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Randomized Controlled Trial of Neo-adjuvant Progesterone and Vitamin D3 in Women With Large Operable Breast Cancer and Locally Advanced Breast Cancer

This study is ongoing, but not recruiting participants.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01608451
First Posted: May 31, 2012
Last Update Posted: October 19, 2016
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Dr Rajendra A. Badwe, Tata Memorial Hospital
  Purpose

Randomized Controlled Trial of Neoadjuvant Progesterone and Vitamin D3 in women with Large Operable Breast Cancer and Locally Advanced Breast Cancer - A Feasibility Study

Primary Progesterone Timing of surgery during the menstrual cycle and its impact on survival in premenopausal women with operable breast cancer has been extensively researched and reinvestigated by Badwe et al in the randomized clinical trial of 'Primary Progesterone Therapy for Operable Breast Cancer' at Tata Memorial Hospital. The underlying assumption was that the presence of unopposed estrogen (in follicular phase) at the time surgery may be deleterious for survival and that circulating progesterone might counteract this deleterious effect.

Vitamin D3 The most prominent physiological role of hormonally active form of vitamin D3, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3 or calcitriol), is regulation of calcium and phosphorous homeostasis and bone metabolism via an intracellular receptor (VDR) which is a member of steroid thyroid hormone super-family of receptors. The VDR receptors are also found in other tissues like breast and prostate.

Vitamin D compounds have also been implicated in promotion of apoptosis in breast cancer cells and evidence suggests that 1,25(OH)2D3 and its synthetic analogues may potentiate responsiveness of breast cancer cells to conventional cytotoxic agents.

Objectives

  1. To see the effect of primary progesterone on survival in women with high risk breast cancer (large operable and locally advanced breast cancer)
  2. To see the effect of Vitamin D3 as an antiproliferative, cytotoxic and apoptotic agent (negative growth regulator) by evaluation of surrogate markers of proliferation and apoptosis.

Inclusion Criteria:

  • Unilateral breast cancer
  • Large operable breast cancer/LOBC (T3N0M0 or T3N1M0) and Locally advanced breast cancer/LABC (T3N1-2M0; T2N2M0)
  • Age <70 years
  • Fit for CT

Exclusion Criteria:

  • Prior Incision Biopsy or Excision Biopsy
  • Metastatic breast cancer
  • Renal failure or deranged Renal Function Test
  • Hypoparathyroidism
  • Pregnant or lactating mothers or women of childbearing age not practicing contraception
  • Patient on any of the following drugs: Magnesium-containing antacids, Digitalis, Phenytoin barbiturates, Thiazide diuretics.
  • Previous history of other cancers except cured skin and cervical carcinoma in situ.

Methodology / Treatment plan

The study drugs (Injectable Progesterone and Vitamin D3) will be tested in the neoadjuvant setting prior to administration of each chemotherapy cycle, in a 2x2 factorial design as below:

Neoadjuvant D3 will be administered as Inj. Arachitol 300,000 IU/ml intramuscular, before each chemotherapy cycle.

Neoadjuvant Progesterone used will be administered as single IM depot injection 500mg 5 days prior to each CT cycle and surgery date.

Primary Objectives Disease-free survival

Secondary Objectives Improvements in overall survival Tumor response


Condition Intervention Phase
Locally Advanced Breast Cancer and Large Operable Breast Cancer Drug: Cholecalciferol Drug: Inj. Progesterone Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Randomized Controlled Trial of Neo-adjuvant Progesterone and Vitamin D3 in Women With Large Operable Breast Cancer and Locally Advanced Breast Cancer.

Resource links provided by NLM:


Further study details as provided by Dr Rajendra A. Badwe, Tata Memorial Hospital:

Primary Outcome Measures:
  • Disease-free survival [ Time Frame: 5 years ]
    Disease-free survival


Secondary Outcome Measures:
  • Improvements in overall survival, Tumor response [ Time Frame: 5 years ]
    Overall Survival


Estimated Enrollment: 800
Study Start Date: September 2007
Estimated Study Completion Date: December 2020
Estimated Primary Completion Date: December 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
No Intervention: No additional treatment
No Injection Vit D3 or Injection Progesterone prior to chemotherapy cycle
Active Comparator: Inj. Proluton
Injection Progesterone 500 mg deep IM before each cycle of NACT (for total 4 cycles) and one injection before surgery.
Drug: Inj. Progesterone
Injection Progesterone 500 mg deep IM before each cycle of NACT (for total 4 cycles) and one injection before surgery.
Other Name: Inj. Proluton Depot
Active Comparator: Inj. Arachitol
Injection Arachitol (Vitamin D3) 300,000 I.U/ml IM before each cycle of NACT (for total 4 cycles) and one injection before surgery.
Drug: Cholecalciferol
Inj Arachitol 300,000 I.U/ml IM before each cycle of NACT (for total 4 cycles) and one injection before surgery.
Other Name: IArachitol
Active Comparator: Inj. Proluton and Inj. Arachitol
Injection Arachitol (Vitamin D3) 300,000 I.U/ml IM and Injection Progesterone 500 mg deep IM before each cycle of NACT (for total 4 cycles) and one injection before surgery.
Drug: Cholecalciferol
Inj Arachitol 300,000 I.U/ml IM before each cycle of NACT (for total 4 cycles) and one injection before surgery.
Other Name: IArachitol
Drug: Inj. Progesterone
Injection Progesterone 500 mg deep IM before each cycle of NACT (for total 4 cycles) and one injection before surgery.
Other Name: Inj. Proluton Depot

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 70 Years   (Adult, Senior)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Unilateral breast cancer
  • Large operable breast cancer/LOBC (T3N0M0 or T3N1M0) and Locally advanced breast cancer/LABC (T3N1-2M0; T2N2M0)
  • Age <70 years
  • Fit for CT

Exclusion Criteria:

  • Prior IB or EB
  • Metastatic breast cancer
  • Renal failure or deranged RFT
  • Hypoparathyroidism
  • Pregnant or lactating mothers or women of childbearing age not practicing contraception
  • Patient on any of the following drugs: Magnesium-containing antacids, Digitalis, Phenytoin barbiturates, Thiazide diuretics.
  • Previous history of other cancers except cured skin and cervical carcinoma in situ.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01608451


Locations
India
Tata Memorial Hospital
Mumbai, Maharashtra, India, 400012
Sponsors and Collaborators
Tata Memorial Hospital
Investigators
Principal Investigator: Rajendra A Badwe, MS (Surgery) Tata Memorial Hospital, Ernest Borges Road, Parel, Mumbai 400 012
  More Information

Publications:
Hrushesky WJ, Bluming AZ, Gruber SA, Sothern RB. Menstrual influence on surgical cure of breast cancer. Lancet. 1989 Oct 21;2(8669):949-52. Erratum in: Lancet 1989 Nov 25;2(8674):1290.
Badwe RA, Gregory WM, Chaudary MA, Richards MA, Bentley AE, Rubens RD, Fentiman IS. Timing of surgery during menstrual cycle and survival of premenopausal women with operable breast cancer. Lancet. 1991 May 25;337(8752):1261-4.
Heer K, Kumar H, Speirs V, Greenman J, Drew PJ, Fox JN, Carleton PJ, Monson JR, Kerin MJ. Vascular endothelial growth factor in premenopausal women--indicator of the best time for breast cancer surgery? Br J Cancer. 1998 Nov;78(9):1203-7.
Senie RT, Rosen PP, Rhodes P, Lesser ML. Timing of breast cancer excision during the menstrual cycle influences duration of disease-free survival. Ann Intern Med. 1991 Sep 1;115(5):337-42.
Mathiasen IS, Colston KW, Binderup L. EB 1089, a novel vitamin D analogue, has strong antiproliferative and differentiation inducing effects on cancer cells. J Steroid Biochem Mol Biol. 1993 Sep;46(3):365-71.
Welsh J. Vitamin D and breast cancer: insights from animal models. Am J Clin Nutr. 2004 Dec;80(6 Suppl):1721S-4S. Review.
Gulliford T, English J, Colston KW, Menday P, Moller S, Coombes RC. A phase I study of the vitamin D analogue EB 1089 in patients with advanced breast and colorectal cancer. Br J Cancer. 1998 Jul;78(1):6-13.
Wang Q, Lee D, Sysounthone V, Chandraratna RAS, Christakos S, Korah R, Wieder R. 1,25-dihydroxyvitamin D3 and retonic acid analogues induce differentiation in breast cancer cells with function- and cell-specific additive effects. Breast Cancer Res Treat. 2001 May;67(2):157-68.
Narvaez CJ, Zinser G, Welsh J. Functions of 1alpha,25-dihydroxyvitamin D(3) in mammary gland: from normal development to breast cancer. Steroids. 2001 Mar-May;66(3-5):301-8. Review.
James SY, Mackay AG, Colston KW. Effects of 1,25 dihydroxyvitamin D3 and its analogues on induction of apoptosis in breast cancer cells. J Steroid Biochem Mol Biol. 1996 Jul;58(4):395-401.
Vink-van Wijngaarden T, Pols HA, Buurman CJ, van den Bemd GJ, Dorssers LC, Birkenhäger JC, van Leeuwen JP. Inhibition of breast cancer cell growth by combined treatment with vitamin D3 analogues and tamoxifen. Cancer Res. 1994 Nov 1;54(21):5711-7.
Sundaram S, Gewirtz DA. The vitamin D3 analog EB 1089 enhances the response of human breast tumor cells to radiation. Radiat Res. 1999 Nov;152(5):479-86.
Chaudhry M, Sundaram S, Gennings C, Carter H, Gewirtz DA. The vitamin D3 analog, ILX-23-7553, enhances the response to adriamycin and irradiation in MCF-7 breast tumor cells. Cancer Chemother Pharmacol. 2001 May;47(5):429-36.
Sundaram S, Sea A, Feldman S, Strawbridge R, Hoopes PJ, Demidenko E, Binderup L, Gewirtz DA. The combination of a potent vitamin D3 analog, EB 1089, with ionizing radiation reduces tumor growth and induces apoptosis of MCF-7 breast tumor xenografts in nude mice. Clin Cancer Res. 2003 Jun;9(6):2350-6.
Zinser GM, Tribble E, Valrance M, Urben CM, Knutson JC, Mazess RB, Strugnell SA, Welsh J. 1,24(S)-dihydroxyvitamin D2, an endogenous vitamin D2 metabolite, inhibits growth of breast cancer cells and tumors. Anticancer Res. 2005 Jan-Feb;25(1A):235-41.
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.
Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr. 1999 May;69(5):842-56. Review.
Cooper LS, Gillett CE, Patel NK, Barnes DM, Fentiman IS. Survival of premenopausal breast carcinoma patients in relation to menstrual cycle timing of surgery and estrogen receptor/progesterone receptor status of the primary tumor. Cancer. 1999 Nov 15;86(10):2053-8.
Cooper LS, Gillett CE, Smith P, Fentiman IS, Barnes DM. Cell proliferation measured by MIB1 and timing of surgery for breast cancer. Br J Cancer. 1998 May;77(9):1502-7.
Saad Z, Bramwell VH, Wilson SM, O'Malley FP, Jeacock J, Chambers AF. Expression of genes that contribute to proliferative and metastatic ability in breast cancer resected during various menstrual phases. Lancet. 1998 Apr 18;351(9110):1170-3. Erratum in: Lancet 1998 Aug 1;352(9125):408.
Ferrières G, Cuny M, Simony-Lafontaine J, Jacquemier J, Rouleau C, Guilleux F, Grenier J, Rouanet P, Pujol H, Jeanteur P, Escot C. Variation of bcl-2 expression in breast ducts and lobules in relation to plasma progesterone levels: overexpression and absence of variation in fibroadenomas. J Pathol. 1997 Oct;183(2):204-11.
Yang Q, Sakurai T, Yoshimura G, Suzuma T, Umemura T, Nakamura M, Nakamura Y, Mori I, Kakudo K. Prognostic value of Bcl-2 in invasive breast cancer receiving chemotherapy and endocrine therapy. Oncol Rep. 2003 Jan-Feb;10(1):121-5.
Harris AL, Zhang H, Moghaddam A, Fox S, Scott P, Pattison A, Gatter K, Stratford I, Bicknell R. Breast cancer angiogenesis--new approaches to therapy via antiangiogenesis, hypoxic activated drugs, and vascular targeting. Breast Cancer Res Treat. 1996;38(1):97-108. Review.
Viens P, Jacquemier J, Bardou VJ, Bertucci F, Penault-Llorca F, Puig B, Gravis G, Oziel-Taïeb S, Resbeut M, Houvenaeghel G, Camerlo J, Birbaum D, Hassoun J, Maraninchi D. Association of angiogenesis and poor prognosis in node-positive patients receiving anthracycline-based adjuvant chemotherapy. Breast Cancer Res Treat. 1999 Apr;54(3):205-12.

Responsible Party: Dr Rajendra A. Badwe, Principal Investigator, Tata Memorial Hospital
ClinicalTrials.gov Identifier: NCT01608451     History of Changes
Other Study ID Numbers: Vitamin D3/377/TMH
TMH project No. 377 ( Other Identifier: Tata Memorial Hospital )
First Submitted: May 22, 2012
First Posted: May 31, 2012
Last Update Posted: October 19, 2016
Last Verified: October 2016

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Vitamins
Vitamin D
Ergocalciferols
Cholecalciferol
Progesterone
Micronutrients
Growth Substances
Physiological Effects of Drugs
Bone Density Conservation Agents
Progestins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists


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