Progesterone and Vitamin D3 in Women With LOBC and LABC - A Feasibility Study - Full Text View

Purpose

Timing of surgery during the menstrual cycle and its impact on survival in pre-menopausal 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 timing of surgery during the menstrual cycle and survival in breast cancer carries two distinct postulates. First, hormonal milieu in the host can modulate metastatic potential of breast cancer and second, events at the time of surgery can influence survival. In light of the interim results of the randomized trial of primary progesterone in women with operable breast cancer showing a significant difference in the node positive high risk tumors (SABCS,2009,Abstract no.72), it is logical to now test the role of primary progesterone in large operable and locally advanced breast cancer.

The active metabolite of vitamin D3, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), has been recognized for over 2 decades as a modulator of cell proliferation and differentiation (cytotoxic and anti-proliferative) in many cell types, including breast cancer. However, it is still unclear as to how 1,25(OH)2D3 and its synthetic analogues act within breast cancer cells to elicit the effects on cellular proliferation and differentiation.[6] Vitamin D3 has been shown to decrease tumor growth in animal models[7] and is now in Phase I clinical trials for human cancers. [8] Based on these observations it is proposed to test the role of vitamin D3 in the neoadjuvant setting as a negative growth regulator and potentiator of chemotherapy by evaluation of tumor response.

Condition	Intervention	Phase
Breast Cancer Locally Advanced Malignant Neoplasm	Drug: Cholecalciferol Drug: Inj. Progesterone Drug: Doxyrubicin or Epirubicin	Phase 1 Phase 2

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Randomized Controlled Trial of Neo-adjuvant Progesterone and Vitamin D3 in Women With LOBC and LABC - A Feasibility Study

Resource links provided by NLM:

Genetics Home Reference related topics: breast cancer

MedlinePlus related topics: Breast Cancer Cancer Vitamin D

Drug Information available for: Progesterone Cholecalciferol Hydroxyprogesterone Hydroxyprogesterone caproate Vitamin D Epirubicin hydrochloride Epirubicin

U.S. FDA Resources

Further study details as provided by Tata Memorial Hospital:

Primary Outcome Measures:

Disease-free survival [ Time Frame: 5 years ] [ Designated as safety issue: No ]
Disease-free survival

Secondary Outcome Measures:

Improvements in overall survival, Tumor response [ Time Frame: 5 years ] [ Designated as safety issue: No ]
Overall Survival

Estimated Enrollment:	800
Study Start Date:	September 2007
Estimated Study Completion Date:	December 2012
Estimated Primary Completion Date:	December 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Active Comparator: No additional treatment 4 cycles of Neoadjuvant Chemotherapy followed by surgery.	Drug: Doxyrubicin or Epirubicin Doxyrubicin - 50mg/m2, 4 cycles (every 21 days) OR Epirubicin - 90mg/m2, 4 cycles (every 21 days) Other Name: Adriamycin or Epirubicin
Experimental: 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
Experimental: 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 300,000 I.U/ml IM before each cycle of NACT (for total 4 cycles) and one injection before surgery. Other Name: Inj.Arachitol
Experimental: Inj. Proluton plus Inj. Arachitol Injection Arachitol (Vitamin D3) 300,000 I.U/ml IM plus Injection Progesterone 500 mg deep IM before each cycle of NACT (for total 4 cycles) and one injection before surgery.	Drug: Cholecalciferol 300,000 I.U/ml IM before each cycle of NACT (for total 4 cycles) and one injection before surgery. Other Name: Inj.Arachitol 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

Show Detailed Description

Eligibility

Ages Eligible for Study:	18 Years to 70 Years
Genders 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

Please refer to this study by its ClinicalTrials.gov identifier: 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
Principal Investigator:	Vani Parmar, DNB	Tata Memorial Hospital, Dr. E Borges Road, Parel Mumbai-12

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
Study First Received:	May 22, 2012
Last Updated:	May 30, 2012
Health Authority:	India: Institutional Review Board

Keywords provided by Tata Memorial Hospital:

Inj. Vitamin D3
Inj. Progesterone
LABC
LOBC

Additional relevant MeSH terms:

Breast Neoplasms
Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Cholecalciferol
Vitamin D
Ergocalciferols
Vitamins
Epirubicin
17-alpha-hydroxy-progesterone caproate
Progesterone
Micronutrients
Growth Substances

Physiological Effects of Drugs
Pharmacologic Actions
Bone Density Conservation Agents
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Progestins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Estradiol Antagonists
Estrogen Antagonists
Estrogen Receptor Modulators
Hormone Antagonists

ClinicalTrials.gov processed this record on May 19, 2013