Oral ONC201 in Treating Patients With Advanced Solid Tumors

PRIMARY OBJECTIVES:

I. To determine the recommended phase II dose of single agent ONC201 orally once every three
weeks.

SECONDARY OBJECTIVES:

I. To characterize pharmacokinetics of ONC201. II. To assess serum biomarkers of therapeutic
response to ONC201. III. To assess preliminary antitumor activity of ONC201 as a single agent
in advanced solid tumors.

OUTLINE: This is a dose-escalation study.

Patients receive ONC201 orally (PO) on day 1. Courses repeat every 21 days for a total of 2
courses.

After completion of study treatment, patients are followed up for 4 weeks.

Inclusion Criteria:

- Patients with an advanced solid tumor that is refractory to standard treatment, or for
which no standard therapy is available, or the subject refuses standard therapy

- Eastern Cooperative Oncology Group (ECOG) performance status =< 1

- All patients must have measurable or evaluable disease defined by Response Evaluation
Criteria In Solid Tumors (RECIST) 1.1 criteria; if the patient has received prior
radiation therapy one measurable lesion must be outside the irradiated field; lesions
within an irradiated field will be followed as non-target lesions and considered
evaluable; if the only site of measurable disease is within a previously irradiated
field then 6 months must have elapsed between the completion of radiation therapy and
entry on study to be considered measurable

- Patients are eligible for enrollment if they have not had prior investigational or
approved cytotoxic chemotherapy within 28 days prior to the first dose (week 1, day
1); 42 days in the case of alkylating agents; 28 days or 5 half-lives (whichever is
less; but not less than 14 days) in case of investigational or approved molecularly
targeted agent; 14 days in the case of radiotherapy; any number of prior therapies is
allowable

- All adverse events grade =< 2 related to prior therapies (chemotherapy, radiotherapy,
and/or surgery) must be resolved, except for alopecia or neuropathy; patients are
eligible for enrollment if they have had no surgery in the prior 6 weeks (minor
surgical procedures such as skin biopsies and port placement done on an outpatient
basis do not require a waiting period)

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Hemoglobin >= 9.0 mg/dL without transfusion in 2 prior weeks

- Total bilirubin within normal range; for patients with liver metastases, serum
bilirubin =< 1.5 x upper limit of normal (ULN)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate transaminase [SGPT]) =< 2.5 x
upper limit of normal

- Measured OR estimated creatinine clearance >= 40 mL/min/1.73 m^2 for patients with
creatinine levels above normal

- Men or women treated or enrolled on this protocol must agree to use double barrier
contraceptives; oral, implantable, or injectable contraceptives are not considered
effective for this study; women of child-bearing potential must have a negative serum
pregnancy test =< 72 hours prior to initiating treatment; subjects must agree to use
double barrier contraceptive therapy for the duration of study participation, and 4
months after completion of ONC201 administration; should a woman become pregnant or
suspect she is pregnant while she or her partner is participating in this study, she
should inform her treating physician immediately

- Tumor specimen (paraffin-embedded block or frozen tissue) from prior resection or
biopsy available that is sufficient to perform pharmacodynamic assays (>= 3 slides for
immunohistochemistry [IHC]) - mandatory for patients in the dose expansion cohort only

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Patients with symptomatic brain metastases are excluded; however, patients with
asymptomatic central nervous system (CNS) metastases may participate in this trial;
the patient must have completed any prior local treatment for CNS metastases > 28 days
prior to study entry including radiotherapy or surgery; patients receiving steroids
for CNS metastases may not participate on this study

- Prior bevacizumab for treatment of glioblastoma or high grade glioma

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to ONC201 or its excipients

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection or psychiatric illness/social situations that would limit compliance with
study requirements

- Patient is unable or unwilling to abide by the study protocol or cooperate fully with
the investigator

- Patients with a known human immunodeficiency virus (HIV)-positive test on combination
antiretroviral therapy are ineligible for the initial first-in-man trial

- Patient has active cardiac disease including any of the following:

- Corrected QT (QTc) > 500 msec on screening electrocardiogram (ECG) (using the QTc
Fridericia [F] formula)

- Angina pectoris that requires the use of anti-anginal medication

- Ventricular arrhythmias except for benign premature ventricular contractions

- Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled
with medication

- Conduction abnormality requiring a pacemaker

- Valvular disease with document compromise in cardiac function

- Symptomatic pericarditis

- Patient has a history of cardiac dysfunction including any of the following:

- Myocardial infraction within the last 6 months, documented by persistent elevated
cardiac enzymes or persistent regional wall abnormalities on assessment of left
ventricular ejection fraction (LVEF) function

- History of documented congestive heart failure (New York Heart Association
functional classification III-IV)

- Documented cardiomyopathy

- Patient with stroke in the last 3 months

- Patients with a history of seizures with in the past 3 months

- Impairment of gastrointestinal (GI) function or GI disease that may significantly
alter the absorption of ONC201 (uncontrolled nausea, vomiting, diarrhea, malabsorption
syndrome, or small bowel resection)

- Patients who have been treated with any hematopoietic colony-stimulating growth
factors (e.g., filgrastim [G-CSF], granulocyte-macrophage colony-stimulating factor
[GM-CSF]) =< 2 weeks prior to starting study drug; erythropoietin or darbepoetin
therapy, if initiated at least 2 weeks prior to enrollment, may be continued

- Women who are pregnant or breast feeding or adults of reproductive potential not
employing an effective method of birth control; double barrier contraceptives must be
used through the trial by both sexes; oral, implantable, or injectable contraceptives
are not considered effective for this study

- Women of child-bearing potential must have a negative serum pregnancy test =< 72 hours
prior to initiating treatment

- Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, must use highly effective contraception during treatment and for 16
additional weeks after stopping treatment; the highly effective contraception is
defined as either:

- True abstinence: when this is in line with the preferred and usual lifestyle of
the subject; periodic abstinence (e.g., calendar, ovulation, symptothermal,
post-ovulation methods) and withdrawal are not acceptable methods of
contraception

- Sterilization: have had surgical bilateral oophorectomy (with or without
hysterectomy) or tubal ligation at least six weeks ago; in case of oophorectomy
alone, only when the reproductive status of the woman has been confirmed by
follow up hormone level assessment

- Male partner sterilization (with the appropriate post-vasectomy documentation of
the absence of sperm in the ejaculate); for female subjects on the study, the
vasectomized male partner should be the sole partner for that patient

- Use of a combination of any two of the following (a+b):

1. Placement of an intrauterine device (IUD) or intrauterine system (IUS)

2. Barrier methods of contraception: condom or occlusive cap (diaphragm or
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal
suppository

- Oral contraception, injected or implanted hormonal methods are not allowed

- Fertile males, defined as all males physiologically capable of conceiving
offspring must use condom during treatment and for an additional 16 weeks after
stopping treatment

- Female partner of male study subject should use highly effective contraception
during dosing of any study agent and for 16 weeks after final dose of study
therapy