Clinical trial NCT03485729
Conditions: Endometrial Cancer Recurrent
Sponsor: Chimerix
Start date: 2018-03-21; Completion date: 2023-01-19
Enrollment: 27 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a Phase 2, Simon two-stage, non-randomized, open-label, 2-arm trial of dordaviprone (ONC201) in women with metastatic or recurrent Type II endometrial cancer who failed at least 1 prior chemotherapy regimen. Patients with histologically confirmed Type II endometrial cancer, including but not limited to serous, clear cell, carcinosarcoma, adenosquamous, and mixed histologies were eligible.

The primary objective of this study was to determine the efficacy of dordaviprone (ONC201) in metastatic type II endometrial cancer.

Note: This study was completed by predecessor company, Oncoceutics, Inc.

Detailed description:
This study included 3 arms: Arm A, Arm B, and Arm C. Dordaviprone (ONC201) was to be administered as a dose of 625 mg by mouth, once or twice each week until disease progression, unacceptable toxicity, or if the patient discontinued for any other reason.

For Arm A and Arm B, ONC201 administration occurred on Days 1, 8, and 15 of each 3-week cycle. For Arm C, ONC201 administration occurred on Days 1, 2, 8, 9, and 15, and 16 of each 3-week cycle.

All patients in Arm A had a biopsy of their tumor one day after the second dose of dordaviprone (ONC201) on Cycle 1, Day 9. All patients in Arm C had a biopsy of their tumor one day after the fourth dose of dordaviprone (ONC201) on Cycle 1, Day 10.

Assessments of objective tumor response were conducted using RECIST version 1.1. Safety was assessed through the reporting of adverse events, measurement of vital signs, electrocardiograms, and clinical laboratory results.

Before the study was terminated, a total of 27 patients were enrolled and received at least 1 dose of dordaviprone (ONC201): 10 patients in Arm A, 14 patients in Arm B, and 3 patients in Arm C.

Arms: arm 1: Patients received 625 mg dordaviprone (ONC201) once weekly on Days 1, 8, and 15 of each 3-week cycle. Patients were required to undergo a biopsy of their tumor one day after their second dose of dordaviprone (ONC201) on Cycle 1, Day 9. arm 2: Patients received 625 mg dordaviprone (ONC201) once weekly on Days 1, 8, and 15 of each 3-week cycle. Patients were not required to undergo a biopsy of their tumor. arm 3: Patients received 625 mg dordaviprone (ONC201) twice weekly on consecutive days on Days 1, 2, 8, 9, 15, and 16 of each 3-week cycle. Patients were required to undergo a biopsy of their tumor one day after their fourth dose of dordaviprone (ONC201) on Cycle 1, Day 10.
Interventions: intervention 1: Dordaviprone (ONC201)
Intervention descriptions: intervention 1: 625 mg dordaviprone (ONC201)

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Title: A Phase II Study of ONC201 in Recurrent or Metastatic Type II Endometrial Cancer 
Protocol Number: ONC012 (NCT03485729) 
Protocol Date: 11 May 2020 (Version 4.0) 


Page 1 of 45 
 
 
 
PROTOCOL TITLE: A Phase II Study of ONC201 in Recurrent or Metastatic Type II 
Endometrial Cancer 
 
Protocol Version: 4 
 
Date: May 11, 2020 
Replaces: 
Version 3 dated 10 April 2018 
Version 2 dated 10 January 2018 
Version 1 dated 07 September 2017 
 
Oncoceutics Study Identifier: ONC012 
 
 
Sponsor: 
Oncoceutics 
3675 Market Street 
 
Philadelphia, PA 19104 
Agent(s): ONC201 
IND: 121496 
 
 
 
 
 
 
 
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. 


Protocol #: ONC012 / Version 4 11May 2020 
Page 2 of 45 
 
 
Study Summary 
 
Title 
A Phase II Study of ONC201 in Recurrent or Metastatic Type II 
Endometrial Cancer 
Short Title 
ONC201 in Type II Endometrial Cancer 
Oncoceutics 
Protocol Number 
ONC012 
IND 
121496 
Regulatory 
Sponsor 
Oncoceutics, Inc. 
Phase 
Phase II 
Methodology 
A Bayesian method will be used for toxicity monitoring based 
on the dose-limiting toxicity (DLT) rate. 
Study Duration 
Approximately 24 months from start of screening to last subject 
processed and finishing the study 


Protocol #: ONC012 / Version 4 11May 2020 
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Endpoints/ 
Objectives 
Primary Objectives: 
• To determine efficacy of ONC201 in metastatic type II 
endometrial cancer 
Secondary Objective: 
• Evaluation of the safety profile of single agent ONC201 
in women with recurrent or metastatic endometrial 
cancers 
• Evaluation of intratumoral ONC201 concentrations in 
women with recurrent or metastatic endometrial cancers 
Primary Endpoint: 
• Progression-free survival rate at 2 months by RECIST 
version 1.1. 
Secondary Endpoints: 
• Safety profile of ONC201 will be determined by type, 
frequency, severity and timing and relationship of 
Adverse Events and lab abnormalities to ONC201. 
• Duration of response and duration of stable disease will 
be determined by the time-period when a response is 
first seen or stable disease until disease progression. 
• Overall response rate by RECIST version 1.1. Median 
PFS will be calculated as the period between the start of 
the treatment until disease progression. 
• Study drug concentration in tumor tissues from patients 
taking once per week or twice per week on two 
consecutive days, about 24 hours after the first or second 
dose respectively 
Arms 
Arm A and C: Patients with biopsiable metastatic or recurrent 
Type II endometrial cancer who failed ≥ 1 prior chemotherapy 
regimen(s). Patients will receive ONC201, 625 mg PO, once 
every week (Arm A) or twice per week on two consecutive days 
(Arm C), respectively. 
Arm B: Patients with metastatic or recurrent Type II 
endometrial cancer who failed ≥ 1 prior chemotherapy 
regimen(s). Patients will receive ONC201, 625 mg PO, once 
weekly. 
Major Eligibility 
Histologically confirmed metastatic or recurrent Type II EC 
(serous, clear cell, carcinosarcoma, adenosquamous and mixed 
histologies) 
Age ≥ 18 years. 
ECOG performance status of 0, 1, or 2 


Protocol #: ONC012 / Version 4 11May 2020 
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Anticipated 
Number of 
Subjects 
Arm A: 6 patients 
Arm B: 24 patients 
Arm C: 6 patients 
Study Drug 
Oral ONC201 provided as 125mg capsules. Subjects will be 
treated with oral ONC201 once every week in Arms A and B. 
Patients in Arm C receive ONC201 625mg twice per week on 
two consecutive days. A treatment cycle is 3 weeks. 
Duration of 
administration 
ONC201 treatment will continue until confirmation of both 
radiographic and/or clinical disease progression, unacceptable 
toxicity, or withdrawal of consent, whichever comes first. 
Statistical 
Methodology 
Arm A: Intratumoral ONC201 concentration in patients will be 
summarized using descriptive statistics. 
Arm B: Simon two-stage, non-randomized, open label, 2-arm 
Phase II trial of ONC201 in women with metastatic or recurrent 
Type II endometrial cancer who failed at least 1 prior 
chemotherapy regimen. 
Arm C: Intratumoral ONC201 concentration in patients will be 
summarized using descriptive statistics. 


Protocol #: ONC012 / Version 4 11May 2020 
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Arm A 
Population 
6 patients with biopsiable metastatic or 
recurrent Type II endometrial cancer who 
failed ≥ 1 prior chemotherapy regimen(s) 
Arm B 
Population 
Up to 24 patients with metastatic or 
recurrent Type II endometrial cancer who 
failed ≥ 1 prior chemotherapy regimen(s) 
Arm C 
Population 
6 patients with biopsiable metastatic or 
recurrent Type II endometrial cancer who 
failed ≥ 1 prior chemotherapy regimen(s) 
Disease Assessment 
Baseline, cycle 3 day 1, cycle 5 day1 
Every 3 cycles beyond cycle 5 
End of treatment 
Follow up 
Performed 30 days (+/-3 days) 
after discontinuation from the 
study 
Survival Follow up 
Performed 30 ±days (+/-7 days) 
after initial Follow Up Visit 
 
Schema 
 
 
 
 
 
 
 
 
Continue treatment until: 
Disease progression or 
Unacceptable toxicity or 
Patient preference 
Arm A & C 
Biopsy 
Baseline 
Arm A: Cycle 1 Day 9 
Arm C: Cycle 1 Day 10 
Treatment 
Single agent ONC201 625mg orally weekly 
Treatment 
Single agent ONC201 625 mg orally, twice 
per week on two consecutive days 


Protocol #: ONC012 / Version 4 11May 2020 
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TABLE OF CONTENTS 
1 
INTRODUCTION ............................................................................................................................... 8 
1.1 
STUDY DISEASE .............................................................................................................................................................. 8 
1.2 
DISEASE CLASSIFICATION & RATIONALE FOR CORRELATIVE SAMPLING ................................................ 8 
1.3 
ENDOMETRIAL CANCER TREATMENT .................................................................................................................... 9 
1.4 
AGENT UNDER INVESTIGATION ................................................................................................................................ 9 
1.5 
STUDY RATIONALE ..................................................................................................................................................... 13 
1.6 
CORRELATIVE TESTING ............................................................................................................................................. 14 
2 
OBJECTIVES ................................................................................................................................... 14 
2.1 
PRIMARY OBJECTIVE .................................................................................................................................................. 14 
2.2 
SECONDARY OBJECTIVES ......................................................................................................................................... 14 
2.3 
PRIMARY ENDPOINT ................................................................................................................................................... 14 
2.4 
SECONDARY ENDPOINTS ........................................................................................................................................... 14 
3 
STUDY PLAN ................................................................................................................................... 14 
4 
ELIGIBILITY CRITERIA .............................................................................................................. 15 
4.1 
INCLUSION CRITERIA .................................................................................................................................................. 15 
4.2 
EXCLUSION CRITERIA ................................................................................................................................................ 16 
4.3 
INCLUSION OF WOMEN AND MINORITIES ........................................................................................................... 17 
4.4 
PREGNANCY ................................................................................................................................................................... 17 
4.5 
SCREENING PROCEDURES ......................................................................................................................................... 18 
4.6 
SUBJECT REGISTRATION ........................................................................................................................................... 19 
5 
TREATMENT PLAN ....................................................................................................................... 19 
5.1 
TREATMENT ADMINISTRATION .............................................................................................................................. 20 
5.2 
CONCOMITANT MEDICATIONS, SUPPORTIVE CARE, EXCLUDED THERAPIES AND RESTRICTIONS 20 
5.3 
DURATION OF THERAPY ............................................................................................................................................ 21 
5.4 
DURATION OF FOLLOW UP ....................................................................................................................................... 21 
5.5 
CRITERIA FOR DISCONTINUATION ......................................................................................................................... 21 
6 
DOSE MODIFICATIONS ............................................................................................................... 22 
7 
STUDY AGENT INFORMATION ................................................................................................. 23 
7.1 
DRUG SUBSTANCE DESCRIPTION ........................................................................................................................... 23 
7.2 
DRUG PRODUCT DESCRIPTION ............................................................................................................................... 24 
7.3 
DRUG PRODUCT SUPPLY, ADMINISTRATION AND INVENTORY .................................................................. 24 
8 
BIOMARKER, CORRELATIVE AND SPECIAL STUDIES ...................................................... 25 
8.1 
TUMOR BIOPSY STUDIES ............................................................................................................................................ 25 
8.2 
BLOOD FOR PHARMACODYNAMICS ANALYSES ................................................................................................. 26 
8.3 
BLOOD FOR IMMUNE CELL STUDIES ...................................................................................................................... 26 
8.4 
BLOOD FOR PHARMACOKINETICS .......................................................................................................................... 26 
9 
STUDY CALENDAR ....................................................................................................................... 27 
10 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS ......................................... 29 
10.1 
DEFINITIONS .................................................................................................................................................................. 29 
10.2 
REPORTING OF SERIOUS ADVERSE EVENTS ....................................................................................................... 30 
10.3 
EXPECTED TOXICITIES ............................................................................................................................................... 31 
10.4 
ADVERSE EVENTS CHARACTERISTICS ................................................................................................................. 31 
10.5 
PREGNANCY ................................................................................................................................................................... 31 
11 
EFFICACY ........................................................................................................................................ 31 
11.1 
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST) ............................................... 31 


Protocol #: ONC012 / Version 4 11May 2020 
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11.2 
DEFINITIONS .................................................................................................................................................................. 32 
11.3 
DISEASE PARAMETERS .............................................................................................................................................. 32 
11.4 
METHODS FOR EVALUATION OF MEASURABLE DISEASE ............................................................................. 33 
11.5 
RESPONSE CRITERIA ................................................................................................................................................... 34 
11.6 
DURATION OF RESPONSE .......................................................................................................................................... 35 
11.7 
PROGRESSION-FREE SURVIVAL .............................................................................................................................. 36 
12 
STATISTICAL CONSIDERATIONS ............................................................................................ 36 
12.1 
PRIMARY ENDPOINT AND INTERIM ANALYSES ................................................................................................. 36 
12.2 
ANALYSIS OF SECONDARY/EXPLORATORY ENDPOINTS ............................................................................... 37 
12.3 
REPORTING AND EXCLUSIONS ................................................................................................................................ 38 
13 
DATA REPORTING / REGULATORY REQUIREMENTS ....................................................... 39 
13.1 
DATA REPORTING ........................................................................................................................................................ 39 
13.2 
DATA COLLECTION ..................................................................................................................................................... 40 
14 
PROTOCOL SIGNATURES ........................................................................................................... 42 
15 
PROTOCOL INVESTIGATOR SIGNATURE PAGE ................................................................. 43 
16 
REFERENCES .................................................................................................................................. 44 


Protocol #: ONC012 / Version 4 11May 2020 
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1 
Introduction 
Study Disease 
Endometrial cancer is the most common gynecologic malignancy in the United States with 
60,050 new cases and 10,470 deaths expected in 2016[1]. Due to a common presentation 
of postmenopausal vaginal bleeding, most patients are diagnosed with uterine-confined 
disease (i.e. stage 1)[1] and thus, will have an overall favorable prognosis with 5 year 
disease-free survival greater than 80%[2]. However, there has been a steady increase in the 
mortality rate for endometrial cancer which has been attributed to higher proportions of 
patients with advanced stage, higher grade and serous histology [3]. 
 
Disease Classification & Rationale for Correlative Sampling 
In 1983, Bokhman and colleagues introduced a classification system of endometrial 
cancers based upon two separate tumorigenic pathways which vary by incidence, risk 
factors and prognosis [4]. Type 1 tumors, which account for 80% of cases, are typically 
grade 1-2 endometrioid tumors associated with a high estrogen state and have an overall 
favorable prognosis. Conversely, type 2 tumors, which account for 10-20% of cases, have 
a less favorable prognosis due to more advanced stage and grade of disease at presentation. 
Tumors in this group can include grade 3 endometrioid, serous, clear cell, mucinous, 
squamous, transitional cell, mesonephric and undifferentiated subtypes. Further, 
endometrial carcinosarcoma are now felt to be dedifferentiated carcinomas consisting of 
carcinomatous and sarcomatous elements. The carcinomatous elements most commonly 
contain high grade serous histology, and therefore these tumors could be considered type 
2 cancers. While this subtype comprises ~10-20% of all endometrial tumors, type II EC 
accounts for up to 40% EC-related deaths [4, 5]. Among the non-endometrioid ECs, 
papillary serous accounts for 17-22% of ECs and clear cell cancer represents 1% to 6% [6]. 
Type 2 cancers, in particular those of serous histology, may have alterations in p53, p16, 
E-cadherin, HER2/neu, PIK3CA, FBXW7, and PPP2R1A [7, 8]. 
 
Endometrial serous carcinoma (ESC) is a high-risk cancer having poorer prognosis because 
it is a fast-growing tumor that infiltrates deeply in the myometrium, and frequently involves 
lymphovascular space invasion and distant metastases. The 5-year survival rate of ESC 
patients is 0-30% (Stage III & IV) and 45-90% (Stage I & II). Clear cell carcinoma is 
usually detected in postmenopausal women, with a mean age of 62-67 years [9]. Grossly 
clear cell carcinomas often form fleshy and soft masses involving most of the endometrial 
surface. Microscopically, the neoplasm can exhibit different patterns, namely solid, 
papillary, tubular and cystic [9]. The clear cytoplasm results from the presence of glycogen, 
and hobnail cells are cells with a naked nucleus that have discharged their glycogen and 
lost most of their cytoplasm. Nuclear atypia is usually marked and mitotic activity is high 
[9]. This subtype comprises of 3% of all EC cases while is responsible for 8% of EC deaths 
[9]. 
 
More recently, The Cancer Genome Atlas Research Network examined 373 recurrent 
endometrial cancers, including 307 endometrioid, 66 serous and 13 mixed histology cases, 
in order to better define tumors by genomic, transcriptomic and proteomic characteristics 
[10]. Based on their analyses, the authors characterized these tumors into 4 groups: POLE 


Protocol #: ONC012 / Version 4 11May 2020 
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ultramutated, microsatellite instability hypermutated, copy-number low and copy-number 
high. The authors suggest that this “genomic-based classification may lead to improved 
management of these patients.” Further, analysis revealed that the PI3K/Akt/mTOR 
pathway is the most frequently altered pathway in endometrial cancer, with 93% of type 1 
vs. 60% of type 2 exhibiting alterations [10]. Therefore, this pathway may be an 
appropriate target for therapy in women with recurrent endometrial cancers. 
 
Endometrial Cancer Treatment 
The mainstay of treatment is surgical staging, including hysterectomy, bilateral salpingo- 
oophorectomy, lymphadenectomy, and peritoneal cytology [11]. Chemotherapy and/or 
radiation therapy may be utilized in patients with early stage disease at high risk for 
recurrence or in those with metastatic disease. Acceptable systemic chemotherapy options 
for recurrent, metastatic or high-risk disease include multiagent regimens such as 
carboplatin/paclitaxel [12], cisplatin/doxorubicin, and cisplatin/doxorubicin/paclitaxel 
[13]. Carboplatin/paclitaxel is often used as the first line therapy due to its lower toxicity 
and equivalent efficacy based on the preliminary findings of GOG 209. Response rates for 
this regimen range from 40-62% with overall survival ranging 13-29 months [12, 14, 15]. 
Single agent regimens generate response rates ranging 21-36% for first-line therapy vs. 4- 
27% when used for second-line therapy [16]; the most effective single agent is paclitaxel. 
 
Targeted therapy options have more recently been examined in this population. Single- 
agent bevacizumab, a monoclonal antibody blocking VEGF-A, was examined in a phase 
II trial of women with persistent or recurrent endometrial cancers who had failed 1-2 prior 
cytotoxic regimens [17]. Clinical response rate was 13.5%. Median progression free and 
overall survival was 4.2 and 10.5 months, and 40.4% survived progression free for at least 
6 months. 
 
Agents targeting the PI3K/Akt/mTOR signaling pathway, in particular temsirolimus and 
everolimus which are rapamycin derivatives that inhibit mTOR, have also been examined 
in this patient population [18, 19]. Single agent temsirolimus resulted in partial responses 
in 4 (14%) chemo-naïve patients vs. 1 (4%) patient who had received one prior line of 
chemotherapy [18]. Clinical outcomes did not correlate with PTEN loss or markers of the 
PI3K/Akt/mTOR pathway. Everolimus was examined in an open label phase 2 trial of 
everolimus in recurrent endometrioid endometrial cancer patients who failed 1-2 prior 
regimens [19]. Of 35 evaluable patients, clinical benefit, defined as complete response + 
partial response + prolonged stable disease (≥8 weeks), was seen in 43% at 8 weeks and 
21% at 20 weeks. Results from these trials have been encouraging, and the authors suggest 
that further investigation is necessary to better define target patient populations as well as 
combinations with chemotherapy. 
 
Agent under Investigation 
ONC201 was discovered in a screen that was performed to identify compounds that would 
activate cell death in tumor cells but not in normal cells. ONC201 is a first-in-class small 
molecule that selectively targets the G-protein coupled receptor DRD2 and activates 
integrated stress response (ISR) in tumor cells to induce tumor cell death. Activation of 
ISR by ONC201 has dual advantage that leads to downstream anti-cancer effects. ONC201 


Protocol #: ONC012 / Version 4 11May 2020 
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mediated ISR activation not only leads to inactivation of Akt and Erk pathways, which are 
pro-survival and proliferation pathways, but also results in activation of TRAIL pathway 
that results in tumor cell death. These effects of ONC201 have been demonstrated in many 
in vitro as well as in vivo experiments. Despite its strong cytotoxicity in tumor cells, 
ONC201 does not induce cell death in normal cells and this is due to only a partial and 
transient activation of one of the pathways that does not lead to significant amount of cell 
death [20] Specifically, activation of ISR in tumor cells decreases protein translation and 
up regulates ATF4 activation, which in turn is responsible of induction of pro-apoptotic 
genes. ATF4 also cooperates with CHOP to down-regulate Akt and Erk activation in tumor 
cells [21, 22]. 
 
The safety profile of ONC201 has been studies in lab animal models and the results are 
very favorable [23]. Exaggerated dosing in rodents and dogs revealed that ONC201 acute 
toxicity occurs at higher than therapeutic doses. Even at the highest doses tested, the drug 
did not achieve a maximum tolerated dose with oral administration in GLP studies. 
Induction of cell death in normal tissues has not been apparent in animal studies with 
ONC201 even at exaggerated dosing levels. 
 
1.4.1 Clinical safety profile of ONC201 
As of 31 December 2019, ONC201 has been administered to more than 250 patients in 
sponsored trials. Please refer to the most recent Investigator’s Brochure for the complete 
safety profile of ONC201. 


Protocol #: ONC012 / Version 4 11May 2020 
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Figure 1. Antitumor activity in metastatic lesions. (A) Waterfall analysis on a lesion-by-lesion basis. 
Best change in lesion size is defined as the maximal reduction or minimal increase in sum of longest 
dimensions of target lesions relative to pretreatment assessment. 25/28 patients had measurable tumors 
at baseline and at least one post-treatment evaluation. Letters above or below bar denotes location of the 
lesion: V = liver; L = lung; N = lymph node; A = adrenal gland; P = primary tumor; B = bone. (B) Metastatic 
lung lesion of an endometrial cancer patient at baseline and after 8 doses of 625mg ONC201. 
1.4.2 Clinical Profile of ONC201 
There were signs of clinical activity in the first-in-human trial that enrolled advanced solid 
tumor patients. After 2 doses of 375mg ONC201, one 72-year-old patient with advanced 
clear cell endometrial cancer had a mixed response with multiple nodes decreasing by 
>30% along with the development of new nodes (see Table 1). Another 
 
56-year old endometrial cancer patient with poorly differentiated carcinoma with papillary 
features experienced prolonged stable disease for 10.5 months and exhibited sustained 
regression of her metastatic lung lesion (Figure 1B). Another 67-year-old patient with 
advanced endometrioid type EC (5 prior lines of therapy) had stable disease for 4 months. 
Both these patients had surgery, radiation, immunotherapy and were treated with 5 
different chemotherapy regimens, including carboplatin, paclitaxel, doxorubicin and 
cisplatin. Waterfall analysis of the 28 patients on a lesion-by-lesion basis revealed tumor 
regressions in prostate and endometrial cancer patients that involved lymph nodes, bone, 
and lung lesions (Figure 1A). 


Protocol #: ONC012 / Version 4 11May 2020 
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EC Subtype 
ONC201 
Best Overall 
Response 
Time on 
Treatment 
(weeks) 
M30 
Induction 
(>50%) 
Dose 
No. of 
doses 
(mg) 
Clear cell 
375 
2 
MR 
6 
Yes 
Endometrioid 
125 
6 
SD 
18 
Yes 
Serous 
250 
14 
SD 
42 
No 
Serous 
625 
2 
PD 
6 
Yes 
Endometrioid 
625 
3 
SD 
9 
No 
Table 1: Tumor responses and pharmacodynamics in the endometrial cancer patients enrolled in 
the first in human study. Abbreviations: MR-mixed response, SD – stable disease, PD – Progressive 
disease 
 
1.4.3 Pharmacokinetics 
Pharmacokinetic (PK) analysis was performed in a Phase I dose escalation study in patients 
with advanced solid tumors. ONC201 was found to have a half-life of 11.3 hours in 
humans. The dose escalation cohorts consisted of single patient and analysis was done on 
plasma obtained within 21 days of drug administration. The LC-MS-MS analysis 
demonstrated that exposure to ONC201 saturated at the dose of 375mg. For the maximum 
dose tested, which was 625mg, Cmax was determined to be 3312 (SD2133) ng/ml. The 
Cmax was reached approximately 1.8 hours after the dose administration. 
 
In a Phase I/II clinical trial of ONC201 in adults with acute leukemias or high-risk 
myelodysplastic syndromes (NCT02392572), 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. Oral doses of ONC201 were given at 125, 
250, 375, 500mg and 625mg, twice each week on two consecutive days (e.g. Monday and 
Tuesday of each week). This dosing schedule maintained systemic concentrations that 
exceeded 1,000ng/mL therapeutic thresholds of ONC201 for >72 hours in patients who 
received 375mg or 625mg. In contrast, exposure with weekly dosing generally maintained 
>1,000 ng/mL concentrations for <24 hours (Figure 2). 
Figure 2. Plasma concentrations of ONC201 administered (A) once per week or (B) twice per week on two 
consecutive days to adults with relapsed/refractory acute leukemias or high-risk myelodysplastic syndromes. Hour 
0 is the baseline sampled before the first dose on ONC201. Error bars reflect SEM of samples from patients enrolled 
to receive the same dose. 


Protocol #: ONC012 / Version 4 11May 2020 
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Figure 2. DRD2 expression in human endometrium specimens. A) Average DRD2 expression (% 
positive area) in normal endometrium (N=11) and endometrial adenocarcinoma (N=32) samples from 
patient-derived tissue microarrays. B) Representative image of DRD2 expression in normal endometrium 
and malignant endometrial adenocarcinoma. 
Study Rationale 
ONC201 is a small molecule which selectively targets the G protein-coupled receptor 
DRD2. Downstream of target engagement, ONC201 activates the integrated stress 
response (ISR) in tumor cell leading to inactivation of Akt and ERK signaling as well as 
 
induction of the TRAIL pathway [24]. These pathways are highly deregulated in a majority 
of Type II EC patients. ONC201 also inhibits dopamine receptor 2 (DRD2), resulting in 
anti-tumor responses in preclinical models [24]. Furthermore, DRD2 expression was 
several fold higher in endometrial adenocarcinoma when compared to normal 
endometrium. 
 
Single agent ONC201 has been examined in open-label Phase I studies in patients with 
advanced, treatment refractory solid malignancies [24, 25]. Due to its differential anti- 
proliferative and pro-apoptotic response in tumor cells, treatment was overall well 
tolerated, and the recommended phase II dose of ONC201 was set at 625mg every three 
weeks. An additional dose-escalation phase I study (NCT02609230) is further evaluating 
weekly versus three-week dosing in patients with advanced solid tumors and multiple 
myeloma. Preliminary data from these phase I studies suggests a possible clinical benefit 
in patients with advanced, chemo-refractory endometrial cancers, with at least one mixed 
response noted in a patient with clear cell histology [17]. 
 
We hypothesize that single agent ONC201 will demonstrate clinical benefit in women with 
recurrent or metastatic type II endometrial cancers. 
 
Systemic exposure with once per week dosing in patients results in concentrations that 
exceed the 1,000ng/mL threshold for ~24 hours. In vitro studies indicate that maximum 
antiproliferative and pro-apoptotic effects of ONC201 can require continuous incubation 
for at least 48 hours in some cancer cell lines. This generated the hypothesis that 


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consecutive day dosing could maintain therapeutic concentrations for >48 hours. As 
summarized in Section 1.4.3, PK results from a Phase I/II indicate that twice per 
administration of ONC201 on two consecutive days maintains >1,000ng/mL systemic 
concentrations for >72 hours in patients who received 375mg or 625mg. Given the safety 
profile of ONC201 and these findings, the safety of twice per week dosing on two 
consecutive days will be evaluated in this clinical trial in addition to weekly dosing. 
 
Correlative Testing 
Correlative testing will be performed on archival tumor tissue, tumor biopsies and blood 
collected pre- and post- treatment. Tumor tissue and blood samples will be used to test the 
markers of response to ONC201 treatment. The status of these markers will be used to 
correlate with treatment outcome. Refer to section 8.0 for details. 
 
2 
Objectives 
Primary Objective 
Determine the efficacy of single agent ONC201 dosed 625mg orally in women with 
metastatic or recurrent endometrial cancer at 2 months after treatment initiation. 
 
Secondary Objectives 
Evaluation of the safety profile of single agent ONC201 in women with recurrent or 
metastatic endometrial cancers. 
 
Primary Endpoint 
Progression-free survival rate at 2 months by RECIST version 1.1. 
 
Secondary Endpoints 
• Safety profile of ONC201 will be determined by type, frequency, severity and 
timing and relationship of Adverse Events and lab abnormalities to ONC201. 
• Duration of response and duration of stable disease will be determined by the 
time-period when a response is first seen or stable disease until disease 
progression. 
• Overall response rate will be determined by RECIST version 1.1. Median PFS 
will be calculated as the period between the start of the treatment until disease 
progression. 
• Study drug concentration in tumor tissues from patients taking once per week or 
twice per week on two consecutive days, about 24 hours after the single dose or 
second dose respectively. 
 
3 
Study Plan 
We propose a Simon two-stage, non-randomized, open label, Phase II trial of ONC201 in 
women with metastatic or recurrent Type II endometrial cancer who failed at least 1 prior 
chemotherapy regimen. Patients with histologically confirmed Type II endometrial cancer, 


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including but not limited to serous, clear cell, carcinosarcoma, adenosquamous, and mixed 
histologies, will be eligible. 
Arm A and C will enroll 6 evaluable patients each. All subjects in Arm A will have a 
biopsy of their tumor one day after the second dose of ONC201 on Cycle 1 Day 9. All 
subjects in Arm C will have a biopsy of their tumor one day after the 4th dose of ONC201 
on Cycle 1 Day 10. 
Arm B will enroll 10-24 evaluable patients. 
ONC201 will be administered at a dose of 625 mg by mouth, once or twice each week until 
disease progression, unacceptable toxicity, or if the patient discontinues for any other 
reason. 
It is anticipated that enrollment into this study will complete in 24 months. 
Radiologic tumor assessment will be performed at baseline, cycle 3 day 1, cycle 5 day 1 
and at the end of every 3 cycles beyond cycle 5 (one cycle = 21 days). All patients including 
those removed from the study due to unacceptable toxicity, will undergo radiologic tumor 
assessment within 30 days of the time of discontinuation (End of treatment). If a scan is 
performed within 30 days of end of treatment is available, the previous scan will be 
accepted. Patients who show disease progression at the first instance could continue to 
receive the treatment for up to 2 more cycles depending upon the percentage of increase in 
the tumor. Patients up to 30% increase in tumor burden would be allowed to continue the 
treatment until the second confirmatory scan if the patient is deriving clinical benefit in the 
treating Physician’s opinion. Patients who continue treatment beyond progression would 
undergo another confirmatory scan at the end of 2 more cycles and if the progression is 
confirmed they will be come off the study. 
 
4 
Eligibility Criteria 
Inclusion Criteria 
1. Histologically confirmed metastatic or recurrent Type II EC (serous, clear cell, 
carcinosarcoma, adenosquamous and mixed histologies). For patients with tumors 
that have mixed histologies, the tumor should have evidence of some tumor cells 
with Type II endometrial cancer features. 
2. Patients must have measurable disease, defined as at least one lesion that can be 
accurately measured in at least one dimension in accordance with RECIST criteria 
v. 1.1 as described in detail in section 11. 
3. Availability of at least 12 unstained slides from archival FFPE tumor tissue. 
Available archived tissue biopsies will be provided for correlative studies. 
4. For Arm A and C, patients must have disease that is amenable to biopsy and must 
be willing to provide consent for a tumor biopsy at baseline (within 30 days of 
beginning ONC201) and at least 1 on-treatment tumor biopsy. 
5. Must have radiographic disease progression after at least 1 line of systemic 
cytotoxic therapy for metastatic disease or with progression within 12 months of 
completing adjuvant chemotherapy. 


Protocol #: ONC012 / Version 4 11May 2020 
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6. Age > 18 years. 
7. ECOG performance status of 0, 1, or 2. 
8. Patients must have adequate bone marrow, hepatic and renal function as defined 
below: 
Leukocytes 
> 3,000/mcL 
Absolute neutrophil count 
> 1,500/mcL 
Platelets 
> 100,000/mcL 
Total bilirubin 
≤1.5 ULN 
AST/ALT (SGOT/SGPT) 
< 2 ULN 
Creatinine 
≤1.5 ULN 
OR 
Creatinine clearance 
> 60 Ml/min/1.73 m2 for patients 
with creatinine levels above ULN calculated using Calvert formula 
9. Life expectancy at least 3 months. 
10. Ability to understand and willingness to sign a written informed consent and 
HIPAA consent document. 
11. Patients must be surgically sterile or be postmenopausal, or must agree to use 
effective contraception during the period of the trial and for at least 90 days after 
completion of treatment. 
 
 
Exclusion Criteria 
1. No prior treatment with ONC201. 
2. Patients who have had chemotherapy or radiotherapy within 4 weeks prior to 
entering the study or those who have not recovered from adverse events due to 
agents administered more than 4 weeks earlier. 
3. The subjects who have not recovered to baseline or CTCAE ≤ Grade 2 from related 
toxicity to all prior therapies will be excluded. Patients with Non-serious adverse 
events such as alopecia, fatigue, weakness, loss of appetite and nausea that are non- 
significant will not be excluded. 
4. Any other prior malignancy from which the patient has been disease free for less 
than 3 years, with the exception of adequately treated and cured basal or squamous 
cell skin cancer, superficial bladder cancer, carcinoma in situ of any site. 
5. The subject is unable to swallow capsules. 
6. Impairment of gastrointestinal (GI) function or GI disease that may significantly 
alter the absorption of ONC201 (uncontrolled nausea, vomiting, diarrhea, 
malabsorption syndrome, or small bowel resection). 


Protocol #: ONC012 / Version 4 11May 2020 
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7. Patients receiving any other investigational agents. 
8. Patients with symptomatic brain metastases are excluded. Patients with 
asymptomatic and treated CNS metastases may participate in this trial. The patient 
must have completed any prior treatment for CNS metastases > 28 days prior to 
study entry including radiotherapy or surgery. Steroids for the treatment of brain 
metastasis are not permitted, and patients must be stable off steroid treatment for 4 
weeks prior to enrollment. 
9. Uncontrolled intercurrent illness including, but not limited to ongoing or active 
infection. Any of the following in the previous 6 months: myocardial infarction, 
severe/unstable angina, coronary/peripheral artery bypass graft, cerebrovascular 
accident, transient ischemic attack or symptomatic pulmonary embolism. 
10. Active inflammatory gastrointestinal disease, chronic diarrhea (unless related to 
underlying malignancy or prior related treatment) or history of abdominal fistula, 
gastrointestinal perforation, peptic ulcer disease, or intra-abdominal abscess within 
6 months prior to study enrollment. Gastroesophageal reflux disease under 
treatment with proton pump inhibitors is allowed. 
11. Known HIV-positive patients on combination antiretroviral therapy. 
12. Active HBV or HCV infection. Other severe acute or chronic medical or psychiatric 
condition or laboratory abnormality that may increase the risk associated with study 
participation or study drug administration, or may interfere with the interpretation 
of study results, or in the judgment of the investigator would make the patient 
inappropriate for entry into the study. 
13. Pregnant or breast feeding. Refer to section 4.4 for further details. 
14. Known 
history 
of 
cardiac 
arrhythmias 
including 
atrial 
fibrillation, 
tachyarrhythmias or bradycardia, unless arrhythmia is controlled and after 
Cardiology has cleared patient to receive ONC201. Receiving therapeutic agents 
known to prolong QT interval will be excluded, however the use of Zofran is 
permitted. History of CHF, or MI or stroke in the last 3 months will be excluded. 
15. Concomitant use of potent CYP3A4/5 inhibitors or inducers during the treatment 
phase of the study and within 72 hours prior to starting study drug administration. 
 
Inclusion of Women and Minorities 
Women, regardless of race, ethnic group or sexual orientation are eligible for this study. 
 
Pregnancy 
The effects of ONC201 on the developing human fetus at the recommended therapeutic 
dose are unknown. For this reason, women of child-bearing potential (WOCBP) must 
agree to use adequate contraception prior to study entry, for the duration of treatment, and 
for at least 3 months after the completion of treatment. 
 
WOCBP is defined as follows: Any female who has experienced menarche and who has 
not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or a 


Protocol #: ONC012 / Version 4 11May 2020 
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bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea > 12 consecutive 
months, or women on hormone replacement therapy (HRT) with documented plasma 
follicle-stimulating hormone (FSH) level > 35 mIU/ml). Even women who are using oral, 
implanted, or injectable contraceptive hormones or mechanical products (diaphragm, 
condoms, spermicides) to prevent pregnancy or practicing abstinence or where partner is 
sterile (e.g. vasectomy), should be considered to be WOCBP. 
 
Should a woman become pregnant or suspect she is pregnant while participating in this 
study, she must inform her treating physician immediately. 
 
Prior to study enrollment, WOBCP must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an unintentional 
pregnancy. 
 
All WOCBP must have a negative pregnancy test within 72 hours prior to receiving the 
first dose of the investigational agent. If the pregnancy test is positive, the patient must not 
receive protocol treatment and must not be enrolled in the study. 
 
Screening Procedures 
After providing informed consent, subjects will undergo screening for eligibility to 
participate in the study. Screening will start within 14 days prior to the first dose of 
ONC201. Subjects who have had an adequate MRI/CT Scan performed as part of routine 
care prior to informed consent but within 30 days of the first dose of ONC201 will not 
have to repeat the baseline MRI. Best efforts should be made to keep the MRI/CT Scan 
technique constant for each patient from baseline and throughout treatment. Refer also to 
the Schedule of Events for details of study procedures. 
 
The following procedures will be performed or obtained at screening for the purpose of 
determining study eligibility. Screening studies, if performed within 2 weeks prior to start 
of treatment, are acceptable for use as baseline (pre-Cycle 1, Day 1 assessments). 
 
Screening Assessments: 
 
Pathology report confirming the diagnosis of Type II Endometrial Cancer 
 
Collection of archived tumor material for research: 12 unstained slides from archival 
FFPE tumor tissue. Available archived tissue biopsies will be provided for correlative 
studies additional details on tumor material collection in the Eligibility Criteria (Section 
4). 
 
A MRI/CT Scan must be obtained within 30 days of the first dose of study treatment. 
 
Medical history, eligibility, and concomitant medications: The subject must be eligible by 
all of the Subject Selection Criteria per Section 4. Concomitant medications will be 
reviewed for allowed or prohibited medications. 
 
Heart Rate (BPM; recorded from the ventricular rate). 


Protocol #: ONC012 / Version 4 11May 2020 
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Physical exam and laboratories: For complete details see the Schedule of Events. 
Complete physical exam, including ECOG assessment 
Vital signs: height (height is only required at screening), weight, temperature, resting 
blood pressure, pulse and respiration rate. 
 
Serum chemistry: sodium, potassium, chloride, bicarbonate, calcium, magnesium, 
phosphorous, random glucose, albumin, total protein, creatinine, blood urea nitrogen 
(BUN), uric acid, ALT, AST, total bilirubin, direct and/or indirect bilirubin, alkaline 
phosphatase (ALP), amylase, lactate dehydrogenase (LDH). 
 
Hematology: WBC count, 3-cell differential (ANC, monocyte count, lymphocyte count), 
hemoglobin, hematocrit, and platelet count 
 
Coagulation test (required at screening only): PT/INR, PT, PTT 
Ca125: Per standard of care 
Pregnancy test (urine or serum β-HCG) for women of child-bearing potential 
 
 
Subject Registration 
In order to begin the patient registration process, the site must obtain a slot for the 
candidate patient from Oncoceutics. At the time of receipt of the signed consent form, 
Oncoceutics 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 Oncoceutics) 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. 
 
Registration approval will be valid for 7-business days from receipt of approval. If the 
potential patient is not treated within those 7 business days, a new registration form must 
be submitted to determine eligibility. 
 
A patient identifier will be assigned at the time of approval. Screening and eligibility 
MUST be entered into Redcap EDC within 7-business days of screening visit. 
 
5 
Treatment Plan 
Treatment will be administered on an outpatient basis. Treatment will be administered as 
described below. Dose delays and modifications should only be done following protocol 
guidelines described in section 6.0. If treatment delays are more than 14 days due to 
toxicity study therapy will be discontinued. 


Protocol #: ONC012 / Version 4 11May 2020 
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Treatment Administration 
 
Regimen description 
Arm 
Agent 
Dose 
Route 
Schedule 
Cycle Length 
A & B 
ONC201 
625mg 
Oral 
Once per week 
3 weeks 
C 
ONC201 
625mg 
Oral 
Twice per week on two 
consecutive days 
3 weeks 
 
One treatment cycle will be defined as 21 days, corresponding to 3 doses of ONC201 (i.e., 
one cycle is 3 weeks) for Arm A and B or 6 doses in Arm C. Beyond cycle 1 week 1 
dose(s), ONC201 capsules will be dispensed on day 1 of every cycle thereafter to be taken 
at home. Patients must complete study drug diary to keep a log of the drug intake. Any 
unused drug should be returned to the site. Any missed doses should be recorded. At home 
patients must take the drug as indicated, however if the drug is missed for reasons not 
related to adverse events +/- 2 days are allowed. The capsules should be swallowed as 
whole and should not be chewed or broken. 
 
Patients should take designated capsules of ONC201 at approximately the same time on 
each drug administration. Patients will be instructed to not eat for 2 hours pre and 2 hours 
post dosing. If the patient vomits after taking ONC201, they should not retake the dose. 
 
Concomitant Medications, Supportive Care, Excluded Therapies and 
Restrictions 
In vitro cytochrome P450 assays were conducted in human hepatocytes. In these studies, 
ONC201 is not an inducer of the CYP450 system (CYP 1A2, 2B6 and 3A4). ONC201 was 
observed to be a mild inhibitor of the CYP450 enzymes (1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 
3A4) at 35-429uM, i.e. at least 3.5-fold above the Cmax observed in the first-in-human 
trial. Studies in human liver microsomes indicate that ONC201 appears to be a major 
substrate of CYP3A4 and a minor substrate of CYP 2B6, 2C8, 2C9 and 2D6. The protein 
binding of ONC201 was found to be 89.8-94.0% in human plasma over the concentration 
range of 0.5 μM to 20 μM with similar findings in other species (mouse 86.2-89.6%, rat 
79.4–83.1%, dog 88.0-89.8%). 
Concurrent use of strong inhibitors or inducers of CYP3A4, 2D6, 1A2, 2C9 and 2C19 
should be avoided. 
 
5.2.1 Corticosteroids 
The use of systemic corticosteroids should be limited to ≤ physiologic replacement doses 
(i.e. prednisone 10 mg/day or equivalent). Short courses of higher dose systemic steroids 
(to treat COPD, for example), are permitted but should be used with caution as no formal 
interaction studies have been completed. Use of non-systemic steroid use is permitted (e.g. 
cream, lotion, inhalers). 
 
5.2.2 Anti-emetic Therapy 
There are no restrictions on the use of antiemetic therapy for this trial. Medications to 
prevent emerging toxicities are permitted as long at their use does not conflict with other 
guidelines in this protocol. 


Protocol #: ONC012 / Version 4 11May 2020 
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5.2.3 5.2.3 Other Anticancer or Experimental Drugs 
Treatment with other anticancer or experimental drugs is not permitted for patients treated 
on this protocol. 
 
5.2.4 5.2.4 Palliative and supportive care 
All palliative and supportive care necessary for optimal care of the patient, excluding 
radiation therapy should be provided while on study. Patients requiring radiation therapy 
for palliation will be removed from the study. Treatment with growth factors is excluded 
except to treat febrile neutropenia. 
 
Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue until one 
of the following criteria applies: 
 
Confirmed radiographic disease progression. In the absence of clinical progression 
and occurrence of radiographic progression, patients will have the option to remain 
on study. 
Intercurrent illness that prevents further administration of treatment 
Unacceptable adverse events 
Patient required > 2 dose reductions 
Patient becomes pregnant 
Patient decides to withdraw from the study 
General or specific changes in the patient’s condition that render the patient 
unacceptable for further treatment in the judgment of the investigator. 
Duration of Follow up 
All subjects will be followed post-treatment until death, withdrawal of permission to record 
at least survival data, or subject is lost to follow-up every 30 days (±7 days) after coming 
off study. When available, tumor imaging will be collected for all patients who accrued to 
the study and receive at least one dose of ONC201. All subjects will be contacted every 30 
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, or mail. The date of death, initiation of any new anti-cancer treatments and date of 
last contact should be documented if this information is available. 
 
Criteria for Discontinuation 
Patients will be removed from study when any of the criteria listed in Section 5.3 applies. 
Patients can also be removed from the study for non-compliance. The reason for study 
removal and the date the patient was removed must be documented in the medical record 
and case report form. 


Protocol #: ONC012 / Version 4 11May 2020 
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6 
Dose Modifications 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03 will be utilized for dose delays and 
dose modifications 
 
Below are dose modifications (Table 6.1 and 6.2) for adverse events that are attributable 
to study drug, including: nausea, vomiting, diarrhea, neutropenia, and thrombocytopenia. 
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 during 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), including Nausea, 
Diarrhea, Neutropenia, Thrombocytopenia, and Other AEs. 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 7 days, 
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. For patients on Arm C, 
the dose modification is for each dose 
**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 a grade 3 or 4 adverse event does not resolve 
within 3 weeks, the patient will be required to come off study, and the interval for testing 
may be reduced after consultation and written approval by Sponsor. 
 
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. 


Protocol #: ONC012 / Version 4 11May 2020 
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7 
Study Agent Information 
The study drug ONC201 is provided as 125 mg free base (approximately 150 mg of 
dihydrochloride), with or without microcrystalline cellulose, filled into hydroxypropyl 
methylcellulose (HPMC) capsule shells. Alternative strengths may be manufactured 
and additional excipients may be used. 
 
The ONC201 drug product capsules are intended for oral administration. 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. 
 
The capsules are to be stored in the original closed container at room temperature (15 
to 30°C). The study drug bottle label bears the following information. If alternative 
strengths are manufactured, the dosage on the label will be inserted in place of ‘125 
mg’. 
 
 
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) 
Mfg date: XX-XXXX 
Batch # xxx-xxx-xxxx-xx 
Sponsor: Oncoceutics, Inc. 
Storage: Preserve in original tightly closed containers at room 
temperature (15 to 30°C) 
Caution: New Drug--Limited by Federal (or United States) 
law to investigational use. 
For Oral Use Only 
ONC201 Capsules, 125 mg 


Protocol #: ONC012 / Version 4 11May 2020 
Page 24 of 45 
 
 
 
Molecular Weight 
386.49 (free base) 
459.41 (salt) 
Molecular Structure 
 
 
Drug Product Description 
7.2.1 Form 
ONC201 will be provided as hydroxypropyl methylcellulose (HPMC) capsules filled with 
the active ingredient (ONC201 dihydrochloride), intended for oral administration. The 
ONC201•2HCl drug substance is a white to off-white solid. The drug product will be 
packaged as 10 or 25 capsules per bottle. The capsules are filled into 30cc high-density 
polyethylene (HDPE) white opaque bottles with induction seal and 28mm white ribbed 
SecuRx polypropylene (PPE) cap. 
 
7.2.2 Storage and Stability 
Based on the current stability data at 40°C/75%RH room temperature (25°C/60%RH) will 
be used for the drug product storage. Drug product stability studies found no change after 
1 month at 40°C/75%RH when stored with or without desiccant. Similarly, no changes 
have been observed when stored at room temperature for 1 year. Clinical trial batches will 
be produced without desiccant. No shelf-life has been established for this product at this 
point. However, representative clinical trial batches have been placed on stability. Any 
batches that are out of specifications will be removed from the trial. 
 
For the ONC201 drug substance, stability results show little to no change in assay, 
impurities or appearance. The only changes observed under the accelerated conditions 
(40°C/75%RH) where a slight increase in moisture content was observed, from 1.2% at 
time 0, to 6.5% at 2 months, and to 6.2% at 3 months. The moisture content plateaued at 
approximately the monohydrate. The increase in moisture content did not result in 
increased impurity levels or decreased potency. These results suggest robust stability of the 
drug substance when stored at room temperature and accelerated conditions. 
 
Drug Product Supply, Administration and Inventory 
7.3.1 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. 
 
7.3.2 Availability 
ONC201 is provided by the Sponsor, Oncoceutics 


Protocol #: ONC012 / Version 4 11May 2020 
Page 25 of 45 
 
 
 
7.3.3 Administration 
Patients will receive ONC201 while in the clinic on day 1 of each cycle. They will take 
ONC201 as inidcated. The study drug, ONC201, will be supplied in capsule form for oral 
dosing. 
 
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 2 days from the 
intended day of administration. A pill diary will be provided to the patient to record dosage, 
time of administration and side effects. 
 
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 a treatment cycle must be noted as an adverse event. 
 
7.3.4 Accountability 
The investigator, or a responsible party designated by the investigator, should maintain a 
careful record of the inventory and disposition of the agent using the NCI Drug 
Accountability Record Form (DARF) or another comparable drug accountability form. 
(See the NCI Investigator’s Handbook for Procedures for Drug Accountability and 
Storage). 
 
7.3.5 Destruction and Return 
Unused supplies of the agent should be returned to the Sponsor within 60 days of the 
completion of the study. Unused supplies of the agent may also be destroyed on-site upon 
completion of the study, after accountability has been audited by the Sponsor or designated 
representative. 
 
8 
Biomarker, Correlative and Special Studies 
Tumor biopsy studies 
Archival tumor tissue will be required for correlative testing (12 FFPE slides). For Arm A 
and C, tumor tissue from baseline and on-treatment biopsies (12 FFPE slides each) will be 
required. The archival tumor tissue will be used for immunohistochemistry (IHC) to test 
for markers of response to ONC201 that are involved in its mechanism of action such as 
DRD2, DRD5, ClpP etc. The baseline and on-treatment tumor tissue from Arm A will be 
used for pharmacodynamic studies. Pharmacodynamic biomarkers include but are not 
limited to ATF4, CHOP, DR5, cleaved caspase-8, cleaved caspase-3, and DNA 
fragmentation. 
 
For patients in Arm A and C, biopsied tumor tissue will be obtained from at least 3 core 
needle biopsies. Tissue will be used for three distinct analyses: intratumoral drug 


Protocol #: ONC012 / Version 4 11May 2020 
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concentration, nucleic acids, and pharmacodynamic analyses. Two of the three tissues will 
be flash frozen and the other sample will be formalin-fixed and paraffin-embedded tissue 
blocks will be prepared for immunohistochemistry. The tissue will be assayed for the 
following markers that have been implicated in the mechanism of action of ONC201 such 
as DRD2, DRD5,ClpP, TGM2, KSR1, ATF4, CHOP, pAkt, pERK, TRAIL, and DR5 
(Allen et al., 2013a; Ishizawa et al., 2016; Kline et al., 2016). In addition, immune cell 
phenotyping may also be assessed in the tumor specimens. 
 
Blood for pharmacodynamics analyses 
Prolactin and other proteins will be measured in serum as pharmacodynamic markers. One 
red-top tube (without anti-coagulant) of blood will be collected at the following time 
points: 
For Arm A and Arm B: Blood draws taken at baseline (pre-dose), 2 hours ± 15 minutes, 
24 ± 1 hours, 48 hours ± 3 hours, 72 hours ± 12 hours, and Day 8 and 15 ± 24 hours 
following the first administration of ONC201. Blood will also be collected pre-dose for 
Cycle 2, Cycle 3 and every odd cycle beyond Cycle 3. 
For Arm C: Blood draws taken at baseline (pre-dose), 2 hours ± 15 minutes, 24 ± 1 hours 
(pre-day 2 dose), 26 ± 2 hours, 48 hours ± 3 hours, 72 hours ± 12 hours, and Day 8 and 15 
± 24 hours following the first administration of ONC201. Blood will also be collected pre- 
dose for Cycle 2, Cycle 3 and every odd cycle beyond Cycle 3. 
 
Refer to lab manual for collection window of samples. Blood will also be collected at the 
end of treatment visit for correlative studies. Immune cytokines and effectors will be 
assessed on serum samples obtained for pharmacodynamic analyses. 
 
Refer to lab manual for Biospecimens processing and handling requirements. 
 
Blood for immune cell studies 
Peripheral blood mononuclear cells (PBMCs) will be harvested and investigated for effects 
of ONC201 on the immune system. One EDTA tube of blood will be collected at the same 
time points as the red-top tubes are collected: Baseline and 2 hours, 24 hours, 48 hours, 
and 72 hours after the first dose of ONC201; Cycle 1 Day 8; Cycle 1 Day 15; pre-dose for 
the first day of cycle 2, cycle 3 and every odd cycle beyond cycle 3. Blood will also be 
collected at the end of treatment visit for correlative studies. Collection of PBMCs is not 
required for Arm C. 
 
Blood for pharmacokinetics 
The plasma obtained prior to the isolation of PBMCs (see Section 8.3) will be used to 
determine concentration of ONC201. No additional blood samples will be collected from 
the patient for these studies. For Arm C, plasma for pharmacokinetics will be collected at 
baseline (pre-dose), 2 hours ± 15 minutes, 24 ± 1 hours (pre-day 2 dose), 26 ± 2 hours, 48 
hours ± 3 hours, 72 hours ± 12 hours, and Day 8 and 15 ± 24 hours following the first 
administration of ONC201. Blood will also be collected pre-dose for Cycle 2, Cycle 3 and 
every odd cycle beyond Cycle 3. 


Protocol #: ONC012 / Version 4 11May 2020 
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9 
Study Calendar 
Study visits and procedures may be scheduled with a +/- 2 business day window except for Screening procedures (-14 days) and neuroimaging 
(MRI/CT) Screening, Cycle3 and every odd cycle day 1 (+/- 7 days). One treatment Cycle is defined as 3 weeks (21 days). 
Study Activity 
Screening 
C1D1 
C1D2 
C1D3 
C1D8 
C1D9 
C1D10 
C1D15 
C1D16 
C2D1 
C2D2 
Cycle 3, and 
every odd 
cycle, day 18 
Off- 
treatment 
Follow-up 
30 days 
(+/- 3 days)5 
Survival 
Follow Up 
(30 +/- 7 
days) 
Informed Consent 
X 
Medical History 
X 
Inclusion/exclusion criteria 
X 
Concurrent meds1 
X 
X 
X 
X 
X 
Physical exam 
X 
X 
X 
X 
X 
Performance Status 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
Serum Pregnancy test 
X 
X 
X 
ONC201 Administration8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Toxicity Assessment1 
X 
X 
X 
X 
X 
Serum Chemistry2 
X 
X 
X 
X 
X 
Radiological tumor 
assessment (CT/MRI 
contrast scans/C/A/P) 
X 
X 
X 
X 
Hematology3 
X 
X 
X 
X 
X 
Coagulation tests: PT/INR, 
PT, PTT 
X 
Blood draws for PK/PD3a 
X 
X 
X 
X 
X 
X 
X 
X 
Archived tumor tissue 
X 
Tumor biopsy 
X 
X4 
X4 
Ca1256 
X 
X 
X 
X 
X 
Survival Follow Up7 
X 
X 


Protocol #: ONC012 / Version 4 11May 2020 
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1 Toxicity/Concomitant Medication Assessment: Will be performed at each patient encounter 
2 Serum Chemistry: K+, Na+, Ca++, Mg++, LDH, ALT, AST, total bilirubin, creatinine, amylase, ALP, bicarbonate, glucose, urea, BUN, 
phosphorous albumin, total protein: Beginning of each cycle 
3Hematology: WBC count, 3-cell differential (ANC, monocyte count, lymphocyte count), hemoglobin, hematocrit, and platelet count will be 
collected at screening, day 1 of treatment cycles, at end of treatment visits and initial follow up visit for all subjects 
3aBlood for PK/PD: must be processed within 2 hours of collection. For Arm A and Arm B: Blood draws taken at baseline (pre-dose), 2 hours ± 
15 minutes, 24 ± 1 hours, 48 hours ± 3 hours, 72 hours ± 12 hours, and Day 8 and 15 ± 24 hours following the first administration of ONC201. 
Blood will also be collected pre-dose for Cycle 2, Cycle 3 and every odd cycle beyond Cycle 3. For Arm C: Blood draws taken at baseline (pre- 
dose), 2 hours ± 15 minutes, 24 ± 1 hours (pre-day 2 dose), 26 ± 2 hours, 48 hours ± 3 hours, 72 hours ± 12 hours, and Day 8 and 15 ± 24 hours 
following the first administration of ONC201. Blood will also be collected pre-dose for Cycle 2, Cycle 3 and every odd cycle beyond Cycle 3. 
4 Tumor Biopsies: For patients in Arm A, tumor biopsy tissue will be collected at screening/baseline (within 30 days of beginning ONC201) and 
tumor biopsy tissue will be collected at cycle 1 day 9 (approximately 24 hours after 2nd dose).  For patients in Arm C, tumor biopsy tissue will 
be collected at screening/baseline (within 30 days of beginning ONC201) and tumor biopsy tissue will be collected at cycle 1 day 10 
(approximately 24 hours after 4th dose). 
5 Follow-up: Patient will be followed every 30 days until withdrawal of permission to record or death. The initial follow-up visit must occur 
within 30 days (+/- 3 days) from EOT visit. Copies of clinical imaging might be obtained after discontinuation of ONC201. Information should 
be collected to assess 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, mail or review of medical records. This information should be updated in the patient record 
and eCRFs. 
6 Ca125 measurement will be carried out at discretion of physician. 
7Survial Follow Up: Every 30 days (+/- 7 calendar days) from initial Follow up visit. All patients will be contacted every 30 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, mail or review of medical records. This information should be updated in the patient record and eCRFs. 
8For Arm A and B ONC201 administration is on Day 1, 8 and 15 of each 3-week cycle. For Arm C, ONC201 administration is on Days 1, 2, 8, 9 
15 and 16 of each 3-week cycle. 


Protocol #: ONC012 / Version 4 11May 2020 
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10 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 the date of initiation of study therapy 
through 30 days following cessation of treatment and at each examination. Serious Adverse 
Events will be followed through 90 days following cessation of treatment. 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. 
 
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 10.1. 
 
Definitions 
Adverse Events (AE) is any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom or disease temporally associated with the use of a medicinal 
(investigational) product, treatment or procedure regardless of whether it is considered 
related to the medical treatment or procedure (NCI CTEP Guidelines March 28, 2011) 


Protocol #: ONC012 / Version 4 11May 2020 
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Serious Adverse Event (SAE) is an AE that is fatal or life threatening, requires inpatient 
hospitalization or prolongation of existing hospitalization (for > 24 hours), persistent or 
significant incapacity or substantial disruption of the ability to conduct normal life 
functions, or is a congenital anomaly/ birth defect. Important medical event that may not 
result in death, be life threatening, or require hospitalization may be considered an SAE 
when, based upon appropriate medical judgment, may jeopardize the subject and may 
require medical or surgical intervention to prevent any of the above outcomes. A “life- 
threatening” adverse event places the patient at immediate risk of death in the judgment of 
the investigator or sponsor. 
 
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 (beyond 
30 days from last dose) 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 90 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 Oncoceutics. 
Deaths, including those from disease progression that occur within 30 days of the last dose 
of ONC201 must be reported to Oncoceutics within 3 days of acknowledgment of patient 
status. 
 
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 Oncoceutics. 
 
Investigators must report to Oncoceutics any serious adverse event (SAE) that occurs after 
the initial dose of study treatment, during treatment, or within 3 days of the last dose of 
treatment on the Sponsor provided SAE form. 
 
SAE reports and any other relevant safety information are to be forwarded to the 
pharmacovigilance@oncoceutics.com and the Oncoceutics facsimile number within 
24 hours of learning of its occurrence: 1-844-245-7650 


Protocol #: ONC012 / Version 4 11May 2020 
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Oncoceutics will submit all required SAE Reports and Annual Progress Reports to the FDA 
as required by FDA or other local regulators. 
 
Investigators must report SAEs to the local IRB following local IRB reporting 
requirements. 
 
All subjects with serious adverse events must be followed up for outcome. 
 
Expected Toxicities 
Updated toxicity information can be found in the Investigator’s Brochure. Please refer to 
this document for expected toxicities and associated frequencies. 
 
Adverse Events 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 
4.03 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.03. A copy of the CTCAE version 4.03 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. 
 
Pregnancy 
All WOCBP should be instructed to contact the Investigator immediately if they suspect 
they might be pregnant (e.g., missed or late menstrual period) at any time during study 
participation. 
 
In the event of a confirmed pregnancy in a patient participating in the study, the site 
Investigator must immediately notify Oncoceutics. 
 
11 Efficacy 
Response Evaluation Criteria in Solid Tumors (RECIST) 
The Response Evaluation Criteria in Solid Tumors (RECIST v 1.1) criteria will be used for 
objective tumor response assessment. Response assessment would be performed at C3D1, 
C5D1 and at the end of every 3 cycles beyond cycle 5. All patients, including those 
removed from the study due to unacceptable toxicity, would undergo radiologic tumor 
assessment at the time of discontinuation (End of treatment). Patients who show disease 
progression at the first instance could continue to receive the treatment for up to 2 more 
cycles if the increase in tumor burden is up to 30%. Patients who continue treatment beyond 


Protocol #: ONC012 / Version 4 11May 2020 
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progression would undergo another confirmatory scan at the end of 2 more cycles, and if 
the progression is confirmed, they will be come off the study. 
 
Definitions 
Evaluable for adverse events. All patients will be evaluable for adverse events from the 
time of their first treatment with ONC201. 
 
Evaluable for progression-free survival. All Arm B patients who have received at one dose 
of ONC201 will be considered evaluable for progress-free survival as the primary endpoint. 
 
Evaluable for objective response. Only those patients who have measurable disease present 
at baseline, have received at least one cycle of therapy, and have had their disease re- 
evaluated will be considered evaluable for response. These patients will have their 
response classified according to the definitions stated below. (Note: Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response. Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease. The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions. 
 
Disease Parameters 
Measurable disease. Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm by chest 
x-ray, as >10 mm with CT scan, or >10 mm with calipers by clinical exam. All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable. 
 
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a 
lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable disease. All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), 
are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 


Protocol #: ONC012 / Version 4 11May 2020 
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‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non- 
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target lesions 
and recorded and measured at baseline. Target lesions should be selected on the basis of 
their size (lesions with the longest diameter), be representative of all involved organs, but 
in addition should be those that lend themselves to reproducible repeated measurements. 
It may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected. A sum of the diameters (longest for non-nodal lesions, 
short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters. If lymph nodes are to be included in the sum, then only the short 
axis is added into the sum. The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
 
Non-target lesions. All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should 
also be recorded at baseline. Measurements of these lesions are not required, but the 
presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up. 
 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. 
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. 
 
CT and MRI This guideline has defined measurability of lesions on CT scan based on the 
assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness greater 
than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. 
MRI is also acceptable in certain situations (e.g. for body scans). 
 
MRI has excellent contrast, spatial, and temporal resolution; however, there are many 
image acquisition variables involved in MRI, which greatly impact image quality, lesion 
conspicuity, and measurement. Furthermore, the availability of MRI is variable globally. 
As with CT, if an MRI is performed, the technical specifications of the scanning sequences 
used should be optimized for the evaluation of the type and site of disease. Furthermore, 
as with CT, the modality used at follow-up should be the same as was used at baseline and 
the lesions should be measured/assessed on the same pulse sequence. It is beyond the scope 


Protocol #: ONC012 / Version 4 11May 2020 
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of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases. Ideally, the same type of scanner should be used and 
the image acquisition protocol should be followed as closely as possible to prior scans. 
Body scans should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET- 
CT is not always of optimal diagnostic CT quality for use with RECIST measurements. 
However, if the site can document that the CT performed as part of a PET-CT is of identical 
diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of 
the PET-CT can be used for RECIST measurements and can be used interchangeably with 
conventional CT in accurately measuring cancer lesions over time. Note, however, that 
the PET portion of the CT introduces additional data which may bias an investigator if it 
is not routinely or serially performed. 
 
Response Criteria 
11.5.1 Evaluation of Target Lesions 
Complete Response (CR): 
Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters 
 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if that 
is the smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more 
new lesions is also considered progressions). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameters while on study 
 
11.5.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis) 
 
Note: If tumor markers are initially above the upper normal limit, they must normalize for 
a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:    Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not normally 
trump target lesion status. It must be representative of overall disease status change, not a 
single lesion increase. 


Protocol #: ONC012 / Version 4 11May 2020 
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Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should 
be confirmed at a later time by the review panel (or Principal Investigator). 
 
11.5.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient's best response 
assignment will depend on the achievement of both measurement and confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD 
/not evaluated 
No 
PR 
SD 
Non-CR/Non-PD 
/not evaluated 
No 
SD 
documented at least once >4 wks. 
from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** Only for non-randomized trials with response as primary endpoint. 
*** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
Note: 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.” Every effort should be made to document the objective progression 
even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
Duration of Response 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date 
that recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started). 


Protocol #: ONC012 / Version 4 11May 2020 
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The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 
Duration of stable disease: Stable disease is measured from the start of the treatment until 
the criteria for progression are met, taking as reference the smallest measurements recorded 
since the treatment started, including the baseline measurements. 
 
Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of treatment 
to time of progression or death, whichever occurs first. Progression-free survival (PFS) is 
defined as the time from registration to objective disease progression or death, whichever 
occurs first. PFS2 will be defined as the percentage of patients who exhibit PFS for >8 
weeks (>56 days). Patients who have not progressed or died and are lost to follow up at 2 
months will be replaced. 
 
12 Statistical Considerations 
Primary Endpoint and Interim analyses 
Arm A and C will assess intratumoral drug concentrations and pharmacodynamics. . Arm 
B will assess progression-free survival rate at two month following treatment initiation as 
primary endpoint. Patients with biopsiable disease may represent a biased subset of the 
overall target population since some sites of metastases will not be amenable to biopsy and 
therefore comparing these patients’ outcomes to historical controls may not be appropriate. 
For this reason, only patients in Arm B will be evaluated for the primary endpoint of PFS2. 
 
No interim analyses will be performed for Arm A or C. Pharmacodynamic effects will be 
evaluated by assessment of tissue biomarkers based on mechanism of action and preclinical 
tumor cell sensitivity studies. IHC analyses for biomarkers such as ATF4, CHOP, and DR5 
will be summarized using descriptive statistics. 
 
Intratumoral ONC201 concentration in patients will be summarized using descriptive 
statistics separately for Arm A and C. The targeted mean intratumoral drug concentration 
of ONC201 is 2.9 µM, since this represents the mean IC50 of ONC201 in cancer cell panels 
profiled for in-vitro efficacy. The null hypothesis is set at a mean of 0.0 and the alternative 
hypothesis is set at a mean of 1.4 to account for an estimated standard deviation of 1.0. A 
sample size of 6 for each arm achieves 80% power to detect this difference of -1.4 between 
the null hypothesis mean and the alternative hypothesis with a significance level (alpha) of 
0.05000 using a two-sided one-sample t-test. This assumes a normal distribution for this 
measurement, which is consistent with prior experience. 
 
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 0.05. 
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 


Protocol #: ONC012 / Version 4 11May 2020 
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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 that is relative to Mean0. Sigma is the 
standard deviation of the population that measures the variability in the population. Effect 
Size, |Mean0-Mean1|/Sigma, is the relative magnitude of the effect under the alternative. 
Effect 
Power 
N 
Alpha 
Beta 
Mean0 Mean1 S 
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 
 
Arm B uses a Simon two-stage mini–max design [27] to evaluate the hypothesis that 
ONC201 will extend progression-free survival at 2 months beyond historical controls for 
this disease, as performed for buparlisib (NCT01397877). Historical controls for type II 
endometrial cancer show the null hypothesis to be 40% progression free survival at 2 
months. To show the alternative hypothesis that >70% of patients exhibiting progression- 
free survival at 2 months with 90% power and an alpha= 5%, 24 evaluable patients are 
required for this arm. The probability for early termination under the null hypothesis is 
63.3%. 
 
An interim futility analysis will be performed for Arm B when the 10 evaluable patients in 
Arm B are evaluable for PFS2, as defined in section 11.7. In stage 1 of the study, if at least 
5 of the first 10 evaluable patients exhibit progress-free survival for at least two months 
from treatment initiation (as defined in section 11.7), recruitment will be continued until a 
total of 24 evaluable patients have been enrolled for this arm. In stage two, if at least 14 
patients demonstrated progress-free survival at 2 months ONC201 will be considered to 
have shown sufficient efficacy to warrant further study. 
 
Analysis of Secondary/Exploratory Endpoints 
All patients enrolled in the study who received at least 1 dose of ONC201 will be evaluated 
in the safety analysis using descriptive statistics including pre-treatment characteristics and 
concomitant treatment. 


Protocol #: ONC012 / Version 4 11May 2020 
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Adverse events and clinical labs will be graded according to NCI CTCAE Version 4.03. 
For labs without CTC grade definitions, results will be summarized as normal, abnormal 
or not done. Summary tables will present frequencies of patients experiencing at least one 
AE categorized by System Organ Class and Preferred Term according to MedDRA 
terminology. Listings will be prepared for each laboratory measure, and will be structured 
to permit review of the data by patient as they progress on treatment. Graphic displays and 
shift tables may be provided, as appropriate, to illustrate the results over time on study. 
ONC201 dose delays, dose modifications, drug exposure and duration of treatment will be 
also summarized. 
 
Duration of response and duration of stable disease will be characterized using Kaplan- 
Meir estimates in the relevant subgroups. 
 
Progression Free Survival (PFS) will be characterized using Kaplan-Meier curves. Median 
PFS will be calculated along with 95% confidence intervals. Patients who are lost to 
follow-up (who withdraw from the study prior to evidence of progression or death) will be 
censored. 
 
Reporting and Exclusions 
12.3.1 Evaluation of toxicity: 
All patients will be evaluable for toxicity from the time of their first treatment with 
ONC201. 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, vital signs and physical 
examinations. 
 
A Bayesian method [27] will be used for toxicity monitoring based on the dose-limiting 
toxicity (DLT) rate. Patients in Arm A and Arm B will be monitored jointly for toxicity. 
Toxicities will be defined according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03. DLT is defined as a clinically significant adverse event or 
abnormal laboratory value assessed as unrelated to disease progression, intercurrent illness, 
or concomitant medications and occurring during the first cycle on study that meets any of 
the following criteria: 
 
• CTCAE grade 3 AST (SGOT) or ALT (SGPT) for > 7 days 
• CTCAE grade 4 AST (SGOT) or ALT (SGPT) of any duration 
• All other clinically significant NCI common terminology criteria that are CTCAE grade 
≥3 (except for electrolyte disturbances responsive to correction within 24 h, diarrhea, 
nausea and vomiting that responds to standard medical care) 
 
An AE must be clinically significant to define DLT e.g. nausea and vomiting < grade 3, 
alopecia, study drug-related fever, electrolyte abnormalities (including K, Na, Cl, HCO3, 
Mg, Ca, bilirubin) that are grade <3 will not define the DLT. 
 
Monitoring for toxicity will follow a Bayesian-based rule for the probability that the rate 
of DLT exceeds a maximal tolerated level of 33%. We will assume a Beta (1,2) prior, 


Protocol #: ONC012 / Version 4 11May 2020 
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which is prior information equivalent to one DLT observed in three treated patients. This 
minimally informative prior is justified as there is some clinical experience with the 
investigational therapy. Early termination for toxicity will be considered based on a 
posterior probability above 75% that the toxicity rate exceeds 33%. Stopping boundaries 
for toxicity monitoring are provided in the table below. 
 
# Patients 
(inclusive) 
Stop the trial if there are at least this 
many DLTs total: 
1 to 2 
Never stop with this many patients 
3 
2 
4 to 6 
3 
7 to 9 
4 
10 to 12 
5 
13 to 15 
6 
16 to 18 
7 
19 to 21 
8 
22 to 24 
9 
25 to 27 
10 
28 to 29 
11 
30 
Always stop with this many patient 
 
12.3.2 Evaluation of response: 
Only those patients who have measurable disease present at baseline, have received at least 
two cycles of therapy, and have had their disease re-evaluated will be considered evaluable 
for response. Each patient will be assigned one of the following categories: 1) complete 
response, 2) partial response, 3) stable disease, 4) progressive disease, 5) early death from 
malignant disease, 6) early death from toxicity, 7) early death because of other cause, or 9) 
unknown (not assessable, insufficient data). [Note: By arbitrary convention, category 9 
usually designates the “unknown” status of any type of data in a clinical database.] 
 
Patients in response categories 4-9 should be considered to have a treatment failure (disease 
progression). An incorrect treatment schedule or drug administration does not result in 
exclusion from the analysis of the response rate. 
 
13 Data Reporting / Regulatory Requirements 
Adverse event lists, guidelines, and instructions for reporting adverse events can be found 
in Section 10. 
 
Data Reporting 
Investigative sites are responsible for completing and submitting data using the electronic 
data capture system. 


Protocol #: ONC012 / Version 4 11May 2020 
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Data Collection 
13.2.1 Data Collection Forms 
Qualified clinical trials study monitors that represent Oncoceutics will complete on-site 
monitoring. Oncoceutics 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. 
 
13.2.2 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 


Protocol #: ONC012 / Version 4 11May 2020 
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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. 
 
13.2.3 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. 
 
13.2.4 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. 
 
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. 


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14 PROTOCOL SIGNATURES 
 
SPONSOR PROTOCOL SIGNATURES 
 
Study Title: 
A Phase II Study of ONC201 in Recurrent or Metastatic Type II 
Endometrial Cancer 
Study Number: 
ONC012 
Version: 
4 
Date: 
11 May 2020 
 
This clinical trial protocol was prepared by: 
 
 
 
 
 
Signed:  
Date: 5/15/2020 
Michael Chiarella 
VP, Clinical Operations 
Oncoceutics, Inc. 
 
This clinical trial protocol was reviewed and approved by: 
 
 
 
 
 
Signed:  
Date: 
5/15/2020 
 
Joshua E. Allen, PhD 
Chief Scientific Officer 
Oncoceutics, Inc. 


Protocol #: ONC012 / Version 4 11May 2020 
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15 PROTOCOL INVESTIGATOR SIGNATURE PAGE 
 
 
PROTOCOL INVESTIGATOR SIGNATURE PAGE 
 
Study Title: 
A Phase II Study of ONC201 in Recurrent or Metastatic Type II 
Endometrial Cancer 
Study Number: 
ONC012 
Version: 
4 
Date: 
11 May 2020 
 
I have read this protocol, and I agree that it contains all necessary details for me and my 
staff to conduct this study as described. 
 
I agree to conduct this study according to this protocol and to comply with its 
requirements, subject to ethical and safety considerations and guidelines, and to conduct 
the study in accordance with the Declaration of Helsinki, International Conference of 
Harmonisation guidelines on Good Clinical Practice (ICH GCP), and applicable regional 
regulatory requirements. 
 
 
 
 
Principal Investigator Name: 
 
 
 
Principal Investigator Signature: 
 
 
 
 
Date: 
 


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