Phase 2 Study of ONC201 in Neuroendocrine Tumors

Primary Objective To demonstrate objective responses using MRI or CT, positron emission
tomography - computerized tomography (PET-CT) and/or PET-MRI imaging. The same CT or MRI
imaging to assess disease burden at study entry will be compared at week 6 and 3 months.
Patients without progression at 3 months will continue treatment and have imaging at 6, 9 and
12 months after study entry. Metabolic response will be compared with study entry PET-CT or
PET-MRI and scans at 6 weeks, 3 months and 12 months.

Secondary Objectives Progression - free Survival: This will be calculated according to
Response Evaluation Criteria In Solid Tumors (RECIST) or Response Assessment in
Neuro-Oncology (RANO) and /or development of new disease

Overall survival: Overall survival will be determined by email or telephone contact.

PG-PG (only): to determine efficacy of ONC201 by reduction in dose of anti-hypertensive
medications.

Study Design: Phase 2 open-label fixed dose study Metastatic neuroendocrine tumors including
PC-PG are rare diseases. This study design has been chosen to see whether ONC201 is
associated with reduction of anti-hypertension medications, safety and significant efficacy
against neuroendocrine tumors, especially PC-PG.

The recommended phase II dose as flat every 3 week dosing of 625mg orally every 3 weeks will
be used. The same imaging at study entry will be used at subsequent time points (CT or MRI
for week 6 and 3, 6, 9, and 12 months; PET-CT or PET-MRI will be at 6 weeks 3 months and 12
months. Imaging modality choice will be influenced by the quality of prior scans of the
subject and will be ordered so clinical comparison is possible.

Inclusion Criteria:

- Subjects must have unresectable, recurrent, locally advanced, or metastatic
neuroendocrine tumor including A) Cohort A. Unresectable, recurrent, locally advanced,
or metastatic Pheochromocytoma-paraganglioma (PC-PG) who have failed or are refractory
to available therapies . N=12. B) Cohort B will include only patients with
unresectable, locally advanced or metastatic tumors who have failed or are refractory
to available therapyOther neuroendocrine cancer varieties as characterized by
expression of neuroendocrine markers on tumor tissue including CD56, synaptophysin, ,
chromogranin and/or presence of a detectable serum or urine biomarker
(3-methoxytyramine, normetanephrine, metanephrines, homovanillic acid (HVA),
vanillylmandelic acid (VMA), and dopamine, Varieties will include neuroblastoma, Ewing
sarcoma, neuroectodermal tumor, clear call sarcoma, myoepithelial tumor, primitive
neuroectodermal tumor (PNET), desmoplastic small round cell tumor, round cell sarcoma,
and unresectable, metastatic or locally advanced , well-differentiated neuroendocrine
tumors who have relapsed or are refractory to at least 2 systemic therapies (e.g.
lanreotide, sunitinib, or everolimus). Patients with small cell carcinomas will not be
included in this clinical trial.N=12

- There is no limit on number of prior therapies.

- Subjects must have normal organ and marrow function as defined below. Studies should
be done within 3 weeks prior to enrollment

- Hemoglobin ≥ 10.0 g/dl

- Leukocytes ≥ 1500/mcL

- Absolute neutrophil count ≥ 1,000/mcL

- Platelet count ≥ 75000/mcL

- Total bilirubin within 1.5 x normal institutional limits

- Aspartate aminotransferase (AST) (SGOT) ≤ 5 X institutional upper limit of normal

- Alanine aminotransferase (ALT) (SGPT) ≤ 5 X institutional upper limit of normal

- Serum Creatinine <3.0mg/dL

- ≥ 1 lesion detectable on CT, MRI, 18FDG PET-CT, or PET-MRI

- Subjects must have the ability to understand and the willingness to sign a written
informed consent document

- Performance status: Karnofsky Performance status ≥ 60%

Exclusion Criteria:

- Subjects not able to take oral drugs

- Subjects receiving any other investigational agents

- Subjects receiving cytotoxic chemotherapy

- Patients who occasionally or regularly use medications that impact dopamine receptor
signaling and can cause side effects in people with neuroendocrine tumors including
PC-PG such as metaclopromide, chlorpromazine, prochlorperazine, droperidol, ephedrine,
pseudoephedrine, fenfluramine, methylphenidate, phentermine, amitryptiline,
imipramine, tranylcypromine, moclobemide, phenelzine, paroxetine, and fluoxetine

- Subjects with uncontrolled intercurrent illness including, but not limited to ongoing
or active infection, symptomatic congestive heart failure, unstable angina pectoris,
cardiac arrhythmia, severe, uncontrolled hypertension (systolic
>150/diastolic>100mmHg) or other symptoms of catecholamine excess after efforts to
achieve adequate alpha blockade then beta blockade

- Psychiatric illness/social situations that would limit compliance with study
requirements including returning for scans, taking oral medication, home monitoring of
blood pressure and heart rate, recording side effects in a self-report diary, or
becoming pregnant while on study drug

- Pregnant and breast-feeding subjects

- Patients with prolactinomas