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

Inclusion Criteria

• •Patients must have histologically confirmed persistent or recurrent invasive metastatic hormone receptor positive, human epidermal growth factor receptor 2 (HER2) normal breast cancer for which standard curative measures do not exist or are no longer effective. Hormone receptor positive is defined as estrogen receptor (ER) positive greater than or equal to 10% by immunohistochemistry (IHC) and/or progesterone receptor (PR) positive greater than or equal to 10% by IHC.HER2 will be considered negative per American Society of Clinical Oncology (ASCO)-College of American Pathologists (CAP) guidelines (HER2 test result as negative if a single test (or both tests) performed show: 1) IHC 1+ as defined by incomplete membrane staining that is faint/barely perceptible and within \>10% of the invasive tumor cells; 2) IHC 0 as defined by no staining observed or membrane staining that is incomplete and is faint/barely perceptible and within less than or equal to 10% of the invasive tumor cells; or 3) ISH negative based on: a) Single-probe average HER2 copy number \<4.0 signals/cell or b) Dualprobe HER2/ chromosome enumeration probe 17 (CEP17) ratio \<2.0 with an average HER2 copy number \<4.0 signals/cell)and HER2 testing must have been performed in a laboratory accredited by the College of American Pathologists (CAP) or another accrediting entity.
• •Patients must have measurable disease, per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
• •Patients must have at least one lesion deemed safe to biopsy and be willing to undergo mandatory biopsies.
• •Hormone receptor + breast cancer (HR+BC) patients must have received prior treatment with at least 2 lines of hormonal treatment (Selective estrogen receptor modulators (SERM), aromatase inhibitor (AI), or fulvestrant) and deemed ineligible for further hormonal therapy. Patients may have received prior chemotherapy and there is no limit to the number of prior chemotherapy.
• •Age greater than or equal to18 years.
• •Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• •Adequate renal function, defined as serum creatinine less than or equal to 1.5 X upper limit of normal (ULN), or measured creatinine clearance greater than or equal to 60 mL/min/1.
• •Adequate hepatic function, defined as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels less than or equal to 3 X ULN and total bilirubin \< 1.5 X ULN, unless known diagnosis of Gilbert's syndrome, where bilirubin less than or equal to 5 mg/dL will be permitted. Gilbert's syndrome will be defined as elevated unconjugated bilirubin, with conjugated (direct) bilirubin within the normal range and less than 20% of the total. Total bilirubin will be permitted up to 5 mg/dL, if patients have historical readings consistent with the definition of Gilbert's syndrome prior to entering study.
• •Adequate bone marrow function, defined as absolute neutrophil (ANC) greater than or equal to 1,500/mm\^3 (greater than or equal to 1.5 X10\^6/L), platelet count greater than or equal to 75,000/mm\^3 (greater than or equal to 75 X10\^6/L), and hemoglobin greater than or equal to 9 mg/dL (transfusion to obtain hemoglobin greater than or equal to 9 mg/dL within 24 hours prior to dosing is allowed).
• •Patients must be able to swallow oral medications (capsules) without chewing, breaking, crushing, opening or otherwise altering the product formulation.
• •The effects of ONC201 on the developing human fetus are unknown. For this reason and because imipridone agents are known to be teratogenic, female patients must either be of non-reproductive potential (i.e., post-menopausal by history: greater than or equal to 60 years old and no menses for greater than or equal to 1 year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry and agree to use contraception or abstinence during the study and for and for at least 4 weeks after the final dose of any study-related medications. Male patients must use at least two forms of contraception during the study and for at least 4 weeks after the final dose of any study-related medications or have a partner who is not of reproductive potential.
• •Ability of subject to understand and the willingness to sign a written informed consent document.
• •Patients must have histologically or cytologically confirmed persistent or recurrent invasive, metastatic triple negative breast cancer (TNBC) for which standard curative measures do not exist or are no longer effective. TNBC, defined as estrogen receptor (ER) negative (ER \< 10%), PR negative (PR \<10%). HER2 will be considered negative per ASCO-CAP guidelines (HER2 test result as negative if a single test (or both tests) performed show: 1) IHC 1+ as defined by incomplete membrane staining that is faint/barely perceptible and within \>10% of the invasive tumor cells; 2) IHC 0 as defined by no staining observed or membrane staining that is incomplete and is faint/barely perceptible and within less than or equal to 10% of the invasive tumor cells; or 3) ISH negative based on: a) Single-probe average HER2 copy number \<4.0 signals/cell or b) Dual-probe HER2/CEP17 ratio \<2.0 with an average HER2 copy number \<4.0 signals/cell) and HER2 testing must have been performed in a laboratory accredited by the College of American Pathologists (CAP) or another accrediting entity.
• •Patients must have received at least one line of prior chemotherapy in the metastatic setting.
• •Patients must have measurable disease, per RECIST 1.1.
• •Patients must have at least one lesion deemed safe to biopsy and be willing to undergo mandatory biopsies.
• •Age greater than or equal to 18 years.
• •ECOG performance status 0 or 1
• •Adequate renal function, defined as serum creatinine less than or equal to 1.5 X upper limit of normal (ULN), or measured creatinine clearance greater than or equal to 60 mL/min/1.
• •Adequate hepatic function, defined as AST and ALT levels less than or equal to 3 X ULN and total bilirubin \< 1.5 X ULN, unless known diagnosis of Gilbert's syndrome, where bilirubin less than or equal to 5 mg/dL will be permitted. Gilbert's syndrome will be defined as elevated unconjugated bilirubin, with conjugated (direct) bilirubin within the normal range and less than 20% of the total. Total bilirubin will be permitted up to 5 mg/dL, if patients have historical readings consistent with the definition of Gilbert's syndrome prior to entering study.
• •Adequate bone marrow function, defined as absolute neutrophil (ANC) greater than or equal to 1,500/mm\^3 (greater than or equal to 1.5 X10\^6/L), platelet count greater than or equal to 75,000/mm\^3 (greater than or equal to 75 X10\^6/L), and hemoglobin greater than or equal to 9 mg/dL (transfusion to obtain hemoglobin greater than or equal to 9 mg/dL within 24 hours prior to dosing is allowed)
• •Patients must be able to swallow oral medications (capsules) without chewing, breaking, crushing, opening or otherwise altering the product formulation.
• •The effects of ONC201 on the developing human fetus are unknown. For this reason and because imipridone agents as well as other therapeutic agents used in this trial are known to be teratogenic. Female patients must either be of non-reproductive potential (i.e., post-menopausal by history: greater than or equal to 60 years old and no menses for greater than or equal to 1 year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry and agree to use contraception or abstinence during the study and for and for at least 4 weeks after the final dose of any study-related medications. Male patients must use at least two forms of contraception during the study and for and for at least 4 weeks after the final dose of any study-related medications or have a partner who is not of reproductive potential.
• •Ability of subject to understand and the willingness to sign a written informed consent document.
• •Patients must have histologically or cytologically confirmed persistent or recurrent advanced or metastatic invasive endometrial cancer (EC) for which standard curative measures do not exist or are no longer effective.
• •Patients must have measurable disease, per RECIST 1.1
• •Patients must have at least one lesion deemed safe to biopsy and be willing to undergo mandatory biopsies.
• •Age greater than or equal to 18 years.
• •ECOG performance status 0 or 1
• •Adequate renal function, defined as serum creatinine less than or equal to 1.5 X upper limit of normal (ULN), or measured creatinine clearance greater than or equal to 60 mL/min/1.
• •Adequate hepatic function, defined as AST and ALT levels less than or equal to 3 X ULN and total bilirubin \< 1.5 X ULN, unless known diagnosis of Gilbert's syndrome, where bilirubin less than or equal to 5 mg/dl will be permitted. Gilbert's syndrome will be defined as elevated unconjugated bilirubin, with conjugated (direct) bilirubin within the normal range and less than 20% of the total. Total bilirubin will be permitted up to 5 mg/dL, if patients have historical readings consistent with...