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

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 greatr 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 the d...