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

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Brief Title

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

Official Title

A Phase 2 Study of ONC201 in Recurrent/Refractory Metastatic Breast Cancer and Advanced Endometrial Carcinoma

Brief 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

      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 reponse to the treatment.

      ...
    

Detailed Description

      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.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Cohort 1 - Progression-free survival (PFS)

Secondary Outcome

 Cohorts 1,2, and 3 - tabulation of adverse event type and grade

Condition

Triple Negative Breast Cancer

Intervention

ONC201

Study Arms / Comparison Groups

 Arm 1
Description:  Single arm divided in three cohorts, each cohort with a different type of metastatic disease: ER + breast cancer, triple negative breast cancer, and endometrial cancer

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

30

Start Date

January 17, 2018

Completion Date

December 30, 2027

Primary Completion Date

August 1, 2022

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, 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...
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Alexandra S Zimmer, M.D., , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT03394027

Organization ID

180034

Secondary IDs

18-C-0034

Responsible Party

Sponsor

Study Sponsor

National Cancer Institute (NCI)


Study Sponsor

Alexandra S Zimmer, M.D., Principal Investigator, National Cancer Institute (NCI)


Verification Date

November 5, 2020