ONC201 in Recurrent/Refractory Metastatic Breast Cancer and Advanced Endometrial Carcinoma

Background: The new drug ONC201 have been shown to kill breast cancer and endometrial cancer cells in the laboratory. The exact mechanism of action is not completely clear yet, but the ONC201 destroys the mitochondria inside the cells. Blocking mitochondrial activity may kill tumor cells, which would shrink tumors. Researchers want to see if ONC201 helps shrink tumors of certain breast or endometrial cancers and if that effect is maintained. Objective: To see if ONC201 shrinks tumors with a lasting effect. Eligibility: Adults ages 18 and older who have metastatic breast cancer (hormone-positive or triple-negative) or metastatic endometrial cancers. Design: Participants will be screened with: * Medical history * Physical exam * Heart, blood, and urine tests * Computed tomography (CT) and bone scans * Review of medical report and tumor sample * Participants will have a tumor biopsy before starting treatment and after 5 weeks taking the study drug. A scan or ultrasound may be used to guide the biopsy. Patients will receive local anesthetic and a needle will remove a small piece of tumor. * The study will be done in 28-day cycles. Every day 1 of each cycle participants will repeat most screening tests, will be seen by the physician and receive a supply of the study drug. * Participants will take the study drug by mouth once every 7 days. They will keep a diary of when they take the drug and any side effects. During cycle 1, participants will get weekly calls to discuss their health and symptoms. Images will be repeated every 2 cycles to evaluate response to the treatment.

Background: * Advanced breast cancer and endometrial cancer have limited treatment options. Current treatments provide a modest improvement in progression free survival, but no treatments improve survival. * ONC201 is the founding member of a novel class of anticancer drugs called imipridones. The exact mechanism of ONC201 is unknown at this time, but preclinical data suggests that it causes global downregulation of mitochondrial genes leading to mitochondrial damage and ultimately non-apoptotic cell death. * Preclinical studies have demonstrated that ONC201 selectively kills various cancer cells, including breast cancer cells (hormone-receptor positive cell lines, human epidermal growth factor receptor 2 (HER2+) cell line as well as triple negative breast cancer cell lines) and endometrial cancer cells, while having little effect on normal cells. * An on-going phase I study of ONC201 has demonstrated clinical benefit in some solid tumors, including endometrial cancer. Objectives: * Cohort 1: To determine the progression free survival (PFS) at 8 months of ONC201 in metastatic hormone receptor positive breast cancer (HR+BC) * Cohort 2: To determine the overall response rate (ORR) of ONC201 in metastatic triple negative breast cancer (TNBC) * Cohort 3: To determine the overall response rate (ORR) of ONC201 in advanced endometrial cancer (EC) Eligibility: Selected Inclusion Criteria * Histologically confirmed metastatic breast cancer or endometrial cancer with appropriate immunohistochemistry (IHC) testing and confirmation of HER2 non-amplification required for the breast cancer cohorts (cohorts 1 and 2) * Age 18 years or older * Female and male breast cancer patients are eligible for the breast cancer cohorts * Eastern Cooperative Oncology Group (ECOG) 0 or 1 * Measurable metastatic disease with greater than or equal to 1 biopsiable lesion with willingness to undergo a biopsy * Cohort 1 Hormone receptor + breast cancer (HR+BC) requires prior treatment with greater than or equal to 2 lines of hormonal treatment. No prior treatment required for cohorts 2/3 (TNBC and EC). * Adequate hematopoietic, hepatic and renal function Selected Exclusion Criteria * Patients who have received chemotherapy in the previous 3 weeks (6 weeks for nitrosoureas or mitomycin); other investigational agents within 3 weeks or a programmed cell death protein 1 (PD1)/programmed death-ligand 1 (PDL1) agent within 4 weeks prior to first dose of study treatment. * Radiotherapy less than or equal to 4 weeks before first dose of study treatment. * Symptomatic central nervous system (CNS) metastases. Asymptomatic or brain metastases treated greater than 4 weeks from first dose of study treatment are allowed. * History of invasive malignancy less than or equal to 3 years * Known history of cardiac arrhythmias including uncontrolled atrial fibrillation, tachyarrhythmias or bradycardia. * History of congestive heart failure (CHF), or myocardial infarction (MI) or stroke in the previous 3 months will be excluded. * Started denosumab or bisphosphonate therapy within 28 days prior to Cycle 1 Day 1 * Human immunodeficiency virus (HIV), Hepatitis B, or Hepatitis C infection Design: * This is a phase II single arm study of ONC201 divided in three cohorts, each cohort with different type of metastatic, advanced disease: * Cohort 1: HR+ breast cancer (male and female) * Cohort 2: Triple negative breast cancer (male and female) * Cohort 3: Endometrial cancer (female only) * All patients will receive ONC201 at the recommended phase 2 dose (RP2D) of 625mg by mouth every 7 days with each cycle being 28 days long. Patients will receive ONC201 as long as they derive clinical benefit or toxicity becomes impeditive * Patients will be evaluated for toxicity every 4 weeks by Common Terminology Criteria for Adverse Events (CTCAE) v5.0 and for response every two cycles (8 weeks) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.