Neoadjuvant Letrozole Plus Metformin vs Letrozole Plus Placebo for ER-positive Postmenopausal Breast Cancer

Study Overview
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Brief Summary
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Preoperative letrozole versus letrozole with metformin in postmenopausal Estrogen receptor positive breast cancer patients Phase II multicenter 1:1 randomized clinical trial Total 208 patients Primary endpoint Clinical response rate Secondary endpoint Pathologic complete response rate Breast conserving surgery rate Percent mammographic density change Ki67(%) change after 4week medication of 2nd core needle biopsy Toxicity profile of neoadjuvant letrozole, metformin

Detailed Description
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To identify the anti-tumor effect of metformin with preoperatively given letrozole in postmenopausal estrogen receptor positive breast cancer patients

Official Title
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Phase II Randomized Study of Neoadjuvant Metformin Plus Letrozole vs Placebo Plus Letrozole for ER-positive Postmenopausal Breast Cancer

Conditions
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Hormone Receptor Positive Malignant Neoplasm of Breast

Intervention / Treatment
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* Drug: Metformin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Estrogen receptor positive breast cancer Clinically measurable tumor size(stage II/III) No evidence of distant metastasis Postmenopause women 'Age≥60yr' OR 'previous bilateral oophorectomy' OR 'FSH>30 with no bleeding history within 1yr' ECOG 0-2 Adequate hepatorenal, bone marrow function 'serum Cr<1.4mg/dL' AND 'Bilirubin< upper limit of normal x 1.5 AND 'AST/ALT < upper limit of normal x 1.8 AND 'ALP < upper limit of normal x 1.8 AND 'Hemoglobin >10 g/dL' AND 'ANC >1,500/mm3' AND 'Platelet >100,000/mm3' Spontaneous signed into the written informed consent Exclusion Criteria: Who does not meet the above inclusion criteria History of other carcinoma Uncontrolled infection History of psychiatric, epileptic disease Male breast cancer Diabetes 'HbA1c≥6.5' OR 'FBS≥126mg/dL' Hypersensitivity or intolerance to metformin Risk of metformin associated lactic acidosis 'Congestive heart disease of NYHA Class llll/IV' OR 'History of other acidosis' OR 'Alcohol intake more than either 3 bottles beer OR 1 bottle Soju' During medication of metformin, sulfonylureas, thiazolidinediones, insulin Diffuse microcalcification in mammogram Multiple OR bilateral OR inflammatory breast cancer Chemotherapy or endocrine therapy within 2yr due to history of breast cancer

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm1_ Metformin<br>Letrozole with concurrent metformin | Drug: Metformin<br>* Metformin HCl 500mg(morning/evening) PO daily x 1week Metformin HCl 1000mg(morning)and 500mg(evening)PO daily x 1week Metformin HCl 1000mg(morning/evening) PO daily x 22weeks<br>* Other names: Arm1_Metformin_experimental;|
| Placebo Comparator: Arm 2_ Letrole alone<br>Letrozole with placebo | Drug: Placebo<br>* Letrozole 2.5mg PO daily + Placebo 1 tablet PO 2/day x 1week Letrozole 2.5mg PO daily + Placebo 2 tablet+ 1 tablet PO x 1 week Letrozole 2.5mg PO daily + Placebo 2 tablet PO 2/day x 22 weeks<br>* Other names: Arm2_Letrozole alone_Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical response rate | Comparing with RECIST 1.1 From baseline to 24week(after completing medication, preoperatively) | 24week(after completing medication, preoperatively) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathologic complete response rate | In case that under postoperative biopsy, residual breast cancer cell is not present in primary lesion and lymph node. | Postoperation(within 26weeks after starting medication) | 
| Changes of Ki67(%) | IHC is performed for formalin-fixed paraffin embedded tissue at the central laboratory. Ki67 is recorded as % and percentage reduction of baseline and Ki67 expressed cell on day28 are compared. | Baseline-4week(second core needle biopsy) | 
| Breast conservation rate | Before pre-operative anti hormone therapy, the patients are classified into following three types Candidate for BCS Marginal for breast conservation surgery Candidate for mastectomy only Inoperable by standard mastectomy Classification of each type shall be determined by each researcher of each institution subjectively. For future separate objective analysis, central institution will collect image file of mammography of each patient. Type of operation being actually performed in each type is compared. (BCS vs mastectomy) | Baseline-postoperation(within 26weeks after starting medication) | 
| Breast density change | Percent mammographic density (%) of cranial-caudal view of opposite breast is measured/compared based on continued variable by using validated computer-assisted thresholding program called Cumulus software (University Toronto, Toronto, Ontario, Canada). | Baseline-24week(after completing medication, preoperatively) | 
| Toxicity profile of letrozole and metformin | based on NCI-CTCAE version 4.0 | throughout the study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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neoadjuvant endocrine therapy, metformin, postmenopausal breast cancer