mTORC1/2 Inhibitor AZD2014 or the Oral AKT Inhibitor AZD5363 for Recurrent Endometrial and Ovarian

PRIMARY OBJECTIVES: I. To determine the maximally tolerated dose (MTD) and recommended phase II dose (RP2D) of the combinations of AZD2014 + olaparib and confirmation of recommended phase 2 dose (RP2D) for the AZD5363 + olaparib combination in patients with recurrent endometrial, recurrent triple negative breast, recurrent high-grade serous ovarian, or recurrent breast cancer, BRCA mutant ovarian cancer. SECONDARY OBJECTIVES: I. To determine the tolerability of the RP2D of AZD2014 + olaparib and AZD5363 + olaparib. II. To determine the safety and observed toxicities of the combination of AZD2014 + olaparib and AZD5363 + olaparib in patients with recurrent endometrial, recurrent triple negative breast, recurrent high-grade serous ovarian, or BRCA mutant ovarian cancer. III. To estimate the activity of these drug combinations at all dose levels in each patient cohort by objective response rate and proportion of patients surviving progression free (PFS) at 6 months. IV. To determine response duration of these combinations at all dose levels. V. To determine the pharmacokinetics (PK) of each agent alone and in combination to assess the presence of any drug interaction between the two co-administered agents. EXPLORATORY TRANSLATIONAL OBJECTIVES: I. To determine if response to therapy is associated with molecular profile of the tumor (including, but not limited to, molecular aberrations in the phosphoinositide-3-kinase \[PI3K\]- v-akt murine thymoma viral oncogene homolog \[AKT\]- mechanistic target of rapamycin \[mTOR\] pathway or defects in homologous recombination) before treatment. II. To examine associations with early changes in functional proteomic biomarkers in tumor biopsies before and after treatment and tumor response in patients with recurrent endometrial, recurrent triple negative breast, recurrent high-grade serous ovarian, or BRCA mutant ovarian cancer treated with the investigational agents. III. To determine the molecular profile of unusual responders (significant regression of disease or progression of disease). IV. To provide data to investigate the relationship between plasma concentrations/exposure and changes in safety and efficacy outputs to facilitate population analysis by sponsor. OUTLINE: This is a dose-escalation study. Patients are assigned to 1 of 3 treatment arms. ARM I (CONTINUOUS AZD2014 DOSING): Patients receive olaparib orally (PO) twice daily (BID) on days 1-28 (days 5-28 of course 1 and alone on days -3 to -1 of week -1) and vistusertib PO BID on days 1-28 (alone on days 1-4 of week 1). ARM II (INTERMITTENT AZD2014 DOSING): Patients receive olaparib PO BID on days 1-28 (days 3-28 on course 1 and alone on days -5 to -3 of week -1) and vistusertib PO BID for 2 days on and 5 days off (alone on days 1-2 of week 1). ARM III (INTERMITTENT AZD5363 DOSING): Patients receive olaparib PO BID on days 1-28 (on days 5-28 of course 1 and alone on days -3 to -1 of week -1) and capivasertib PO BID for 4 days on and 3 days off (alone on days 1-4 of week 1). In all arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up within 4 weeks.