A Phase III Randomized Trial of Metformin vs Placebo in Early Stage Breast Cancer

OBJECTIVES:

Primary

- To compare invasive disease-free survival of patients with hormone receptor positive
early-stage breast cancer treated with metformin vs placebo in addition to standard
adjuvant therapy.

Secondary

- To compare overall survival of these patients.

- To compare distant disease-free survival of these patients.

- To compare breast cancer-free interval in these patients.

- To compare changes in body mass index in these patients.

- To compare adverse events in these patients.

- To compare other medical endpoints, including a new diagnosis of diabetes mellitus or
cardiovascular hospitalization (including an emergency room visit or overnight stay) or
death (stroke or myocardial infarction), in these patients.

- To compare health-related quality of life measured using the EORTC QLQ-C30 (supplemented
by a trial-specific checklist), the Block Alive Screener, and physical activity items
from the Nurses Health Study Questionnaire II on a subset of these patients.

- To compare embedded correlative science outcomes including plasma insulin and molecular
markers of metformin action in these patients.

- To compare metabolic parameters including metabolic components of the insulin resistance
syndrome as defined by the ATP III criteria in a subset of these patients.

OUTLINE: This is a multicenter study. Patients are stratified according to hormone-receptor
status (estrogen receptor- and/or progesterone receptor- positive vs both receptors
negative), body mass index (≤ 30 vs > 30 kg/m²), HER2 status (positive vs negative), and
prior chemotherapy (any vs none). Patients are randomized to 1 of 2 treatment arms.

- Arm I: Patients receive oral metformin hydrochloride twice daily (once daily in weeks
1-4). Treatment continues for up to 5 years in the absence of disease progression or
unacceptable toxicity.

- Arm II: Patients receive oral placebo twice daily (once daily in weeks 1-4). Treatment
continues for up to 5 years in the absence of disease progression or unacceptable
toxicity.

Blood and tumor samples are collected periodically for correlative studies.

Patients may complete quality-of-life, physical activity, and diet questionnaires at baseline
and at 6, 12, 24, 36, 48, and 60 months. (Sub-set of patients).

After completion of study treatment, patients are followed annually.

Eligibility Criteria:

- Subjects must have histologically confirmed invasive breast cancer and be enrolled in
the trial within 12 months after the first histologic diagnosis of invasive breast
cancer. A core biopsy interpreted as invasive cancer meets this criterion; otherwise,
the date of first histologic diagnosis will be the date of first surgical procedure
that identifies invasive cancer (biopsy, lumpectomy or mastectomy). Neoadjuvant
subjects should have no evidence of clinical T4 disease prior to chemotherapy and
surgery. Bilateral breast carcinoma is allowed provided diagnoses are synchronous -
that is, within 3 months of one another - and at least one of the two breast
carcinomas meet the eligibility criteria and neither violates the eligibility
criteria.

- All subjects (both adjuvant and neo-adjuvant) must have sentinel lymph node biopsy
and/or axillary lymph node dissection.

Sentinel lymph node biopsy alone is allowed in the following instances:

1. sentinel lymph node biopsy is negative: pN0

2. sentinel lymph node biopsy is positive for isolated tumour cells only: pN0 (i+)

3. * clinically node negative, T1-2 tumours with sentinel lymph node biopsy positive in ≤
2 lymph nodes without extra-capsular extension or matted nodes and undergoing breast
conserving surgery and tangential whole breast irradiation (* excludes subjects
treated with neo-adjuvant systemic therapy)

Definitive surgery and/or chemotherapy have been completed at least 4 weeks prior to
randomization. Surgical margins must be clear of invasive carcinoma. If there is
microscopic residual ductal in situ disease present at lumpectomy or total mastectomy
margins, further excision is highly recommended. If further excision is not undertaken, the
subject may still be entered on study, provided that in addition to breast or chest wall
irradiation, a boost to the tumour bed is delivered. In situ lobular disease at the margin
is acceptable.

Adjuvant subjects with the following pT pN combinations are eligible:

- pT1c, pN0 AND negative estrogen and progesterone receptors AND HER2 negative OR

- pT2N0 and at least one of the following tumour characteristics: histologic grade 3,
lymphovascular invasion, negative estrogen and progesterone receptors, HER2 positive,
Oncotype Dx recurrence score ≥ 25 (or if Oncotype Dx recurrence score is not
available, Ki67 > 14%) OR

- Subjects with pT3, pN0 OR

- Subjects with pT1-3, pN1-3

The eligibility of neo-adjuvant subjects is assessed on the basis of cTNM. The same
eligible TNM combinations apply.

- HER2 status must be known. (Positive = 3+ over-expression by IHC in > 30% of invasive
tumour cells OR HER2 gene amplification by FISH/CISH > 6 HER2 gene copies per nucleus,
OR a FISH/CISH ratio: HER2 gene copies to chromosome 17 signals of ≥ 2.2. All other
results will be considered negative).

- Patients must have had a bilateral mammogram within 12 months prior to randomization,
unless the initial surgery was a total mastectomy, in which case only a mammogram of
the remaining breast is required. (Subjects with bilateral total mastectomies and no
mammogram within 12 months prior to randomization must, instead, have a physical
examination of the chest wall to ensure there is no residual or recurrent disease at
the time of randomization. The date of this examination is used in place of the
mammogram date on the eligibility checklist.)

- Investigations, including chest X-ray or CT chest, bone scan (with radiographs of
suspicious areas) and abdominal ultrasound or liver scan or CT abdomen have been
performed between the first histologic diagnosis and the time of randomization.

- Chest X-Ray, 2 view (or Chest CT) is mandatory

- Bone scans (with x-rays of abnormal areas) are required only if there are signs
or symptoms of metastatic disease

- Abdominal imaging is required only if there are signs or symptoms of metastatic
disease

- Hematology investigations (WBC, Granulocytes, Platelets, Hemoglobin) have been
completed within 28 days prior to randomization and results are available.

- Biochemistry investigations have been completed within 28 days prior to randomization
and values are within the parameters required by the protocol.

AST < 1.8 X ULN; ALT < 1.8 X ULN; Alkaline Phosphatase < 2 X ULN; Serum Creatinine < 115
μmol/L (1.3mg/dL) Serum Bilirubin < institution ULN (except for subjects with Gilbert's
Disease who are eligible despite elevated serum bilirubin level)

- ECOG Performance Status of 0,1 or 2 (at baseline evaluation visit within 28 days prior
to randomization).

- Age ≥ 18 and < 75 and life expectancy of at least 5 years (18 years of age was used as
a cut-off due to the lack of data indicating that breast cancer is a health issue in
the < 18 years age group and metformin safety in pediatric patients has not been
confirmed. Age > 80 carries increased risk of lactic acidosis and study intervention
is for 5 years).

- Subjects must be accessible for treatment and follow-up. Investigators must assure
themselves the subjects randomized on this trial will be available for complete
documentation of the treatment, adverse events, and follow-up.

- In accordance with NCIC CTG policy, protocol treatment is to begin within 10 working
days of patient randomization.

- Subject consent must be obtained according to local Institutional and/or University
Human Experimentation Committee requirements. It will be the responsibility of the
local participating investigators to obtain the necessary local clearance, and to
indicate in writing to the NCIC CTG Study Coordinator that such clearance has been
obtained, before the trial can commence in that centre. Because of differing
requirements, a standard consent form for the trial will not be provided but a sample
form is given. A copy of the initial full board REB approval and approved consent form
must be sent to the central office. The patient must sign the consent form prior to
randomization or registration. Please note that the consent form for this study must
contain a statement which gives permission for the NCIC CTG and monitoring agencies to
review patient records (see Section 16 for further details).

For the first 888 eligible English or French-speaking subjects only (sub-set enrollment
completed 2011NOV04):

- Subject is able (i.e. sufficiently fluent) and willing to complete the Quality of Life
(EORTC QLQ C-30 and Trial Specific Checklist) in English or French. The baseline
assessment must already have been completed at the time of enrollment. Inability
(illiteracy in English or French, loss of sight or other equivalent reason) to
complete questionnaires will not make the patient ineligible for the study; however,
ability but unwillingness to complete the questionnaires will make the patient
ineligible. (Once the target number of 888 subjects is achieved, this criterion will
no longer need to be fulfilled.) [See Appendix VI]. Sub-set enrollment completed
2011NOV04.

- English-speaking subjects who have completed the Quality of Life Questionnaire who are
able (i.e. sufficiently fluent) and willing to complete Nurses Health Study II
Physical Activity Questionnaire and Block Alive Screener in English. The baseline
assessment must already have been completed at the time of enrollment. Inability
(illiteracy in English, loss of sight or other equivalent reason) to complete
questionnaires will not make the patient ineligible for the study; however, ability
but unwillingness to complete the questionnaires will make the patient ineligible.
(This component of the study will close at the same time as the Quality Of Life
sub-study.) Closed to new patient enrollment as of 2011NOV04.

Ineligibility Criteria:

- Subjects with a history of other malignancies, except: adequately treated non-melanoma
skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumours
curatively treated with no evidence of disease for ≥ 5 years.

- Subjects with locally recurrent or metastatic breast carcinoma. (Subjects with prior
invasive breast cancer at any time are not eligible. Subjects with prior DCIS only in
either breast are eligible provided the DCIS has been curatively treated including
surgery, radiotherapy and/or Tamoxifen).

- Subjects whose axillary node status is unknown.

- Known diabetes (type 1 or 2) or baseline fasting glucose > 7.0 mmol/L (126 mg/dL).
(Sampled and assayed according to local institution's procedures.)

- Known hypersensitivity or intolerance to metformin.

- Any condition associated with increased risk of metformin-associated lactic acidosis
(e.g. congestive heart failure defined as New York Heart Association {NYHA} Class III
or IV functional status [see Appendix IX], history of acidosis of any type; habitual *
Currently taking metformin, sulfonylureas, thiazolidinediones or insulin for any
reason.

- Current or planned pregnancy or lactation in women of child-bearing potential. Men
should not father a child. (An effective method of birth control should be used while
on study treatment which could include abstinence, IUD, condoms or other barrier
methods of birth control because the safety of metformin in pregnancy or in male
fertility has not been established).

- Concurrent or planned participation in randomized trials of weight loss or exercise
interventions or trials targeting insulin, IGF-1 or their receptors, or involving P13K
inhibitors (at the time of randomization)*.

- These interventions would interfere with the primary endpoint. (Also, in general,
double randomizations in breast cancer trials for MA.32 patients are permitted only if
the patient meets all the eligibility criteria for MA.32 and the sponsor of the
previous trial has no objection to the patient also being enrolled in MA.32).