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

September 7, 2018 updated by: Seoul National University Hospital

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

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

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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

Study Type

Interventional

Enrollment (Actual)

208

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Korea, Republic of
      • Seoul, Korea, Republic of, 110-744
        • Seoul National University Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 80 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: QUADRUPLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Arm1_ Metformin
Letrozole with concurrent metformin
Drug: Metformin
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
Other Names:
  • Arm1_Metformin_experimental
PLACEBO_COMPARATOR: Arm 2_ Letrole alone
Letrozole with placebo
Drug: Placebo
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
Other Names:
  • Arm2_Letrozole alone_Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Clinical response rate
Time Frame: 24week(after completing medication, preoperatively)
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
Time Frame: 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.
Postoperation(within 26weeks after starting medication)
Changes of Ki67(%)
Time Frame: 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.
Baseline-4week(second core needle biopsy)
Breast conservation rate
Time Frame: 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)
Baseline-postoperation(within 26weeks after starting medication)
Breast density change
Time Frame: 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).
Baseline-24week(after completing medication, preoperatively)
Toxicity profile of letrozole and metformin
Time Frame: throughout the study
based on NCI-CTCAE version 4.0
throughout the study

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Seoul National University Hospital

Investigators

  • Principal Investigator: Wonshik Han, MD PhD, Seoul National University Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 2012

Primary Completion (ACTUAL)

April 1, 2018

Study Completion (ACTUAL)

August 1, 2018

Study Registration Dates

First Submitted

April 17, 2012

First Submitted That Met QC Criteria

April 29, 2012

First Posted (ESTIMATE)

May 1, 2012

Study Record Updates

Last Update Posted (ACTUAL)

September 10, 2018

Last Update Submitted That Met QC Criteria

September 7, 2018

Last Verified

June 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • KBCSG 013

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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