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CTSU NCIC MA.32 - "A Phase III Randomized Trial of Metformin versus Placebo on Recurrence and Survival in Early Stage Breast Cancer"
Treatment Plan (Supplied Drug: Metformin/placebo)
Start w/i 10 working days of randomiz
Metformin: 850mg, PO, BID, x 5 yrs (includes 4-wk ramp-up of 850mg, PO, QD)
vs
Placebo: 1 caplet, PO, BID, x 5 yrs (includes 4-wk ramp-up of 1 caplet, PO, QD)
Eligibility
Histol-confirmed invasive breast cancer. Must be enrolled w/i 12 mos after 1st histologic dx of invasive breast cancer. A core bx interpretation is acceptable; otherwise the date of 1st histologic dx will be date of 1st surgical procedure that identifies invasive cancer. TNM staging (AJCC v7) must be 1 of the combinations listed below. Neo-adjuv pts must have no clinical T4 disease prior to chemo & surgery. Bilat breast cancer is allowed if dxs are synchronous (w/i 3 mos of each other) & >1 of breast cancers meets the eligiblity criteria & neither violates the eligibility criteria.
Both adjuv & neo-adjuv pts must have SN bx &/or axillary LN dissection. SN bx alone is allowed if:
SN bx is negative: pN0
SN bx is positive for isolated tumor cells only: pN0(i+)
Clinically node negative T1-2 tumors w/SN bx positive in <2 lymph nodes w/o extracapsular extension or matted nodes & undergoing breast conserving surgery & whole breast RT (no subjects treated w/neo-adjuv systemic therapy)
Definitive surgery &/or chemo completed >4 wks pre-randomiz. Clear margins. If microscopic residual ductal in situ disease is present at lumpectomy or total mastectomy margins, further exicision is highly recommended. If further excision not done, pt may still be enrolled, if in addition to breast or chest wall RT, a boost to tumor bed is delivered. In situ lobular disease at margin is allowed.
Eligible combinations for adjuv pts:
pT1c, pN0, & >1 of the following: Histol grade 3, lymphovascular invasion, negative ER & PgR receptors, HER2+, Oncotype Dx recurrence score >25 (or Ki67 >14% if Oncotype Dx not available)
pT2-3, pN0
pT1-3, pN1-3
Eligibility for neo-adjuv pts is based on cTNM (same eligible TNM combinations apply).
ER & PgR status must be known. (Receptor positive by ERICA or PgRICA vs both receptors negative. Recommended that ER & PgR assays be considered positive if >1% positive tumor nuclei in sample on testing in presence of expected reactivity of internal (normal epithelial elements) & external control.
HER2 status known. Positive = 3+ overexpression by IHC in >30% of invasive tumor cells or HER2 gene amplification by FISH/CISH >6 HER2 gene copies/nucleus or FISH/CISH ratio: HER2 gene copies to chromosome 17 signals of >2.2. All other results considered negative.
Bilat mammogram w/i 12 mos pre-randomiz (unless initial surgery was a total mastectomy - only a mammogram of remaining breast is necessary). Pts w/bilat total mastectomies & no mammogram w/i 12 mos pre-randomiz must have a PE of chest wall to r/o residual or recur disease - date of PE is used in place of mammogram date.
CXR or CT chest, bone scan (w/xrays of suspicious areas), & abdominal US or liver scan or CT abdomen performed between 1st histol dx & randomiz.
CXR or chest CT is mandatory.
Bone scan (w/xrays of abnormal areas) are required if alk phos is elevated or symptoms of mets.
Abdominal imaging required only if SGOT, SGPT, or alk phos are abnormal or symptoms of mets.
Within 28 days pre-randomiz: WBC; granulocytes; platelets; Hgb; SGOT <1.8x ULN; SGPT <1.8x ULN; alk phos <2x ULN; serum creat <1.3mg/dL; serum bili <IULN (except pts w/Gilbert's disease who are eligible even if serum bili is elevated; ECOG perf status 0-2.
Age >18 & <75 w/life expectancy >5 yrs.
Accessible for tx & FU.
Sufficiently fluent and willing to complete QOL asmt. Inability to complete questionnaires will not make pt ineligible for study.
Sufficiently fluent and willing to complete Nurses Health Study II Physical Activity Questionnaire & Block Alive Screener. Inability to complete questionnaires will not make pt ineligible for study.
No other prior invasive malignancies except adequately treated non-melanoma skin cancer, curatively treated in situ cervical cancer, or other solid tumors curatively treated & disease-free >5 yrs.
No locally recurrent or mets breast cancer. No prior invasive breast cancer at any time.
No known Type 1 or 2 diabetes or fasting glucose >7.0 mmol/L (126mg/dL) - sampled & assayed using local institution's procedures.
No known hypersensitivity or intolerance to Metformin.
No condition associated w/increased risk of Metformin-associated lactic acidosis (i.e., CHF, hx of acidosis of any type, habitual intake of >3 alcoholic drinks/day).
No current Metformin, sulfonylureas, thiazolidenediones, or insulin for any reason.
No currrent/planned pregnancy or nursing women of childbearing potential. Must have negative pregnancy test w/i 7 days pre-randomiz. Men should not father a child. Must use effective contraception while on study tx.
No concurrent or planned participation in randomized trials for weight loss; exercise interventions; trials targeting insulin, IGF-1, or their receptors; or involving P13K inhibitors (at randomiz).
PRE-STUDY REQUIREMENTS:
H&P (w/date of LMP, menopausal status, ht, wt, waist & hip msmts, BP, perf status, BMI, smoking hx, alcohol intake)*
Pathology of prim tumor (histology, ER/PgR, HER2, pTNM)
WBC, granulocytes, platelets, Hgb, MCV*
SGOT, SGPT, alk phos, serum creat, serum bili, serum B12, fasting glucose*
Bilat mammogram (w/i 12 mos pre-randomiz; MRI may not be substituted)
CXR or chest CT (mandatory)**
Bone scan w/xrays of abnormal areas (if elevated alk phos or symptoms of mets)**
Abdominal imaging (if elevated SGOT, SGPT, or alk phos or symptoms of mets)**
Negative pregnancy test (if applicable; w/i 7 days pre-randomiz)
Blood samples for correlative science (fasting insulin [mandatory]; extra samples for other research [optional])*#
Tumor block submission (w/pt's consent & when requested by Queen's Univ. Dept. of Pathology)
Current meds & indications**
Baseline AE eval (residual AE from prior therapy & baseline symptoms, using current CTCAE version)**
QOL asmts (EORTC QLQ-C30, Trial Specific Checklist)*
Physical Activity items (Nurses Health Study II), Block Alive Screener*
* Within 28 days pre-randomiz. Samples going to Central Lab & not required for eligibility may be drawn after randomiz & prior to start of study tx.
** Between date of 1st histol dx & date of randomiz
# One tube for immediate glucose analysis (mandatory; using standard institutional practice), light green-tops w/lithium heparin for plasma; red-top tubes for serum, & lavender-top tube for DNA. Process per protocol. The green, red, & lavender tubes must be stored at -80oC until shipment on dry ice (q 3-6 mos) to a central lab.
Signed informed consent.