Conditions: Glioma
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 73
Healthy volunteers: no

Brief summary:
This was a Phase 2, open-label, 2-arm study of dordaviprone (ONC201) in patients with recurrent H3 K27M- mutant glioma.

The primary assessment of dordaviprone (ONC201) involved evaluating its anti-tumor activity through the overall response rate according to the Response Assessment in Neuro-Oncology (RANO) criteria for high-grade glioma (HGG).

Detailed description:
This study included 2 arms:

* Arm A included patients with recurrent H3 K27M-mutant glioma.
* Arm B included patients with recurrent H3 K27M-mutant glioma, but excluded patients with the following:

  * Primary malignant lesion located in the pons or spinal cord.
  * Atypical non-astrocytic histologies such as ependymoma, ganglioma and pleomorphic xanthoastrocytoma, or pilocytic astrocytoma and subependymal giant cell astrocytoma (SEGA).
  * Prior bevacizumab treatment of \>4 doses of \>7.5 mg/kg

Patients received dordaviprone (ONC201) 625 mg once weekly.

The primary assessment of dordaviprone (ONC201) involved evaluating its anti-tumor activity through the overall response rate according to the Response Assessment in Neuro-Oncology (RANO) criteria for high-grade glioma (HGG). Safety was also assessed, with evaluations including the reporting of adverse events, as well as measurements of vital signs and clinical laboratory results.

This study was terminated by an administrative protocol amendment (17 January 2023). The decision to terminate the study was not related to any safety concerns with dordaviprone (ONC201). Before the study was terminated, a total of 73 patients were enrolled and received at least 1 dose of dordaviprone (ONC201).

Arms:
arm 1: Patients received 625 mg dordaviprone (ONC201) once weekly.

Arm A included patients with recurrent H3 K27M-mutant glioma including those with diffuse intrinsic pontine glioma (DIPG), primary spinal tumors, and some atypical histologies. arm 2: Patients received 625 mg dordaviprone (ONC201) once weekly.

Arm B included patients with recurrent H3 K27M-mutant glioma, but excluded patients with the following:

* Primary malignant lesion located in the pons or spinal cord.
* Atypical non-astrocytic histologies such as ependymoma, ganglioma and pleomorphic xanthoastrocytoma, or pilocytic astrocytoma and subependymal giant cell astrocytoma (SEGA).
* Prior bevacizumab treatment of \>4 doses of \>7.5 mg/kg

Interventions: intervention 1: Dordaviprone (ONC201)
Intervention descriptions: intervention 1: Dordaviprone (ONC201) is a central nervous system (CNS)-penetrant, small-molecule imipridone that acts as a mitochondrial caseinolytic protease P (ClpP) agonist and a dopamine receptor D2 (DRD2) antagonist.

Protocol document:
Prot_000.pdf: 
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1 
 
Oncoceutics, Inc. 
Protocol ONC013 
Version 04 / November 19, 2019 
 
 
 
PROTOCOL TITLE: A phase II, open-label study of ONC201 in adults with 
recurrent high-grade glioma 
 
Protocol Version 04 
 
Date:  November 19, 2019 
 
Oncoceutics Study Identifier: ONC013  
 
 
 
 
 
Overall Principal Investigator:  
Andrew B. Lassman, MD 
Department of Neurology & Herbert Irving Comprehensive Cancer Center  
Columbia University Irving Medical Center 
710 West 168th Street 
New York, NY 10032  
 
Sponsor: 
Oncoceutics, Inc. 
3675 Market Suite 
Suite 200 
Philadelphia, PA 19104 
 
Agent(s): ONC201 
 
IND: 136090 
 
 
Version 01:  10/19/17 
Version 02 (Amendment 1):  04/16/18 
Version 03 (Amendment 2):  04/23/18 
Version 04 (Amendment 3):  11/19/2019 
 
 
 
CONFIDENTIAL 
----------------------------------------------- 
The information contained in this protocol is the confidential property of the Sponsor. It is 
intended solely for the recipient clinical investigator(s) for the purposes of conducting the 
clinical protocol and may not be reproduced or disclosed to third parties without proper 
authorization from the Sponsor. 
 


2 
 
 
ONC201 in recurrent high-grade glioma 
Protocol #ONC013 / Version #4 November 19, 2019 
 
Study Summary 
 
Title 
A phase II, open-label study of ONC201 in adults with recurrent 
high-grade glioma 
Short Title 
ONC201 in recurrent high-grade glioma 
Oncoceutics 
Protocol Number 
ONC013 
IND 
136090 
Overall Principal 
Investigator 
Andrew B. Lassman, MD 
Department of Neurology & 
Herbert Irving Comprehensive Cancer Center 
Columbia University Irving Medical Center 
Regulatory 
Sponsor 
Oncoceutics, Inc. 
Phase 
Phase II 
Methodology 
Open-label, two arm 
Study Duration 
Approximately 24 months from start of screening to last 
subject processed and finishing the study 
Objectives 
Primary Objective: 
x To estimate the overall response rate (ORR) by RANO-HGG of 
ONC201 in adults with recurrent histone H3 K27M mutant 
glioma 
Secondary Objectives: 
x To estimate the overall response rate (ORR) by RANO-LGG of 
ONC201 in adults with recurrent histone H3 K27M mutant 
glioma 
x Assess the safety, toxicities and tolerability of ONC201 in 
adults with recurrent high-grade glioma (HGG); 
x Estimate the median progression-free survival (PFS), PFS at 2 and 
6 months, overall survival (OS), and median duration of response; 
Exploratory 
Objectives 
x Assess the association of ORR with tumor markers including: 
location (thalamus, brainstem, spinal cord); Histone H3 mutation 
(H3F3A / H3.3 vs HIST1H3B / H3.1); dopamine receptor D2 
(DRD2) and dopamine receptor D5 (DRD5) expression; 
x Assess the association of ORR with circulating markers including: 
Induction of serum prolactin; early activation of NK cells; 
immune cytokines and effectors in the serial serum samples by 
enzyme-linked immunosorbent assay (ELISA); 


3 
 
 
ONC201 in recurrent high-grade glioma 
Protocol #ONC013 / Version #4 November 19, 2019 
Number of Subjects 
Target enrollment is 95 evaluable subjects for the study.Thirty-nine 
(39) for Arm A and 56 for Arm B. 
 
Major 
Inclusion/Exclusion 
Criteria 
Key Inclusion criteria: Histologically confirmed diagnosis of 
HGG (any histology, including but not limited to glioblastoma, 
astrocytoma, and oligodendroglioma); presence of histone H3 
K27M mutation; unequivocal evidence of progressive disease 
on contrast-enhanced brain CT or MRI as defined by RANO 
criteria; measurable disease by RANO-HGG criteria; previous 
therapy with at least radiotherapy; no more than two prior 
episodes of recurrence; interval of at least 90 days from the 
completion of radiotherapy to the first dose of ONC201; age 
 years. .36 
 
Key Exclusion Criteria: Presence of diffuse leptomeningeal 
disease or evidence of CSF dissemination; tumors with known 
IDH1 (isocitrate dehydrogenase 1) or known IDH2 mutations 
Study Product, 
Dose, Route, 
Regimen 
 
ONC201, 625 mg once weekly, oral 
Duration of 
administration 
ONC201 treatment will continue if tolerated until disease progression, 
unacceptable toxicity, or withdrawal of consent, whichever comes first. 
Statistical 
Methodology 
Primary Efficacy Analysis: Simon's two-stage design (Simon, 1989) 
will be used. The null hypothesis that the true response rate is 0.01 will 
be tested against a one-sided alternative.  
 
Arm A 
In the first stage, 17 patients will be accrued. If there are 0 responses in 
these 17 patients, the study will be stopped. Otherwise, 22 additional 
patients will be accrued for  a total of 39.  
 
Arm B 
In the first stage of Arm B, 17 patients will be accrued.  If there are 0 
responses in these 17 patients, the study will be stopped.  Otherwise, 
39 additional patients will be accrued for a total of 56.  At least 3 
responses will be required in order for success to be claimed (i.e. for 
the null hypothesis (p0 0.01) to be rejected in favor of the alternative 
(p1 .10) with 80% power, alpha=0.025).  
 
Patients will be analyzed separately in each arm.   


4 
 
 
ONC201 in recurrent high-grade glioma 
Protocol #ONC013 / Version #4 November 19, 2019 
 
TABLE OF CONTENTS 
Study Summary ........................................................................................................................................ 2 
1. 
OBJECTIVES ....................................................................................................................................... 7 
1.1 General Study Design .................................................................................................................... 7 
1.2 Primary Objective .......................................................................................................................... 8 
1.3 Secondary Objectives .................................................................................................................... 8 
1.4 Exploratory Objectives ................................................................................................................. 8 
1.5 Endpoints .......................................................................................................................................... 8 
2. 
BACKGROUND .................................................................................................................................. 9 
2.1 Study Disease ................................................................................................................................... 9 
2.2 IND Agent ......................................................................................................................................... 10 
2.3 Clinical Studies .............................................................................................................................. 18 
2.4 Rationale for ONC201 in Glioblastoma and Histone H3 K27M Gliomas .................... 20 
2.5 Correlative Studies Background ............................................................................................. 24 
3. 
PARTICIPANT SELECTION ......................................................................................................... 25 
3.1 Inclusion Criteria .......................................................................................................................... 25 
3.2 Exclusion Criteria ......................................................................................................................... 27 
3.3 Inclusion of Women and Minorities ....................................................................................... 28 
4. 
REGISTRATION PROCEDURES .................................................................................................. 28 
5. 
TREATMENT PLAN ....................................................................................................................... 28 
5.1 Treatment Regimen ..................................................................................................................... 28 
5.2 Screening Procedures ................................................................................................................. 29 
5.3 Baseline Procedures .................................................................................................................... 30 
5.4 On-Treatment Procedures ........................................................................................................ 31 
5.5 Efficacy Procedures ..................................................................................................................... 32 
5.6 End of Treatment Visit ................................................................................................................ 33 
5.7 General Concomitant Medication and Supportive Care Guidelines ........................... 34 
5.8 Criteria for Taking a Participant Off Protocol Therapy .................................................. 35 
5.9 Duration of Follow Up ................................................................................................................. 35 
5.10 
Criteria for Taking a Participant Off Study ................................................................. 36 
6. 
DOSING DELAYS/DOSE MODIFICATIONS .............................................................................. 36 
7. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS .......................................... 37 


5 
 
 
ONC201 in recurrent high-grade glioma 
Protocol #ONC013 / Version #4 November 19, 2019 
7.1 Reporting of Serious Adverse Events .................................................................................... 38 
7.2 Adverse Event Characteristics ................................................................................................. 39 
8. 
PHARMACEUTICAL INFORMATION ........................................................................................ 40 
8.1 Drug Substance Description ..................................................................................................... 40 
8.2 Drug Product Description.......................................................................................................... 41 
8.3 Drug Product Supply, Administration and Inventory ...................................................... 42 
9. 
BIOMARKER, CORRELATIVE, IMAGING SUBMISSION AND SPECIAL STUDIES ......... 43 
9.1 Predictive Tumor Biomarker Studies ................................................................................... 43 
9.2 Circulating Pharmacodynamic Analyses .............................................................................. 43 
9.3 Immune Cell Studies .................................................................................................................... 44 
9.4 ONC201 Plasma Analyses .......................................................................................................... 44 
9.5  Imaging submission ..................................................................................................................... 44 
10 SCHEDULE OF EVENTS ................................................................................................................ 46 
11. MEASUREMENT OF EFFECT ....................................................................................................... 48 
11.1 
Response Assessment Criteria ........................................................................................ 48 
11.2 
Definitions .............................................................................................................................. 48 
11.3 
Disease Parameters ............................................................................................................ 48 
11.4 
Response/Progression Categories ................................................................................ 49 
11.5 
Methods for Evaluation of Disease ................................................................................ 50 
11.6 
Evaluation of Best Response ............................................................................................ 51 
12. DATA REPORTING / REGULATORY REQUIREMENTS ....................................................... 51 
12.1 
Data Reporting ...................................................................................................................... 51 
12.2 
Data Collection ...................................................................................................................... 51 
13. STATISTICAL CONSIDERATIONS ............................................................................................. 54 
13.1 
Study Design .......................................................................................................................... 54 
13.2 
Study Population .................................................................................................................. 54 
13.3 
Statistical Methods for Efficacy and Safety Analyses ............................................... 54 
13.4 
Demographic and Baseline Characteristics ................................................................ 56 
14 PROTOCOL SIGNATURES ............................................................................................................ 57 
REFERENCES ............................................................................................................................................ 58 
APPENDIX A:  KARNOFSKY PERFORMANCE STATUS (KPS) CRITERIA ................................ 60 
APPENDIX B:  TABLE OF EIAEDS AND NON-EIAEDS* ................................................................. 61 
APPENDIX C: MDASI PRO Questionnaire ...................................................................................... 62 
APPENDIX D: NANO Scale Assessment ........................................................................................... 64 


6 
 
 
ONC201 in recurrent high-grade glioma 
Protocol #ONC013 / Version #4 November 19, 2019 


7 
 
 
ONC201 in recurrent high-grade glioma 
Protocol #ONC013 / Version #4 November 19, 2019 
1. 
OBJECTIVES 
 
The primary objective of this trial is to determine the efficacy and safety of ONC201, an oral 
small molecule imipridone DRD2 antagonist, in adult subjects with recurrent HGG.  
 
1.1 
General Study Design 
 
This is an open-label, two arm study. The trial will enroll a total of up to 95 subjects. 
Arm A will enroll up to a total of 39 evaluable subjects and Arm B will enroll up to a 
total of 56 evaluable subjects.  A Bayesian monitoring approach will be applied to assess 
safety throughout the trial. 
 
After screening procedures and registration, all subjects will be treated with oral ONC201 
(625 mg) once every week. All subjects will remain on study until confirmed progressive 
disease, unacceptable toxicity, death, withdrawal of consent, or another protocol criterion 
for subject withdrawal is met, whichever comes first. One treatment cycle will be defined 
as 28 days (4 weeks), corresponding to 4 doses of ONC201. 
 
Subjects will be evaluated for efficacy approximately every 8 weeks with neuroimaging 
and clinical evaluation. Neuroimaging studies contrast-enhanced brain MRI or CT for 
patients unable to undergo MRI) will be performed at baseline and every 8 weeks after 
treatment initiation. Tumor response will be evaluated by the Response Assessment in 
Neuro-Oncology (RANO) criteria, both criteria for HGG and low-grade glioma (LGG). 
 
Subjects will be evaluated for safety if they have received any study drug. Toxicity 
assessments will be continuous during the treatment phase. Adverse events will be 
monitored throughout the trial and graded in severity according to the guidelines outlined 
in the NCI Common Terminology Criteria for Adverse Events (CTCAE) version  5. 
 
End of treatment assessments will be performed within 30 days after last drug 
administration, unless the subject is unable to travel due to deteriorating medical 
condition. Post-treatment, all participants will be followed until resolution or stabilization 
of any serious or reportable adverse events occurring during treatment or starting within 
30 days of last study drug. Assessments may continue for ongoing reportable adverse 
events. 
 
Subjects who discontinue study drug must continue to be followed for collection of 
outcome and/or survival follow-up data until death, withdrawal of permission to record at 
least survival data, or subject is lost to follow-up. Following the end of treatment 
assessments, all subjects will be contacted every 30 days (±7 days) to assess for study- 
treatment related toxicities, initiation of any new anti-cancer treatments, and survival 
status. Contact may be performed by a site visit, telephone contact, e-mail, fax, or mail. 


8 
 
 
ONC201 in recurrent high-grade glioma 
Protocol #ONC013 / Version #4 November 19, 2019 
 
1.2 
Primary Objective 
 
x To estimate the overall response rate of ONC201, assessed by RANO-HGG 
criteria, in adult patients with recurrent histone H3 K27M glioma. 
 
1.3 
Secondary Objectives 
 
x Assess ORR. according to RANO-LGG, criteria for non-contrast enhancing 
lesions.  
x Assess the safety, toxicities and tolerability of ONC201 in adults with recurrent 
high- grade glioma; 
 
x Estimate the median PFS, PFS at 2 and 6 months,median OS, and median 
duration of response; 
 
1.4 
Exploratory Objectives 
 
x Assess the association of ORR with tumor markers including: location (thalamus, 
brainstem, spinal cord); Histone H3 mutation (H3F3A / H3.3 vs HIST1H3B / 
H3.1); DRD2 and DRD5 expression; 
 
x Assess the association of ORR with circulating markers including: Induction of 
serum prolactin; early activation of NK cells; immune cytokines and effectors in 
the serial serum samples by ELISA; 
 
1.5 
Endpoints 
 
-Efficacy 
x Response by RANO-HGG 
x Response by RANO-LGG 
x Duration of response by either RANO-HGG or RANO-LGG 
x Progression free survival by RANO-HGG 
x Progression-free survival by RANO-LGG  
x Overall survival 
 
-Safety 
x Adverse events 
x Laboratory evaluations 
x KPS status 
x Vital signs 
x Physical examinations 
 
-Other 
x Quality of life Assessment by MDASI Patient Reported Outcomes Questionnaire 
x NANO (Neurologic Assessment in Neuro-Oncology) 
 
 


9 
 
 
ONC201 in recurrent high-grade glioma 
Protocol #ONC013 / Version #4 November 19, 2019 
 
2. BACKGROUND 
 
2.1 
Study Disease 
 
According to the 2007 World Health Organization (WHO) Classification of Tumors of 
the Central Nervous System (CNS), astrocytoma (a major type of glioma) is classified 
into grades I, II, III and IV based on histology. Grade I and II astrocytoma are 
considered low grade glioma (LGG), while grade III (anaplastic astrocytoma) and IV 
astrocytoma/gliomas as well as Grade III oligodendroglioma are considered HGG. 
Grade IV glioma, or Glioblastoma Multiforme (GBM), is the most common and lethal 
primary CNS malignancy and accounts for over 15% of all brain cancers (Patel et al., 
2014). The 5-year survival rate for GBM remains at <10% (Stupp et al., 2009). In 2014, 
there were over 23,300 new cases of cancer involving the brain and nervous system and 
over 14,000 deaths (Siegel et al., 2014). Although initial treatment typically includes 
surgery, radiation and chemotherapy, HGG usually recurs less than 6-8 months from 
initial diagnosis.(Gorlia, et. al. 2012).  There are limited choices for treating recurrent 
disease.  Bevacizumab was approved for treating recurrent GBM, but studies repeatedly 
demonstrated outcomes lacking in overall survival benefit from its use.(Wick, et. al. 
2017, Gilbert, et. al. 2014) Thus, recurrent HGG has an unmet clinical need with poor 
survival and limited treatment options that offer meaningful therapeutic benefit. 
 
In the 2016 edition of WHO classification of CNS tumors, Diffuse Midline Glioma 
(DMG) with Histone H3 K27M mutant is recognized as a distinct disease entity. Any 
DMG with the H3 K27M mutation is classified as grade IV (Louis et al, 2016).  Histone 
H3 is one of the proteins that comprise the octameric nucleosome and there are 3 
variants: H3.1, H3.2, and H3.3. H3.3 is a replication-dependent H3 variant that 
represents only a small portion of the total cellular histone H3 pool (Bush et al, 2013). 
Recently, recurring heterozygous hotspot mutations in H3F3A and H3F3B, the only two 
genes in mammals that encode H3.3, were discovered in pediatric and young-adult high-
grade astrocytomas. These mutations include K27M (lysine 27 to methionine amino acid 
substitution), as well as other recurrent amino acid substitutions at positions G34 and 
K36, of which the predominant mutations include G34R/V and K36M. Although both 
H3F3A and H3F3B encode H3.3 with identical amino acid sequences, the H3.3 K36M 
mutation occurs predominantly in H3F3B whereas the other mutations are almost 
exclusive to H3F3A (Behjati et al, 2013). 
 
Different mutations in H3.3 segregate by distinct types of tumors. The K27M mutation 
is prevalent in pediatric diffuse intrinsic pontine glioma (DIPG) and HGG, primarily 
restricted to midline locations (spinal cord, thalamus, pons, brainstem) in children and 
younger adults (Schwartzentruber et al, 2012; Sturm et al, 2012; Fontebasso et al, 2014; 
Aihara et al, 2014). The G34R/V mutations predominantly associate with pediatric 
glioblastoma in the cerebral hemispheres (Schwartzentruber et al, 2012). The 
mechanisms by which histone H3 alterations mediate their oncogenic effects are still 
poorly understood, although there is some evidence that H3 K27M mutations alter global 
epigenetic states, including lower overall histone H3 K27M trimethyl (H3K27me3) 
levels and reduced polycomb repressive complex 2 (PRC2) activity. 
 
The H3K27M mutation may present in patients with leptomeningeal dissemination as 


10 
 
 
ONC201 in recurrent high-grade glioma 
Protocol #ONC013 / Version #4 November 19, 2019 
well as tumors not originating from the midline CNS structures. No prospective trials 
exclusive to histone H3 K27M mutant gliomas have been conducted and therefore 
prospectively collected outcome data are lacking. However, survival data are well 
published for DIPG, the vast majority of which contain histone H3.3 or H3.1 K27M 
mutations (Schwartzentruber et al, 2012; Sturm et al, 2012; Wu et al, 2012).  In pediatric 
DIPG, from the time of diagnosis, median overall survival is 9 months, no chemotherapy 
has proven efficacy in this disease, and no therapy has proven effective at progression 
after radiotherapy (Cohen et al, 2011; Bailey et al, 2013; Rizzo et al, 2015; Chassot et a, 
2012). Novel therapies are desperately needed for treatment of H3 K37M mutant 
gliomas. 
 
2.2 
IND Agent 
 
ONC201 is a first-in-class small molecule (imipridone) selective DRD2 antagonist that 
functions by activating the integrated stress response (ISR) in tumors cells, leading to 
downstream anticancer effects that include inactivation of prosurvival Akt and ERK 
signaling along with induction and activation of the TRAIL apoptosis pathway (Allen et 
al., 2013). ONC201 has demonstrated broad spectrum antitumor efficacy in numerous  
solid and liquid tumor preclinical models, including cell lines and patient samples that 
are refractory to chemotherapy and targeted therapies.  This is independent of mutations 
in genes such as p53, KRAS, Raf, EGFR. ONC201 is orally available, has demonstrated 
a  wide therapeutic window preclinically, is highly stable and water soluble, and is able 
to  penetrate the blood-brain barrier. 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. ONC201 has demonstrated antitumor activity in high grade gliomas, 
as demonstrated use in in vitro, ex vivo, and in vivo models. In early clinical studies 
ONC201 has been well tolerated. The safety profile along with its mechanism of action 
makes ONC201 suited to address gliomas by potentially circumventing limitations of 
available therapies. 
 
For complete details of ONC201, please refer to the Investigator's Brochure. 
 
2.2.1 Preclinical Efficacy in High Grade Glioma 
 
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 results 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 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. 


11 
 
 
ONC201 in recurrent high-grade glioma 
Protocol #ONC013 / Version #4 November 19, 2019 
 
In addition to potent in vitro activity, ONC201 shrinks temozolomide-resistant GBM 
xenografts (Figure 1A) and prolongs the survival of mice with orthotopic xenografts 
as a monoagent and in combination with bevacizumab (Figure1B). Corroborating 
observations by other investigators have demonstrated the compelling monoagent 
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.
 
 
 
 
 
 
 
ONC201 demonstrates p53-independent activity in human GBM cell lines in the 
low micromolar range (Figure 2). ONC201 exerts a strong cytotoxic effect, 
unlike temozolomide, against tumor cells isolated from a freshly resected GBM 
 
 
GI50 GBM 
 
 
72 hours 
 
 
with ONC201 or DMSO (n = 
3). 
GBM 
 following 
 with 
ONC201
(72 hr).
Figure 1 (A) 
Relative tumor 
size (compared to 
day 0) 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) on 
day 0 (n = 8). (B) 
Overall survival 
of mice harboring 
SF767 intracranial 
tumors treated 
with a single oral 
dose of vehicle (n 
= 8), ONC201 
(25 mg/kg, n = 7), 
bevacizumab 


12 
 
 
ONC201 in recurrent high-grade glioma 
Protocol #ONC013 / Version #4 November 19, 2019 
with an oligodendroglial component that was previously resected and irradiated. 
Observations by external investigators demonstrate the compelling monoagent 
efficacy of ONC201 in radio- and chemo-resistant GBM cell lines (Figure 3) and 
3D neurosphere cultures (Figure 4).
 
 
 
 
2.2.2
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 5). ATF4 upregulates CHOP, 
which is also a transcription factor that regulates several apoptosis-related genes 
such as the TRAIL-receptor DR5. ATF4 and CHOP upregulate expression of 
TRB3, which interacts directly with Akt to decrease its kinase activity. TRB3 also 
Figure 4 ONC201 kills newly diagnosed and recurrent GBM 
neurospheres. Cell viability of neurosphere GBM cultures following 
ONC201 t
t
t (72 h )
Proposed
of
 
ONC201 
 of 
  
 
 


13 
 
 
ONC201 in recurrent high-grade glioma 
Protocol #ONC013 / Version #4 November 19, 2019 
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. 
 
2.2.3 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 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 a slight increase 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. 
 
 
2.2.3.1 Non-GLP Safety Studies 
 
Non-GLP studies were conducted in rats and dogs to assess clinical 
observations and body weight with ONC201. 
 


14 
 
 
ONC201 in recurrent high-grade glioma 
Protocol #ONC013 / Version #4 November 19, 2019 
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, 
pilerection, 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 absolute or organ to body or organ to brain weights. 


15 
 
 
ONC201 in recurrent high-grade glioma 
Protocol #ONC013 / Version #4 November 19, 2019 
 
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. 
 
On Day 3 the 225 mg/kg females also had increased glucose, cholesterol, 
sodium and chloride. Sodium and chloride were statistically significantly 


16 
 
 
ONC201 in recurrent high-grade glioma 
Protocol #ONC013 / Version #4 November 19, 2019 
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. 
 
2.2.4 
Pharmacokinetic Studies 
 
2.2.4.1 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. 
 
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 


17 
 
 
ONC201 in recurrent high-grade glioma 
Protocol #ONC013 / Version #4 November 19, 2019 
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 6; 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 at1.8 hours 
following administration (Tmax). The mean volume of distribution was 369 
L, consistent with a large distributive YROXPH0HDQ$8&ZDVKȝJP/
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. 
Figure 6 ONC201 pharmacokinetic parameters  
 
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 
 
    
 
    
 
    
 
    
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Chimerix, Inc. 
Statistical Analysis Plan v1.0, 01Dec2023 
ONC013 
 
 
 
Statistical Analysis Plan 
 
ONC013 
 
A phase II, open-label study of ONC201 in adults with recurrent 
high-grade glioma 
 


Chimerix, Inc. 
Statistical Analysis Plan v1.0, 01Dec2023 
ONC013 
 
I confirm that I have reviewed this document and agree with the content. 
 
APPROVALS 
Approved by:  
Tom Brundage 
Vice President, Biostatistics 
Chimerix
 
 
Signature/Date: 
 


Chimerix, Inc. 
Statistical Analysis Plan v1.0, 01Dec2023 
ONC013 
 
 
Table of Contents 
1. 
Introduction ........................................................................................................................................... 4 
2. 
General Conventions ............................................................................................................................. 4 
3. 
Analyses ................................................................................................................................................ 4 
 
 
 


Chimerix, Inc. 
Statistical Analysis Plan v1.0, 01Dec2023 
ONC013 
 
 
1. Introduction 
This abbreviated Statistical Analysis Plan (SAP) describes the statistical analyses to be conducted for the 
Study ONC013. For simplicity, reference is made to existing Integrated Summary of Safety (ISS) and 
Integrated Summary of Efficacy (ISE) SAPs when approaches are the same. 
Study ONC013 is a Phase II, open-label, multi-center clinical trial of ONC201 in adult recurrent glioma 
with two arms. All subjects receive oral ONC201 at 625 mg every week. All subjects remain on study 
until progressive disease, unacceptable toxicity or withdrawal of consent. For other study details, refer to 
the study protocol. 
2. General Conventions 
The All Treated Analysis Set includes all patients who receive at least one dose of ONC201. This will be 
used for all analyses. 
Unless otherwise specified, continuous variables will be summarized using descriptive statistics [number 
of observations, mean, standard deviation (SD), median, 1st (Q1) and 3rd (Q3) quartiles, minimum and 
maximum]. Categorical variables will be summarized as number (percent) of patients. 
Day 1 is defined as the date of the first dose of study drug. For events that occur on or after Day 1, study 
day is defined as (date of event - date of Day 1 + 1). For events that occur prior to Day 1, study day is 
defined as (date of event - date of Day 1). There is no Day 0. Baseline is defined as the last observed 
measurement on or before the date of the first dose of study drug. 
In general, other than for partial dates, missing data will not be imputed and will be treated as missing. 
Unless otherwise specified, partial dates will be imputed using the following rules: 
• 
If year is missing, do not impute. 
• 
If only day is missing, impute day as 1st of the month for start dates, end of the month for end 
dates, and 15th of the month for other dates. 
• 
If day and month are missing, impute as January 1st for start dates, December 31st for end dates, 
and July 1st for other dates. 
3. Analyses 
All analyses will be presented by Arm and for All Patients. Otherwise, specified patient disposition, study 
drug usage, prior/concomitant/post-ONC201 medications, demographic and baseline characteristics, 
adverse events, and laboratories will use methods and summaries defined in the ISS SAP. 
Laboratory boxplots will be presented for all tests with at least 60 patients having numeric baseline 
results: one plot per test, time on the x-axis, value on the y-axis. The plots will not be broken out by arm 
(i.e. only the All Patients group). Only Baseline and Cycles 2-12 will be presented. For Cycles 2-12, 
nominal visits will be used; if multiple values are associated with a visit, the highest value will be used 
for chemistry tests and lowest value will be used for hematology tests. 
The following efficacy analyses will be performed: best overall response, overall response rate, disease 
control rate, duration of response, progression-free survival, and overall survival. All analyses will be 
based on the investigator-assessed overall RANO response. Discontinuation of treatment due to 
progressive disease will also be considered. All analyses, aside from overall survival, will be censored at 


Chimerix, Inc. 
Statistical Analysis Plan v1.0, 01Dec2023 
ONC013 
 
 
the earlier of: (1) last disease assessment or (2) last assessment prior to initiation of other anticancer 
therapy. 
Cycle 1 (2hr, 24hr, 48hr, 72hr) ONC201 plasma concentrations will be summarized descriptively, 
including geometric mean and %CV. BLQ results will be imputed as zero. 
Collected data contributing to presented tables and figures will be listed. 
Other analyses specified in the protocol will either not be completed, or will be defined outside the scope 
of this plan. 
 
 


Chimerix, Inc. 
Statistical Analysis Plan v1.0, 01Dec2023 
ONC013 
 
 
Following is a complete list of the tables, figures, and listings to be prepared (with clarifying notes in 
parentheses). 
Number 
Description 
Table 1.1 
Patient Disposition 
Table 1.2 
Demographics and Baseline Characteristics 
Table 1.3 
Study Drug Usage 
Table 1.4.1 
Prior Medications 
Table 1.4.2 
Concomitant Medications 
Table 1.4.3 
Post-ONC201 Medications 
Table/Figure 2.1 
Progression-free Survival 
Table/Figure 2.2 
Overall Survival 
Table 2.3 
Response Rate (includes ORR, BOR, and DCR) 
Table/Figure 2.4 
Duration of Response 
Table 3.x.1* 
Treatment-emergent Adverse Events (TEAE) 
Table 3.x.2* 
TEAE Grade 3 and Above 
Table 3.x.3* 
Serious TEAE 
Table 3.x.4* 
TEAE Leading to Death 
Table 3.x.5* 
TEAE Leading to Study Drug Discontinuation, Reduction, or Interruption 
Table 3.x.6* 
Study Drug Related TEAE 
Table 3.x.7* 
Study Drug Related TEAE Grade 3 and Above 
Table 3.x.8* 
Study Drug Related Serious TEAE 
Table 3.x.9* 
Study Drug Related TEAE Leading to Death 
Table 3.x.10* 
Study Drug Related TEAE Leading to Study Drug Discontinuation, Reduction, 
or Interruption 
Table 3.x.11* 
TEAE by Maximum Severity (overall only) 
Table 3.x.12* 
Study Drug Related TEAE by Maximum Severity (overall only) 
Table 4.x.1* 
Graded Laboratory Results (maximum post-baseline) 
Table 4.x.2* 
Graded Treatment-emergent Laboratory Results (maximum on-treatment, result 
only counted if > Baseline Grade) 
Table 5.1 
Plasma Concentrations 
Figure 4.1 
Boxplot of Laboratory Results 
Listing 1.1 
Patient Disposition 
Listing 1.2 
Demographics and Baseline Characteristics 
Listing 1.3 
Study Drug Usage 
Listing 1.4 
Other Medications 
Listing 2.1 
Efficacy Outcomes 
Listing 3.1 
Adverse Events 
Listing 3.2 
AE Leading to Death 
Listing 3.3 
AE Leading to Study Drug Discontinuation, Reduction, or Interruption 
Listing 4.1 
Listing of Graded Laboratory Results (includes all results for a patient/test where 
at least one on-treatment result is Grade 1) 
Listing 5.1 
Plasma Concentrations 
 
 
x=1: all post-baseline, x=2: prior to initiation of other anticancer therapy