A Phase II Trial of Neoadjuvant MK-2206 in Combination With Either Anastrozole if Postmenopausal or Anastrozole and Goserelin if Premenopausal in Women With Clinical Stage 2 or 3 PIK3CA Mutant Estrogen Receptor Positive and HER2 Negative Invasive Breast Cancer
I. To determine the pathologic complete response (pCR) rate of neoadjuvant MK-2206 (Akt
inhibitor MK-2206) in combination with anastrozole (goserelin [goserelin acetate] is added
if premenopausal) in women with clinical stage II or III
phosphatidlinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutated
estrogen receptor (ER)+/human epidermal growth factor receptor 2 (HER2)- breast cancer.
I. To determine the safety profile of neoadjuvant MK-2206 in combination with anastrozole
(goserelin is added if premenopausal) in women with clinical stage II or III PIK3CA mutated
ER+/HER2- breast cancer.
II. To estimate the rate of clinical response and radiologic response using the World Health
Organization (WHO) criteria.
I. For pre and post-menopausal women separately, to examine serum estradiol levels prior to
pre-registration, prior to registration, after 2 cycles of anastrozole plus MK-2206 (cycle 3
day 1) and pre surgery.
II. To examine the percent change in the apoptotic index after 2 weeks of combination
therapy with MK-2206 and anastrozole (cycle 1 day 17) relative to apoptotic index after 4
weeks of treatment with anastrozole alone (pre MK-2206).
III. To examine the change in Ki67 levels after 2 weeks of combination therapy with MK-2206
and anastrozole (cycle 1 day 17) relative to that after 4 weeks of treatment with
anastrozole alone (pre MK-2206).
IV. To estimate the proportion of patients whose Ki67 values is at most 10% after 2 weeks of
combination therapy with MK-2206 and anastrozole (cycle 1 day 17) among those whose Ki67 was
more than 10% or more after 4 weeks of treatment with anastrozole alone (pre MK-2206).
V. To examine the pharmacodynamic effect of MK-2206 in combination with anastrozole (or
anastrozole in combination with goserelin) on PI3K pathway signaling using serially
collected tumor specimens.
VI. To explore molecular mechanisms which could affect tumor response to combination MK-2206
and anastrozole (or anastrozole in combination with goserelin) in PIK3CA mutant ER+ breast
VII. To examine the PIK3CA mutation status in circulating plasma DNA prior to and following
therapy on serially collected peripheral blood (pre anastrozole, pre MK-2206, cycle 1 day
17, and at the time of surgery) and to correlate with tumor tissue PIK3CA status.
VIII. To examine PIK3CA mutation status of the residual cancer collected at the time of
surgery post 4 cycles of neoadjuvant MK-2206 and anastrozole.
Patients receive Akt inhibitor MK-2206 orally (PO) on days 2, 9, 16, and 23; anastrozole PO
daily on days 1-28; and goserelin acetate subcutaneously (SC) on day 1 (premenopausal
patients only). Treatment repeats every 28 days for 4 courses in the absence of disease
progression or unacceptable toxicity.
Standard of care surgery (breast and axillary lymph node surgery) is performed 1-3 weeks
following the last dose of Akt inhibitor MK-2206.
After completion of study treatment, patients are followed up for 30-60 days.
Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Pathological complete response (pCR) based on tumor Ki-67 value
A ninety percent confidence interval for the true pathologic complete response rate will be calculated using the Duffy-Santer approach.
Up to day 17 of course 1
United States: Food and Drug Administration
|Washington University School of Medicine||Saint Louis, Missouri 63110|
|University of Chicago Comprehensive Cancer Center||Chicago, Illinois 60637-1470|