia. Hypercalcemia was not observed. The RP2D of 1,25-D3 was 60 mcg/m2. 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/m2 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.

Original languageEnglish (US)
Pages (from-to)1173-1182
Number of pages10
JournalCancer chemotherapy and pharmacology
Volume71
Issue number5
DOIs
StatePublished - May 2013

Keywords

  • CYP24A1-SNPs
  • Calcitriol
  • Lung cancer

ASJC Scopus subject areas

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

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