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

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ClinicalTrials.gov Identifier: NCT01589367
Recruitment Status : Recruiting
First Posted : May 1, 2012
Last Update Posted : April 19, 2018
Sponsor:
Information provided by (Responsible Party):
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


Condition or disease Intervention/treatment Phase
Hormone Receptor Positive Malignant Neoplasm of Breast Drug: Metformin Drug: Placebo Phase 2

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  (Clinical Trial)
Estimated Enrollment : 208 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Phase II Randomized Study of Neoadjuvant Metformin Plus Letrozole vs Placebo Plus Letrozole for ER-positive Postmenopausal Breast Cancer
Study Start Date : May 2012
Estimated Primary Completion Date : April 2018
Estimated Study Completion Date : October 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer
U.S. FDA Resources

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 Name: 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 Name: Arm2_Letrozole alone_Placebo



Primary Outcome Measures :
  1. Clinical response rate [ Time Frame: 24week(after completing medication, preoperatively) ]
    Comparing with RECIST 1.1 From baseline to 24week(after completing medication, preoperatively)


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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)


  4. 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).

  5. Toxicity profile of letrozole and metformin [ Time Frame: throughout the study ]
    based on NCI-CTCAE version 4.0



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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Senior)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01589367


Contacts
Contact: Wonshik Han, MD PhD 82-2-2072-1958 hanw@snu.ac.kr
Contact: Yumi Kim, MD yumssky@gmail.com

Locations
Korea, Republic of
Seoul National University Hospital Recruiting
Seoul, Korea, Republic of, 110-744
Contact: Wonshik Han, MD PhD    82-2-2072-1958    hanw@snu.ac.kr   
Contact: Yumi Kim, MD       yumssky@gmail.com   
Sub-Investigator: Yumi Kim, MD         
Sponsors and Collaborators
Seoul National University Hospital
Investigators
Principal Investigator: Wonshik Han, MD PhD Seoul National University Hospital

Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Seoul National University Hospital
ClinicalTrials.gov Identifier: NCT01589367     History of Changes
Other Study ID Numbers: KBCSG 013
First Posted: May 1, 2012    Key Record Dates
Last Update Posted: April 19, 2018
Last Verified: June 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by Seoul National University Hospital:
neoadjuvant endocrine therapy
metformin
postmenopausal breast cancer

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Metformin
Letrozole
Hypoglycemic Agents
Physiological Effects of Drugs
Antineoplastic Agents
Aromatase Inhibitors
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists