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

Phase 2

Completed

• Conditions: Hormone Receptor Positive Malignant Neoplasm of Breast
• Interventions: Drug: Metformin; Drug: Placebo

• Registration Number: NCT01589367
• Lead Sponsor: Seoul National University Hospital

Brief Summary

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

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

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2012-04-17
• Study First Submitted QC: 2012-04-29
• Study Start: 2012-05
• Study First Posted: 2012-05-01
• Status Verified: 2017-06
• Primary Completion: 2018-04
• Study Completion: 2018-08
• Last Update Submitted: 2018-09-07
• Last Update Posted: 2018-09-10

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 208

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm1_ Metformin	Metformin	Letrozole with concurrent metformin
Arm 2_ Letrole alone	Placebo	Letrozole with placebo

Primary Outcome Measures

Name	Time	Method
Clinical response rate	24week(after completing medication, preoperatively)	Comparing with RECIST 1.1 From baseline to 24week(after completing medication, preoperatively)

Secondary Outcome Measures

Name	Time	Method
Toxicity profile of letrozole and metformin	throughout the study	based on NCI-CTCAE version 4.0
Breast conservation rate	Baseline-postoperation(within 26weeks after starting medication)	Before pre-operative anti hormone therapy, the patients are classified into following three types; 1. Candidate for BCS; 2. Marginal for breast conservation surgery; 3. Candidate for mastectomy only; 4. 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)
Breast density change	Baseline-24week(after completing medication, preoperatively)	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).
Pathologic complete response rate	Postoperation(within 26weeks after starting medication)	In case that under postoperative biopsy, residual breast cancer cell is not present in primary lesion and lymph node.
Changes of Ki67(%)	Baseline-4week(second core needle biopsy)	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.

Trial Locations

Locations (1)

Seoul National University Hospital; 🇰🇷 Seoul, Korea, Republic of