ONC201 in Recurrent/Refractory Metastatic Breast Cancer and Advanced Endometrial Carcinoma
Condition: Triple Negative Breast Cancer; Endometrial Cancer; Hormone Receptor Positive, HER2 Negative Breast Cancer
MeSH terms: Breast Neoplasms; Endometrial Neoplasms; Triple Negative Breast Neoplasms
Intervention: ONC201
Intervention description: 625 mg by mouth every 7 days; each cycle = 28 days. Patients will receive ONC201 as long as they derive clinical benefit or toxicity becomes impeditive.
Intervention MeSH terms: TIC10 compound
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 30.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Imipridones; TNBC; Metastatic; Male Breast Cancer

Summary:

      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.
    

Eligibility criteria:

        -  INCLUSION CRITERIA FOR COHORT 1: HORMONE RECEPTOR POSITIVE BREAST CANCER:

          -  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.

        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
             programmed cell death protein 1 (PD1)/programmed death-ligand 1 (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 corrected Q wave T wave (QT) interval by Fridericia (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.

          -  Human immunodeficiency virus (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 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.

          -  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
             cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) 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
             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.

        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...