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

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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.

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References

  1. Azzoli CG, Temin S, Aliff T, Baker S Jr, Brahmer J, Johnson DH et al (2011) 2011 Focused Update of 2009 American Society of Clinical Oncology Clinical Practice Guideline Update on Chemotherapy for Stage IV Non-Small-Cell Lung Cancer. J Clin Oncol 29(28):3825–3831

    Article  PubMed  Google Scholar 

  2. Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J et al (2002) Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346(2):92–98

    Article  PubMed  CAS  Google Scholar 

  3. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A et al (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355(24):2542–2550

    Article  PubMed  CAS  Google Scholar 

  4. Deeb KK, Trump DL, Johnson CS (2007) Vitamin D signalling pathways in cancer: potential for anticancer therapeutics. Nat Rev Cancer 7(9):684–700

    Article  PubMed  CAS  Google Scholar 

  5. Hershberger PA, McGuire TF, Yu WD, Zuhowski EG, Schellens JH, Egorin MJ et al (2002) Cisplatin potentiates 1,25-dihydroxyvitamin D3-induced apoptosis in association with increased mitogen-activated protein kinase kinase kinase 1 (MEKK-1) expression. Mol Cancer Ther 1(10):821–829

    PubMed  CAS  Google Scholar 

  6. Liu M, Lee MH, Cohen M, Bommakanti M, Freedman LP (1996) Transcriptional activation of the Cdk inhibitor p21 by vitamin D3 leads to the induced differentiation of the myelomonocytic cell line U937. Genes Dev 10(2):142–153

    Article  PubMed  CAS  Google Scholar 

  7. Rassnick KM, Muindi JR, Johnson CS, Balkman CE, Ramnath N, Yu WD et al (2008) In vitro and in vivo evaluation of combined calcitriol and cisplatin in dogs with spontaneously occurring tumors. Cancer Chemother Pharmacol 62(5):881–891

    Article  PubMed  CAS  Google Scholar 

  8. Fakih MG, Trump DL, Muindi JR, Black JD, Bernardi RJ, Creaven PJ et al (2007) A phase I pharmacokinetic and pharmacodynamic study of intravenous calcitriol in combination with oral gefitinib in patients with advanced solid tumors. Clin Cancer Res 13(4):1216–1223

    Article  PubMed  CAS  Google Scholar 

  9. Trump DL, Hershberger PA, Bernardi RJ, Ahmed S, Muindi J, Fakih M et al (2004) Anti-tumor activity of calcitriol: pre-clinical and clinical studies. J Steroid Biochem Mol Biol 89–90(1–5):519–526

    Article  PubMed  Google Scholar 

  10. Muindi JR, Wilson JW, Peng Y, Capozolli MJ, Johnson CS, Trump DL (2003) A limited sampling method for the estimation of serum calcitriol area under the curve in cancer patients. J Clin Pharmacol 43(8):894–900

    Article  PubMed  CAS  Google Scholar 

  11. Smith DC, Johnson CS, Freeman CC, Muindi J, Wilson JW, Trump DL (1999) A Phase I trial of calcitriol (1,25-dihydroxycholecalciferol) in patients with advanced malignancy. Clin Cancer Res 5(6):1339–1345

    PubMed  CAS  Google Scholar 

  12. Muindi JR, Peng Y, Potter DM, Hershberger PA, Tauch JS, Capozzoli MJ et al (2002) Pharmacokinetics of high-dose oral calcitriol: results from a phase 1 trial of calcitriol and paclitaxel. Clin Pharmacol Ther 72(6):648–659

    Article  PubMed  CAS  Google Scholar 

  13. Kepner JL, Chang MN (2004) Samples of exact k-stage group sequential designs for Phase II and Pilot studies. Control Clin Trials 25(3):326–333

    Article  PubMed  Google Scholar 

  14. Fossella F, Pereira JR, von Pawel J, Pluzanska A, Gorbounova V, Kaukel E et al (2003) Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol 21(16):3016–3024

    Article  PubMed  CAS  Google Scholar 

  15. Kubota K, Watanabe K, Kunitoh H, Noda K, Ichinose Y, Katakami N et al (2004) Phase III randomized trial of docetaxel plus cisplatin versus vindesine plus cisplatin in patients with stage IV non-small-cell lung cancer: the Japanese Taxotere Lung Cancer Study Group. J Clin Oncol 22(2):254–261

    Article  PubMed  CAS  Google Scholar 

  16. Muindi JR, Johnson CS, Trump DL, Christy R, Engler KL, Fakih MG (2009) A phase I and pharmacokinetics study of intravenous calcitriol in combination with oral dexamethasone and gefitinib in patients with advanced solid tumors. Cancer Chemother Pharmacol 65(1):33–40

    Article  PubMed  CAS  Google Scholar 

  17. Chen G, Kim SH, King AN, Zhao L, Simpson RU, Christensen PJ et al (2011) CYP24A1 is an independent prognostic marker of survival in patients with lung adenocarcinoma. Clin Cancer Res 17(4):817–826

    Article  PubMed  CAS  Google Scholar 

  18. Freireich EJ, Gehan EA, Rall DP, Schmidt LH, Skipper HE (1966) Quantitative comparison of toxicity of anticancer agents in mouse, rat, hamster, dog, monkey, and man. Cancer Chemother Rep 50(4):219–244

    PubMed  CAS  Google Scholar 

  19. Chadha MK, Tian L, Mashtare T, Payne V, Silliman C, Levine E et al (2010) Phase 2 trial of weekly intravenous 1,25 dihydroxy cholecalciferol (calcitriol) in combination with dexamethasone for castration-resistant prostate cancer. Cancer 116(9):2132–2139

    PubMed  CAS  Google Scholar 

  20. Trump DL, Muindi J, Fakih M, Yu WD, Johnson CS (2006) Vitamin D compounds: clinical development as cancer therapy and prevention agents. Anticancer Res 26(4A):2551–2556

    Google Scholar 

  21. Shen H, Bielak LF, Ferguson JF, Streeten EA, Yerges-Armstrong LM, Liu J et al (2010) Association of the vitamin D metabolism gene CYP24A1 with coronary artery calcification. Arterioscler Thromb Vasc Biol 30(12):2648–2654

    Article  PubMed  CAS  Google Scholar 

  22. Wjst M, Heimbeck I, Kutschke D, Pukelsheim K (2010) Epigenetic regulation of vitamin D converting enzymes. J Steroid Biochem Mol Biol 121(1–2):80–83. doi:10.1016/j.jsbmb.2010.03.056

    Google Scholar 

  23. Muindi JR, Nganga A, Engler KL, Coignet LJ, Johnson CS, Trump DL (2007) CYP24 splicing variants are associated with different patterns of constitutive and calcitriol-inducible CYP24 activity in human prostate cancer cell lines. J Steroid Biochem Mol Biol 103(3–5):334–337

    Article  PubMed  CAS  Google Scholar 

  24. Roff A, Wilson RT (2008) A novel SNP in a vitamin D response element of the CYP24A1 promoter reduces protein binding, transactivation, and gene expression. J Steroid Biochem Mol Biol 112(1–3):47–54

    Article  PubMed  CAS  Google Scholar 

  25. St-Arnaud R, Arabian A, Travers R, Barletta F, Raval-Pandya M, Chapin K et al (2000) Deficient mineralization of intramembranous bone in vitamin D-24-hydroxylase-ablated mice is due to elevated 1,25-dihydroxyvitamin D and not to the absence of 24,25-dihydroxyvitamin D. Endocrinology 141(7):2658–2666

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Supported by grants from the NIH R21CA128193-01-A, VA Merit I01CX000333-02 to NR, UL1RR024986 and University of Michigan’s Cancer Center Support Grant (5 P30 CA46592), by the use of the Cancer Center Clinical Trials Office Core.

Conflict of interest

None.

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Authors and Affiliations

  1. Division of Medical Oncology, Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, 1500 East Medical Center Drive, Ann Arbor, MI, 48109, USA

    N. Ramnath, G. P. Kalemkerian, K. B. Cease & D. E. Brenner

  2. Biostatistics Core, Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA

    S. Daignault-Newton

  3. Veterans Administration Ann Arbor Healthcare System, Ann Arbor, MI, USA

    N. Ramnath, K. B. Cease, D. E. Brenner & S. Troeschel

  4. Departments of Medicine and Pharmacology, Roswell Park Cancer Institute, Buffalo, NY, USA

    G. K. Dy, J. R. Muindi, A. Adjei, C. S. Johnson & D. L. Trump

  5. College of Pharmacy, University of Michigan, Ann Arbor, MI, USA

    V. L. Elingrod

  6. St. Joseph’s Hospital, Ann Arbor, MI, USA

    P. J. Stella

Authors
  1. N. Ramnath
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  2. S. Daignault-Newton
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  3. G. K. Dy
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  4. J. R. Muindi
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  7. G. P. Kalemkerian
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  12. C. S. Johnson
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  13. D. L. Trump
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Correspondence to N. Ramnath.

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Ramnath, N., Daignault-Newton, S., Dy, G.K. et al. A phase I/II pharmacokinetic and pharmacogenomic study of calcitriol in combination with cisplatin and docetaxel in advanced non-small-cell lung cancer. Cancer Chemother Pharmacol 71, 1173–1182 (2013). https://doi.org/10.1007/s00280-013-2109-x

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  • DOI: https://doi.org/10.1007/s00280-013-2109-x

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