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A phase I and pharmacokinetics study of intravenous calcitriol in combination with oral dexamethasone and gefitinib in patients with advanced solid tumors

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Abstract

Purpose

The primary objective of this study was to determine the maximum tolerated dose (MTD) of intravenously (i.v.) calcitriol administered in combination with a fixed oral dose of dexamethasone and gefitinib in patients with refractory solid tumors.

Methods

A fixed oral dose of dexamethasone of 4 mg/day was given every 12 h × 3 doses starting 12 h prior to i.v. calcitriol administration. Calcitriol was administered i.v. over 1 h on weeks 1, 3, and weekly thereafter. The starting calcitriol dose level was 57 μg and escalation occurred in cohorts of three patients until the MTD was defined. Gefitinib was given at a fixed oral daily dose of 250 mg starting at week 2 (day 8). Serum calcitriol PK studies were performed on day 1 (calcitriol + dexamethasone) and on day 15 (calcitriol + dexamethasone + gefitinib).

Results

A total of 20 patients were treated. Dose-limiting hypercalcemia was observed in two out of the four patients receiving 163 mcg/week of calcitriol. Mean (±SE) peak serum calcitriol concentration (C max) at the MTD (125 μg/week calcitriol) was 11.17 ± 2.62 ng/ml and the systemic exposure (AUC0–72 h) of 53.30 ± 10.49 ng h/ml. The relationship between calcitriol dose and either C max or AUC was linear over the 57–163 μg dose range.

Conclusions

The addition of a low dose of dexamethasone allowed the safe escalation of calcitriol to the MTD of 125 μg/week. This dose level resulted in serum calcitriol concentrations that are associated with pre-clinical antitumor activity. However, no antitumor activity was noted clinically in patients with solid tumors.

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References

  1. Tsuchiya H, Morishita H, Tomita K, Ueda Y, Tanaka M (1993) Differentiating and antitumor activities of 1α, 25-dihydroxyvitamin D3 in vitro and 1 α-hydroxyvitamin D3 in vivo on human osteosarcoma. J Orthop Res 11:122–130

    Article  PubMed  CAS  Google Scholar 

  2. Testa U, Masciulli R, Tritarelli E, Pustorino R, Mariani G, Martucci R, Barberi T, Camagna A, Valtieri M, Peschle C (1993) Transforming growth factor-ß potentiates vitamin D3-induced terminal monocytic differentiation of human leukemic cell lines. J Immunol 150:2418–2430

    PubMed  CAS  Google Scholar 

  3. Eisman JA, Barkla DH, Tutton PJ (1987) Suppression of in vivo growth of human cancer solid tumor xenografts by 1, 25-dihydroxyvitamin D3. Cancer Res 47:21–25

    PubMed  CAS  Google Scholar 

  4. Chung I, Wong MK, Flynn G, Yu WD, Johnson CS, Trump DL (2006) Differential antiproliferative effects of calcitriol on tumor-derived and matrigel-derived endothelial cells. Cancer Res 66:8565–8573

    Article  PubMed  CAS  Google Scholar 

  5. Hershberger PA, Modzelewski RA, Shurin ZR, Rueger RM, Trump DL, Johnson CS (1999) 1, 25-dihydroxycholecalciferal (1, 25–D3) inhibits the growth of squamous cell carcinoma and down-modulates p21 (waf1/Cip1) in vitro and in vivo. Cancer Res 59:2644–2649

    PubMed  CAS  Google Scholar 

  6. Bernardi RJ, Trump DL, Yu WD, McGuire TF, Hershberger PA, Johnson CS (2001) Combination of 1α, 25-dihydroxyvitamin D3 with dexamethasone enhances cell cycle arrest and apoptosis: role of nuclear receptor cross-talk and Erk/Akt signaling. Clin Cancer Res 7:4164–4173

    PubMed  CAS  Google Scholar 

  7. 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 10:821–829

    Google Scholar 

  8. Wang X, Studzinski GP (2001) Activation of extracellular signal-regulated kinases (ERKs) defines the first phase of 1, 25-dihydroxyvitamin D3-induced differentiation of HL60 cells. J Cell Biochem 80:471–482

    Article  PubMed  CAS  Google Scholar 

  9. Tong WM, Kállay E, Hofer H, Hulla W, Manhardt T, Peterlik M, Cross HS (1998) Growth regulation of human colon cancer cells by epidermal growth factor and 1, 25-dihydroxyvitamin D3 is mediated by mutual modulation of receptor expression. Eur J Cancer 34:2119–2125

    Article  PubMed  CAS  Google Scholar 

  10. Bernardi R, Johnson C, Trump D (2002) ZD1839 (Iressa), a selective epidermal growth factor receptor tyrosine kinase inhibitor (EGDR-TKI), enhances the antiproliferative effects of calcitriol (1, 25-dihydroxyvitamin D3) in squamous cell carcinoma: effects on ERK and Akt [abstract 3883]. Proc Am Assoc Cancer Res 43:783

    Google Scholar 

  11. Fakih MG, Trump DL, Muindi JR, Black JD, Bernardi RJ, Creaven PJ, Schwartz J, Brattain MG, Hutson A, French R, Johnson CS (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 13:1216–1223

    Article  PubMed  CAS  Google Scholar 

  12. Davidson TG (2001) Conventional treatment of hypercalcemia of malignancy. Am J Health Syst Pharm 58(Suppl 3):S8–S15

    PubMed  Google Scholar 

  13. Jibani M, Hodges NH (1985) Prolonged hypercalcemia after exposure to vitamin D3. Br Med J 290:748–749

    Article  CAS  Google Scholar 

  14. Klein RG, Arnaud SB, Gallagher JC, Deluca HF, Riggs BL (1977) Intestinal calcium absorption in exogenous hypercortisonism. Role of 25-hydroxyvitamin D and corticosteroid dose. J Clin Invest 60:253–259

    Article  PubMed  CAS  Google Scholar 

  15. Suzuki Y, Ichikawa Y, Saito E, Homma M (1983) Importance of increased urinary calcium excretion in the development of secondary hyperparathyroidism of patients under glucocorticoid therapy. Metabolism 32:151–156

    Article  PubMed  CAS  Google Scholar 

  16. Yu WD, McElwain MC, Modzelewski RA, Russell DM, Smith DC, Trump DL, Johnson CS (1998) Enhancement of 1, 25-dihydroxyvitamin D3-mediated antitumor activity with dexamethasone. J Natl Cancer Inst 90:134–141

    Article  PubMed  CAS  Google Scholar 

  17. Therasse P, Arbuck SG, Eisenhauer EA et al (2000) European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205–216

    Article  PubMed  CAS  Google Scholar 

  18. 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 5:1339–1345

    PubMed  CAS  Google Scholar 

  19. Kane KF, Langman MJ, Williams GR (1996) Antiproliferative responses to two human colon cancer cell lines to vitamin D3 are differently modified by 9-cis-retinoic acid. Cancer Res 56:623–632

    PubMed  CAS  Google Scholar 

  20. Akhter J, Goerdel M, Morris DL (1996) Vitamin D3 analogue (EB 1089) inhibits in vitro cellular proliferation of human colon cancer cells. Br J Surg 83:229–230

    Article  PubMed  CAS  Google Scholar 

  21. Muindi JR, Peng Y, Potter DM, Hershberger PA, Tauch JS, Capozzoli MJ et al (2002) Pharmacokinetics of high dose calcitriol: results obtained during a phase one trial of calcitriol and paclitaxel. Cancer Pharmacol Ther 72:648–659

    Article  CAS  Google Scholar 

  22. Beer TM, Munar M, Henner WD (2001) A phase I trial of pulse calcitriol in patients with refractory malignancies: pulse dosing permits substantial dose escalation. Cancer 91:2431–2439

    Article  PubMed  CAS  Google Scholar 

  23. Beer TM, Javle M, Lam GN, Henner WD, Wong A, Trump DL (2005) Pharmacokinetics and tolerability of a single dose of DN-101, a new formulation of calcitriol, in patients with cancer. Clin Cancer Res 11:7794–7799

    Article  PubMed  CAS  Google Scholar 

  24. Beer TM, Javle MM, Ryan CW, Garzotto M, Lam GN, Wong A, Henner WD, Johnson CS, Trump DL (2007) Phase I study of weekly DN-101, a new formulation of calcitriol, in patients with cancer. Cancer Chemother Pharmacol 59:581–587

    Article  PubMed  CAS  Google Scholar 

  25. Muindi JR, Modzelewski RA, Peng Y, Trump DL, Johnson CS (2004) Pharmacokinetics of 1α, 25-dihydroxyvitamin D3 in normal mice after systemic exposure to effective and safe antitumor doses. Oncology 66:62–66

    Article  PubMed  CAS  Google Scholar 

  26. Ma Y, Yu WD, Hershberger PA, Flynn G, Kong RX, Trump DL, Johnson CS (2008) 1alpha, 25-Dihydroxyvitamin D3 potentiates cisplatin antitumor activity by p73 induction in a squamous cell carcinoma model. Mol Cancer Ther 7:3047–3055

    Article  PubMed  CAS  Google Scholar 

  27. Hershberger PA, Yu WD, Modzelewski RA, Rueger RM, Johnson CS, Trump DL (2001) Calcitriol (1, 25-dihydroxycholecalciferol) enhances paclitaxel antitumor activity in vitro and in vivo and accelerates paclitaxel-induced apoptosis. Clin Cancer Res 7:1043–1051

    PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by Grants CA67267, CA85142, CA63502, and CA95045 from the NIH and career development award MRSG-04-270-01 to Marwan G. Fakih from the American Cancer Society.

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Authors and Affiliations

  1. Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA

    Josephia R. Muindi, Donald L. Trump, Renee Christy, Kristie L. Engler & Marwan G. Fakih

  2. Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA

    Candace S. Johnson

Authors
  1. Josephia R. Muindi
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  2. Candace S. Johnson
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  3. Donald L. Trump
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  4. Renee Christy
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  5. Kristie L. Engler
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  6. Marwan G. Fakih
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Correspondence to Marwan G. Fakih.

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Muindi, J.R., Johnson, C.S., Trump, D.L. et al. 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, 33–40 (2009). https://doi.org/10.1007/s00280-009-1000-2

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  • DOI: https://doi.org/10.1007/s00280-009-1000-2

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