Cancer Chemotherapy and Pharmacology

, Volume 71, Issue 5, pp 1173–1182

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
Original Article

DOI: 10.1007/s00280-013-2109-x

Cite this article as:
Ramnath, N., Daignault-Newton, S., Dy, G.K. et al. Cancer Chemother Pharmacol (2013) 71: 1173. doi:10.1007/s00280-013-2109-x

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/m2 and cisplatin 75 mg/m2 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/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.

Keywords

Calcitriol Lung cancer CYP24A1-SNPs 

Supplementary material

280_2013_2109_MOESM1_ESM.docx (20 kb)
Supplementary material 1 (DOCX 19 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • N. Ramnath
    • 1
    • 3
  • S. Daignault-Newton
    • 2
  • G. K. Dy
    • 4
  • J. R. Muindi
    • 4
  • A. Adjei
    • 4
  • V. L. Elingrod
    • 5
  • G. P. Kalemkerian
    • 1
  • K. B. Cease
    • 1
    • 3
  • P. J. Stella
    • 6
  • D. E. Brenner
    • 1
    • 3
  • S. Troeschel
    • 3
  • C. S. Johnson
    • 4
  • D. L. Trump
    • 4
  1. 1.Division of Medical Oncology, Department of Internal MedicineUniversity of Michigan Comprehensive Cancer CenterAnn ArborUSA
  2. 2.Biostatistics Core, Comprehensive Cancer CenterUniversity of MichiganAnn ArborUSA
  3. 3.Veterans Administration Ann Arbor Healthcare SystemAnn ArborUSA
  4. 4.Departments of Medicine and PharmacologyRoswell Park Cancer InstituteBuffaloUSA
  5. 5.College of PharmacyUniversity of MichiganAnn ArborUSA
  6. 6.St. Joseph’s HospitalAnn ArborUSA

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