Oral ONC201 in Adult Recurrent Glioblastoma
Phase: PHASE2
Conditions: Glioblastoma, Diffuse Midline Glioma, H3 K27M Glioma, Thalamic Glioma, Infratentorial Glioma, Basal Ganglia Glioma
Sponsor: Jazz Pharmaceuticals

Protocol ONC006 
Version 14 / June 3, 2021 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol Title: Oral ONC201 in Adult Recurrent Glioblastoma 
Protocol Number: ONC006 (NCT02525692) 
Protocol Date: 03 June 2021 (Version 14.0) 
 
 

Protocol ONC006 
Version 14 / June 3, 2021 
1 
 
 
 
 
PROTOCOL TITLE: Oral ONC201 in Adult Recurrent Glioblastoma 
 
Protocol Number: ONC006 
Protocol Version: 14 
 
Date: June 3, 2021 
 
 
Sponsor: 
Chimerix, Inc 
2505 Meridian Parkway, Suite 100 
Durham, NC 27713 
Investigational Agent: ONC201 
IND: 121496 
 
Prior Versions: 
 
Protocol version 
Date of version 
Version 1 
Not Issued 
Version 2 
10/20/15 
Version 3 
Not Issued 
Version 4 
1/6/17 
Version 5 
Not Issued 
Version 6 
Not Issued 
Version 7 
5/26/17 
Version 8 
Not Issued 
Version 9 
11/7/17 
Version 10 
6/1/18 
Version 11 
Not Issued 
Version 12 
10/1/18 
Version 13 
9/16/19 
Version 14 
6/3/21 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 

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TABLE OF CONTENTS 
1. 
OBJECTIVES ..................................................................................................................................... 4 
1.1 
Study Design ......................................................................................................................................... 4 
1.2 
Primary Objectives ............................................................................................................................ 4 
1.3 
Secondary Objectives ........................................................................................................................ 4 
1.4 
Intratumoral Correlatives ............................................................................................................... 5 
1.5 
Endpoints .............................................................................................................................................. 5 
2. 
BACKGROUND ................................................................................................................................ 5 
2.1 
Study Disease ....................................................................................................................................... 5 
2.2 
IND Agent ............................................................................................................................................... 6 
2.3 
Clinical Studies ................................................................................................................................. 15 
2.4 
Rationale ............................................................................................................................................. 18 
2.5 
Correlative Studies Background ................................................................................................ 19 
3. 
PARTICIPANT SELECTION ....................................................................................................... 20 
3.1 
Eligibility Criteria ............................................................................................................................ 20 
3.2 
Exclusion Criteria ............................................................................................................................ 22 
3.3 
Inclusion of Women and Minorities .......................................................................................... 23 
4. 
REGISTRATION PROCEDURES ................................................................................................ 23 
5. 
TREATMENT PLAN ..................................................................................................................... 24 
5.1 
Treatment Regimen ........................................................................................................................ 24 
5.2 
Pre-Treatment Criteria ................................................................................................................. 25 
5.3 
Treatment and Evaluation Cycles .............................................................................................. 26 
5.4 
End of Treatment Visit ................................................................................................................... 26 
5.5 
General Concomitant Medication and Supportive Care Guidelines .............................. 27 
5.6 
Criteria for Taking a Participant Off Protocol Therapy ..................................................... 27 
5.7 
Duration of Follow Up .................................................................................................................... 28 
5.8 
Criteria for Taking a Participant Off Study ............................................................................. 28 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ............................................................................ 29 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ....................................... 30 
7.1 
Reporting of Serious Adverse Events ....................................................................................... 31 
7.2 
Expected Toxicities ......................................................................................................................... 32 
7.3 
Adverse Event Characteristics .................................................................................................... 32 
8. 
PHARMACEUTICAL INFORMATION ...................................................................................... 32 
8.1 
Drug Substance Description ........................................................................................................ 33 
8.2 
Drug Product Description............................................................................................................. 33 
8.3 
Drug Product Supply, Administration and Inventory ........................................................ 34 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES .................................................... 35 
9.1 
Pharmacodynamic Studies ........................................................................................................... 35 
9.2 
ONC201 Plasma Concentration ................................................................................................... 36 
10. 
STUDY CALENDAR .................................................................................................................. 37 
11. 
MEASUREMENT OF EFFECT................................................................................................. 39 
11.1 
Definitions .......................................................................................................................................... 39 

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11.2 
Disease Parameters ........................................................................................................................ 40 
11.3 
Response/Progression Categories ............................................................................................ 40 
11.4 
Methods for Evaluation of Disease ............................................................................................ 42 
11.5 
Evaluation of Best Response ........................................................................................................ 42 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ................................................. 42 
12.1 
Data Reporting ................................................................................................................................. 42 
12.2 
Data Collection ................................................................................................................................. 43 
13. 
STATISTICAL CONSIDERATIONS ....................................................................................... 45 
13.1 
Study Design ...................................................................................................................................... 45 
13.2 
Interim Analyses .............................................................................................................................. 48 
13.3 
Statistical Methods for Efficacy Analyses ................................................................................ 49 
13.4 
Demographic and Baseline Characteristics ........................................................................... 49 
14. 
PROTOCOL SIGNATURES...................................................................................................... 50 
REFERENCES .......................................................................................................................................... 51 
APPENDIX A: KARNOFSKY PERFORMANCE STATUS (KPS) CRITERIA............................... 52 
APPENDIX B: TABLE OF EIAEDs AND NON-EIAEDs* ................................................................................................ 53 
APPENDIX C: NEUROLOGIC ASSESSMENT IN NEURO-ONCOLOGY (NANO) SCALE ......... 54 
APPENDIX D: MD Anderson Symptom Inventory - Brain Tumor (MDASI - BT) ............. 56 

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1. OBJECTIVES 
 
The primary objective of this phase II trial is to determine the efficacy of oral ONC201, an oral 
small molecule DRD2 antagonist that induces the integrated stress response to inactivate Akt and 
ERK signaling and induce the pro-apoptotic TRAIL pathway in adults with adult recurrent 
gliomas. Secondary objectives include assessment of intratumoral drug concentrations, safety, 
overall radiographic response (ORR), ORR duration, overall survival (OS), and progression-free 
survival (PFS) and correlation with serum and tumor tissue biomarkers. 
 
1.1 
Study Design 
 
This is a Phase II multi-center clinical trial with six arms and appropriate stopping rules 
for poor efficacy. 
 
All subjects in Arm A will receive oral ONC201 every 3 weeks and all subjects in Arm 
B, C, D, E, and F will receive oral ONC201 every 1 week. 
 
Arm A, B, D, and F will enroll 16-30 evaluable patients each. Arm C will enroll 
6 patients who have sufficient resected tumor tissue for correlative studies. Arm E will 
enroll 12 patients who have sufficient resected tumor tissue for correlative studies. All 
subjects in Arm C and E will have surgical resection of their tumor 1 day after the second 
(or more) dose of ONC201. 
 
All subjects will remain on study treatment until progressive disease, unacceptable 
toxicity, or withdrawal of consent. 
 
All patients will undergo clinical evaluation after each cycle (3 weeks). Neuroimaging 
studies (contrast-enhanced brain MRI or CT for patients unable to undergo MRI) will be 
performed at baseline, at 8 weeks from treatment initiation, and then every 8 weeks 
thereafter. 
 
1.2 
Primary Objectives 
 
To evaluate the anti-tumor activity of ONC201 among patients with recurrent 
glioblastoma or recurrent WHO Grade IV gliomas when treated with ONC201 as 
assessed by the 6-month progression-free survival (PFS6) rate using the Response 
Assessment in Neuro-Oncology (RANO) criteria, for high-grade glioma (HGG). 
 
1.3 
Secondary Objectives 
 
• Assess the intratumoral concentration of ONC201 in glioma biopsies. 
• Estimate the Overall Survival (OS). 
• Estimate the Overall PFS 
• Estimate the Overall Radiographic Response (ORR) rate based on RANO-HGG and 
RANO for low-grade glioma (RANO-LGG) criteria. 
• Estimate the ORR duration. 

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• Correlate clinical outcome with serum and archival tumor tissue biomarkers. 
• Assess the safety, toxicities, and tolerability of ONC201 in adults with recurrent HGG. 
 
1.4 
Intratumoral Correlatives 
 
• To determine the intratumoral concentration of ONC201 achieved in 
patients treated with ONC201 
• To characterize the pharmacodynamic effects of ONC201 on tumor through IHC 
analysis of ATF4, CHOP, and DR5 on resected tumors of patients exposed to ONC201 
 
1.5 
Endpoints 
-Efficacy 
• Response by RANO-HGG 
• Response by RANO-LGG 
• Duration of Response by either RANO-HGG or RANO-LGG 
• Progression-free survival by RANO-HGG or RANO-LGG 
• Overall survival 
 
-Safety 
• Adverse events 
• Laboratory evaluations 
• KPS status 
• Vital signs 
• Physical examinations 
 
-Other 
• Quality of Life (MDASI-BT) 
• NANO 
 
2. BACKGROUND 
 
2.1 
Study Disease 
 
In 2014, there were over 23,300 new cases of cancer involving the brain and nervous 
system and over 14,000 deaths (Siegel 2014). GBM is the most common and lethal 
primary malignancy of the central nervous system (CNS) and occurs for over 15% of all 
brain cancers (Patel 2014). Despite standard of care therapies which include surgical 
resection, radiation and chemotherapies, the 5-year survival rate for GBM remains at 
<10% (Stupp 2009). Thus, GBM is an obvious unmet clinical need with dismal survival 
and limited treatment options that offer meaningful survival benefit. Disease recurrence is 
common and occurs within months of the completion of first line treatment. The choice 
of therapy after recurrence is limited. In a phase II study, patients treated with 
bevacizumab for recurrent disease achieved a 48% PFS-6 (Friedman 2009). 

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Unfortunately, the PFS-6 observed in studies of bevacizumab did not confer a survival 
advantage (Wick 2017). Large meta-analyses of clinical trials evaluating efficacy of 
salvage therapeutics (excluding bevacizumab) consistently reported PFS-6 rates of 9-11% 
(Ballman 2007; Lamborn 2008; Wu 2010). Therefore, GBM is a difficult-to-treat disease 
with a large unmet need for innovative, safe, and effective therapies useful in recurrent 
GBM. 
 
2.2 
IND Agent 
 
ONC201 is a first-in-class small molecule with consistent antitumor activity in difficult- 
to-treat cancers as demonstrated using in vitro, ex vivo, and in vivo models. Favorable 
attributes of ONC201 observed in preclinical models include antitumor efficacy with 
infrequent administration, broad-spectrum activity independent of mutations or tumor 
type, orally active, high safety margins, synergistic activity with many approved 
therapies, highly stable, highly water soluble, and ability to penetrate the blood-brain 
barrier. The mechanism of action of ONC201 appears to involve the activation of the 
integrated stress response (ISR) that causes a downstream inactivation Akt and ERK 
signaling as well as induction of the pro-apoptotic TRAIL pathway. The efficacy of 
ONC201 has been demonstrated in numerous solid and liquid tumor cell lines and patient 
samples that are refractory to chemotherapy and targeted therapies. Importantly, ONC201 
is effective in tumor cells harboring diverse mutations in genes such as p53, KRAS, Raf, 
EGFR and others that result in resistance to chemotherapy and targeted therapies. 
 
• 
Preclinical Efficacy and Tolerability 
 
ONC201 induces cell death in a broad spectrum of tumor types harboring diverse 
mutations in genes such as p53, KRAS, Raf, EGFR and others that result in resistance to 
chemotherapies and targeted agents. ONC201 induces caspase-mediated apoptosis in 
cancer cell lines and exhibits broad-spectrum cytotoxicity in vitro. ONC201 exhibits 
promising anticancer activity that has been demonstrated in multiple malignancies in 
preclinical models that include subcutaneous, orthotopic, and transgenic models in 
addition to a large body of in vitro data that demonstrate its cytotoxic effects and its 
mechanism of action. ONC201 displays single agent anti-tumor effects (Figure 2.1) in 
subcutaneous and orthotopic colon cancer, subcutaneous triple negative breast cancer, 
subcutaneous non-small cell lung cancer, subcutaneous and orthotopic intracranial 
glioblastoma, and immunocompetent lymphoma transgenic mouse models. ONC201 also 
cooperates extensively with paclitaxel, docetaxel, and bevacizumab. We have chosen to 
target GBM for ONC201 development given the wealth of positive preclinical 
information that was generated with the study drug. 
 
Preclinical efficacy studies revealed that ONC201 has peak efficacy when administered 
at 25 mg/kg orally once every two weeks. Administering doses more frequent than every 
2 weeks or at doses higher than 25 mg/kg did not yield additional efficacy. To begin to 
estimate the safety margin of ONC201 in vivo, exploratory exaggerated dosing studies 
were conducted in mice. ONC201 was administered IP to cohorts of mice as a single dose 
either as an IP bolus or fractionated IP dose. The single bolus dose was well tolerated up 

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Figure 2.1 ONC201 antitumor activity in subcutaneous xenografts. Subcutaneous 
xenografts in athymic nude mice receiving a single dose of ONC201 (100 mg/kg, IP). 
Data shown is approximately 1 week following single dose administration and relative to 
the tumor size on the day of administration. 
 
to 220 mg/kg. At 250 mg/kg, single rapidly administered IP doses of ONC201 caused 
labored breathing, dyspnea, and death. A dose of 250 mg/kg ONC201 administered IP 
and divided into four equivalent doses was well-tolerated. Preclinical efficacy of 
ONC201 in mice was achieved at doses as low as 12.5 mg/kg with maximal efficacy 
observed in at least one model at 25 mg/kg. Administering ONC201 twice a week in nude 
mice at 25 mg/kg caused a mild reversible skin rash following two weeks of 
administration that was not observed with weekly administration. 
 
In addition to potent in vitro activity, ONC201 shrinks temozolomide-resistant GBM 
xenografts (Figure 2.2A) and prolongs the survival of mice with orthotopic xenografts as 
a single agent and in combination with bevacizumab (Figure 2.2B). Corroborating 
observations by other investigators have demonstrated the compelling single agent 
efficacy of ONC201 in radio- and chemo-resistant GBM cell lines. Other studies have 
demonstrated highly potent cytotoxic activity with ONC201 in three-dimensional 
neurosphere cultures of newly diagnosed and recurrent GBM patient samples. 
 
 
 

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Figure 2.3 GI50 GBM cell lines 
at 72 hours after treatment with 
ONC201 or DMSO (n = 3). 
Figure 2.4 T98G TMZ-resistant and radio-resistant 
GBM cells following treatment with ONC201 at 
indicated concentrations (72 hr). 
 
 
ONC201 demonstrates p53-independent activity in human GBM cell lines in the low 
micromolar range (Figure 2.3). ONC201 exerts a strong cytotoxic effect, unlike 
temozolomide, against tumor cells isolated from a freshly resected GBM with an 
Figure 2.2 (A) Relative tumor size in a subcutaneous xenograft of T98G in 
mice treated with a single dose of vehicle, ONC201 (30 mg/kg, orally), or 
bevacizumab (10 mg/kg, iv) (n = 8). (B) Survival of mice harboring SF767 
intracranial tumors with a single oral dose of vehicle (n = 8), ONC201 
(25 mg/kg, n = 7), bevacizumab (bev) (10 mg/kg, iv, n = 6), or ONC201and 
bevacizumab (n = 7) at 2 weeks after implantation. 
A 
ONC201

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Figure 2.6 Proposed model of ONC201 
mechanism of action in tumor cells. 
 
oligodendroglial component that was previously resected and irradiated. Observations by 
external investigators demonstrate the compelling single agent efficacy of ONC201 in 
radio- and chemo-resistant GBM cell lines (Figure 2.4) and 3D neurosphere cultures 
(Figure 2.5). 
 
 
 
 
• 
Mechanism of Action 
 
ONC201 is a selective antagonist of the G protein-coupled receptor DRD2 that was 
identified through a phenotypic screen as a p53-independent small molecule inducer of 
TRAIL gene transcription in tumor 
cells. A series of gene expression 
profiling and cell signaling 
investigations have unraveled signaling 
pathways that are engaged in tumor 
cells following ONC201 treatment. 
 
Downstream of target engagement, 
ONC201 activates the integrated stress 
response (ISR), which is the same 
signaling pathway activated by ER 
stress-inducing compounds such as 
proteasome inhibitors (e.g. 
bortezomib). When the ISR is activated 
by ER stress-inducing compounds, the 
pathway is often referred to as the ER 
stress response. ONC201 causes an 
early-stage increase in the 
phosphorylation of eIF2-alpha at serine 
51, which results in attenuation of protein translation and upregulation of the 
transcription factor ATF4 (Figure 2.6). ATF4 upregulates CHOP, which is also a 
transcription factor that regulates several apoptosis-related genes such as the TRAIL- 
Figure 2.5 ONC201 kills newly diagnosed and recurrent GBM neurospheres. Cell 
viability of neurosphere GBM cultures following ONC201 treatment (72 hr). 

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receptor DR5. ATF4 and CHOP upregulate expression of TRB3, which interacts directly 
with Akt to decrease its kinase activity. TRB3 also serves as a scaffold protein in the 
MAPK signaling pathway that can negatively regulate this pathway. Decreased levels of 
phospho-MEK, -ERK, and -Akt have been documented in response to ONC201. The 
decreased ERK and Akt kinase activity results in less phosphorylated Foxo3a, which is a 
transcription factor that regulates both the TRAIL and DR5 genes. Dephosphorylated 
Foxo3a undergoes nuclear translocation and activation in response to ONC201. 
 
In summary, ONC201 inhibits DRD2 to cause downstream activation of ATF4, which 
causes induction of genes that lead to apoptosis. DRD2 antagonism also downregulates 
Akt and ERK activity to cooperatively induce complementary downstream apoptotic 
effects. ONC201 may not activate eIF2-alpha through PERK. This distinct mechanism 
may explain the lack of cross-resistance between ONC201 and other ER stress-inducing 
agents such as bortezomib. In addition, ONC201 has enhanced antitumor efficacy in 
combination with bortezomib that may be explained by engaging parallel stimuli that lead 
to an enhanced activation of the ISR in tumor cells. 
 
• 
Nonclinical Safety/Toxicology Studies in Animals 
 
In rats and dogs, ONC201 was better tolerated when administered orally compared to 
intravenously. In rat non-GLP studies, the No-Observed Adverse Effect Level (NOAEL) 
was 225 mg/kg with oral administration compared to 100 mg/kg with a 2 hour infusion 
and 50 mg/kg with a 30 minutes infusion. Non-GLP clinical observations in rodents 
included decreased activity, altered gait, and mortality. In dog non-GLP studies, the 
NOAEL dose was at least 120 mg/kg with oral administration and clinical observations 
were limited to emesis and changes in fecal consistency. The non-GLP studies only 
evaluated at clinical observations, weight gain, food consumption and gross findings at 
necropsy. In general the toxicology/safety studies indicate that the acute toxicities 
associated with ONC201 are limited to the day of administration and are reversible. 
 
In dog GLP studies, the NOAEL was at least 42 mg/kg. Observations were limited to 
decreased activity, decreased food consumption, emesis, salivation, and/or soft, loose or 
mucous feces. In rat GLP studies, the NOAEL was at least 125 mg/kg. Observations 
included decreased activity, decreased food consumption, decreased body weight, and 
abnormal stance and gait. Minor changes in serum chemistries were noted, largely in the 
225 mg/kg rats that included slight increases in cholesterol and chloride. The 
significance of these findings is unknown as other clinical chemistry and histology did 
not corroborate this observation (e.g. liver findings). Rats receiving 125 or 225 mg/kg 
ONC201 had mild edema and inflammation that was primarily submucosal in the 
stomach and was completely resolved by day 19. 
 
2.2..1 
Non-GLP Safety Studies 
 
Non-GLP studies were conducted in rats and dogs to assess clinical observations 
and body weight with ONC201. 

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Non-GLP toxicology studies in rats 
The ability of rats to tolerate ONC201 by intravenous administration was 
explored as a function of infusion time. Clinical observations with intravenous 
administration included decreased activity, salivation, abnormal gait and stance, 
labored respiration, pale skin, nasal discharge, prostration during the dose, mild 
body twitching, and red discharge from the mouth. 
 
The NOAEL following administration of ONC201 to Sprague-Dawley rats by a 
30-minute intravenous infusion was 50 mg/kg. The NOAEL following 
administration of ONC201 to Sprague-Dawley rats by a 2-hour intravenous 
infusion was 100 mg/kg. Administration of 100 mg/kg ONC201 by intravenous 
infusion over 30 minutes resulted in the death of one male rat. Administration of 
200 mg/kg ONC201 by a 2-hour infusion resulted in the death of both animals 
during the infusion period. Following these observations, the tolerance of oral 
ONC201 was explored given the potential to lower acute toxicity by lowering 
Cmax. Clinical observations with oral exaggerated doses of ONC201 included 
decreased activity, abnormal gait and stance, prostration, irregular respiration, 
moderate twitching, red discharge on the muzzle, scant feces, hunched posture, 
not eating, piloerection, and skin cold to touch. The NOAEL following 
administration of ONC201 to Sprague-Dawley rats by oral gavage was 
225 mg/kg. 
 
Non-GLP toxicology studies in dogs 
In parallel to non-GLP toxicology studies in rats, the ability of beagle dogs to 
tolerate ONC201 was explored. No deaths were observed at any doses in dogs. 
The NOAEL following the 30-minute intravenous infusion of ONC201 to beagle 
dogs is considered to be at least 33.3 mg/kg. The 2 hour-intravenous infusion of 
16.7 mg/kg ONC201 was not associated with any clinical signs of toxicity. 
Therefore the NOAEL following a 2 hour-intravenous infusion of ONC201 to 
beagle dogs is considered to be greater than 16.7 mg/kg, though higher doses 
were not explored as the oral route was selected for further development based on 
observations in rats. The NOAEL with oral ONC201 was considered to be at least 
120 mg/kg in dogs. Clinical observations at doses of 66.7 to 120 mg/kg were 
limited to emesis and changes in fecal consistency. 
 
2.2.3.2 GLP Toxicology and Safety Studies 
 
Single Dose Oral Toxicity Study in Dogs (GLP) 
A GLP study was performed to evaluate the toxicity and toxicokinetics of 
ONC201 following a single oral dose to Beagle dogs followed by a 2-day or an 
18-day recovery period. Dogs received a single dose of 0, 4.2, 42, or 120 mg/kg 
by oral gavage. There was no mortality observed in this study. There were no 
definitive ONC201-related effects on group mean body weight or body weight 
gain, ECG rhythm or morphology, mean heart rate or arterial blood pressure, 
urinalysis, hematology parameters, coagulation parameters, clinical chemistry 
parameters, erythrocyte morphology, gross findings on necropsy, changes in 

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absolute or organ to body or organ to brain weights. 
 
Although not statistically significant, there were some dose-related decreases in 
group mean food consumption for the first week following dosing. The 120 
mg/kg females had statistically significantly decreased group mean food 
consumption compared to the vehicle control group on Days 14, 15 and 18. There 
were no clinical signs of toxicity noted following a single dose of 4.2 mg/kg 
ONC201. At a dose of 42 mg/kg and 120 mg/kg, some dogs had clinical 
observations at approximately 1 hour post-dose including decreased activity, 
emesis, salivation, and/or soft, loose or mucous feces. Of uncertain relationship to 
ONC201 administration was the unusual finding of mononuclear cell 
inflammation in the blood vessels of the brain, which was multifocal and mild in 
one high dose female at Day 3, multifocal and minimal in one high dose female at 
Day 19, and minimal and focal in one control female at Day 19. Similar findings 
were not noted in any male animal. 
 
Based on the results of this study, the NOAEL following oral administration of 
ONC201 at single doses of 4.2, 42 or 120 mg/kg to Beagle dogs is considered to 
be at least 42 mg/kg. 
 
Single Dose Oral Toxicity and Toxicokinetic Study in Rats with a 19-Day 
Recovery and a 30-Minute Intravenous Infusion Toxicokinetic Arm (GLP) 
 
A GLP study was performed to evaluate the toxicity of ONC201 following a 
single oral dose in Sprague-Dawley rats with necropsy after a 2-day or an 18-day 
recovery period. Rats received 0, 12.5, 125, or 125 mg/kg ONC201 by oral 
gavage. 
 
There was no mortality observed in this study. There were no definitive ONC201- 
related effects on coagulation parameters, clinical chemistry parameters, gross 
findings at necropsy. There were no clinical signs of toxicity noted at single doses 
up to 125 mg/kg ONC201. There were no ONC201-related statistically 
significant changes in hematology parameters or clinical chemistries outside of 
the historical control range for these values. 
 
At a dose of 225 mg/kg, clinical signs of toxicity were limited on the day of dose 
administration to one out of twenty males and one out of twenty females that 
showed signs of decreased activity and abnormal gait and stance. The male was 
also noted to have increased respiration. All were normal by Day 2. No ONC201 
related changes were noted during the functional observational battery (CNS 
activity) performed on Day 1 between 1 and 2 hr post-dose with the exception of 
one 225 mg/kg female noted as having decreased activity. A statistically 
significant decrease in group mean body weight gain was noted on Day 7 for the 
225 mg/kg males. A statistically significant decrease in group mean food 
consumption was noted on Day 7 for the 225 mg/kg males. 

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On Day 3 the 225 mg/kg females also had increased glucose, cholesterol, sodium 
and chloride. Sodium and chloride were statistically significantly increased for the 
125 mg/kg females. Only cholesterol and chloride were outside historical control 
ranges for this laboratory on day 19. As the increase in cholesterol was only noted 
for the females and no corresponding liver findings were observed, the 
significance of this finding is unknown. Though within normal historical control 
values for these laboratories, chloride remained increased for the 225 mg/kg 
males while cholesterol remained increased for the 225 mg/kg females. 
 
Changes in brain and liver weights were noted but did not occur in a dose- 
dependent manner and no microscopic changes were noted for in these organs for 
the high dose females. These changes were considered incidental and unrelated to 
treatment. At the Day 3 necropsy, ONC201-related minimal to mild edema and/or 
mixed cell inflammation was present in the non-glandular stomach of 225 mg/kg 
males and females. This edema and inflammation was primarily submucosal, 
although in some animals the inflammation involved the serosa or mesentery. 
Two males and one female had minimal focal ulceration of the overlying 
squamous epithelium. Similar stomach findings were seen in 125 mg/kg animals, 
with a lower incidence than in 225 mg/kg. There was complete resolution of all 
stomach lesions at the Day 19 necropsy, indicating full recovery. 
 
Based on the results of this study, the NOAEL following oral administration of 
ONC201 at single doses of 12.5, 125 or 225 mg/kg to Sprague-Dawley rats is 
considered to be at least 125 mg/kg. 
 
Evaluation of the Effect of ONC201 Dihydrochloride on Respiratory Function 
Following Single-Dose Administration in Rats (GLP) 
 
A GLP study was performed to determine the potential effects of ONC201 
dihydrochloride on respiratory function in rats following a single oral gavage 
administration. Twenty four (6/group) male rats received 0, 12.5, 125, or 225 
mg/kg ONC201 by oral gavage and were monitored in plethysmographic 
chambers. The oral administration of ONC201 dihydrochloride at 12.5 and 125 
mg/kg did not induce any biologically relevant effects on respiratory rate, tidal 
volume or minute volume in conscious male rats. A marginal to moderate 
transient decrease in respiratory rate and minute volume was observed following 
the oral administration of ONC201 dihydrochloride at 225 mg/kg, which resolved 
by 2 hours. 
 
• 
Pharmacokinetic Studies 
 
2.2..1 Pharmacokinetic Studies in Animals 
 
The measured half-life of ONC201 in mice is ~6 hours with intravenous 
administration as measured by an HPLC-UV assay. 

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In rats, exposure to ONC201 was dose-dependent and approximately dose- 
proportional. Exposure to ONC201 was slightly greater in female rats after a 
single oral gavage dose. Plasma T1/2,e ranged from 2.3 to 8.4 hours in 7 of 
8 profiles. Clearance ranged from 7.5 to 23.5 L/hr/kg in 7 of 8 profiles. Volume 
of distribution ranged from ~49 to ~103 L/kg in 6 of 8 profiles. 
 
In dogs, exposure to ONC201 following oral gavage dosing at 4.2, 42, and 120 
mg/kg ONC201 was dose-dependent and increased with greater ONC201 dose 
levels. Exposure to ONC201 was similar in male and female dogs with the 
observation that all mean male Cmax and AUC values were slightly greater than 
those corresponding female values. Elimination of ONC201 from plasma was 
similar between the mid and high dose levels; mean T1/2,e ranged from 4.6 to 
7.8 hours. Mean T1/2,e following the low dose of 4.2 mg/kg was ~1 hour [the 
half-life determined for dogs in the low dose group may represent more of a 
distribution phase half-life rather than the terminal plasma elimination half-life]. 
Overall elimination of ONC201 was greater following the low dose. 
 
2.2.4.2 Pharmacokinetic Studies in Humans 
 
In a phase I dose escalation clinical trial of ONC201 in advanced solid tumors, the 
pharmacokinetics of single agent ONC201 was determined by LC-MS-MS 
analysis of plasma collected in the first cycle of therapy within 21 days of drug 
administration (Fig 2.7; Table 2.1). Trends of increasing exposure with dose were 
consistent with dose proportionality. Patients receiving 625mg ONC201 exhibited 
a mean half-life of 11.3 hours and achieved a Cmax of 3.6 ug/mL (~9.3 uM), 
which occurred at 1.8 hours following administration (Tmax). The mean volume 
of distribution was 369 L, consistent with a large distributive volume. 
 
Mean AUC was 37.7 h.μg/mL and mean CL/F was 25.2 L/h. Generally, CL/F was 
observed to be variable but consistent across all dose groups. There were no 
apparent relationships between drug CL/F and patient sex and age. Noticeable, 
shallow trends were observed with patient weight and BSA. An overall increase 
in CL/F was observed as weight and BSA increased. Although a slight upward 
trend was observed, there was no strong correlation between CL/F and CLCR. 
 
Stronger correlations were observed with the distributive volume estimate and 
patient weight and BSA. An increase in volume of distribution was observed with 
increasing patient weight or BSA, as expected. Trends of decreasing exposure 
with increasing weight were observed in plots of Cmax/Dose and AUC/Dose 
versus patient weight. Weight normalized CL/F was plotted versus Dose, showing 
a similar trend to un-normalized CL/F. 

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**Refer to the current version of the IB for more up-to-date information on 
clinical safety and study progress.** 
 
 
 
Figure 2.7: Mean ONC201 plasma concentrations versus time following 
the first dose of ONC201. Concentrations are shown as (A) A mean for 
each dose cohort, or (B) for individuals treated at 625 mg. 
 
 
 
 
Table 2.1 ONC201 pharmacokinetic parameters determined in 
patients receiving 625 mg ONC201 (n=24). 
 
 
 
 
2.3 
Clinical Studies 
 
 
The clinical safety of ONC201 has been evaluated in a phase I clinical trial. The design 
was an open-label, dose-escalation phase I trial of single agent ONC201 in patients with 
advanced, refractory tumors who had exhausted or refused standard treatment options for 
their respective indications. The primary objective of this study was to determine the 
recommended phase II dose (RP2D) of ONC201 administered orally in patients with 
advanced cancers, as well as to evaluate the safety and tolerability of the drug. Secondary 
objectives included pharmacokinetics and pharmacodynamics evaluation of ONC201 and 
preliminary assessment of anti-tumor efficacy. 
 
An accelerated dose escalation design was employed to reduce the number of patients 
treated at potentially sub-therapeutic dose and to accelerate the determination of the 
recommended phase II dose. Ten evaluable (aged 47-80 years) received oral ONC201 

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once every 3 weeks at five dose levels ranging from 125 to 625 mg. The study design 
included only one patient per cohort until any patient experiences a grade 2 adverse event 
during the first cycle of treatment, defined as 21 days. Five dose levels (125 mg, 250 mg, 
375 mg, 500 mg, 625 mg) were selected for the study. Enrollment at each subsequent 
dose level required that all patients enrolled at the prior dose level completed Cycle 1 
dosing and were evaluated 21 days later to assess safety. 
 
On average, patients received 3.1 doses of ONC201. Nine out of ten patients completed 
at least 2 cycles, 4 patients completed at least four cycles, and one patient received 
> 6 cycles. 625 mg was the highest dose administered and was determined to be the 
RP2D that surpassed the absorption saturation threshold by two dose levels. The only 
adverse event during the dose escalation phase that was possibly attributed to ONC201 
was a low grade fever. No drug-related toxicities Grade >1 were observed in any patients 
in this study. Explorative laboratory studies and physical exams did not reveal any drug- 
related abnormalities. Similarly, cardiovascular assessments revealed no drug-related 
effects. Three MedWatch reports were filed with the FDA that reported events that were 
not attributed to the study drug. 
 
Clinical and laboratory results indicated that the drug possessed biologically activity in 
the treated patients. Patient #3, a 72 year old with advanced clear cell endometrial 
(uterine) cancer had a mixed objective response with >50% decrease in lymphadenopathy 
(10/11 afflicted lymph nodes responded) after 2 doses. Patient #4, a 62-year-old male 
with renal cancer and bone metastasis with debilitating pain in the clavicle experienced 
relief from his clavicular pain. Patient #6, a 69-year-old patient with prostate 
adenocarcinoma, has received 7 doses of ONC201 and has stable disease. Patient #8, a 
71-year old colon cancer patient had stable disease for at least 12 weeks with 4 doses of 
ONC201. 
 
A 47-year-old male with appendiceal cancer (patient #2) had CA27.29 tumor biomarker 
of 30 units that was in the abnormal range, which decreased to 20 units (normal range) 
after 4 doses of ONC201. Given the heterogeneity of the tumor types in the enrolled 
patients, no widely used biomarker was available to uniformly assay all patient samples. 
Since most solid tumors express cytokeratin-18, the serum M30 assay was selected to 
detect a caspase-cleaved form of cytokeratin-18 that occurs during apoptosis. Clinical 
studies have demonstrated the M30 assay to be predictive of clinical response 
(Demiray 2006) in solid tumors. Induction of the M30 assay for apoptosis was noted in 
67% of patients treated at the RP2D with a range of 1.25- to 4-fold increase. 
 
An expansion phase of this Phase I trial with ONC201 enrolled 18 additional patients 
with advanced solid tumors to confirm the tolerability of the 625mg ONC201 RP2D. The 
only adverse events among the 18 patients enrolled in the expansion phase that were 
attributed as possibly-related to ONC201 were: nausea (1 patient), emesis (2 patients), 
and increased level of serum amylase (2 patients). All of these adverse events were 
Grade 1 and reversed rapidly. Laboratory studies and physical exams did not reveal any 
drug-related abnormalities. Similarly, cardiovascular assessments revealed no drug- 
related effects. 

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Another arm of this study has been opened to evaluate weekly dosing. Three patients 
have been treated with 375mg ONC201 on a weekly basis and six patients have been 
treated with 625mg on a weekly basis. There have been no reports to the sponsor of any 
drug-related adverse events in any of these patients. All three 375mg and six of the 
625mg patients have successfully completed the DLT window (21 days). Based on 
these findings, the recommended administration schedule of ONC201 is 625mg once 
every week. 
 
A clinical trial is currently being conducted at the MD Anderson Cancer Center 
investigating the safety of ONC201 in patients with acute leukemias and 
myelodysplastic syndrome (study #2014-0731; NCT02392572). Thus far, 3 patients 
have been enrolled in this study that dosed one patient at 125mg once every three 
weeks, the other patient at 250mg once every three weeks and a third patient at 375mg 
once every three weeks. There were 3 reported instances of febrile neutropenia, lung 
infection (pneumonia) and gastrointestinal disorders. None of these were attributed as 
drug-related by the Investigator. 
 
Study #2014-0632 (NCT02420795) being conducted at the MD Anderson Cancer 
center, is a 3+3 design dose-escalation design to determine the safety of ONC201 in 
patients with relapsed/refractory Non-Hodgkin’s Lymphoma (NHL). Thus far, 2 
patients have been enrolled in this this trial, of ONC201 dosed at 125mg once every 
three weeks. No adverse events have been reported. 
 
Study #PH-077 (NCT02609230) is a Phase I dose-escalation study of ONC201 in 
patients with solid tumors and multiple myeloma, being conducted at Fox Chase Cancer 
Center. Thus far, 5 patients have received ONC201 125mg once every 3 weeks. Patient 
1 experienced an SAE that was initially assessed as possibly drug related (progressed 
from Grade 2 fatigue at baseline to Grade 3 fatigue). The patient had brain metastases at 
baseline and rapid progression of underlying disease and associated symptoms within 
2 weeks of initiating ONC201 treatment. The SAE attribution that triggered the initial 
report is under reassessment based on the evidence of progressive underlying disease. 
 
Early in this study, ONC006 (NCT02525692), seventeen glioblastoma patients were 
treated with 625mg ONC201 q3w as part of Arm A. Prior therapy included radiation, 
surgery, temozolomide, and others except for bevacizumab. Two of 17 patients had 
methylated MGMT; two of 17 patients had no measurable disease at enrollment due to 
salvage surgery. PFS6 was 11.8% with one confirmed partial response by RANO. This 
response occurred in a 22-year-old patient with a secondary glioblastoma possessing a 
H3.3 K27M mutation. Both lesions regressed, overall by 96% after and the patient 
remained on study after >18 months. Six of 17 patients stable disease or a partial 
response as their best overall response by RANO. One patient enrolled after salvage 
surgery was disease-free after > 10 months and remained on therapy. OS has not been 
reached with a median follow-up of 38 weeks (range 4-5). ONC201 was very well 
tolerated with no drug-related SAEs or discontinuation due to toxicity. Two possibly- 
related AEs occurred: one grade 3 neutropenia that did not recur upon rechallenge and 

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one grade 2 allergic reaction that was manageable. Plasma PK at 2 hours post-dose was 
median 2,586 ng/mL (range 1,320-3,660), serum prolactin induction was observed as a 
surrogate marker of target engagement, and DRD2 was expressed in all evaluated 
archival tumor specimens. 
 
Following the response in Arm A, preclinical studies of H3 K27M glioma have indicated 
that tumor cells with this specific mutation are highly responsive to ONC201. 
Furthermore, a patient in Arm B with recurrent H3 K27M glioma recently exhibited an 
unconfirmed complete regression of her thalamic lesion on her first 8 week MRI 
evaluation. 
 
2.4 
Rationale 
 
• 
Rationale for GBM 
 
The first public disclosure of ONC201 is an expired Boehringer Ingelheim patent that 
described ONC201 (and a series of other unrelated small molecules) as having potential 
CNS activity, e.g. as an anticonvulsant (Stähle 1971) An in vitro efficacy screen indicated 
that GBM is more sensitive to ONC201 relative to most other types of solid tumors 
(Figure 2.7). One of the key features in the selection process that identified ONC201 as 
an anticancer agent was its ability to penetrate the blood-brain barrier to address tumors 
residing in the CNS, unlike many available therapies. Ensuing animal studies revealed 
that ONC201 rapidly traverses the blood-brain barrier, is highly bioactive in the brain, 
does not appear to be neurotoxic, and is potently cytotoxic to all tested GBM tumors in 
vitro, ex vivo, and in vivo (Allen 2013b) ONC201 has p53-indepenent activity against 
GBM cell lines, including those with resistance to chemotherapy and radiotherapy. In 
addition to cell lines, ONC201 exerts potent anticancer activity in recurrent GBM 
samples resistant to all standard-of-care therapies. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ONC201 is a first-in-class small molecule that activates the integrated stress response 
(ISR) in tumors cells that leads to downstream anticancer effects that include inactivation 
of prosurvival Akt and ERK signaling along with induction and activation of the TRAIL 
Figure 2.7 In vitro efficacy screen indicating the high 
sensitivity of GBM (brain cancer) to ONC201. 
9 
8 
7 
6 
5 
4 
3 
2 
1 
0 
Average IC50 

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apoptosis pathway (Allen 2013). The efficacy of ONC201 has been consistently 
demonstrated in numerous in vitro and in vivo experiments (subcutaneous, orthotopic, 
and transgenic) by multiple institutions. Despite its strong cytotoxicity in tumor cells, 
ONC201 does not induce cell death in normal cells. In vivo studies indicate that the 
safety margin (ratio of therapeutic dose to lowest dose with a mild adverse event) of 
ONC201 is at least 10-fold in rats and dogs in GLP toxicology studies. The profile of 
ONC201 is well suited for an oncology product: preclinical efficacy with infrequent 
administration, broad-spectrum activity independent of mutations or disease type, orally 
active, compelling safety profile, combines synergistically and safely with many 
approved therapies, highly active by employing a combination of established anti- 
tumor/pro-apoptotic pathways, highly stable, water soluble, and penetrates the blood- 
brain barrier. The high safety and efficacious profile along with its mechanism of action 
makes ONC201 perfectly suited to address GBM by circumventing limitations of 
available therapies. 
 
• 
Rationale for dose schedule 
 
ONC201 will be administered once every three weeks for Arm A and once every one 
week for Arm B and Arm C. These infrequent dosing schedules are selected based on the 
preclinical findings that these schedules are effective and well tolerated in mouse models. 
This observation is rationalized by the sustained intratumoral activity of the molecule for 
several days to weeks following a single dose of the drug. 
 
In preclinical studies, ONC201 acute toxicity is transient and generally resolves within 
several hours of administration. Preclinical data with ONC201 suggests saturation of 
efficacy at a human equivalent of 125mg. A dose of 625 mg is expected to exceed the 
dose (and associated Cmax) with maximal efficacy by 5-fold and thus higher doses may 
not be explored. 
 
The frequency of once a week dosing is being evaluated based on the excellent clinical 
safety and PK observations in the first-in-human study. 
 
2.5 
Correlative Studies Background 
 
The novel mechanism of ONC201 involves DRD2 antagonism, which causes 
downstream induction of integrated stress response and the dual inactivation of Akt and 
ERK that cause downstream effects, such as TRAIL and DR5 induction, suggests several 
molecular markers of response in ONC201-treated cancer patients. Immunohistochemical 
assays for FFPE tumor tissues have been developed for a panel of predictive and 
pharmacodynamic biomarkers based on mechanism of action and preclinical tumor cell 
sensitivity studies. Predictive biomarkers for archival specimens include DRD2, DRD5 
(an opposing family member), and two proteins that couple to GPCRs called TGM-2 and 
KSR-1. These and other markers of the status of the molecular mechanism of ONC201 
will be assessed on archival tumor tissue samples and serum specimens for all patients. 
 
For Arm C, archival and post-treatment (salvage surgery) tumor tissue will be assayed to 

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determine intratumoral ONC201 concentrations and molecular markers of response to 
ONC201. Pharmacodynamic markers for pre- and post-treatment tissue include ATF4, 
CHOP, and DR5 that are robustly upregulated during activation of the integrated stress 
response. 
 
3. PARTICIPANT SELECTION 
 
3.1 
Eligibility Criteria 
 
1. For Arms A, B and C: Histologically confirmed World Health Organization Grade 
IV glioblastoma. 
For Arm D: Must have a WHO Grade IV glioma and the tumor must harbor a histone 
H3 K27M mutation detected in a Clinical Laboratory Improvement Amendment 
(CLIA) certified laboratory by immunohistochemistry or DNA sequencing test on any 
glioma tumor sample. The H3 K27M mutation is often reported as H3 K28M in gene 
sequencing assays. 
For Arm E: Must have clinical and/or radiographic evidence of a midline glioma 
(involving the brainstem, thalamus, spinal cord, hypothalamus, basal ganglia, 
brainstem [non-DIPG], cerebellum, cerebellar peduncle, midline cortex, corpus 
collosum, pineal region, optic tract, or optic chiasm), and be eligible for salvage 
surgical resection as deemed by the site Investigator. 
For Arm F: Must have a diffuse midline glioma involving the brainstem, thalamus or 
spinal cord, without the H3 K27M mutation or with unknown H3 mutation status at 
the time of enrollment. 
 
2. Unequivocal evidence of progressive disease on contrast-enhanced brain CT or MRI 
as defined by RANO-HGG Criteria, or have documented recurrent glioblastoma or 
WHO Grade IV glioma on diagnostic biopsy. For Arm E, patients are not required to 
have evidence of recurrent disease for inclusion. 
 
3. Previous first line therapy with at least radiotherapy and temozolomide. For patients 
with tumors that exhibit unmethylated MGMT promoter, prior treatment with 
temozolomide is not required. For Arms D, E, and F, previous first line therapy with 
at least radiotherapy. 
 
4. For Arm A or D: Any number of recurrences are allowable. 
For Arm B: First recurrence (only) WHO Grade IV glioma. First recurrence is 
defined as progression following initial therapy (i.e., radiation ± chemotherapy). For 
participants who had prior therapy with radiation or chemotherapy for a low-grade 
glioma, the surgical diagnosis of a high-grade glioma will be considered the first 
recurrence. For patients who did not get additional treatment following surgery and 
diagnosis of low-grade glioma, surgical diagnosis of high-grade glioma will not be 
considered the first recurrence. Instead, progression after treatment will be considered 
first recurrence. 
For Arm C: Patients must have clinical and/or radiographic evidence of first 
recurrence of glioblastoma and be eligible for salvage surgical resection as deemed by 

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the site Investigator. 
For Arm E: Recurrent disease is not required. Patients must have a midline glioma 
(defined as a glioma involving the pons, thalamus, spinal cord, hypothalamus, basal 
ganglia, brainstem [non-DIPG], cerebellum, cerebellar peduncle, midline cortex, 
corpus collosum, pineal region, optic tract, or optic chiasm), and be eligible for 
salvage surgical resection as deemed by the site Investigator. 
 
5. Interval of at least 90 days from the completion of radiotherapy to the first dose of 
ONC201. If patients are within 90 days of radiotherapy, then the progressive lesion 
must be outside of the high-dose radiation target volume or have unequivocal 
evidence of progressive tumor on a biopsy specimen. 
 
6. From the projected start of scheduled study treatment, the following time periods 
must have elapsed: 5 half-lives from any investigational agent, 4 weeks from 
cytotoxic therapy (except 23 days for temozolomide and 6 weeks from nitrosoureas), 
6 weeks from antibodies, or 4 weeks (or 5 half-lives, whichever is shorter) from other 
anti-tumor therapies. 
 
7. All adverse events Grade > 1 related to prior therapies (chemotherapy, radiotherapy, 
and/or surgery) must be resolved, except for alopecia. 
 
8. Male or Female age ≥16 years. 
 
9. Karnofsky Performance Status (KPS) ≥ 60 (see Appendix A). 
 
10. Adequate organ and marrow function as defined below, all screening labs should be 
performed within 14 days of treatment initiation: 
• leukocytes 
≥ 3,000/mcL 
• absolute neutrophil count 
≥ 1,500/mcL 
• platelets 
≥ 100,000/mcL 
• hemoglobin 
> 8.0 g/dL 
• total bilirubin 
≤ 2.0 x upper limit of normal 
• AST (SGOT)/ALT (SGPT) 
≤ 2.5 × upper limit of normal 
• creatinine 
≤ upper limit of normal 
OR 
• creatinine clearance 
≥60 mL/min/1.73 m2 for patients with 
creatinine levels above normal. 
 
11. CT or MRI within 14 days prior to start of study drug. 
 
12. Corticosteroid dose must be stable or decreasing for at least 5 days prior to the 
baseline CT or MRI scan. For Arm B: Corticosteroid dose must be stable or 
decreasing for at least 2 weeks prior to study entry. 
 
13. The effects of ONC201 on the developing human fetus are unknown. For this reason, 

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women of childbearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry and for 
the duration of study participation. 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. Male subjects should agree to use adequate 
method of contraception starting with the first dose of study therapy through 120 days 
after the last dose of therapy. 
 
14. Archival tissue for evaluation of correlative objectives (if available). Archival tissue 
is required for Arms B and C. 
 
15. Ability to understand and the willingness to sign a written informed consent 
document. 
 
3.2 
Exclusion Criteria 
 
1. History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to ONC201 or its excipients. 
 
2. Current or planned participation in a study of an investigational agent or using an 
investigational device. 
 
3. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection or psychiatric illness/social situations that would limit compliance with 
study requirements. 
 
4. Active infection requiring systemic therapy. 
 
5. Prior stereotactic radiotherapy, convection enhanced delivery (CED) or 
brachytherapy must have had a biopsy to confirm radiographic progression is 
consistent with progressive tumor and not treatment-related necrosis. If the recurrent 
lesion is outside of any prior high-dose radiation target volume or distant from the 
prior CED or brachytherapy site, subjects will be considered eligible 
 
6. Pregnant women because ONC201 is novel agent with unknown 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. 
 
7. Known HIV-positive test on combination antiretroviral therapy. 
 
8. Known history of cardiac arrhythmias including atrial fibrillation, tachyarrhythmias 
or bradycardia. Receiving therapeutic agents known to prolong QT interval will be 
excluded. Patients on sertraline which has the conditional risk of prolonging the QT 
interval will be allowed on study if they hold sertraline on the day of ONC201 
administration. History of CHF, or MI or stroke in the last 3 months will be excluded. 

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9. Active illicit drug use or diagnosis of alcoholism. 
 
10. For Arms A, B, C, prior bevacizumab for treatment (allowable for Arms D, E, and 
F). 
 
11. Tumors with known IDH1 (isocitrate dehydrogenase 1) or known IDH2 mutations as 
determined by immunohistochemistry for the IDH1 R132H variant or by direct 
sequencing. IDH1/2-mutant gliomas have a markedly longer overall survival rate 
compared to those with IDH1/2-wildtype glioma (Parsons 2008; Yan 2009), 
indicating IDH1/2-mutant gliomas have a distinct natural history. 
 
12. Known additional malignancy that is progressing or requires active treatment within 
3 years of start of study drug. Exceptions include basal cell carcinoma of the skin, 
squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone 
potentially curative therapy. 
 
13. Any surgery (not including minor diagnostic procedures such as lymph node biopsy) 
within 2 weeks of baseline disease assessments; or not fully recovered from any side 
effects of previous procedures. 
 
14. Concomitant use of moderate to strong CYP3A4/5 inhibitors during the treatment 
phase of the study and within 72 hours prior to starting study drug administration. 
 
15. Concomitant use of potent CYP3A4/5 inducers, which include enzyme inducing 
antiepileptic drugs (EIAEDs) (see Appendix B), during the treatment phase of the 
study and within 2 weeks prior to starting treatment. 
 
16. Planned concurrent use Optune™. Prior use of the device is allowable. 
 
17. For Arm D and F: Evidence of leptomeningeal spread of disease. 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
4. REGISTRATION PROCEDURES 
 
The investigator is responsible for enrolling only those patients who have met all eligibility 
criteria. The investigator is required to register each patient with the Study sponsor prior to 
enrollment. After a patient signs the informed consent form, the investigator notifies the 
medical monitor. The investigator must provide de-identified patient source documentation 
and a registration form prior to the initiating study treatment. A patient identifier will be 
assigned at the time of approval. Screening and eligibility MUST be entered into electronic 
data capture (EDC) within 7-business days of the screening visit. 

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5. TREATMENT PLAN 
 
5.1 
Treatment Regimen 
 
One cycle is defined as three weeks. ONC201 will be provided as an oral capsule at a 
strength of 125mg per capsule (alternative strengths may be manufactured). For patients 
enrolled in Arm A, treatment with ONC201 will be administered once every three weeks 
in the clinic at the RP2D of 625mg. 
 
For patients in Arm B, C, D, E, and F, ONC201 will be administered weekly (i.e., days 1, 
8, and 15 of each cycle) at the RP2D of 625mg. For all participants, C1D1 dose will be 
taken in clinic. All other doses may be taken at home. 
 
For Arm C and E, subjects must be evaluated prior to dosing for the first dose after 
surgery (i.e. the dose that would occur approximately one week post-surgery). For Arm C 
and E, ONC201 initiation will be scheduled so that surgical resection will be performed 
approximately 24 hours after at least the second dose of ONC201 (6 patients for each 
arm). 
 
If it is not possible to coordinate the timing on the surgery and administration of ONC201 
on consecutive days, deviation from this timing is permitted. For Arm C and E, patients 
will continue weekly dosing one week after surgical resection if the patient is deemed by 
the treating physician to be sufficiently recovered from surgery; patients requiring a delay 
of >3 weeks should go off protocol therapy. Arm C and E participants will be required to 
undergo pretreatment evaluation (to include vitals, physical examination, laboratories), 
prior to dosing for this day (i.e. if surgery occurs 24 hours after cycle 1 day 8, patients 
will be required to undergo clinical and laboratory evaluation on cycle 1 day 15). This 
dose may still be taken at home after the clinical evaluation. Patients in Arm C and E 
who after surgery are found to have insufficient resected tumor tissue for correlative 
studies will continue on treatment but will not count towards accrual of Arm C or E. 
 
ONC201 should be taken with a glass of water and consumed over as short a time as 
possible. Patients should swallow the capsules as a whole and not chew them. Do not 
crush or empty the capsule. If vomiting occurs during the course of treatment, no 
re-dosing of the patient is allowed before the next scheduled dose. The occurrence and 
frequency of any vomiting during an ONC201 treatment must be noted as an adverse 
event (AE). 
 
Reported adverse events and potential risks are described in Section 7. Appropriate dose 
modifications are described in Section 6. No investigational or commercial agents or 
therapies other than those described below may be administered with the intent to treat 
the participant's malignancy. 

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5.2 
Pre-Treatment Criteria 
 
Hematologic lab values should be re-evaluated on cycle 1 day 1 and need to meet 
eligibility parameters to start treatment. All patients must sign an informed consent prior 
to any study-specific procedure. All patients will be screened for Karnofsky performance 
status (KPS). 
 
For screening, patients will have the following hematologic, serum chemistry, 
coagulation, urine and pregnancy tests done at the treating institution or in a local lab 
within 14 days of treatment initiation: 
 
SCREENING FOR ELIGIBILITY 
Hematology Panel 
Blood Chemistry Panel 
Others 
ANC 
AST (SGOT) 
Pregnancy test 
Platelet count 
ALT (SGPT) 
Urine (blood, protein, leukocyte esterase, 
glucose, creatinine, microscopic 
examination of the sediment) 
Hematocrit 
Creatinine 
Coagulation tests (PT, PTT, and INR) 
Hemoglobin 
Total and direct bilirubin 
RBC count 
Alkaline phosphatase 
WBC count with 
differential 
Calcium 
LDH 
Magnesium 
Phosphate 
Potassium 
Random glucose 
Sodium 
BUN 
Albumin 
Total protein 
 
 
The evaluations below will be performed within 14 days prior to start of treatment. 
Screening studies, if performed within 2 weeks prior to start of treatment, are acceptable 
for use as baseline: 
• Patients will undergo complete history including history of concomitant medications, 
physical examination, measurement of vital signs (pulse, sitting or supine blood 
pressure, respiratory rate, temperature) and weight, and clinical assessment of KPS. 
In addition, provide imaging files and assessments from initial diagnosis, surgery 
planning, post-surgical, post chemoradiation, schedule and unscheduled MRIs. 

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• For Arms A, B, C and D, pathology report confirming a diagnosis acceptable per 
eligibility criteria specified for the intended arm. For Arms E and F, radiology or 
pathology report confirming a diagnosis acceptable per eligibility criteria specified 
for the intended arm. 
• A 12-lead ECG will be performed. 
• For Arms D and F, a contrast-enhanced brain MRI and entire spine MRI (or CT if 
MRI is contraindicated) must be obtained within 14 days of the first dose of study 
treatment. 
 
5.3 
Treatment and Evaluation Cycles 
 
At the beginning of each treatment cycle (i.e., every 3 weeks) patients will also have 
safety laboratory studies, physical examination, assessment of KPS, and complete the 
MDASI questionnaire. During discussion of the patient’s progress, adverse events and 
concomitant medications will be collected by targeted questioning. 
 
Patients who remain on study will have tumor response assessments performed at 
8 weeks (± 7 days) after initiation of therapy and then every 8 weeks (± 7 days) 
thereafter. 
 
In addition to reassessment scans, confirmatory scans should also be obtained not less 
than 4 weeks following initial documentation of objective response (OR). To be assigned 
a status of PR or CR, changes in tumor measurements must be confirmed by repeat 
assessments that should be performed no less than 4 weeks after the criteria for response 
are first met. 
 
Patients are to return to the clinic every 3 weeks during the first 6 months on trial. If after 
6 months, the patient and the investigator may agree to extend the interval for clinic visits 
to every 9 weeks (3 cycles). The laboratory assessments must still be performed every 
three weeks but may be done locally. Brain MRI or CT (for patients who cannot receive 
MRI scans) will be repeated every 8 weeks, with a 10-day window is allowed after the 
first 6 cycles. 
 
Unscheduled visits: If a brain surgery or biopsy is scheduled during the active study or 
within 30 days from the end of treatment date, the investigator may obtain tumor tissue 
with patient’s consent. 
 
5.4 
End of Treatment Visit 
 
Following completion of treatment, for patients who discontinue for toxicity or 
withdrawal, tumor imaging is at the judgment of the investigator, suggested to be no less 
than every 8-12 weeks in appropriate setting. 
 
If patients come off treatment for progression of disease, intolerance, or patient 
withdrawal, they will be seen for assessments of efficacy and safety. 
Patients will have repeat safety labs, a clinical examination, weight and KPS assessments, 
and concurrent medications. 

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If tumor assessments have not been done within the prior 4 weeks, these will be obtained 
within the next 2 weeks after the End of Treatment Visit. 
 
After the end of treatment, each subject will be followed for 30 days for adverse event 
monitoring and 30 days (or until start of next line of anticancer therapy) for serious 
adverse event reporting. 
 
Participants removed from protocol therapy for unacceptable adverse events (Section 7) 
will be following until resolution or stabilization of the adverse event. 
 
Subjects who discontinue for reasons other than progressive disease will have post- 
treatment follow-up for disease status until disease progression, initiating a non-study 
cancer treatment, withdrawing consent or becoming lost to follow-up. 
 
Subjects will be followed for survival every 30 days after stopping treatment with 
ONC201. 
 
5.5 
General Concomitant Medication and Supportive Care Guidelines 
 
Because the potential for interaction of ONC201 with other concomitantly administered 
drugs through the cytochrome P450 system is not known, the clinical source 
documentation will capture the concurrent use of all other drugs, over-the-counter 
medications, and/or alternative therapies. The Sponsor should be alerted if the patient is 
taking any agent known to affect or with the potential to affect selected CYP450 
isoenzymes. 
 
Any medication taken by a subject during the course of the study and the reason for its 
use will be documented in the clinical source documentation. 
 
5.6 
Criteria for Taking a Participant Off Protocol Therapy 
 
Duration of therapy will depend on individual response, evidence of disease  
progression and tolerance. Treatment will be discontinued for progression of disease, 
intolerance (defined as NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0 Grade 4, Grade 3, or intolerable Grade 2 toxicity that does not return to 
Grade 1 or baseline after 3 week interruption of treatment or reduction of dose) despite 
dose modification, or patient withdrawal. A patient who experiences a DLT is able to 
remain on study at a reduced dose (see section 6), if deemed by the physician to be safe 
and beneficial for the patient to continue. 
 
In the absence of treatment delays due to adverse events, treatment may continue until 
one of the following criteria applies: 
 
• Confirmed radiographic disease progression. Treatment beyond radiographic 
progression, with prior agreement by the Sponsor’s medical representative and 
investigator, may be allowed if considered in the best interest of the patient. This 
may include the addition of bevacizumab and/or radiotherapy as clinically indicated 

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and per local standard practice. 
• Intercurrent illness that prevents further administration of treatment, 
• Unacceptable adverse event(s), 
• Treatment interruption for more than 3 consecutive weeks due to intolerance despite 
appropriate dose modification, 
• Participant decides to withdraw from the study, or 
• General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the opinion of the treating investigator, 
• Global deterioration of health-related symptoms, 
• Protocol non-compliance, 
• Pregnancy, 
• Lost to follow-up, or 
• Study termination by Sponsor. 
 
If a patient does not return for a scheduled visit, every effort should be made to contact 
the patient. In any circumstance, every effort should be made to document patient 
outcome, if possible. The Investigator should inquire about the reason for withdrawal, 
request that the patient to return all unused investigational product(s), request the patient 
to return for a final visit, if applicable, and follow-up with the patient regarding any 
unresolved adverse events. 
 
If the patient withdraws from the trial and also withdraws consent for disclosure of future 
information, then no further evaluations should be performed and no additional data 
should be collected. The Sponsor may retain and continue to use any data collected 
before such withdrawal of consent. 
 
5.7 
Duration of Follow Up 
 
After documented disease progression each subject will be followed by telephone or 
medical record review for overall survival. When available, subsequent cancer treatment 
information and disease imaging up to two years after end of treatment visit will be 
obtained for patients after discontinuing ONC201 treatment. 
 
Participants will be followed up for survival until one of any of the following criteria 
apply: lost to follow-up, withdrawal of consent, death. 
 
5.8 
Criteria for Taking a Participant Off Study 
 
Patients will be removed from study when any of the criteria listed in Section 5.4 applies. 
The reason for study removal and the date the patient was removed must be documented 
in the clinical source documentation. 
 
Severe adverse events, availability of new adverse toxicology in animals, and financial 
difficulties due to withdrawal of funds may result in stopping the trial. An investigator, 
Sponsor, or IRB may take such actions. If the trial is terminated for safety reasons, 
subjects will be notified immediately and assured that appropriate treatment and follow- 

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up will be available.  If an investigator terminates the trial, the investigator will inform 
the Sponsor, subjects, and IRB about the reason for such action. Similarly, if the Sponsor 
terminates the trial, it will inform the investigators, the IRB, and the subjects of the 
reason for such an action. Similar notifications will be sent by the IRB if it takes such an 
action. 
 
The reason for taking a participant off study, and the date the participant was removed, 
must be documented in the clinical source documentation. 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 5.0 will be utilized for dose delays and dose 
modifications 
 
Below are dose modifications (Table 6.1) for adverse events that are attributable to study 
drug. If a patient experiences other adverse events, or several adverse events and there are 
conflicting recommendations based on Grade, the investigator will use the recommended 
dose adjustment that reduces the dose. Dose modifications will be made based on an adverse 
event that occurs any time during a cycle. 
 
Criteria for disrupting treatment, dose modification, or discontinuation are listed in Table 6.1. 
Dose modifications are per the clinical judgment of the investigator and agreement of the 
subject, the treatment will be resumed according to the table below. Dose modification may 
not be required for adverse events that are clinically manageable. 
 
Table 6.1 Dose adjustment rules for Adverse Events (AEs) Attributable to Study Drug. 
Alopecia does not require dose adjustments. 
 
CTCAE Grade 
Management/Next Dose for ONC201 
≤ Grade 2 
No change  in dose 
Grade 3 or 4* 
Hold until < Grade 2. If resolved to < Grade 2 within 3 weeks, 
resume dosing at 500mg if previously dosed at 625mg or resume 
dosing at 375mg if previously dosed at 500mg.** 
*Patients requiring a delay of >3 weeks should go off protocol therapy. Patients with 
grade 3 neutropenia associated with fever should also go off therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
 
Participants who experience an adverse event that requires a treatment delay or dose 
reduction should be monitored with appropriate laboratory testing or other clinical evaluation 
at least weekly until resolution; if the adverse event does not resolve within 3 weeks, the 
interval for testing may be reduced after consultation and written approval by Sponsor. 

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For holds for reasons other than treatment related toxicities, if the participant does not meet 
criteria to resume treatment within 6 weeks of the event precipitating the hold, the study 
agent(s) may be restarted with approval from the Sponsor, as long as there has been no 
significant evidence of disease progression (e.g., by clinical findings, symptoms, tumor 
markers) during the treatment interruption. 
 
7. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol- 
specified procedure, whether or not considered related to the medicinal product or protocol- 
specified procedure. Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the ONC201, is also an adverse event. 
 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events. Examples 
of this may include, but are not limited to, onset of menses or menopause occurring at a 
physiologically appropriate time. 
 
Adverse events may occur during the course of the use of ONC201 product in clinical trials 
or within the follow-up period specified by the protocol, from overdose (whether accidental 
or intentional), from abuse and from withdrawal. Adverse events may also occur in screened 
subjects during any pre-allocation baseline period as a result of a protocol-specified 
intervention, including washout or discontinuation of usual therapy, diet, placebo treatment 
or a procedure. 
 
Progression of the cancer under study is not considered an adverse event. 
 
All adverse events will be recorded from the time of initiation of study therapy through 
completion of the safety follow-up period. This period is from the time of discontinuation of 
ONC201 treatment until 30 days after discontinuation of treatment or until initiation of a new 
post-discontinuation anticancer treatment, whichever comes first. If a patient initiates a new 
anticancer treatment within 30 days after discontinuing ONC201, the safety follow-up visit 
should be conducted prior to the start of that new line of therapy, if possible. Regardless of 
the end of the safety follow-up period or any new therapies, all SAEs that are deemed at least 
possibly related to ONC201 should be reported to the Sponsor and followed to resolution. 
 
Both adverse events and Serious Adverse Events will not be collected for subjects during the 
pre-screening period (for determination of archival tissue status) as long as that subject has 
not undergone any protocol-specified procedure or intervention. If the subject requires a 
blood draw, fresh tumor biopsy etc., the subject is first required to provide consent to the 
main study and AEs will be captured according to guidelines for standard AE reporting. 

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All SAEs and AEs related to study treatment or leading to discontinuation should be 
followed until resolution, stabilization, the event is otherwise explained, or the participant is 
lost to follow-up. 
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. All 
Adverse Events regardless of seriousness or relationship to the Investigational Product will 
be recorded in the Case Report Forms. Serious Adverse Events should be reported per the 
requirements described in Section 7.1. 
 
7.1 
Reporting of Serious Adverse Events 
 
Serious Adverse Events: A serious adverse event is any adverse event occurring at any 
dose or during any use of ONC201 that: 
• Results in death; 
• Is life threatening; 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization; 
• Is a congenital anomaly/birth defect; 
• Is a new cancer (that is not a condition of the study); 
• Is associated with an overdose; 
• Is another important medical event 
 
Progression of the cancer under study is not considered an adverse event. 
 
Any serious adverse event, or follow up to a serious adverse event, including death due to 
any cause other than progression of the cancer under study that occurs to any subject 
from the time of initiation of therapy through 30 days following cessation of treatment, or 
the initiation of new anti-cancer therapy, whichever is earlier, whether or not related to 
ONC201, must be reported within 24 hours to the Sponsor. 
 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to ONC201 that is brought to the attention of the investigator at 
any time outside of the time period specified in the previous paragraph also must be 
reported immediately to the Sponsor. 
 
SAE reports and any other relevant safety information are to be forwarded to the 
Sponsor email noted on the Sponsor Contact List. 
The Sponsor will submit all required SAE Reports and Annual Progress Reports to the 
FDA as required by FDA or other local regulators. 
 
All subjects with serious adverse events must be followed up for outcome. 
 
Investigators must report to the Sponsor any serious adverse event (SAE) that occurs 
after the initial dose of study treatment, during treatment, or within 30 days of the last 

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dose of treatment on the SAE form provided by the Sponsor. 
 
Investigators should report SAEs to their governing IRB following their governing- 
IRB’s reporting requirements. 
 
7.2 
Expected Toxicities 
 
For further information related to preclinical and clinical safety experience with 
ONC201, including expected adverse events, please refer to the Investigator's Brochure. 
 
7.3 
Adverse Event Characteristics 
 
• CTCAE term (AE description) and grade: 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. All 
appropriate treatment areas should have access to a copy of the CTCAE version 5.0. A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
8. PHARMACEUTICAL INFORMATION 
 
The investigational drug product is a hydroxypropyl methylcellulose (HPMC) capsule filled 
with ONC201 dihydrochloride salt, intended for oral administration. Each capsule of drug 
product contains 125mg of anhydrous ONC201 free base (equivalent to 148.8 mg of 
ONC201.2HCl). ONC201 capsules are manufactured using the following excipients: 
microcrystalline cellulose, sodium starch glycolate, and magnesium stearate. 
 
The product is stored in a multi-dose container. The capsules are packaged in high-density 
polyethylene (HDPE) white opaque bottles, closed with an induction seal and capped with a 
white ribbed SecuRx® polypropylene (PPE) cap. 
 
Each ONC201 bottle will be labelled in accordance with applicable regulatory requirements 
and will include the following minimum information: 
• Name of study drug and strength 
• Sponsor name 
• Batch Number 
• Storage condition 
• Route of administration 
• Applicable caution statement according to in-country requirements 

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8.1 
Drug Substance Description 
 
Compound Code(s) 
ONC201•2HCl 
Alternative Name(s) 
ONC201 
TIC10 
NSC-350625 
Chemical Name(s) 
7-benzyl-4-(2-methylbenzyl)-1,2,6,7,8,9- 
hexahydroimidazo[1,2-a]pyrido[3,4- 
e]pyrimidin-5(4H)-one 2HCl 
Molecular Formula 
C24H26N4O (free base) 
C24H26N4O•2HCl (salt) 
Molecular Weight 
386.49 (free base) 
459.41 (salt) 
Molecular Structure 
 
 
8.2 
Drug Product Description 
 
8.2.1 Form 
 
The investigational drug product is a hydroxypropyl methylcellulose (HPMC) capsule 
filled with ONC201 dihydrochloride salt, intended for oral administration. Each capsule 
of drug product contains 125mg of anhydrous ONC201 free base (equivalent to 148.8 mg 
of ONC201.2HCl). ONC201 capsules are manufactured using the following excipients: 
microcrystalline cellulose, sodium starch glycolate, and magnesium stearate. 
 
The drug product will be packaged as 10 capsules per bottle. The capsules are filled into 
a 30cc high-density polyethylene (HDPE) white opaque bottle sealed with a 28 cc child- 
resistant SecuRx polypropylene (PPE) cap with a heat induction seal. 
 
8.2.2 Storage and Stability 
 
ONC201 should be stored at controlled room temperature (i.e., 15°C to 25°C [59°F to 
77°F]), with excursions permitted to 30°C (86°F). 
 
The investigator or qualified designee must confirm appropriate temperature conditions 
have been maintained during transit for all study drug received and must report and 

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resolve any discrepancies before use of the study drug. 
 
8.3 
Drug Product Supply, Administration and Inventory 
 
8.3.1 Handling 
 
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe 
disposal of the chemotherapeutic agent in a self-contained and protective environment. 
 
8.3.2 Availability 
 
ONC201 is provided by the Sponsor. A sufficient quantity of study supplies will be 
supplied to the investigator (or qualified designee) at each study center by the Sponsor or 
Sponsor-authorized depot. Once received at the study center, ONC201 should be stored 
in accordance with the storage conditions, in a securely locked area, with limited access 
to authorized site staff. 
 
Only patients enrolled in the study may receive study drug and only authorized site staff 
may prepare, supply, or administer study drug. 
 
If a subject cannot physically visit a study site, the site may choose to ship the study drug 
direct to the patient. Upon patient consent and regulatory approval, investigational 
product may be delivered to his/her designated location (e.g., home, office) via a 
Chimerix approved direct to patient courier service. Study drug pick up and delivery 
must be arranged by the study site with the direct to patient courier service . In 
compliance with data privacy regulations, the vendor has a data privacy system in place 
to cover any local obligations. 
 
8.3.3 Administration 
 
Patients will receive ONC201 while in the clinic for C1D1. Patients can take medications 
at home for other dosing. The study drug, ONC201, will be supplied in capsule form for 
oral dosing. 
 
Study patient will receive a 3-week supply of ONC201 during office visit for the first 
6 cycles (not applicable to Arm A, which is closed). After the first 6 cycles, the 
Investigator can prescribe a supply up to 10-weeks beyond the first 6 cycles considering 
an allowed 10-day window for repeating MRI every 8 weeks. 
 
Patients should take the dose of ONC201 specified by their physician 2 hours prior or 
2 hours following food or a meal. If the patient vomits after taking ONC201, they should 
not retake the dose. Missed doses will not be made up, if more than 3 days from the 
intended day of administration. 
 
ONC201 should be taken with a glass of water and consumed over as short a time as 

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possible. Patients should swallow the capsules as a whole and not chew them. Do not 
crush or empty the capsule. If vomiting occurs during the course of treatment, no 
re-dosing of the patient is allowed before the next scheduled dose. The occurrence and 
frequency of any vomiting during a treatment cycle must be noted as an adverse event. 
 
8.3.4 Accountability 
 
The investigator (or qualified designee) is responsible for ensuring adequate 
accountability of all used and unused study drug. This includes acknowledgment of 
receipt of the shipment(s) of study drug (date, quantity, and condition), participant 
dispensing records, and returned or destroyed capsules. Dispensing records will 
document the dispensing of the study drug to individual participants (including date 
dispensed, and participant identifier number), the initials of the person(s) dispensing the 
study drug, and the return and/or disposal of the study drug. All study drug records must 
be maintained at the site and copies must be submitted to the Sponsor at the end of the 
study. 
 
8.3.5 Destruction and Return 
 
After verification of the study drug records by the study monitor, all remaining study 
drug supplies should be destroyed according to directions provided by the Sponsor (or its 
designee) and/or any applicable site-specific standard operating procedures. If necessary, 
unused study drug supplies may be returned to the appropriate depot with prior approval 
from the Sponsor (or its designee). If study drug is approved for onsite destruction by the 
Sponsor, the investigator must maintain accurate records for all study drug destroyed. 
Records must show the identification and quantity of each unit destroyed, the method of 
destruction, and person who disposed of the drug. 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 
Pharmacodynamic Studies 
 
As part of this study we will retrieve archived tumor tissue samples at the time of 
enrollment for subjects enrolled in this study to conduct future correlative assays to 
measure biomarkers of therapeutic response to ONC201 including molecular markers 
involved in the mechanism of action of ONC201. The mechanism of action of ONC201 
appears to alter the expression or phosphorylation of several proteins involved in cell 
signaling pathways that govern tumor cell survival and cell death. To assay such changes, 
serum samples will be obtained for subsequent analysis of pharmacodynamic effects of 
ONC201. 
 
One tube of blood for serum PD samples will be taken at baseline on Day 1 of Cycle 1 
(prior to ONC201 dosing), and again on Day 2 and 8 of Cycle 1, then again at pre-dose 
on subsequent cycles, and at the follow-up visit at the end of treatment, for correlative 
studies. 

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To obtain serum, one (1) tube of 6 mL of peripheral blood will be collected without 
anticoagulant. The sample will be allowed to clot, and serum will be harvested by 
iterative centrifugation. Serum will be divided into 2-3 mL aliquots and stored 
cryogenically. Detailed procedures and supplies are described in the lab manual 
associated with this protocol. 
 
Archival tumor assessments of cell signaling pathways that are associated with ONC201 
will be conducted on tissue obtained from participants. If available, a minimum of 
1 formalin-fixed paraffin-embedded (FFPE) archival tumor tissue block (preferred) or a 
minimum of 10 FFPE unstained sections from most recent pre-registration biopsy/surgery 
are to be submitted within 60 days of registration. 
 
For patients in Arm C and E, both archival as well as freshly resected tumor tissue will be 
collected. The tumor may be resected using neuronavigation or intraoperative MRI, 
enabling resection of enhancing tumor and resection or biopsy of non-enhancing tumor. 
Surgical resection of the non-enhancing lesions should be performed only in the 
non-eloquent areas that show FLAIR changes on MRI. Tissue may be collected from 
both the enhancing core and non-enhancing edge of individual tumors. Tissue should be 
separated into enhancing and non-enhancing specimens. Tissue will then be divided into 
four samples. The diameter of tissue will be approximately 0.3 to 0.5 cm for each of the 
4 pieces of the tumor that will be preserved. Three will be flash frozen for RNA, DNA, 
protein, and drug concentration analyses. The fourth sample will be formalin-fixed and 
paraffin-embedded tissue blocks will be prepared for immunohistochemistry. If possible, 
a cross section of the resected tissue spanning the tumor and normal margins is requested 
for the formalin-fixed specimen. The tissue will be assayed for the following markers that 
have been implicated in the mechanism of action of ONC201 such as DRD2, DRD5, 
TGM2, KSR1, ATF4, CHOP, pAkt, pERK, TRAIL, and DR5 (Allen 2013a; 
Ishizawa 2016; Kline 2016). 
 
Please refer to the study laboratory manual for shipping instructions. 
 
9.2 
ONC201 Plasma Concentration 
 
For each patient, one (1) EDTA tube of 6 mL of blood will be collected in EDTA tubes at 
baseline on Day 1 of Cycle 1 (prior to ONC201 dosing), and again 2 hours (± 15 minutes) 
following the first dose of ONC201, and then not again until the follow-up visit at the end 
of treatment. All samples will be processed to produce plasma that will be stored 
cryogenically until analysis. A detailed procedure is provided in the lab manual. 

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10. STUDY CALENDAR 
 
Study visits and procedures may be scheduled with a ± 3 business day window except for the 
Screening visit and neuroimaging (contrast-enhanced CT or MRI) (± 7 days). One 
Treatment Cycle is defined as 3 weeks (21 days). One Evaluation Cycle is defined as 
8 weeks (56 days ± 7 days). ONC201 will be administered every 3 weeks for patients in 
Arm A and every week for patients in Arm B, C, D, E, and F. 
 
Screening / 
Baseline 
CXD1 
(All 
Arms) 
D2C1 
for All 
Arms 
D8C1 
for All 
Arms 
D15C1 
for Arms 
C and E 
only10 
Unscheduled 
visit, or 
brain 
surgery 
Evaluation 
Cycles 
End of 
Treatment 
/ Follow-up 
Within 
28 days of 
Treatment 
(21± 3 
days)14 
Every 
8 weeks 
(56 ± 7 
days) 
(30 ±3 days 
post last 
dose) 
Medical/RX 
history, including 
prior CT/MRI 
scans11 
X 
Physical exam, 
Neurologic exam, 
KPS, Height, 
weight1 
X 
X 
X 
X 
X 
Vital signs2 
X 
X 
X 
X 
X 
12-lead ECG 
X 
X 
X 
X 
X 
Hematology3 
X 
X 
X 
X 
X 
Full serum 
chemistries3 
X 
X 
X 
X 
X 
MDASI 
questionnaire 
X 
X 
X 
Coagulation tests 
X 
X 
Pregnancy test4 
X 
X 
Disease assessment5 
X 
X 
X 
Screening brain/spine
CT/MRI10 
X 
AEs12 
 
Con-meds 
 
Blood sample for 
ONC201 plasma 
concentration 
X7 
X 
Fresh tumor tissue13 
X 
X 
Blood sample for PD 
X8 
X8 
X8 
X 
Disease status and 
survival6 
X 
Archival tumor 
tissue 
X9 

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1. 
Determine if significant weight loss or gain (± 10%). Abbreviated PE on Day 1 of each treatment cycle or as 
clinically indicated. Neurological assessments will use the NANO scale. 
2. 
Vital signs: systolic and diastolic blood pressure, respiration, pulse, oral temperature prior to treatment on day 1 
of each cycle. Vitals will also be required 2 hours after dosing for day 1 of cycles 1 and 2. 
3. 
Obtain and review prior to each dose of ONC201 on Day 1 of each subsequent cycle, or more frequently if 
clinically indicated. 
4. 
Pregnancy Test – baseline within 7 days of start of treatment and at end of study - urine or serum in women of 
child-bearing potential. A female of childbearing potential is a sexually mature woman who: 1) has not 
undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 
24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). 
5. 
Neuroimaging (disease assessments) must be taken within 7 days prior to physician visit. Disease assessments 
will be performed at 8 weeks and then every 8 weeks (± 7 days) thereafter until patients come off study. 
6. 
Every month via telephone for all subjects for 1 year. 
7. 
Obtain blood sample for cycle 1 day 1 only at baseline prior to ONC201 dosing and again at 2 hours 
(± 15 minutes) post-administration of ONC201. 
8. 
Obtain blood sample for PD pre-dose on day 1 of cycle 1, Day 2, and pre-dose on Day 8 of cycle 1. For cycles 2 
and beyond, only pre-dose blood samples on day 1 of each cycle will be collected. 
9. 
Obtain archival tumor tissue (if available) at the time of enrollment, in accordance with the laboratory manual. 
For Arm C and E, patients must be clinically evaluated prior taking the dose immediately following surgery. 
Typically surgery will occur 24 hours after the second dose of treatment, meaning that for day 15 of cycle 1 
(ie, the dose following surgery), patients will be evaluated prior to taking this dose. Drug may be taken at home 
after this assessment. However, if surgery is not planned to occur until after the third dose of treatment, subjects 
will not be required to have an evaluation on day 15 of cycle 1. The dose immediately following surgery would 
fall on day 1 of cycle 2, a day where all patients are required to come into clinic for clinical and laboratory 
assessment. 
10. 
Baseline brain MRI, with and without contrast is required within 14 days from C1D1. Brain CT is acceptable for 
patients who are not able to conduct MRI scans. Entire MRI scans with and without contrast is required for 
patients to be screened for arms D and F. 
11. 
Provide imaging files and assessments from initial diagnosis, surgery planning, post-surgical, post 
chemoradiation, scheduled and unscheduled MRIs. 
12. 
The safety follow-up period lasts until 30 days after discontinuation of study treatment or date initiation of a new 
anticancer therapy after discontinuation of ONC201. 
13. 
Fresh tumor tissue to be collected for both arm C and E from surgery occurring prior to C1D15 (timing may vary 
depending on surgical schedule and other factors without being considered a protocol deviation). Fresh tumor 
collection may be obtained from unscheduled brain tumor surgery while patient is on active treatment and until 
30 days from last ONC201 dose. 
14. 
If a patient completes 6 cycles the patient may be seen every 8 weeks for routine assessment of physical exam, 
and AE/concomitant medication assessment. 

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11. MEASUREMENT OF EFFECT 
 
After signing informed consent patients will undergo screening procedures including baseline 
radiologic imaging by contrast-enhanced CT scan or MRI within 14 days prior to initiating 
study drugs. 
 
Patients who remain on study will have tumor assessments performed at 8 weeks (± 1 week) 
after initiation of therapy and then every 8 weeks (± 1 week) thereafter. In addition to 
reassessment scans, confirmatory scans should also be obtained not less than 4 weeks 
following initial documentation of objective response. To be assigned a status of PR or CR 
changes in tumor measurements must be confirmed by repeat assessments that should be 
performed no less than 4 weeks after the criteria for response are first met. 
 
Efficacy will be assessed by the RANO response criteria as noted below. RANO-HGG and 
RANO-LGG will be used for each evaluation to assess contrast-enhancing lesions and T2/FLAIR 
hyper-intense lesions, respectively. 
 
11.1 
Definitions 
 
Evaluable for Efficacy and Safety 
Patients who have received at least one dose of study drug will be considered evaluable 
for efficacy and safety. These patients will have response classified according to the 
definitions stated below. 
 
Evaluable for Intratumoral Concentrations 
Patients in Arms C and E must have sufficient tumor tissue from biopsy to permit 
quantitation of intratumoral concentrations of ONC201 to be considered evaluable for 
these arms. Patients found to have insufficient tissue may continue treatment, but will be 
replaced. 
 
Evaluable Non-Target Disease Response 
Patients who have lesions present at baseline that are evaluable but do not meet the 
definitions of measurable disease (a+b >10mm), have received at least one cycle of 
therapy, and have had their disease re-evaluated will be considered evaluable for 
nontarget disease. The response assessment is based on the presence, absence, or 
unequivocal progression of the lesions. 
 
Disease Parameters 
For the purposes of this study, patients should be reevaluated for response at 8 weeks of 
therapy and then every 8 weeks thereafter. In addition to baseline scan(s), confirmatory 
scans should also be obtained not less than 4 weeks following initial documentation of 
objective response. 
 
ORR by RANO-HGG is defined as the proportion of subjects in the analysis population who 
have confirmed complete response (CR) or partial response (PR) using RANO-HGG criteria. 
Radiographic assessments will be performed by the investigator for the primary endpoint, but 
may also be separately assessed by blinded independent central review. Duration of response 

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is defined as time from first RANO-HGG response (only if confirmed) to disease progression 
in subjects who achieve a PR or better. 
 
ORR by RANO-LGG is defined as the proportion of subjects in the analysis population who 
have confirmed CR, PR, or minor response (MR) using RANO-LGG criteria determined by 
the investigator (but may be separately assessed by blinded independent central review). 
Duration of response is defined as time from first RANO-LGG response (only if confirmed) 
to disease progression in subjects who achieve a MR or better. 
 
11.2 
Disease Parameters 
 
Measurable Disease 
Bi-dimensionally, contrast-enhancing, measurable lesions with clearly defined margins 
by CT or MRI scan, with a minimal diameter of 1 cm, and visible on 2 axial slices which 
are at least 5 mm apart with 0 mm skip. Measurement of tumor around a cyst or surgical 
cavity, if necessary, requires a minimum thickness of 3 mm. If there are too many 
measurable lesions to measure at each evaluation, the investigator must choose the largest 
two to be followed before a participant is entered on study. The remaining lesions will be 
considered non-measurable for the purpose of objective response determination. Unless 
progression is observed, objective response can only be determined when all measurable 
and non-measurable lesions are assessed. 
 
Non-Measurable Evaluable Disease 
Unidimensionally measurable lesions, masses with margins not clearly defined, lesions 
with maximal diameter < 1cm. 
 
11.3 
Response/Progression Categories 
The modified RANO Response Criteria to be used in this study are summarized below. If 
changes in the primary field lesions lead to assessment of progressive disease, this 
assessment must be confirmed at least 4 weeks later. 
 
11.3.1 Complete response (CR). All of the following criteria must be met: 
a) Complete disappearance of all enhancing measurable and non-measurable disease 
sustained for at least 4 weeks. In the absence of a confirming scan at least 4 weeks 
later, this scan will be considered only stable disease. 
b) No new lesions. 
c) All measurable and non-measurable lesions must be assessed using the same 
techniques as baseline. 
d) Participants must be on no steroids or on physiologic replacement doses only. 
e) Stable or improved non-enhancing (T2/FLAIR) lesions. 
f) Stable or improved clinically, for clinical signs and symptoms present at baseline 
and recorded to be disease related. 
 
Participants with non-measurable disease cannot have a complete response. The best 
response possible is stable disease. 

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11.3.2 Partial response (PR). All of the following criteria must be met: 
a) Greater than or equal to 50% decrease compared to baseline in the sum of 
products of perpendicular diameters of all measurable enhancing lesions sustained 
for at least 4 weeks. In the absence of a confirming scan at least 4 weeks later, this 
scan will be considered only stable disease. 
b) No progression of non-measurable disease. 
c) No new lesions. 
d) All measurable and non-measurable lesions must be assessed using the same 
techniques as baseline. 
e) The steroid dose at the time of the scan evaluation should be no greater than the 
dose at time of baseline scan. 
f) Stable or improved non-enhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared to baseline scan. 
g) Stable or improved, for clinical signs and symptoms present at baseline and 
recorded to be disease related clinically. 
 
Participants with non-measurable disease cannot have a partial response. The 
best response possible is stable disease. 
 
11.3.3 Progressive disease (PD). 
Any of the following criterion must be met: 
a) > 25% increase in sum of the products of perpendicular diameters of enhancing 
lesions (over best response or baseline if no decrease) on stable or increasing 
doses of corticosteroids. 
b) Any new enhancing measurable lesion. 
c) Clear clinical deterioration not attributable to other causes apart from the tumor 
(e.g., seizures, medication side effects, complications of therapy, cerebrovascular 
events, infection, etc.). The definition of clinical deterioration is left to the 
discretion of the investigator but it is recommended that a decline in the 
Karnofsky Performance Score (KPS) from 100 or 90 to 70 or less, a decline in 
KPS of at least 20 from 80 or less, or a decline in KPS from any baseline to 50 or 
less, for at least 7 days, be considered neurologic deterioration, unless attributable 
to co-morbid events or changes in corticosteroid dose. 
d) Failure to return for evaluation due to death or deteriorating condition. 
 
11.3.4 Minor Response (MR). 
Apply to T2/FLAIR hyper-intense lesions only. All of the following criteria must be met: 
a) 25–50% reduction in perpendicular diameters of lesion 
b) No new lesions. 
c) The steroid dose at the time of the scan evaluation should be no greater than the 
dose at time of baseline scan. 
d) Stable or improved, for clinical signs and symptoms present at baseline and 
recorded to be disease related clinically. 
 
11.3.5 Stable disease (SD). 
All of the following criteria must be met: 

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a) Does not qualify for CR, PR, or progression. 
b) All measurable and non-measurable sites must be assessed using the same 
techniques as baseline. 
c) Stable clinically. 
 
11.3.6 Unknown response status. 
Progressive disease has not been documented and one or more measurable or non- 
measurable lesions have not been assessed. 
 
11.4 
Methods for Evaluation of Disease 
 
All measurements should be taken and recorded in metric notation using a ruler, calipers, 
or a digital measurement tool. All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 4 weeks before the beginning 
of the treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
11.5 
Evaluation of Best Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). If a response recorded at one 
scheduled MRI does not persist at the next regular scheduled MRI, the response will still 
be recorded based on the prior scan, but will be designated as a non-sustained response. If 
the response is sustained, i.e. still present on the subsequent MRI at least four weeks 
later, it will be recorded as a sustained response, lasting until the time of tumor 
progression. Participants without measurable disease may only achieve SD or PD as their 
best “response.” 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for reporting adverse events can be found in 
Section 7. 
 
12.1 
Data Reporting 
 
Investigative sites are responsible for completing and submitting data and/or data forms 
according to the user requirements of the EDC system. 

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12.2 
Data Collection 
 
12.2.1 Data Collection Forms 
 
Qualified clinical trial study monitors that represent the Sponsor will complete onsite (or 
remote) monitoring. the Sponsor will be responsible for all data management and 
statistical analysis. 
 
Case Report Forms will be completed in a timely manner. Case Report Form completion 
may be formally delegated to other study personnel listed in the delegation of authority 
(DOA) form and signed by the PI. 
 
The following steps will be taken to ensure accurate, consistent, complete, and reliable 
data: 
 
1. 
The Sponsor or designee will conduct an initiation meeting at the study site 
prior to the start of the study. The study protocol, procedures and CRFs will be 
reviewed in detail and the study personnel will be trained to carry out the 
procedures defined in the protocol. 
2. 
The Investigator will be provided with a Study Site Binder for storing study 
related regulatory and study site documentation; e.g., study logs and forms. 
3. 
All written study documentation entries must be made in blue or black ink. The 
investigator must review all entries for completeness and accuracy. When 
changes or corrections are made on any study documentation, the person 
making the change must draw a single line through the error, then initial and 
date the correction. 
4. 
Periodic monitoring visits will be conducted on a regular basis by the Sponsor 
or designee in order to verify the accuracy of data entered on each CRF against 
the raw data from source documents at the site. Items needing 
correction/clarification will be identified and brought to the attention of the 
study site personnel and Principal Investigator, and corrections will be made as 
appropriate. 
5. 
The CRF will then be sent to the Sponsor or designee for final review and data 
management. The study database will be validated using appropriate validation 
processes. 
6. 
The Sponsor or designee may perform a regulatory audit of the study site, and 
may include a complete review of the overall study conduct, regulatory 
documentation, and selected subject CRFs and source documents. 
 
12.2.2 Registration and Eligibility 
At the time of receipt of the signed consent form, the Sponsor medical monitor must be 
notified via email to initiate eligibility review. The study staff must include de-identified 
patient source documentation, the completed New Patient Registration Form (provided 
by the Sponsor) and a tentative therapy start date. Correspondence from the Sponsor for 
patient registration approval will be granted within 48 hours of receipt of adequate 
documentation. 

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A patient identifier will be assigned at the time of approval. Screening and eligibility 
MUST be entered into EDC within 7 business days of screening visit. 
 
12.2.3 Patient Consent Form 
 
Informed consent must be obtained before protocol-specified procedures or interventions 
are carried out. The investigator will explain the nature of the study and will inform the 
subject that participation is voluntary and that they can withdraw at any time. A copy of 
the signed consent form will be given to every participant and the original will be 
maintained with the subject’s records. 
 
The consent form must be approved by the IRB and be acceptable to the Sponsor. 
Consent forms must be written so as to be understood by the prospective subject. The 
Informed Consent should be translated and certified into the local language of the 
respondent, as deemed necessary. Informed consent will be documented by the use of a 
written consent form approved by the IRB and signed and dated by the subject and by the 
person who conducted the informed consent discussion. The signature confirms the 
consent is based on information that has been understood. Each signed informed consent 
form must be kept on file by the investigator for possible inspection by Regulatory 
Authorities and/or the Sponsor or its designee. The subject should receive a copy of the 
signed and dated written informed consent form and any other written information 
provided to the subjects, and should receive copies of any signed and dated consent form 
updates and any amendments to the written information provided to subjects. 
 
12.2.4 Site Monitoring 
 
To ensure compliance with current federal regulations and the ICH guidelines, data 
generated by this study must be available for inspection upon request by representatives 
of the FDA, national and local health authorities, the Sponsor and duly authorized 
representative of any entity providing support for this trial. Contractors of the Sponsor 
will conduct routine monitoring or audit activities for this study. The general scope of 
such visits would be to inspect study data (regulatory requirements), source 
documentation and CRF completion in accordance with current FDA Good Clinical 
Practices (GCP), the ICH guidelines and the respective local and national government 
regulations and guidelines. 
 
12.2.5 Institutional Review Board Approval 
 
This protocol, the informed consent document, relevant supporting information and all 
types of patient recruitment and advertisement information must be submitted to the local 
IRB for review and must be approved before the study is initiated. An amendment to 
remove a life-threatening situation can by implemented by the Investigator prior to 
obtaining IRB approval by the site. In such situations, the IRB must be notified 
immediately and the amendment forwarded to the IRB for their consideration. 

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The investigator is responsible for keeping their local IRB informed of the progress with 
study renewal at least once a year. The investigator must also keep the local IRB 
informed of any significant adverse events, per local institutional guidelines. 
 
Records Retention: FDA regulations (21 CFR 312.62) require clinical investigators to 
retain all study- related documentation, including source document and CRFs, long 
enough to allow the sponsor to use the data to support marketing applications. If this 
study is conducted under an IND, all records must be maintained for: 
 
• 
Two years after the FDA approved the marketing application, or 
• 
Two years after the FDA disapproves the application for the indication being studied, 
or 
• 
Two years after the FDA is notified by the sponsor of the discontinuation of trials and 
that an application will not be submitted. 
 
For all studies, including studies with FDA-IND exemption, the 
Investigator/Institution/Sponsor will take measures to prevent accidental or premature 
destruction of study documents. For such studies conducted under IND exemption, 
records will be retained for a minimum of seven (7) years past official study termination. 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design 
 
Arm A will accrue at least 16 evaluable patients. Arms B, D, and F will accrue 
16-30 evaluable patients each. Arms C will accrue 6 evaluable patients who have 
sufficient resected tumor tissue for correlative studies. Arm E will accrue 12 evaluable 
patients who have sufficient resected tumor tissue for correlative studies. Patients in 
Arm C or E who after surgery are found to have insufficient resected tumor tissue for 
correlative studies will continue on treatment but will not count towards accrual of that 
arm. Data on these patients will be collected. In order to accrue 6 patients onto Arm C 
with sufficient tissue for correlatives following surgical resection, a total of 12 patients 
could be enrolled onto Arm C. In order to accrue 12 patients onto Arm E with sufficient 
tissue for correlatives following surgical resection, up to 18 patients could be enrolled 
onto Arm E. 
 
The study duration is expected to be 7 years: 6 years for accrual, and 1 year for 
follow-up on the last participant enrolled. 
 
Efficacy analyses will be performed separately for each arm. Patients enrolled in arms 
other than Arm D with a known H3 K27M mutation in their glioma may be included in 
the analyses of Arm D. Among recurrent glioblastoma patients, large meta-analyses of 
clinical trials evaluating a wide array of salvage therapeutics (excluding bevacizumab) 
have consistently reported PFS-6 rates of 9-11% (Ballman 2007; Lamborn 2008; 
Wu 2010). If the true PFS-6 rate on the current study for patients receiving ONC201 
were 30% or higher, there would be interest in further investigation of this treatment 
regimen. Therefore, this study will be used to detect a difference of 20% using a one- 

Protocol ONC006 
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sided binomial test. Statistically, the hypothesis that will be tested is: 
 
H0: p<=0.1 versus H1: p>0.3 
where p is the proportion of patients achieving PFS-6. Enrollment of 30 patients will 
yield 84% power to detect a 20% difference at an alpha level of 0.05 (one-sided exact 
test). 
 
The primary efficacy endpoint is PFS-6, defined as the proportion of subjects in the 
analysis population who remain progression-free for at least six months following 
initiation of study therapy. Response for the primary analysis will be determined by the 
investigator assessment, and a confirmation assessment is required per RANO. If 
patients discontinue protocol therapy at or before 6 months without tumor imaging 
performed, the patient will be treated in the primary endpoint analysis as a treatment 
failure. Adjustments will not be made for multiple comparisons. 
 
Secondary efficacy endpoints include: (1) ORR defined as the proportion of subjects in 
the analysis population who have complete response (CR) or partial response (PR) using 
RANO criteria; (2) duration of response, defined as time from first RANO response to 
disease progression in subjects who achieve a PR or better; (3) progression-free survival 
(PFS), defined as the time from initiation of study therapy to the first documented 
disease progression according to RANO or death due to any cause, whichever occurs 
first; and (4) overall survival (OS). 
 
Additional supportive analyses of duration of response and PFS will be conducted using 
RANO criteria, in which a confirmation assessment of disease progression must be 
obtained at least 4 weeks after the initial disease assessment indicating progressive 
disease. 
 
Safety will be assessed by quantifying the toxicities and grades experienced by subjects 
who have received ONC201, including serious adverse events (SAEs). Other safety 
endpoints include laboratory safety assessments, KPS status, and vital signs. 
 
The predictive utility of intratumoral DRD5 expression will be evaluated in archival 
tumor specimens based on an inverse correlation with ONC201 efficacy in cancer cell 
lines. Among the 15 available archival tumor tissue specimens in Arm A, all had 
expression of DRD2 and 8/17 patients had low expression of DRD5. Patients with 
PFS>5 month had no detectable expression of DRD5 unlike those with PFS<5 months. 
In addition, 4/8 DRD2+DRD5- and 0/7 DRD2+DRD5+ patients were still alive with a 
median follow-up of 47.4 weeks. Based on these findings, DRD2+DRD5- patients are 
expected to have improved PFS and OS in response to ONC201 administration. For Arm 
B and Arm C, %DRD2 and %DRD5 positive cells (strong/total) will be quantified using 
image analysis algorithms for detection of DRD2 and DRD5 immunolabeling area and 
intensity (Visiopharm VIS software). Arms B and C will be combined for these 
analyses. Patients with pathologist-verified DRD5 staining area in the biopsy of 
>0.018% strong positive or >1% total positive will be classified as DRD5+. DRD5+ 
versus DRD5- patients will be compared for key clinical outcomes using a likelihood 

Protocol ONC006 
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ratio chi-square test (ORR) or log-rank test (PFS, OS). Significance will be declared if 
the two-sided p-value is <0.05, with no adjustments for multiple comparisons. Because 
the assay for quantifying the %DRD5 strong positive cells or %DRD5 total positive 
cells is still being developed to be more precise, the data will also be normalized into 
Z-scores as a second and independent method of identifying patients as DRD5-positive 
or negative. Patients with negative Z-scores will be grouped into the DRD5- cohort and 
patients with positive Z-scores will be grouped into the DRD5+ cohort. The same 
comparisons for clinical outcome will be performed as above. 
 
Pharmacodynamic effects will be evaluated by assessment of tissue biomarkers based on 
mechanism of action and preclinical tumor cell sensitivity studies. IHC ATF4, CHOP, 
and DR5 will be summarized using descriptive statistics. 
 
Intratumoral ONC201 concentration in patients with recurrent GBM will be summarized 
using descriptive statistics separately for Arm C and E separately. A sample size of 6 
achieves 80% power to detect a difference of -1.4 between the null hypothesis mean of 
0.0 and the alternative hypothesis mean of 1.4 with an estimated standard deviation of 
1.0 and with a significance level (alpha) of 0.05000 using a two-sided one-sample t-test. 
We are looking for an effect size of 2.9 since the target threshold for intratumoral drug 
concentrations is 2.9 uM representing the IC50 of ONC201 in cancer cell panels profiled 
for in-vitro efficacy. 
 
Below you will find a table with calculations of minimal effect size corresponding to 
differing SDs for a sample size of 6 patients at 80% power and a two sided alpha of 0.5. 
 
Power 
N 
Alpha 
Beta 
Mean0 
Mean1 
S 
Effect 
Size 
0.80000 6 0.05000 
0.20000 
0.0 
1.4 
1.0 
1.435 
0.80000 6 0.05000 
0.20000 
0.0 
1.5 
1.0 
1.435 
0.80000 6 0.05000 
0.20000 
0.0 
1.6 
1.1 
1.435 
0.80000 6 0.05000 
0.20000 
0.0 
1.7 
1.2 
1.435 
0.80000 6 0.05000 
0.20000 
0.0 
1.8 
1.3 
1.435 
0.80000 6 0.05000 
0.20000 
0.0 
1.9 
1.3 
1.435 
0.80000 6 0.05000 
0.20000 
0.0 
2.0 
1.4 
1.435 
0.80000 6 0.05000 
0.20000 
0.0 
2.1 
1.5 
1.435 
0.80000 6 0.05000 
0.20000 
0.0 
2.2 
1.5 
1.435 
0.80000 6 0.05000 
0.20000 
0.0 
2.3 
1.6 
1.435 
0.80000 6 0.05000 
0.20000 
0.0 
2.4 
1.7 
1.435 
0.80000 6 0.05000 
0.20000 
0.0 
2.5 
1.7 
1.435 
0.80000 6 0.05000 
0.20000 
0.0 
2.6 
1.8 
1.435 
0.80000 6 0.05000 
0.20000 
0.0 
2.7 
1.9 
1.435 
0.80000 6 0.05000 
0.20000 
0.0 
2.8 
2.0 
1.435 
0.80000 6 0.05000 
0.20000 
0.0 
2.9 
2.0 
1.435 

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References 
Machin, D., Campbell, M., Fayers, P., and Pinol, A. 1997. Sample Size Tables for 
Clinical Studies, 2nd Edition. Blackwell Science. Malden, MA. 
Zar, Jerrold H. 1984. Biostatistical Analysis (Second Edition). Prentice-Hall. 
Englewood Cliffs, New Jersey. 
 
Report Definitions 
Power is the probability of rejecting a false null hypothesis. It should be close to one. 
N is the size of the sample drawn from the population. To conserve resources, it should 
be small. Alpha is the probability of rejecting a true null hypothesis. It should be small. 
Beta is the probability of accepting a false null hypothesis. It should be small. 
Mean0 is the value of the population mean under the null hypothesis. It is arbitrary. 
Mean1 is the value of the population mean under the alternative hypothesis. It is relative 
to Mean0. Sigma is the standard deviation of the population. It measures the variability 
in the population. Effect Size, |Mean0-Mean1|/Sigma, is the relative magnitude of the 
effect under the alternative. 
 
13.2 
Interim Analyses 
 
For Arm A, a futility interim analysis will be conducted after 16 patients are enrolled. 
Since PFS-6 requires at least six months post-study initiation follow-up for subjects 
without progressive disease, the binary endpoint PFS rate at two months (PFS-2) will be 
used to determine whether the accrual should be suspended after sixteen patients have 
accrued. If out of the first 16 patients enrolled, only 7 or less patients are observed to be 
progression free during the first 2 months after treatment initiation, further accrual in this 
arm will be discontinued. Assuming exponential distribution, the null and alternative for 
the PFS6 are translated into 0.44 vs. 0.67 rates for the PFS2. Under these rates the 
chances of observing 7 or less progression free patients out of the first 16 are 0.6 under 
the null and 0.046 under the alternative. 
 
For Arm B, D, and F, separately, a futility interim analysis will be conducted after 
16 patients who are evaluable for efficacy are enrolled. Since PFS-6 requires at least six 
months post-study initiation follow-up for subjects without progressive disease, the 
binary endpoint PFS rate at two months (PFS-2) will be one criteria used to determine 
whether the accrual should be suspended after sixteen patients have accrued. If out of the 
first 16 patients who are evaluable for efficacy are enrolled, there is no objective response 
and only 7 or less patients are observed to be progression free during the first 2 months 
after treatment initiation, further accrual in this arm will be discontinued. Assuming 
exponential distribution, the null and alternative for the PFS6 are translated into 0.44 vs. 
0.67 rates for the PFS2. Under these rates the chances of observing 7 or less progression 
free patients out of the first 16 are 0.6 under the null and 0.046 under the alternative. 
 
No interim analyses will be conducted for Arm C or E. 

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13.3 
Statistical Methods for Efficacy Analyses 
 
Efficacy analyses will be performed separately for each arm. Subgroup analyses of the 
primary tumor location within the brain (e.g. thalamus) and the H3 K27M mutation will 
be performed across all cohorts. For PFS and OS endpoints, Kaplan-Meier (KM) curves 
and median estimates from the KM curves will be provided as appropriate. Subjects 
without efficacy evaluation data or without survival data will be censored at Day 1, as 
appropriate. Participants without measurable disease will not be included in the analysis 
of ORR. 
 
13.4 
Demographic and Baseline Characteristics 
 
Baseline characteristics will be assessed by the use of tables and/or graphs for each 
cohort separately. No statistical hypothesis tests will be performed on these 
characteristics. The number and percentage of subjects screened, the primary reasons for 
screening failure, and the primary reason for discontinuation will be displayed. 
Demographic variables (e.g., age, gender), baseline characteristics, primary and 
secondary diagnoses, and prior and concomitant therapies will be summarized by arm 
either by descriptive statistics or categorical tables. 

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14. PROTOCOL SIGNATURES 
 
SPONSOR PROTCOL SIGNATURES 
 
Study Title: 
Oral ONC201 in Adult Recurrent Glioblastoma 
Study Number: 
ONC006 
Version: 
14 
Date: 
03 June 2021 
 
 
 
 
This clinical trial protocol was reviewed and approved by: 
 
 
 
Signature and Date:   
 

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Ballman, K.V., Buckner, J.C., Brown, P.D., Giannini, C., Flynn, P.J., LaPlant, B.R., and Jaeckle, K.A. 
(2007). The relationship between six-month progression-free survival and 12-month overall survival end 
points for phase II trials in patients with glioblastoma multiforme. Neuro-oncology 9, 29-38. 
 
REFERENCES 
 
Allen, J.E., Krigsfeld, G., Mayes, P.A., Patel, L., Dicker, D.T., Patel, A.S., Dolloff, N.G., Messaris, E., 
Scata, K.A., Wang, W., et al. (2013b). Dual inactivation of Akt and ERK by TIC10 signals Foxo3a 
nuclear translocation, TRAIL gene induction, and potent antitumor effects. Science translational medicine 
5, 171ra117. 
Friedman HS1, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, Yung WK, Paleologos N, 
Nicholas MK, Jensen R, Vredenburgh J, Huang J, Zheng M, Cloughesy T. Bevacizumab alone and in 
combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009 Oct 1;27(28):4733-40. doi: 
10.1200/JCO.2008.19.8721. 
 
Kline, C.L., Van den Heuvel, A.P., Allen, J.E., Prabhu, V.V., Dicker, D.T., and El-Deiry, W.S. (2016). 
ONC201 kills solid tumor cells by triggering an integrated stress response dependent on ATF4 activation 
by specific eIF2alpha kinases. Sci Signal 9, ra18. 
Lamborn, K.R., Yung, W.K., Chang, S.M., Wen, P.Y., Cloughesy, T.F., DeAngelis, L.M., Robins, H.I., 
Lieberman, F.S., Fine, H.A., Fink, K.L., et al. (2008). Progression-free survival: an important end point in 
evaluating therapy for recurrent high-grade gliomas. Neuro-oncology 10, 162-170. 
Patel, M.A., Kim, J.E., Ruzevick, J., Li, G., and Lim, M. (2014). The future of glioblastoma therapy: 
synergism of standard of care and immunotherapy. Cancers 6, 1953-1985. 
Siegel, R., Ma, J., Zou, Z., and Jemal, A. (2014). Cancer statistics, 2014. CA: a cancer journal for 
clinicians 64, 9-29. 
Stähle, H., Könne, H., and W., K. (1971). Imidazo[1,2-a]pyrido[4,3-d]pyrimidine, deren 
 
Säreadditionssalze und Verfahren zu deren Herstellung (Germany: C.H. Boehringer Sohn). 
Stupp, R., Hegi, M.E., Mason, W.P., van den Bent, M.J., Taphoorn, M.J., Janzer, R.C., Ludwin, S.K., 
Allgeier, A., Fisher, B., Belanger, K., et al. (2009). Effects of radiotherapy with concomitant and adjuvant 
temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5- 
year analysis of the EORTC-NCIC trial. The Lancet Oncology 10, 459-466. 
Wick W, Gorlia T, Bendszus M, Taphoorn M, Sahm F, Harting I, Brandes AA, Taal W, Domont J, Idbaih 
A, Campone M, Clement PM, Stupp R, Fabbro M, Le Rhun E, Dubois F, Weller M, von Deimling A, 
Golfinopoulos V, Bromberg JC, Platten M, Klein M, van den Bent MJ. Lomustine and Bevacizumab in 
Progressive Glioblastoma. N Engl J Med. 2017 Nov 16;377(20):1954-1963. 
Wu, W., Lamborn, K.R., Buckner, J.C., Novotny, P.J., Chang, S.M., O'Fallon, J.R., Jaeckle, K.A., and 
Prados, M.D. (2010). Joint NCCTG and NABTC prognostic factors analysis for high-grade recurrent 
glioma. Neuro-oncology 12, 164-172. 
Ishizawa, J., Kojima, K., Chachad, D., Ruvolo, P., Ruvolo, V., Jacamo, R.O., Borthakur, G., Mu, H., 
Zeng, Z., Tabe, Y., et al. (2016). ATF4 induction through an atypical integrated stress response to 
ONC201 triggers p53-independent apoptosis in hematological malignancies. Sci Signal 9, ra17. 

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APPENDIX A: KARNOFSKY PERFORMANCE STATUS (KPS) CRITERIA 
 
 
Percent 
Description 
100 
Normal, no complaints, no evidence of disease. 
90 
Able to carry on normal activity; minor signs or symptoms of disease. 
80 
Normal activity with effort; some signs or symptoms of disease. 
70 
Cares for self, unable to carry on normal activity or to do active work. 
60 
Requires occasional assistance, but is able to care for most of his/her needs. 
50 
Requires considerable assistance and frequent medical care. 
40 
Disabled, requires special care and assistance. 
30 
Severely disabled, hospitalization indicated. Death not imminent. 
20 
Very sick, hospitalization indicated. Death not imminent. 
10 
Moribund, fatal processes progressing rapidly. 
0 
Dead. 

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APPENDIX B: TABLE OF EIAEDS AND NON-EIAEDS* 
 
CYP3A4 enzyme-inducing antiepileptic 
drugs 
Non-CYP3A4 enzyme-inducing 
antiepileptic drugs 
Carbamazepine 
Oxcarbazepine 
Phenytoin 
Fosphenytoin 
Phenobarbital 
Primidone 
Levetiracetam 
Valproic acid 
Lacosamide 
Gabapentin 
Topiramate 
Lamotrigine 
Tiagabine 
Zonisamide 
Clonazepam 
Clonozam 
Pregabalin 
 
* This is a partial list. A comprehensive list of EIAEDs can be found at The University of Indiana 
(http://medicine.iupui.edu/clinpharm/ddis/) has a comprehensive list of EIAEDs which should be 
consulted. 

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APPENDIX C: NEUROLOGIC ASSESSMENT IN NEURO-ONCOLOGY (NANO) SCALE 
Scoring assessment is based on direct observation and testing performed during 
clinical evaluation and is not based on historical information or reported symptoms. 
Please check 1 answer per domain. Please check “Not assessed” if testing for that 
domain is not done. Please check “Not evaluable” if a given domain cannot be scored 
accurately due to pre-existing conditions, co-morbid events and/or concurrent 
medications. 
Study #, Participant # and Initials:  
 
  
/  
 
Date Assessment Performed (day/month/year):     
 
  
Study time point (i.e. cycle 1, day 1, etc):    
 
Assessment performed by (please print name):    
 
 
 
Domains 
Key Considerations 
Gait 
0 
Normal 
1 
Abnormal but walks without assistance 
2 
Abnormal and requires assistance 
(companion, cane, walker, etc.) 
3 
Unable to walk 
Not assessed 
Not evaluable 
 
Strength 
0 
Normal 
1 
Movement present but decreased 
against resistance 
2 
Movement present but none against resistance 
3 
No movement 
Not assessed 
Not evaluable 
 
Ataxia (upper extremity) 
0 
Able to finger to nose touch without difficulty 
1 
Able to finger to nose touch but difficult 
2 
Unable to finger to nose touch 
Not assessed 
Not evaluable 
 
Sensation 
0 
Normal 
1 
Decreased but aware of sensory modality 
2 
Unaware of sensory modality 
Not assessed 
Not evaluable 
• 
Recommend evaluating major body areas 
separately (face, limbs and trunk) 
• 
Score should reflect worst performing area 
• 
Sensory modality includes but not limited to 
light touch, pinprick, temperature and 
proprioception 
• 
Patients with baseline level 2 function in one 
major body area can be scored based on 
• 
Non-evaluable if strength is compromised 
• 
Trunk/lower extremities assessed by gait 
domain 
• 
Particularly important for patients with 
brainstem and cerebellar tumors 
• 
Score based on best response of at least 3 
• 
Test each limb separately 
• 
Recommend assess proximal (above knee or 
elbow) and distal (below knee or elbow) 
major muscle groups 
• 
Score should reflect worst performing area 
• 
Patients with baseline level 3 function in one 
major muscle group/limb can be scored based 
on assessment of other major muscle 
groups/limb 
• 
Walking is ideally assessed by at least 10 steps 

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Study #, Participant # and Initials:  
 
  
/  
 
Date Assessment Performed (day/month/year):     
 
 
Study time point (i.e. cycle 1, day 1, etc):    
 
Visual Fields 
0 
Normal 
1 
Inconsistent or equivocal partial 
hemianopsia (≥quadrantopsia) 
2 
Consistent or unequivocal partial 
hemianopsia (≥quadrantopsia) 
3 
Complete hemianopsia 
Not assessed 
Not evaluable 
Facial Strength 
0 
Normal 
1 
Mild/moderate weakness 
2 
Severe facial weakness 
Not assessed 
Not evaluable 
Language 
0 
Normal 
1 
Abnormal but easily conveys meaning 
to examiner 
2 
Abnormal and difficulty conveying 
meaning to examiner 
3 
Abnormal. If verbal, unable to convey 
meaning to examiner. OR non-verbal 
(mute/global aphasia) 
Not assessed 
Not evaluable 
Level of Consciousness 
0 
Normal 
1 
Drowsy (easily arousable) 
2 
Somnolent (difficult to arouse) 
3 
Unarousable/coma 
Not assessed 
Not evaluable 
Behavior 
0 
Normal 
1 
Mild/moderate alteration 
2 
Severe alteration 
Not assessed 
Not evaluable 
• 
Particularly important for frontal lobe tumors 
• 
Alteration includes but is not limited to apathy, 
disinhibition and confusion 
• 
Consider subclinical seizures for significant 
alteration 
• 
None 
 Assess based on spoken speech. Non-verbal cues 
or writing should not be included. 
 Level 1: Includes word finding difficulty; few 
paraphasic errors/neologisms/word 
substitutions; but able to form sentences 
(full/broken) 
• 
Level 2: Includes inability to form sentences (<4 
words per phrase/sentence); limited word 
output; fluent but “empty” speech. 
• 
Particularly important for brainstem tumors 
• 
Weakness includes nasolabial fold flattening, 
asymmetric smile and difficulty elevating 
• 
Patients who require corrective lenses should 
be evaluated while wearing corrective lenses 
• 
Each eye should be evaluated and score should 
reflect the worst performing eye 

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APPENDIX D: MD ANDERSON SYMPTOM INVENTORY - BRAIN TUMOR (MDASI - BT) 
 

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Appendix E: STUDY PARTICIPANT SELF-ADMINISTRATION INSTRUCTIONS 
 

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