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

Study Overview
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Brief Summary
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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 To see the effect of primary progesterone on survival in women with high risk breast cancer (large operable and locally advanced breast cancer) 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

Official Title
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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.

Conditions
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Locally Advanced Breast Cancer and Large Operable Breast Cancer

Intervention / Treatment
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* Drug: Cholecalciferol
* Drug: Inj. Progesterone


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: No additional treatment<br>No Injection Vit D3 or Injection Progesterone prior to chemotherapy cycle | |
| Active Comparator: Inj. Proluton<br>Injection Progesterone 500 mg deep IM before each cycle of NACT (for total 4 cycles) and one injection before surgery. | Drug: Inj. Progesterone<br>* Injection Progesterone 500 mg deep IM before each cycle of NACT (for total 4 cycles) and one injection before surgery.<br>* Other names: Inj. Proluton Depot;|
| Active Comparator: Inj. Arachitol<br>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<br>* Inj Arachitol 300,000 I.U/ml IM before each cycle of NACT (for total 4 cycles) and one injection before surgery.<br>* Other names: IArachitol;|
| Active Comparator: Inj. Proluton and Inj. Arachitol<br>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<br>* Inj Arachitol 300,000 I.U/ml IM before each cycle of NACT (for total 4 cycles) and one injection before surgery.<br>* Other names: IArachitol;Drug: Inj. Progesterone<br>* Injection Progesterone 500 mg deep IM before each cycle of NACT (for total 4 cycles) and one injection before surgery.<br>* Other names: Inj. Proluton Depot;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-free survival | Disease-free survival | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvements in overall survival, Tumor response | Overall Survival | 5 years |