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

 <TAB>Medical history

 <TAB>Physical exam

 <TAB>Heart, blood, and urine tests

 <TAB>CT and bone scans

 <TAB>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 reponse 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, 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 ORR of ONC201 in advanced endometrial cancer (EC)

 Eligibility:

 Selected Inclusion Criteria

 -  Histologically confirmed metastatic breast cancer or endometrial cancer with appropriate
 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

 -  ECOG 0 or 1

 -  Measurable metastatic disease with greater than or equal to 1 biopsiable lesion with
 willingness to undergo a biopsy

 -  Cohort 1 (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 PD1/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 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 CHF, or 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

 -  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 CTCAE v5.0 and for response

 every two cycles (8 weeks) by RECIST 1.1.
-  INCLUSION CRITERIA FOR COHORT 1: HORMONE RECEPTOR POSITIVE BREAST CANCER:

 -  Patients must have histologically confirmed persistent or recurrent invasive
 metastatic hormone receptor positive, 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 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) Dualprobe 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 measurable disease, per RECIST 1.1.

 -  Patients must have at least one lesion deemed safe to biopsy and be willing to undergo
 mandatory biopsies.

 -  HR+BC patients must have received prior treatment with at least 2 lines of hormonal
 treatment (SERM, 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.

 -  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 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.

 EXCLUSION CRITERIA FOR COHORT 1: HORMONE RECEPTOR POSITIVE BREAST CANCER:

 -  Patients who have received chemotherapy in the previous 3 weeks (6 weeks for
 nitrosoureas or mitomycin); other investigational agents within 3 weeks or a PD1/PDL1
 agent within 4 weeks prior to first dose of study enrollment.

 -  Patients who have undergone radiotherapy within 4 weeks of first dose of study
 treatment.

 -  Patients with a history of another invasive malignancy within the last 3 years.

 -  Patients with symptomatic brain metastases or leptomeningeal involvement. Patients
 with asymptomatic or brain metastases that have been treated with radiation at least 4
 weeks prior to first dose of study treatment are allowed.

 -  History of allergic reactions attributed to compounds of similar chemical or biologic
 composition to imipridones or other agents used in study.

 -  Patients with a mean QTcF interval of > 500 msec or receiving therapeutic agents known
 to prolong the QT interval

 -  Known history of cardiac arrhythmias including uncontrolled atrial fibrillation,
 tachyarrhythmias or bradycardia, history of congestive heart failure, or myocardial
 infarction or stroke in the previous 3 months will be excluded.

 -  Known history of gastrointestinal illnesses that would preclude the absorption of
 ONC201, which is an oral agent.

 -  Patients with bone metastases who have initiated denosumab or bisphosphonate therapy
 within 28 days prior to Cycle 1 Day 1.

 -  Pregnant women are excluded from this study because ONC201 has the potential for
 teratogenic or abortifacient effects. Because there is an unknown but potential risk
 for adverse events in nursing infants secondary to treatment of the mother with
 ONC201, breastfeeding should be discontinued if the mother is treated with ONC201.
 These potential risks may also apply to other agents used in this study.

 -  HIV-positive patients on combination antiretroviral therapy are ineligible because of
 the potential for pharmacokinetic interactions with ONC201.

 -  Patients who have known active Hepatitis B, or Hepatitis C infections.

 INCLUSION CRITERIA FOR COHORT 2: TRIPLE NEGATIVE BREAST CANCER:

 -  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 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.

 -  Eligible patients may or may not have received prior chemotherapy and there is no
 limit to the number of prior chemotherapy. Patients are also eligible if they have
 received treatment with immunotherapy, such PD-1 inhibitors, PD-L1 inhibitors or CTLA4
 inhibitors.

 -  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
 Gilber'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.

 EXCLUSION CRITERIA FOR COHORT 2: TRIPLE NEGATIVE BREAST CANCER:

 -  Patients who have received chemotherapy in the previous 3 weeks (6 weeks for
 nitrosoureas or mitomycin); other investigational agents within 3 weeks or a PD1/PDL1
 agent within 4 weeks prior to first dose of study treatment.

 -  Patients who have undergone radiotherapy within 4 weeks of first dose of study
 treatment.

 -  Patients with a history of another invasive malignancy within the last 3 years.

 -  Patients with symptomatic brain metastases or leptomeningeal involvement. Patients
 with asymptomatic or brain metastases that have been treated with radiation at least 4
 weeks prior to first dose of study treatment are allowed.

 -  History of allergic reactions attributed to compounds of similar chemical or biologic
 composition to imipridones or other agents used in study.

 -  Patients with a mean QTcF interval of > 500 msec or receiving therapeutic agents known
 to prolong the QT interval

 -  Known history of cardiac arrhythmias including uncontrolled atrial fibrillation,
 tachyarrhythmias or bradycardia, history of congestive heart failure, or myocardial
 infarction or stroke in the previous 3 months will be excluded.

 -  Known history of gastrointestinal illnesses that would preclude the absorption of
 ONC201, which is an oral agent

 -  Patients with bone metastases who have initiated denosumab or bisphosphonate therapy
 within 28 days prior to Cycle 1 Day 1.

 -  Pregnant women are excluded from this study because ONC201 has the potential for
 teratogenic or abortifacient effects. Because there is an unknown but potential risk
 for adverse events in nursing infants secondary to treatment of the mother with
 ONC201, breastfeeding should be discontinued if the mother is treated with ONC201.
 These potential risks may also apply to other agents used in this study.

 -  HIV-positive patients on combination antiretroviral therapy are ineligible because of
 the potential for pharmacokinetic interactions with ONC201.

 -  Patients who have known active Hepatitis B, or Hepatitis C infections.

 INCLUSION CRITERIA FOR COHORT 3: ENDOMETRIAL CANCER:

 -  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.

 -  Women with endometrial cancer must have had at least one prior line of therapy in the
 metastatic/recurrent setting but there is no limit to the number of prior chemotherapy
 lines. Patients are eligible if they have received treatment with immunotherapy, such
 PD-1 inhibitors, PD-L1 inhibitors or CTLA4 inhibitors.

 -  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...