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

Tata Memorial Hospital

Status and phase: Terminated; Phase 3

Conditions: Locally Advanced Breast Cancer and Large Operable Breast Cancer

Treatments: Drug: Inj. Progesterone; Drug: Cholecalciferol

Study type: Interventional

Funder types: Other

Identifiers

NCT01608451

Vitamin D3/377/TMH

TMH project No. 377 (Other Identifier)

Details and patient eligibility

About

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

Enrollment: 800 patients

Sex: Female

Ages: 18 to 70 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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800 participants in 4 patient groups

No additional treatment

No Intervention group

Description:

No Injection Vit D3 or Injection Progesterone prior to chemotherapy cycle

Inj. Proluton

Active Comparator group

Description:

Injection Progesterone 500 mg deep IM before each cycle of NACT (for total 4 cycles) and one injection before surgery.

Treatment:

Drug: Inj. Progesterone

Inj. Arachitol

Active Comparator group

Description:

Injection Arachitol (Vitamin D3) 300,000 I.U/ml IM before each cycle of NACT (for total 4 cycles) and one injection before surgery.

Treatment:

Drug: Cholecalciferol

Inj. Proluton and Inj. Arachitol

Active Comparator group

Description:

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.

Treatment:

Drug: Cholecalciferol

Drug: Inj. Progesterone