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Hormone Receptor Positive Malignant Neoplasm of BreastPhase 2NCT01589367

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

A Phase 2 study testing Metformin in people with Hormone Receptor Positive Malignant Neoplasm of Breast, run by Seoul National University Hospital at 1 site in South Korea.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 to 80 years, women only
What is being tested?
Metformin
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
208 participants
Where
1 siteSouth Korea
Study dates
May 2012to Aug 2018
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 80 years
  • Women only
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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'
Show all 12Show fewer
  • 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

Trial locations and contacts

1 site in 1 country.

South Korea1 site

  • Seoul National University Hospital

    Seoul, 110-744

Other trials in South Korea

About this study

Official title: 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

Read the detailed description

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

Being tested
Metformin, Placebo
Keywords
neoadjuvant endocrine therapy, metformin, postmenopausal breast cancer

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • MetforminDrug

    Also called Arm1_Metformin_experimental

    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

  • PlaceboDrug

    Also called Arm2_Letrozole alone_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

Study groups in NCT01589367
Study groupRoleWhat they receive
Arm1_ MetforminExperimentalLetrozole with concurrent metformin
Receives: Drug: Metformin
Arm 2_ Letrole alonePlacebo comparatorLetrozole with placebo
Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Clinical response rate

    Comparing with RECIST 1.1 From baseline to 24week(after completing medication, preoperatively)

    Measured: 24week(after completing medication, preoperatively)

Secondary outcomes (5)

  1. Pathologic complete response rate

    In case that under postoperative biopsy, residual breast cancer cell is not present in primary lesion and lymph node.

    Measured: Postoperation(within 26weeks after starting medication)

  2. 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.

    Measured: Baseline-4week(second core needle biopsy)

  3. Breast conservation rate

    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)

    Measured: Baseline-postoperation(within 26weeks after starting medication)

  4. 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).

    Measured: Baseline-24week(after completing medication, preoperatively)

  5. Toxicity profile of letrozole and metformin

    based on NCI-CTCAE version 4.0

    Measured: throughout the study

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted1 May 2012 (estimated)
  2. Study startMay 2012
  3. Primary completionApr 2018
  4. Study completionAug 2018

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
208 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01589367
Sponsor's protocol ID
KBCSG 013
Status last verified
Jun 2017
First submitted
17 Apr 2012
Last updated
10 Sep 2018
Results posted
No
Data monitoring committee
Yes
Individual data sharing
Undecided

Publications

  • Fisher B, Bryant J, Wolmark N, Mamounas E, Brown A, Fisher ER, Wickerham DL, Begovic M, DeCillis A, Robidoux A, Margolese RG, Cruz AB Jr, Hoehn JL, Lees AW, Dimitrov NV, Bear HD. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol. 1998 Aug;16(8):2672-85. doi: 10.1200/JCO.1998.16.8.2672.

    PubMed 9704717

  • Wolmark N, Wang J, Mamounas E, Bryant J, Fisher B. Preoperative chemotherapy in patients with operable breast cancer: nine-year results from National Surgical Adjuvant Breast and Bowel Project B-18. J Natl Cancer Inst Monogr. 2001;(30):96-102. doi: 10.1093/oxfordjournals.jncimonographs.a003469.

    PubMed 11773300

  • van der Hage JA, van de Velde CJ, Julien JP, Tubiana-Hulin M, Vandervelden C, Duchateau L. Preoperative chemotherapy in primary operable breast cancer: results from the European Organization for Research and Treatment of Cancer trial 10902. J Clin Oncol. 2001 Nov 15;19(22):4224-37. doi: 10.1200/JCO.2001.19.22.4224.

    PubMed 11709566

  • Toi M, Nakamura S, Kuroi K, Iwata H, Ohno S, Masuda N, Kusama M, Yamazaki K, Hisamatsu K, Sato Y, Kashiwaba M, Kaise H, Kurosumi M, Tsuda H, Akiyama F, Ohashi Y, Takatsuka Y; Japan Breast Cancer Research Group (JBCRG). Phase II study of preoperative sequential FEC and docetaxel predicts of pathological response and disease free survival. Breast Cancer Res Treat. 2008 Aug;110(3):531-9. doi: 10.1007/s10549-007-9744-z. Epub 2007 Sep 19.

    PubMed 17879158

  • Guarneri V, Broglio K, Kau SW, Cristofanilli M, Buzdar AU, Valero V, Buchholz T, Meric F, Middleton L, Hortobagyi GN, Gonzalez-Angulo AM. Prognostic value of pathologic complete response after primary chemotherapy in relation to hormone receptor status and other factors. J Clin Oncol. 2006 Mar 1;24(7):1037-44. doi: 10.1200/JCO.2005.02.6914.

    PubMed 16505422

  • Aapro M, Monfardini S, Jirillo A, Basso U. Management of primary and advanced breast cancer in older unfit patients (medical treatment). Cancer Treat Rev. 2009 Oct;35(6):503-8. doi: 10.1016/j.ctrv.2009.04.002. Epub 2009 Sep 16.

    PubMed 19762156

  • Eiermann W, Paepke S, Appfelstaedt J, Llombart-Cussac A, Eremin J, Vinholes J, Mauriac L, Ellis M, Lassus M, Chaudri-Ross HA, Dugan M, Borgs M; Letrozole Neo-Adjuvant Breast Cancer Study Group. Preoperative treatment of postmenopausal breast cancer patients with letrozole: A randomized double-blind multicenter study. Ann Oncol. 2001 Nov;12(11):1527-32. doi: 10.1023/a:1013128213451.

    PubMed 11822750

  • Mlineritsch B, Tausch C, Singer C, Luschin-Ebengreuth G, Jakesz R, Ploner F, Stierer M, Melbinger E, Menzel C, Urbania A, Fridrik M, Steger G, Wohlmuth P, Gnant M, Greil R; Austrian Breast, Colorectal Cancer Study Group (ABCSG). Exemestane as primary systemic treatment for hormone receptor positive post-menopausal breast cancer patients: a phase II trial of the Austrian Breast and Colorectal Cancer Study Group (ABCSG-17). Breast Cancer Res Treat. 2008 Nov;112(1):203-13. doi: 10.1007/s10549-007-9843-x. Epub 2007 Dec 22.

    PubMed 18158620

  • Semiglazov VF, Semiglazov VV, Dashyan GA, Ziltsova EK, Ivanov VG, Bozhok AA, Melnikova OA, Paltuev RM, Kletzel A, Berstein LM. Phase 2 randomized trial of primary endocrine therapy versus chemotherapy in postmenopausal patients with estrogen receptor-positive breast cancer. Cancer. 2007 Jul 15;110(2):244-54. doi: 10.1002/cncr.22789.

    PubMed 17538978

  • Ben Sahra I, Laurent K, Loubat A, Giorgetti-Peraldi S, Colosetti P, Auberger P, Tanti JF, Le Marchand-Brustel Y, Bost F. The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level. Oncogene. 2008 Jun 5;27(25):3576-86. doi: 10.1038/sj.onc.1211024. Epub 2008 Jan 21.

    PubMed 18212742

  • Bowker SL, Majumdar SR, Veugelers P, Johnson JA. Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin: Response to Farooki and Schneider. Diabetes Care. 2006 Aug;29(8):1990-1. doi: 10.2337/dc06-0997. No abstract available.

    PubMed 16873829

  • Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. BMJ. 2005 Jun 4;330(7503):1304-5. doi: 10.1136/bmj.38415.708634.F7. Epub 2005 Apr 22. No abstract available.

    PubMed 15849206

  • Guppy A, Jamal-Hanjani M, Pickering L. Anticancer effects of metformin and its potential use as a therapeutic agent for breast cancer. Future Oncol. 2011 Jun;7(6):727-36. doi: 10.2217/fon.11.49.

    PubMed 21675836

  • Garcia A, Tisman G. Metformin, B(12), and enhanced breast cancer response to chemotherapy. J Clin Oncol. 2010 Jan 10;28(2):e19; author reply e20. doi: 10.1200/JCO.2009.25.7857. Epub 2009 Nov 30. No abstract available.

    PubMed 19949002

  • Jiralerspong S, Palla SL, Giordano SH, Meric-Bernstam F, Liedtke C, Barnett CM, Hsu L, Hung MC, Hortobagyi GN, Gonzalez-Angulo AM. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol. 2009 Jul 10;27(20):3297-302. doi: 10.1200/JCO.2009.19.6410. Epub 2009 Jun 1.

    PubMed 19487376

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Metformin in people with Hormone Receptor Positive Malignant Neoplasm of Breast, run by Seoul National University Hospital at 1 site in South Korea.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 10 Sep 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in South Korea. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Clinical response rate (time frame: 24week(after completing medication, preoperatively)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01589367, which also lists 32 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Sep 2018.

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