ONC201 With and Without Methionine-Restricted Diet in Patients With Metastatic Triple Negative Breast Cancer

PRIMARY OBJECTIVES:

I. To determine response rate to ONC201 with and without a methionine-restricted diet in
patients with metastatic triple negative breast cancer (TNBC).

SECONDARY OBJECTIVES:

I. To determine progression-free survival (PFS) to ONC201 with and without a
methionine-restricted diet in patients with metastatic TNBC.

II. To determine clinical benefit rate (response rate plus stable disease) at 4- months to
ONC201 with and without a methionine-restricted diet in patients with metastatic TNBC.

III. To determine overall survival (OS) to ONC201 with and without a methionine-restricted
diet in patients with metastatic TNBC.

IV. To determine the safety of adding a methionine-restricted diet to ONC201 in patients with
metastatic TNBC.

V. To assess metabolic indices in patients with metastatic TNBC treated with ONC201 and a
methionine-restricted diet.

VI. To assess the expression of TRAIL receptor in circulating tumor cells (CTCs) prior,
during and upon progression in patients with metastatic TNBC treated with ONC201 with and
without a methionine-restricted diet.

EXPLORATORY OBJECTIVES:

I. To determine time to development of brain metastases or worsening of brain metastases in
patients with metastatic TNBC treated with ONC201 with and without a methionine-restricted
diet.

OUTLINE: Participants are randomized to 1 of 2 arms.

ARM A: Participants receive Akt/ERK inhibitor ONC201 orally (PO) on days 3, 10, and 17.
Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

ARM B: Participants receive Akt/ERK inhibitor ONC201 PO on days 3, 10, and 17. Participants
also receive methionine-restricted diet PO on days 1-5, 8-12, and 15-19. Courses repeat every
21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up every 3 months for 2 years.

Inclusion Criteria:

- Metastatic or unresectable TNBC (estrogen receptor [ER] < 1%, progesterone receptor
[PR] < 1% and HER2 negative either by immunohistochemistry [IHC] or in situ
hybridization method by American Society of Clinical Oncology [ASCO]-College of
American Pathologists [CAP] guidelines)

- Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
within 28 days prior to registration

- Written informed consent and Health Insurance Portability and Accountability Act
(HIPAA) authorization for release of personal health information. NOTE: HIPAA
authorization may be included in the informed consent or obtained separately

- Any number of prior lines of systemic therapy for metastatic disease

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1

- Prior cancer treatment must be completed at least 14 days prior to registration and
the subject must have recovered from all reversible acute toxic effects of the regimen
(other than alopecia) to =< grade 1 or to baseline prior to initiation of that
therapy. Other than neuropathy, which must have resolved to =< grade 2

- No active central nervous system (CNS) metastatic disease; subjects with prior
definitive treatment of their CNS disease by surgical resection, stereotactic body
radiation therapy (SBRT) or whole-brain radiotherapy (WBRT) > 28 days ago will be
eligible if asymptomatic and off systemic steroids

- Life expectancy of greater than 12 weeks

- Absolute neutrophil count (ANC) > 1.5 x 10^3/uL

- Platelet count >= 100 x 10^3/uL

- Hemoglobin >= 9 g/dL

- Total bilirubin < 1.5 x upper limit of normal (ULN)

- Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) and
alanine aminotransferase (ALT)/serum glutamic-pyruvic transaminase (SGPT) < 1.5 x ULN

- Creatinine < ULN (institutional normal)

- Females of childbearing potential must have a negative serum pregnancy test within 7
days prior to registration. NOTE: Females are considered of childbearing potential
unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal
ligation, or bilateral oophorectomy), they are naturally postmenopausal for at least
12 consecutive months

- Females of childbearing potential must be willing to abstain from heterosexual
activity or must agree to use adequate contraception (hormonal or barrier method) for
the duration of study participation and for 90 days after discontinuation of study
treatment

- Ability of the subject to understand and comply with study procedures for the entire
length of the study

- Able to swallow ONC201

Exclusion Criteria:

- No prior therapy with TRAIL receptor agonists

- Active infection requiring systemic therapy. Patients with a known history of human
immunodeficiency virus (HIV) must have a CD4 count >= the institutional lower limit of
normal within 28 days prior to registration. Patients with HIV must also be on a
stable antiretroviral regimen for >= 28 days before registration

- Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the
mother is being treated on study)

- Known additional malignancy that is active and/or progressive requiring treatment;
exceptions include basal cell or squamous cell skin cancer, in situ cervical or
bladder cancer, or other cancer for which the subject has been disease-free for at
least three years

- Treatment with any investigational drug agent =< 14 days prior to registration or
within 5 half-lives of that investigational product, whichever is longer

- Subject who has received radiotherapy =< 14 days prior to registration, and who has
not recovered to grade 1 or better from related side effects of such therapy (except
alopecia)

- Subject who has had major surgery =< 14 days prior to registration or has not
recovered from major side effects of the surgery (tumor biopsy is not considered as
major surgery)

- Known hypersensitivity to any of the excipients of ONC201

- Any impairment of gastrointestinal (GI) function or GI disease that may significantly
alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled
nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)

- Any concurrent severe and/or uncontrolled medical condition that would, in the
investigator's judgment, cause unacceptable safety risks, contraindicate subject
participation in the clinical study or compromise compliance with the protocol (e.g.
chronic pancreatitis, chronic active hepatitis, active untreated or uncontrolled
fungal, bacterial or viral infections, etc.)

- Patients who follow a vegan or vegetarian diet