Chemotherapy Studies that Involve Taxol(Paclitaxel) in various combinations & taxol with high dose pulsed calcitriol

This page covers the following protocols:

• Taxol plus Emcyt. Table 1.

• Taxol (paclitaxel), carboplatin,  Estramustine Phosphate(Emcyt). Table 2.

• Taxol and High Dose Calcitriol Combinations.

See also Chemo Update on Taxol and Taxol vs taxotere for additional information on Taxol.

The case for taxol and high dose pulsed administration of calcitriol is rather weak. 

Taxol has been combined with calcitriol in only one phase I clinical trial.  There are also pre-clinical studies.   

Table 1. Taxol (paclitaxel), ± Estramustine Phosphate(Emcyt). 

a. The authors also list the Median PFS 10.1 mo for Arm A and 9.7 mo for Arm B.  The Median OS 20.3 mos for Arm A vs  15.9 mos for Arm B.

(1)Vaughn DJ, Brown AW Jr, Harker WG, Huh S, Miller L, Rinaldi D, Kabbinavar F. Multicenter Phase II study of estramustine phosphate plus weekly paclitaxel in patients with androgen-independent prostate carcinoma, Cancer. 2004 Feb 15;100(4):746-50.

 (2)Berry WR, Hathorn JW, Dakhil SR, Loesch DM, Jackson DV, Gregurich MA, Newcomb-Fernandez JK, Asmar L., Phase II randomized trial of weekly paclitaxel with or without estramustine phosphate in progressive, metastatic, hormone-refractory prostate cancer, Clin Prostate Cancer. 2004 Sep;3(2):104-11.  

(3) Gary R. Hudes, Judith Manola, John Conroy, Thomas Habermann, George Wilding, Phase II Study of Weekly Paclitaxel (P) by 1-Hour Infusion Plus Reduced-Dose Oral Estramustine (EMP) in Metastatic Hormone-Refractory Prostate Carcinoma (HRPC): a Trial of the Eastern Cooperative Oncology Group; 2001 ASCO Annual Meeting, Abstract No: 697. 

Table 2. Taxol (paclitaxel), carboplatin,  Estramustine Phosphate(Emcyt). 

a. The authors also list the Median PFS 10.1 mo for Arm A and 9.7 mo for Arm B.  The Median OS 20.3 mos for Arm A vs  15.9 mos for Arm B.

b. This study had 12 patients with DVTs and 2 pulmonary embolisms (25% of the patients.)  Patients then rec’d anticoagulation. Extend of disease: 23 bone metastases only; 8 soft tissue metastases only and 25 both bone and soft tissue metastases.

(1) A Meluch, F. A. Greco, H. A. Burris, J. B. Erland, R. A. Khan, G. I. Rodriguez, J. G. Gandhi, J. D. Hainsworth; Weekly paclitaxel/estramustine phosphate plus carboplatin administered either weekly or every 4 weeks in the treatment of hormone refractory prostate cancer (HRPC): A randomized phase II trial of the Minnie Pearl Cancer Research Network.  ASCO 2004, Abstract 4659.

(2) William R Berry, D. Friedland, M. A Gregurich, J. Fleagle, D. Jackson, M. Mirabel, L. Asmar, A phase-II study of weekly carboplatin (C), taxol (T) and estramustin (E)(TEC) in patients (pts) with hormone-refractory prostate cancer (HRPC), 

2002 ASCO Annual Meeting,  Abstract No: 2440.

 (3) Kelly WK, Curley T, Slovin S, Heller G, McCaffrey J, Bajorin D, Ciolino A, Regan K, Schwartz M, Kantoff P, George D, Oh W, Smith M, Kaufman D, Small EJ, Schwartz L, Larson S, Tong W, Scher H., Paclitaxel, estramustine phosphate, and carboplatin in patients with advanced prostate cancer, J Clin Oncol. 2001 Jan 1;19(1):44-53.       

 Other taxol protocols include:

 - Taxol 90 mg/sq m, 3 of 4 weeks plus Carboplatin AUC 5, 1st wk of 4-wk cycle; HDPC. (Benson).

 - Taxol 80mg/m2, carboplatin AUC 2, Estramustine 140mg TID day before, day of and day after taxol; 6 of 8 weeks. (MDA).

 Taxol and High Dose Calcitriol Combinations

Taxol has been combined with calcitriol in only one phase I clinical trial.  There are also pre-clinical studies.   

In 1999, Trump et al first studied pre-clinical models (PC-3 and rats) of D3 and paxlitaxel and found that high dose calcitriol (D3) potentiates the efficacy of paclitaxel.  The phase I trial of this combination used the following doses and schedule. Calcitriol, orally, days 1, 2, 3.  Dose escalated from 4mcg QD x 3.

Paclitaxel, 80 mg/m2, day 3. This was repeated 4 weeks on and 2 weeks off (q6 weeks).

Note that they used a 3 day in a row dosing schedule as opposed to Beer et al’s day before only dosing of calcitriol.  Only 3 patients had been started as of the abstract submittal date (no toxicity seen).

Muindi et al 2001 published the results of this clinical trial. There were 36 patients in groups of 3 to 9 patients and calcitriol was dose escalated. The maximum dose administered was 38 micrograms for 3 consecutive days each week. They found no dose-limiting toxicity; the serum calcitriol AUC was not proportional to the given calcitriol dose (this may be what Beer et al discovered – that you can only get just so much calcitriol into the serum – it saturates at around .5mcg/kg of body weight).

The concentrations they were able to achieve were similar to those used in vivo/vitro studies that showed enhanced cytotoxicity on with paclitaxel.  The treatments were with 80mg/m2 taxol and were repeated 6 weeks on and 2 weeks off.  The trial was stopped early as they found no dose limiting toxicity. 

Reference 4 summarizes some more recent studies of this combination. They appear to be re-stating some of the results from the same phase I clinical trial as above.  Here’s their summary, “While an MTD was not reached, escalation was completed through 38 µg calcitriol daily for 3 days weekly + 80 mg/sqm paclitaxel weekly.  While myelosuppression was observed, no serum calcium levels greater than 11 mg/dL were observed. The synergism of this combined therapy in preclinical models is important as it offers the potential for the enhancement of a potent antitumor agent (paclitaxel) with what appears to be a very safe regimen of calcitriol. The clinical trial suggests that paclitaxel may reduce the potential for calcitriol-induced hypercalcemia, as the weekly total dose of calcitriol in this trial is almost 12x the usual weekly dose of oral calcitriol. The addition of paclitaxel enhances cell killing by calcitriol, while limiting calcium levels in the blood.”

References for Taxol/High dose calcitriol Combinations 

1. Trump Donald , Rueger Robert , Hershberger Pamela , Modzelewski Ruth , Chandr Belani, Egorin Merrill , Johnson Candace,  Preclincal and Phase 1 Studies of the Combination of Calcitriol (1,25[OH][Subscript 2]Vitamin D[3]) and Paclitaxel: Synergistic Antitumor Activity and Reduced Toxicity.  1999 ASCO Annual Meeting, Abstract No: 890.

2. Pamela A. Hershberger, Wei-Dong Yu, Ruth A. Modzelewski, Robert M. Rueger, Candace S. Johnson and Donald L. Trump, Calcitriol (1,25-Dihydroxycholecalciferol) Enhances Paclitaxel Antitumor Activity in Vitro and in Vivo and Accelerates Paclitaxel-induced Apoptosis, Clinical Cancer Research Vol. 7, 1043-1051, April 2001.

3. Muindi JR, Peng Y, Potter DM, Hershberger PA, Tauch JS, Capozzoli MJ, Egorin MJ, Johnson CS, Trump DL.,  Pharmacokinetics of high-dose oral calcitriol: results from a phase 1 trial of calcitriol and paclitaxel, Clin Pharmacol Ther. 2002 Dec;72(6):648-59.

4. Modulation of Paclitaxel Antitumor Effects by Calcitriol: Preclinical and Clinical Studies of Mechanisms, Toxicity, and Efficacy in Prostate Cancer. http://cdmrp.army.mil/annreports/2004annrep/pdf/4_pcrp.pdf

Author: Howard Hansen, 4/10/2006