Phase 2 Study of ONC201 in Neuroendocrine Tumors
Phase: PHASE2
Conditions: Recurrent Neuroendocrine Tumor, Metastatic Neuroendocrine Tumor
Sponsor: Peter Anderson



ONC201 in neuroendocrine cancers     Phase 2 
Peter Anderson MD, PhD (PI) 
CASE 2716 (I
) IRB17-808 
 
 
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INVESTIGATIONAL PHARMACY 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
SPONSOR:  
 
 
Case Comprehensive Cancer Center  
 
 
 
 
 
 
SUPPORT/FUNDING: 
 
Sarcoma Research Fund and Oncoceutics 
 
SUPPLIED AGENT 
 
ONC201 
 
IND #:  
 
 
 
 

ONC201 in neuroendocrine cancers     Phase 2 
Peter Anderson MD, PhD (PI) 
CASE 2716 (I
5) IRB17-808 
 
 
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SUMMARY OF CHANGES 
 
 
Protocol 
Date 
Section 
Change 
1-15-17 
1.2.2 
Weekly dosing safety experience updated as per FDA request 
 
4.1.1 
Cohort B inclusion criteria  defined as per FDA guidance 
 
11.2 
Study calendar virtual visits for responding patients updated as per FDA 
10-11-17 
Face page Change of study personnel 
 
Summary 
p6 
IRB-17-808 information added; also age 14 and higher 
 
Table of 
contents 
8.5  RedCap Cloud is database 
 
1.22 
Table 1 is from Jan 2017 (legend) 
Pediatric experience added 
 
2.3 
bombesin omitted form exploratory objective (SCLC not on this trial) 
 
4.1.3 
Age 14 years and older – same as summary p6  
 
4.1.7 
Performance scale Karnofsky if 16 or older, Lansky if <16 
 
Page 22 
Figure 6  legend updated 
 
Table 2 
Anti-hypertensive instructions to reflect those with normal bp being 
blocked prior to ONC201 and formulary change of metoprolol preferred 
to atenolol at Cleveland Clinic 
 
6.4 
Correction # weekly ONC201 doses in 1year  is 52 
 
8.5 
IND compliant Data base is REDCap Cloud 
 
9.0 
Parameters of bp to make it easier and more research-subject friendly 
on the Clinical Research Unit  (+/- min or hours for time points instead 
of exact times) 
 
11.1 
Screening can be done 4 weeks before starting- reflects reality of delays 
in scheduling CRU and not needing to repeat scans 
 
Table 5 
Omit markers of SCLC since not in this trial; More accurate  description 
of PK/PD ad prolactin time points possible to do in our clinic 
 
13.0  
REDCap Cloud is the database 
 
14.0 
Correction on times being analyzed 
 
Appendix 
1 
For PC-PG subjects normotensive on low dose alpha and beta blockade 
a more realistic MAP 
 
 
 
09/13/2018 
Footer 
Updated version date of protocol 
 
Staff 
Updated staff to reflect current study team 
 
Study 
Schema 
Removed Study Schema from page 5 
 
 
Removed “for a maximum of 1 year (52 doses).” from interventions 

ONC201 in neuroendocrine cancers     Phase 2 
Peter Anderson MD, PhD (PI) 
CASE 2716 (I
) IRB17-808 
 
 
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Version date:   11/30/2020 
 
Protocol 
Date 
Section 
Change 
 
1.2.2 
Added language of additional pediatric experience on this protocol 
 
2.2.2 
Changed method of capturing overall survival 
 
3.0 
Changed study time points to reflect additional treatment past one year 
 
3.4 
Removed 1 year endpoint 
 
4.0 
Added language that allows for an administrative memo to waive 
inclusion/exclusion of potential patients on a case by case basis. Must 
be approved by the PI and IRB before treatment can begin 
 
5.0 
RedCap Cloud was named as the IND compliant database being utilized 
 
6.1 
Language added to allow therapy after 1 year 
 
6.2 
Language removed to allow therapy beyond 1 year 
 
6.4 
Language removed to allow therapy beyond 1 year 
 
6.5 
Language changed to reflect new follow-up protocol 
 
7.0 
Language added to mention additional study visits. 
 
9.0 
Changed language in subsequent doses section to allow for additional 
therapy beyond 1 year and to remove language regarding virtual visits 
 
10.1.3 
Updated PD timing 
 
11.2 
Study calendar revised to allow for therapy beyond 1 year, to remove 
the virtual visit language and update PD timing. 
 
Table 8 
Updated PD timing 
 
 
 
6/10/2020 
Face Page Change of study personnel; address, and phone numbers updates; 
funding updated 
 
footer 
Updated to 6/1/2020 version 
 
summary 
Brief background/Rationale: Safety paragraph updated to include 
weekly d1d2 dosing 
Primary objective: RANO eliminated (no brain tumors on this study) 
 
summary 
Secondary objective: deleted anti-hypertensive medication objective 
 
summary 
Exploratory objective: deleted prolactin and PK 
 
summary 
updated to include an additional 12 patients with d1d2 weekly dosing 
 
summary 
Interventions updated ONC201 dosing on 2 consecutive days weekly  
 
1.2 
Aes and ¼  2017 typos corrected to AEs and 1/4/2017 
 
1.2 
Weekly dosing section updated to include total of N=25 
 
1.3 
Revised to update current experience in CASE2716 (instead of ongoing 
other trials in 2017) and summary provided in table 2. 
 
1.3 
ONC201 in Neuroendocrine Tumors at Cleveland Clinic (6/2020): 
paragraphs and table 3 inserted to summarize experience until 6/2020 
 
1.4 
table numbers revised to tables 4 and 5. 

ONC201 in neuroendocrine cancers     Phase 2 
Peter Anderson MD, PhD (PI) 
CASE 2716 (I
) IRB17-808 
 
 
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Version date:   11/30/2020 
 
Protocol 
Date 
Section 
Change 
6/10/2020 
1.5 
Sentences about possible anti-hypertension effect deleted 
 
1.5 
Secondary objectives revised tocorrespond to protocol summary 
 
1.5 
updated to reflect deletion of table 4 section 6.3 
 
2.1 
Primary objective: update of language to reflect reality of imaging 
current image scheduling and review with patients is not as easy as in 
pre-COVID-19 for a variety of reasons including travel, prior 
authorization and then 2nd read of scans if imaging must be done closer 
to patient’s home by their primary oncologist. 
 
2.21 
RANO deleted 
 
2.22 
Anti-hypertension medication objective deleted [good clinical care for 
PC-PG patients no longer requires a bp log if well controlled and/or 
use of a wireless bp cuff that imports data into EPIC via MyChart] 
 
2.3 
biomarker analysis will be only clinically relevant blood tests (as in 
protocol summary) 
 
3.0 
updated to reflect next 12 patients will have day1day2 weekly dosing 
of ONC201; Flat dosing of 625mg orally on 2 consecutive days will be 
used 
 
3.1 
Revised to more inclusive neuroendocrine tumor cohort C 
 
3.2 
Number of subjects amended to an additional 12 
 
4.1.1 
Inclusion criteria for neuroendocrine tumors more specific 
 
4.2.4 
dopamine interaction medication list deleted; others renumbered 
 
5.0 
Addition of research nurse acknowledged 
 
6.1 
amended and simplified for d1d2 weekly dosing.  The figure with once 
weekly dosing is deleted 
 
6.2 
amended to reflect day1d2 schedule and simplified including deletion 
of CRU admission 
 
6.3.1  
Palliative radiotherapy (e.g. painful non-target bone metastases) 
allowed at week 6 instead of 12 
 
6.3.2 
RFA changed to thermal ablatio so included cryoablation 
 
6.3.3  
Language inserted to allow drugs for symptom control 
 
7.0 
2x/week schedule is inserted and bolded as follows: ONC201 (625 mg 
po) will be administered Day1, Day 2 weekly (start of week +/- 1 
day) 
 
7.0 
Evaluation window specified during COVID-19 pandemic 
 
8.0 
updated according to Investigators Brochure (version 6   11-2019) and 
IRB 17-808 consent form with inclusion of a revised table 5 
 
8.4.1 
Staff for SAE reporting updated to Research Nurse 
 
9.0 
drug information is amended to reflect d1d2 weekly schedule and 
permission by sponsor to send ONC201 supplies via express courier 
with tracking information directly drug to patients. 

ONC201 in neuroendocrine cancers     Phase 2 
Peter Anderson MD, PhD (PI) 
CASE 2716 (
) IRB17-808 
 
 
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Version date:   11/30/2020 
 
Protocol 
Date 
Section 
Change 
6/10/2020 
10.0 
Prolactin markers and PK /PD have been deleted 
 
11.1.1 
Prolactin deleted 
 
11.1.2 
treatment period labs and imaging windows have been updated 
 
11.1.2 
Since studying d1d2 weekly dosing is a major focus protocol states 
” Weekly ONC201 study drug dosing +/- 1 day.” 
 
11.1.2 
Study calendar: Table 5 renumbered to Table 6; footnotes updated to 
reflect protocol summary 
 
12.0 
Section on ability to reduce anti-hypertension medication deleted 
including table 6 in prior version 
 
12.0 
Weeks used instead of dose# used to be consistent with d1d2 weekly 
schedule 
 
12.0 
References to RANO deleted (no CNS tumors on this study) 
 
13.0 
“An IND compliant database (REDCap) similar to other Oncoceutics 
ONC201 trials also be used” is now specified 
 
13.2.1 
Written Informed Consent: text inserted to facilitate virtual visits 
offering timely and more complete discussion of indications, risks, and 
alternatives before obtaining written informed consent signatures 
during COVID-19 pandemic. Written informed consent is still required. 
 
14.0 
Paragraph 1 updated to include current age (14) and cohort C as having 
2x drug exposure as cohort A+B. 
 
14.0 
RANO text deleted 
 
14.0 
DSRCT and SCLC language deleted concerning subset analysis 
 
14.0 
Statistics Paragraphs revised and updated because (cohorts A+B) met 
primary endpoints- with reference to table 3, efficacy language for 
cohort C inserted 
 
14.0 
Hypertension evaluation and analysis deleted 
 
14.0 
paragraph on type 1 and II errors deleted [Since study met endpoints 
using cohorts A+B] 
 
14.0 
paragraph about effect on hypertension deleted 
 
14.0 
Paragraph on potential catecholamine release and hypertension deleted 
 
14.0 
exploratory objective modified to be consistent with protocol summary 
 
14.0  
Prolactin deleted 
 
15.0 
Appendix section deleted 
 
16.0 
Renumbered to 15.0 References 
11/30/2020 
8.0 
Updated Adverse Events 
 
 
 
 
 
 
 

ONC201 in neuroendocrine cancers     Phase 2 
Peter Anderson MD, PhD (PI) 
CASE 2716 (I
) IRB17-808 
 
 
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ONC201 in neuroendocrine cancers     Phase 2 
Peter Anderson MD, PhD (PI) 
CASE 2716 (
) IRB17-808 
 
 
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PROTOCOL SUMMARY 
 
Protocol Number/Title 
CASE2716 IRB 17-808 Phase 2 Study of ONC201 in 
Neuroendocrine Tumors  
Study Phase 
Phase 2  
Brief 
Background/Rationale 
 
 
 
ONC201 is a first-in-class oral drug that was discovered in a 
phenotypic screen for p53-independent inducers of tumor-selective 
pro-apoptotic pathways. ONC201 has highly specific binding to a 
member of the dopamine receptor family of G-coupled protein 
receptors, 
DRD2. 
According 
to 
the 
TCGA 
database 
pheochromocytoma-paraganglioma (PC-PG) tumors have been 
shown to overexpress DRD2 far more than any other cancer. Other 
neuroendocrine tumors also likely have high DRD2 expression.   
 
Because PC-PG have abundant DRD2 receptors and DRD2 
inhibition imparts anti-tumor efficacy without killing normal cells 
via induction of ATF4/CHOP and dual inhibition of Akt and ERK 
signaling, a phase 2 study of ONC201 in PC-PG and other 
neuroendocrine tumors will determine whether inhibition of DRD2 
is effective in neuroendocrine cancers including PC-PG. 
 
ONC201 has demonstrated a favorable safety profile in 24 patients 
with neuroendocrine tumors. New data shows a dosing on 2 
consecutive days per week is safe in other varieties of cancer. This 
study will collect safety and efficacy data using this schedule. 
Primary Objective  
Primary Endpoints: PC-PG:  To demonstrate objective responses 
using MRI, CT, PET-CT and/or PET-MRI imaging using RECIST 
changes in 18FDG uptake 
Secondary Objectives 
All patients: Determine progression-free survival and overall 
survival. To document incidence and severity of adverse events that 
are drug-related. 
Exploratory Objective(s) 
To determine time course of ONC201 efficacy in PC-PG and other 
neuroendocrine tumors by measurement blood biomarkers as 
clinically indicated (for example in PC-PG  normetanepherine, 
metanepherines, and chromogranin A). 
Correlative Objective(s) 
Correlative Endpoint: Blood samples will be stored for future 
analysis of ONC201 biomarkers. Samples will be obtained before 
treatment and at 6 weeks and 3 months. 
Sample Size 
N=36 (12 PC-PG and 12 other neuroendocrine cancers; an 
additional 12 patients with d1d2 weekly schedule). Age 14 and 
older; genders: both; both cohorts to start at same time 
Disease sites/Conditions 
Recurrent or metastatic neuroendocrine tumors including PC-PG 
Interventions 
ONC201 625 mg po on 2 consecutive days weekly  (N=12) 
  
 
 

ONC201 in neuroendocrine cancers     Phase 2 
Peter Anderson MD, PhD (PI) 
CASE 2716 (
) IRB17-808 
 
 
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Version date:   11/30/2020 
 
 
ABBREVIATIONS  
 
 
 
 
 
AYA 
Adolescents and Young Adults  
AE 
Adverse Event 
CCCC 
Case Comprehensive Cancer Center 
CCF 
Cleveland Clinic Foundation 
ccfBio 
Biomarker tests done at Cleveland Clinic  
ccfDNA 
Circulating cell-free DNA 
ccfRNA 
Circulating cell-free RNA 
CR 
Complete Response 
CRF 
Case Report Form 
CT 
Computed Tomography 
DR4 
Death receptor 4 (TRAIL-R1) 
DR5 
Death receptor 5 (TRAIL-R2) 
DRD2 
Dopamine-like receptor D2  
DSTC 
Data Safety and Toxicity Committee 
FADD 
FAS-associated death domain 
FDA 
Food and Drug Administration 
FDG 
18-fluro-deoxy-glucose 
GLP 
Good Laboratory Practices 
ICF 
Informed Consent Form 
IRB 
Institutional Review Board 
MR 
Mixed Response 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximally Tolerated Dose 
NCI 
National Cancer Institute 
ONC201 TC10;7-benzyl-4-(2-methylbenzyl)-1,2,6,7,8,9-hexahydroimidazo[1,2-
a]pyrido[3,4-e]pyrimidin-5(4H)-one2HCl : MW 459 
PET 
Positron Emission Tomography  
PR 
Partial Response 
PRMC 
Protocol Review and Monitoring Committee 
RECIST 
Response evaluation criteria in solid tumors 
RFA 
Radiofrequency Ablation 
RP2D 
Recommended Phase 2 dose 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SOC 
Standard of Care 
TRAIL 
Tumor necrosis factor-related apoptosis inducing ligand 
TC10 
TRAIL inducing compound 10 (ONC201) 
 
 

ONC201 in neuroendocrine cancers     Phase 2 
Peter Anderson MD, PhD (PI) 
CASE 2716 (
) IRB17-808 
 
 
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TABLE OF CONTENTS 
 
1.0  
INTRODUCTION  
 
1.1 
Background of neuroendocrine tumors including pheochromocytoma- paraganglioma (PC-
PG)  
1.2  
Name/description of ONC201 
1.3  
Experience with ONC201 in Neuroendocrine Tumors: (as of June 2020) 
1.4 
Symptom control in neuroendocrine tumors including PC-PG 
1.5  
Rationale: TCGA DRD2 data 
 
1.6 
Background and rationale of exploratory studies 
 
2.0 
OBJECTIVES 
2.1 
Primary objective: efficacy by imaging  
2.2  
Secondary objectives: safety + efficacy trends using blood pressure  
2.3 
Exploratory objective: biomarker trends 
2.4 
Correlative objective: banking of plasma  
 
3.0 
STUDY DESIGN 
3.1 
Phase 2 study design  
3.2 
Number of subjects 
3.3 
Replacement of subjects 
3.4 
Expected duration of treatment and subject participation 
 
4.0  
SUBJECT SELECTION 
4.1 
Inclusion criteria 
4.2  
Exclusion criteria 
4.3 
Inclusion of women and minorities 
 
5.0 
REGISTRATION  
 
 
6.0  
TREATMENT PLAN 
6.1 
Treatment regimen overview  
 
Pre-treatment alpha then beta blockade  
6.2  
General concomitant medications and supportive care guidelines 
6.3 
Other therapy allowed while on study 
6.4 
Criteria for removal from study 
6.5 
Duration of follow-up 
 
7.0 
DOSE DELAYS / DOSE MODIFICATIONS 
 
8.0 
ADVERSE EVENTS AND POTENTIAL RISKS 
8.1  
ONC201 adverse events 
8.2 
Definitions 
8.3 
Serious adverse event report form 
8.4 
Reporting procedures for serious adverse event  
8.5 
Serious adverse events and OnCoreTM and other data base (RedCap Cloud) 

ONC201 in neuroendocrine cancers     Phase 2 
Peter Anderson MD, PhD (PI) 
CASE 2716 (I
) IRB17-808 
 
 
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8.6 
Data Safety Toxicity Committee 
8.7 
Data and Safety Monitoring Plan 
 
9.0 
PHARMACEUTICAL INFORMATION  
9.1 
Investigational agent(s) 
 
9.2 
Commercial agent(s) 
 
10.0 
EXPLORATORY/CORRELATIVE  
10.1  Exploratory: biomarkers 
10.2 
Correlative study: banking of plasma  
 
11.0 
STUDY PARAMETERS AND CALENDAR 
11.1 
Study parameters 
11.2 
Calendar 
 
12.0 
MEASUREMENT OF EFFECT  
 
13.0 
RECORDS TO BE KEPT/REGULATORY CONSIDERATIONS 
13.1 
Data reporting 
13.2 
Regulatory considerations  
 
 
14.0 
STATISTICAL CONSIDERATIONS 
 
15.0 REFERENCES 
 
  
 
 

ONC201 in neuroendocrine cancers     Phase 2 
Peter Anderson MD, PhD (PI) 
CASE 2716 (
) IRB17-808 
 
 
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1.0 
Introduction  
 
1.1 
Background of pheochromocytoma-paraganglioma (PC-PG)  
 
PC-PG are rare neuroendocrine tumors characterized by neuroendocrine features. Over 50% of 
patients have either a germline or somatic susceptibility mutation [1-4]. TCA enzyme mutations 
(e.g. SDHx, FH, and MDH2) are associated with pseudohypoxia and activation of hypoxia 
inducible signaling pathways involved in transformation, invasiveness, and metastatic potential [5, 
6]. Additional germline and somatic mutations have been observed in patients with PC-PG 
including VHL, EPAS1, RET, NF1, TEMEM127, MAX, H-RAS, HIF 2 alpha, ATRX, PHD1 and 
PHD2 [1, 7-12] .  
 
 Catecholamine production (e.g. normetanepherine, metanepherinine, methoxytyramine [13]), 
neuroendocrine markers (chromogranin A, synaptophysin), and very high glucose uptake on 
18FDG-PET imaging studies [14-17] are common in PC-PG and other neuroendocrine tumors. 
However, about 10% of PC-PG patients can be “biochemically silent” [6, 15, 18, 19] .  About half 
of therapy-naïve newly diagnosed PC-PG patients will experience progression within 1 year [20]. 
Despite appearance of metastases, PC-PG can be a chronic and indolent metastatic cancer 
associated with good performance and excellent quality of life. Nevertheless, many patients 
require chronic life-long anti-hypertensives to control side-effects of catecholamine excess and 
about 30% of PC-PG patients had died in the largest series reported to date which involved 132 
patients (27 children and 105 adults) seen at NIH in 2000-2014 [6].  Recently the Uppsala group 
demonstrated that considerable genetic heterogeneity can also exist within and between PC-PG 
tumor lesions of the same patient [7]. Treatment options for PC-PG patients with metastases 
remain limited and include local control with surgery, radiofrequency ablation [21], radiotherapy 
[22], and relatively ineffective chemotherapy regimens which may include VEGF inhibitors [18, 
23].  131I-MIBG (iobenguane I-131, Azedra), a high specific activity beta-emitter that binds 
dopamine receptors, is being tested to ameliorate hypertension in patients 12 years old and older 
with PC-PC [24]. The primary endpoint of this clinical trial is reduction of hypertension 
medications by 50% in 25% of subjects.  
 
1.2  
Name and Description of Investigational Agent: ONC201 
 
Figure 1 ONC 201   
 
 
Chemical name: 7-benzyl-4-(2-methylbenzyl)-1,2,6,7,8,9-hexahydroimidazo [1,2-a] pyrido [3,4-
e]pyrimidine 5(4H) –one.2HCl .(benzyl-benzylmethy-imipridone); MW 459 
 

ONC201 in neuroendocrine cancers     Phase 2 
Peter Anderson MD, PhD (PI) 
CASE 2716 (
 IRB17-808 
 
 
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1.2.1  Preclinical Data: ONC201  
Abnormal energy metabolism towards glycolysis, the Warburg effect, [5, 14-17, 25-29] and signals 
including Akt and ERK contribute towards proliferative, pro-survival, and anti-apoptosis phenotypes of 
cancer cells including PC-PG [30-39]. Another cancer–specific inhibitor is TNF-related apoptosis inducer 
ligand (TRAIL) which facilitates tumor-specific suppression in DR4/DR5 death receptor bearing cells [30, 
31, 35, 40-80]. TRAIL binds DR4/5 death receptors on cancer cells to cause apoptosis but not in normal 
cells due to multiple redundant pathways in non-neoplastic tissue [76]. ONC201 was discovered during a 
screen of over 2000 compounds for activity that would promote apoptosis in cancer cells in a p53 
independent manner [30]. This TRAIL + DR5 inducing small molecule was active against hematologic 
malignancies including lymphoma [81-83], glioblastoma [84], and solid tumors including hepatocellular 
carcinoma xenografts, chemotherapy–resistant colorectal stem-like cells, and stem cells of desmoplastic 
small round cell tumor [35, 43, 85, 86].  
 
Experimental profiling predicted ONC201 has specific binding to DRD2, DRD3; weak DRD4, but not to 
DRD1 or DRD5[87, 88]. The ratio of DRD2/3/4 versus DRD1/DRD5 seems important in the malignant 
cell proliferation [89] and induction of anti-tumor effects via dopamine receptors [88] [87, 88, 90-92]. In 
summary, ONC201 is associated with TRAIL induction, an integrated stress response, and apoptosis in 
hematologic malignancies and solid tumors [30, 35, 41-43, 55, 61, 77, 82-84, 87, 88, 93-95]; (fig 2).  
Hundreds of cell lines have been tested against ONC201. So far lymphomas and neuroblastomas are among 
are the most responsive [55, 82]. Of all tumors tested for DRD2 in TCGA, pheochromocytoma-
paraganglioma (PC-PG) has the very highest expression (fig. 3)[87]. A possible common theme cancer 
would be predicted to have DRD2 is neural and neuroendocrine biomarkers as detected by CD56 (neural 
cell adhesion molecule), chromogranin, and synaptophysin[96, 97], or dopaminergic metabolites such as 
norepinephrine, metanepherines, vanillylmandelic acid (VMA), or homovanillylmandelic acid (HVA). 
 
Figure 2. ONC201 is a first-in class small molecule that imparts anti-tumor effects via ATF4>CHOP[81], 
dual inhibition of Akt and ERK signaling, and subsequent TRAIL induction to induce an integrated stress 
response[85] and apoptosis [93].  Stereospecific ONC201 binding occurs via the G-coupled protein receptor 
(GPCR), dopamine-like DRD2 receptor[87]. 
 
 

ONC201 in neuroendocrine cancers     Phase 2 
Peter Anderson MD, PhD (PI) 
CASE 2716 
) IRB17-808 
 
 
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Figure 3.  Tumor Expression of DRD2 in TCGA. PC-PG tumors (red bar) have the highest 
amounts of DRD2 RNA. Also DRD2 receptors were not mutated in PC-PG 
 
 
Figure 4. Preclinical ONC201 pharmacokinetics and pharmacodynamics.  ONC201 is 
eliminated from plasma, followed by a delayed and sustained activation of TRAIL and apoptotic 
cell death of tumor cells (cleaved caspase-8). Data courtesy of Oncoceutics.  
 

ONC201 in neuroendocrine cancers     Phase 2 
Peter Anderson MD, PhD (PI) 
CASE 2716 
) IRB17-808 
 
 
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Drugs or drug combinations that possess an oncology efficacy profile similar to ONC201 (dual 
PI3K>Akt and Ras>Raf>MEK1/2>.ERK pathway inhibition) are typically very toxic. 
Nevertheless, the initial safety profile of ONC201 was favorable. Exaggerated dosing in rodents 
and dogs revealed that ONC201 acute toxicity occurred only at substantially higher than 
therapeutic doses.  
 
Even at the highest doses tested, the drug did not achieve a maximum tolerated dose (MTD) with 
oral administration in good laboratory practices GLP studies [98].  
 
1.2.2 Clinical Data 
 
Very few drug-related side effects have been observed with ONC201 in humans [93].  AE were few, there 
were no AEs greater than grade 1, and a MTD was not reached in the first-in-human phase I trial. 
Based on preclinical studies [98] and this trial, the recommended phase 2 dose level and schedule 
of ONC201 in adults is 625 mg (5 tablets) weekly. With this schedule caspase-cleaved cytokeratin-
18, a mark of apoptosis, was detected in ONC201-treated patients, which has been shown to 
correlate with responses against cancer [99-101].   
 
 
Patients Treated With Weekly Dosing 
As of January 4, 2017, a total of 31 cancer patients with various malignancies in late stages and 
refractory to standard therapies, have been enrolled in 4 independent investigator-initiated 
clinical trials, and received oral ONC201 on a weekly schedule at various doses up to 625 mg, as 
summarized in Table 1 below.  Individual patients have received up to 21 weekly doses of 
ONC201.   
 
Table 1.  Number of Patients Who Received ONC201 Weekly By Dose and Site (01-2017) 
Site 
Cancer Institute 
of New Jersey 
(CINJ) 
Fox Chase 
Cancer Center 
(FCCC) 
MD Anderson 
Cancer Center 
(MDACC) 
MD Anderson 
Cancer Center 
(MDACC) 
Total 
Patients 
Tumor Type 
Prostate, 
Endometrial, 
Colon, GBM 
All-comers 
solid 
Non-Hodgkin’s 
Lymphoma 
Acute Leukemias 
 
Clinical Trial 
# 
NCT02324621 
NCT02609230 
NCT02420795 
NCT02392572 
 
125mg 
 
 
2 
1 
3 
250mg 
 
4* 
 
1 
5 
375mg 
3 
4 (2 on study) 
 
1 
8 
500mg 
 
 
 
2 (on study) 
2 
625mg 
12** (3 on 
study) 
 
1 
 
13 
Total 
Patients 
15 
8 
3 
5 
31 
*Included is one patient was replaced after the first dose of ONC201 due to progressive disease 
**Included is one patient was replaced after the first dose of ONC201 due to non-compliance. 
 
Currently, all clinical studies utilizing weekly dosing are being conducted under investigator-
initiated INDs; thus, data entry and reporting are being performed under the supervision of the 

ONC201 in neuroendocrine cancers     Phase 2 
Peter Anderson MD, PhD (PI) 
CASE 2716 (
) IRB17-808 
 
 
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individual site Investigators.   Data reported here represent interim information as provided to 
Oncoceutics from the individual sites1/4/ 2017.  Seven patients remain active in the 4 trials, and 
these studies continue to accrue patients.  Thus, this information does not represent a final 
clinical database. 
 
Overall ONC201 Safety Experience  
In accordance with research agreements, reports of adverse events (AEs) are provided by the 
investigators to Oncoceutics as requested on a periodic basis, with reports of serious adverse 
events (SAEs) provided within specified timeframes.   
 
At Cleveland Clinic as of June 2020 a total 25 patients have been treated with weekly ONC201 
dosing including N=23 on CASE 2716 (IRB17-808;IND 1
) and 2 additional patients using 
single patient IND. To-date, there have been no deaths attributed to study drug.  There have been 
no SAEs assessed by the Investigator as “probably” or “definitely” related to study drug, and no 
discontinuation of ONC201 due to toxicity has been reported.   
 
Assessing adverse reactions in cancer patients can be challenging relative to underlying disease.  
Thus far, the most common AEs reported as possibly related to ONC201 were mild/moderate 
nausea, vomiting, anorexia and fatigue, which are not uncommon in advanced cancer patients.    
 
Safety Experience from Every Three Week ONC201 Dosing 
Available clinical safety information from a dosing schedule administering ONC201 every 3 
weeks (q3wk) is summarized in the Investigator’s Brochure. In brief, data are available from 29 
patients treated at CINJ and 17 patients at MGH and DFCI (total of 46 patients). Note that these 
patients are in addition to the 31 patients described above in the weekly dosing section.  Forty-
one of these 46 patients received 625 mg doses of ONC201 every 3 weeks and establish a benign 
safety profile of the study drug. Other than one instance of Grade 3 neutropenia that was 
attributed as possibly drug related, none of these patients experienced a possibly or probably 
related >Grade 2 AE. 
 
One report of a non-serious Grade 2 allergic reaction that was probably related to study drug 
occurred. Two patients with GBM remain on study medication after 14 doses of 625 mg of 
ONC201, including one patient who continues to exhibit a partial response.  
 
Safety Experience from Weekly ONC201 Dosing  
Similar to every 3 week dosing, weekly oral doses of ONC201 ranging from 125 mg to 625 mg 
have been generally safe and well-tolerated. 
 
Below is a summary of safety information reported to Oncoceutics for each trial where patients 
have received weekly dosing of ONC201. 
 
Cancer Institute of New Jersey (solid tumor trial) 
Database information on AEs from patients receiving weekly dosing is not currently available.   
No SAE reports have been received to-date. 
 
375mg: 3 patients dosed. Median 21 doses (Range: 18-29 doses). 

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625mg: 12 patients dosed. Median 11.5 doses (Range 1-21 doses). 3 patients have received 21 
doses and are still on protocol.  
 
MD Anderson Cancer Center (NHL trial) 
A total of 3 patients have been dosed with ONC201 weekly.  No Aes >Grade 2 were attributed as 
possibly, probably or definitely related to study drug. SAE reports are summarized in the table 
below, with no SAE attributed to ONC201. 
 
125mg: 2 patients (#5 and #7) dosed. Median 7.5 doses (13 & 2 doses, respectively).  
 
625mg: 1 patient (#9) dosed (5 doses).  
 
Patient 
# 
Patient 
Description 
Dose 
Level/Schedule 
SAE 
Grade 
PI Attribution To 
Study Drug 
9 
57 yr. female 
625mg/weekly 
Edema – limbs 
5 
Unlikely Related 
 
 
MD Anderson Cancer Center (acute leukemia trial) 
A total of 5 patients have been dosed with ONC201 weekly, in a dose escalation design ranging 
from 125mg (1 patient – 7 doses), 250mg (1 patient – 8 doses), 375mg (1 patient – 6 doses) to 
500mg (2 patients – 7 and 3 doses, respectively), with the 2 patients receiving 500mg weekly 
doses of ONC201 remaining on study. No SAEs or Aes of any grade have been reported to 
Oncoceutics as possibly, probably, or definitely related to study drug.   
 
 
Fox Chase Cancer Center (solid tumors) 
Eight patients with various advanced solid tumors have received ONC201 weekly, ranging from 
250mg to 375mg. No SAEs were reported to Oncoceutics as probably or definitely related to 
study drug.  No Aes >Grade 2 were attributed as possibly, probably or definitely related to study 
drug. 
 
250mg: 4 patients. Median 3 doses (Range: 1-6).  SAE reports received are summarized in the 
table below, with no SAE currently attributed to ONC201.  
 
375mg: 4 patients. Median 3 doses (Range: 2-5). Two patients remain on protocol treatment. 
No SAEs reported as of January 4th, 2017  
 
Patient 
# 
Patient 
Description 
Dose 
Level/Schedule 
SAE 
Grade 
PI Attribution To Study 
Drug 
11 
36 yr. male 
250mg/weekly 
Hemorrhage 
5 
No causality established, 
currently under review 
13 
67 yr. female 
250mg/weekly 
Stroke 
4 
Unlikely related 
 
 
Additional evidence the DRD2 engagement by ONC201 was shown by dopamine agonist effects in this 
early clinical trial: 10/11 patients showed 2-fold induction of prolactin [87].  

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Pediatric Experience 
As of September 8, 2017, 6 pediatric patients from age 3-17 have been treated with ONC201 
under compassionate use protocols. No treatment-related adverse events have been reported by 
investigators to Oncoceutics. Three patients have progressed and 3 patients remain on 
therapy.   One patient, a 26kg 8 year old male who received 375mg ONC201 q1w PO, had 
limited PK sampling with 9uM plasma concentration of ONC201 at 2 hours following the first 
dose (approximate Tmax). This result is consistent with the adult PK experience. One Patient 
was enrolled on this protocol at the age of 17 and has most recently completed the Month 6 study 
visit at the time of this protocol amendment.  Brain tumor patients <18 years old have also been 
treated (as per Oncoceutics at Society of Neuro-Oncology June 2018) with low toxicity and 
potential efficacy against K27M midline gliomas. 
1.2.3 Clinical Pharmacokinetics  
 
In the first-in human clinical trial, the blood ONC201 level was ~0.1ug/ml at 48 hr. Cmax 
occurred at an average of 1.8 hr.; half-life was 9.6 hr (SD1.8) hours.  ONC201 AUC was 26.3 
(SD10.8) h.mg/mL which is consistent with a large distributive volume [93]. ONC201 appeared 
to saturate absorption at 375mg; drug was detected at approximately 48 hr and none in 7 days 
(figure 5).  There was no evidence of ONC-201 accumulation. Table 1 summarizes ONC201 PK 
parameters at the recommended phase 2 dose (RP2D) of 625 mg po. Although ONC201 has 
rapid oral absorption, a large volume of distribution, and detection at 48 hr, anti-cancer activity is 
associated with TRAIL production beyond 48 hours that is sustained for up to 3 weeks and 
associated with apoptosis in the M30 assay at 3 weeks [93]. 
 
         Table 2.  ONC201 PK at Recommended Weekly Phase 2 Dose   (RP2D; N=6) 
Parameter 
Cmax 
Tmax 
AUClast 
t1/2 
AUC 
Vz/F 
CL/F   
   (units) 
ng/mL 
hours h.ng/mL 
hours h.ng/mL 
Liters L/hour 
    Mean 
3312 
1.8 
25515  
9.6 
26344 
381 
27.2 
     SD                     2133 
1.3 
10677  
1.8 
10763 164 
11.0 
 
 
Figure 5.  Weekly ONC201 PK for 375, 500 and 625 mg. ref[93]                 Above-625 mg (N=6)  
 
Twice per week (day 1 and day 2) ONC201 Dosing  
 

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neuroendocrine tumor (NET). ONC201 was exceptionally well tolerated. All patients were able 
to maintain or improve KPS while on study. No adverse effects on bp were seen including worse 
hypertension. The only ONC201-related AE was temporary grade 1 neurocognitive dysfunction 
(N=1) for ~36 hours after weekly ONC201 dosing in 1/10 PC-PG patients and one NET patient 
had grade 1 fatigue for 2 days after ONC201 but improved GI symptoms (less frequent diarrhea 
since starting ONC201).  PC-PG patients had the most clinical benefit; 4/10 PC-PG patients 
remain on study at 32, 26, 28, and 8 months with stable or improved KPS.  A DSRCT patient 
achieved a PR at 3 months and has been treated 32 months and continues to have KPS=100%. 
An ACC patient was initially responsive (PR), but rapidly progressed in liver A patient with high 
tumor burden of GI NET patient had -10% reduction by RECIST at 3 months and remains on 
treatment>6 months with improved KPS (80%). MTC may be responsive (1 no response, 2 
stable and slightly improved by RECIST at 6 months). 
 
ONC201 given as weekly dosing has been very well tolerated with excellent quality of life and 
extended clinical benefit against some neuroendocrine tumors. Although ONC201 has some 
activity against neuroendocrine tumors, especially PC-PG, increased efficacy may be possible 
with weekly day 1 day 2 dosing.  
 
Table 3. Experience with ONC201 in Neuroendocrine Tumors at Cleveland Clinic 
 
 
 
 
 
 
Progression 
Treatment 
 
Time on Study 
Neuroendocrine tumor types  N 
at 3 months 
>3 months  
 
>24 months 
PC-PG, MTC, NET 
 
13 
5/13 (38%) 
7/13 (53%) 
 
3/13 (23%) 
DSRCT, CSS, ACC, NBL 
12 
9/12 (75%) 
4/12 (25%) 
 
1/12 (8%) 
 
 
 
 
Total 25 
14/25(56%) 
11/25 (44%)  
4/25 (16%) 
 
 
1.4 
Symptom control in neuroendocrine tumors including PC-PG 
 
Common signs and symptoms in patients with PC-PG are related to catecholamine excess. These 
include (in decreasing order of frequency[1]):  
 headache 
 sweating 
 palpitations,  
 hypertension,  
 pallor,  
 weakness & fatigue,  
 nervousness 
 nausea,  
 hyperglycemia,  
 flushing,  
 weight loss 
 
Alpha blockade first with doxazosin (or phenoxybenzamine) and then beta blockade (e.g. 
propranolol or atenolol) are the standard of care for PC-PG patients experiencing symptoms such 

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as headaches or hypertension and/or requiring surgery or radiation to avoid symptoms associated 
with catecholamine release [102-104] . Some PC-PG patients are on chronic anti-hypertensives to 
control symptoms.  
 
Because of potential interaction with dopamine receptors, medications that are dopamine agonists 
including and some psychotropic medications are relatively contraindicated; see also table 3 
section 6.2 [102, 105]. 
 
1.5 
Rationale  
 
Experimental profiling has determined that ONC201 specifically and directly antagonizes DRD2, 
DRD3, but not to DRD1, DRD4, or DRD5 [87]. DRD2 is a G protein-coupled receptor (GCPR) 
that is involved in many functions and is not only present on neural cells binding norepinepherine 
or epinephrine, but also signaling in lymphocytes and cells involved in hormone signaling [92, 
106-113].  
 
Thus, ONC201 is the first anti-cancer drug to bind a GPCR [87, 90-92]. PC-PG have more DRD2 
receptors than gastropancreatic neuroendocrine tumors [114]. It would be expected that other 
tumors with neural or neuroendocrine differentiation and catecholamine biomarkers would have 
high DRD2 expression [89, 96, 97]. Many subjects with neuroendocrine cancers that release 
dopamine or are driven in an autocrine manner by dopamine have indolent, but serious disease. 
This is particularly true for PC-PG. Ability to control symptoms of catecholamine excess in PC-
PG is usually done with alpha and beta blockade.    
 
Thus, the primary objective will be to demonstrate objective responses using MRI or CT and also 
PET-CT or PET-MRI imaging. Secondary objectives will be to determine progression-free 
survival and overall survival and to determine incidence and severity of AE comparing the well 
tolerated once weekly schedule with dosing d1d2 weekly schedule. 
 
1.6 
Background and rationale of exploratory studies 
 
The finding that DRD2 is a highly specific target of ONC201 led to analysis of DRD2 in cancers 
using TCGA data [87].  Since PC-PG have the highest DRD2 expression of all cancers in the panel 
(figure 2), studying ONC201 in PC-PG and similar neuroendocrine tumors may determine whether 
it is possible to preselect for patients with that would have both high ONC201 binding and 
excellent surrogate plasma biomarkers including normetanepherine and metanepherines [102], and 
possibly bombesin (progastrin-releasing peptide; ref [115-119]),  
 
 
2.0  
Objectives 
 
2.1  
Primary Objective  
To demonstrate objective responses using MRI or CT, PET-CT and/or PET-MRI imaging.  The 
same CT or MRI imaging to assess disease burden at study entry will be compared at week 6 and 
3 months. Patients without progression at 3 months will continue treatment and have imaging 
approximately every 3 months after study entry. 
 

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2.2 
Secondary Objectives 
 
2.21. Progression – free Survival. 
This will be calculated according to RECIST and /or development of new disease 
 
2.2.2 Overall survival:  
Overall survival will be by searching for obituaries and/or utilizing the social security death 
index.    
 
2.3 Exploratory Objective:  
 
All patients To determine time course of ONC201 efficacy by measurement clinically indicated 
blood biomarkers such as normetanepherine, metanepherines, and/or chromogranin A..  
 
2.4 
Correlative Objective(s): NA 
 
Plasma will be collected in BCT tubes, then frozen and stored for future studies of an exploratory 
nature. 
 
 
3.0 
Study Design: Phase 2 open-label fixed dose study 
 
This study design has been chosen to see whether ONC201 given 2 consecutive days weekly (d1, 
D2 schedule) has similar safety and better efficacy against neuroendocrine tumors, especially PC-
PG.  Flat dosing of 625mg orally on 2 consecutive days will be used. The same imaging at study 
entry will be used at subsequent time points (CT or MRI for week 6, month 3 and every 3 months 
after that while on therapy; PET-CT or PET-MRI will be at 6 weeks 3 months and 12 months and 
then yearly while on therapy. Imaging modality choice will be influenced by the quality of prior 
scans of the subject and will be ordered so clinical comparison is possible.    
 
3.1  
Dose escalation / cohorts  
 There will be one Cohort C with  12 neuroendocrine tumor patients on the day1, day2 weekly 
schedule 
 
3.2 
Number of Subjects  
Cohorts A and B will be closed to accrual after patients currently receiving weekly ONC201 roll 
over to Cohort C.  A total of 12 patients receiving twice/week d1d2 ONC201 will be accrued. 
 
3.3 
Replacement of Subjects 
  
Subjects will be replaced if enrolled, but not able to get 6week imaging evaluation.  
 
3.4  
Expected Duration of Treatment and Subject Participation 
 

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Length of treatment will be until progression at two consecutive time points  
 
4.0 
Subject Selection 
 
All inclusion and exclusion eligibility criteria in the following sections must be met for a subject 
to be considered eligible for this study unless an administrative letter is obtained that will allow 
one or more of the inclusion/exclusion criteria to be waived. This will be done on a case by case 
basis and will be reviewed by the PI and IRB before treatment can begin.  
 
4.1 Inclusion Criteria 
 
 
4.1.1 “Subjects must have a unresectable, recurrent, locally advanced, refractory, or 
metastatic neuroendocrine tumor including pheochromocytoma-paraganglioma (PC-PG), 
DSRCT, Ewing Sarcoma or PNET, or any neuroendocrine tumor with a catecholamine or 
dopamine biomarker or autocrine or paracrine dependence on dopamine including 
cholangiocarcinoma and adrenal cortical carcinoma (ACC). N=12”N=12 
 
 
4.1.2 There is no limit on number of prior therapies. 
 
 
4.1.3 Age ≥14 years.   
 
 
4.1.4 Subjects must have normal organ and marrow function as defined below.  Studies 
should be done within 3 weeks prior to enrollment 
 Hemoglobin ≥ 10.0 g/dl  
 Leukocytes ≥ 1500/mcL 
 Absolute neutrophil count ≥ 1,000/mcL 
 Platelet count ≥ 75000/mcL 
 Total bilirubin within 1.5 x normal institutional limits 
 AST (SGOT) ≤ 5 X institutional upper limit of normal 
 ALT (SGPT) ≤ 5 X institutional upper limit of normal 
 Serum Creatinine <3.0mg/dL 
 
 
4.1.5   1 lesion detectable on CT, MRI,  18FDG PET-CT,  or PET-MRI 
 
 
4.1.6 Subjects must have the ability to understand and the willingness to sign a written 
informed consent document. 
 
 
4.1.7: Karnofsky or if <16 years old Lansky Play Performance status ≥ 60%  
 

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4.2 
Exclusion Criteria 
The presence of any of the following will exclude a subject from study enrollment. 
 
 
4.2.1 Subjects not able to take oral drugs 
 
 
4.2.2 Subjects receiving any other investigational agents.  
 
4.2.3 Subjects receiving cytotoxic chemotherapy 
 
4.2.4 Subjects with uncontrolled intercurrent illness including, but not limited to ongoing 
or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, severe, uncontrolled hypertension (systolic >150/diastolic>100mmHg) or 
other symptoms of catecholamine excess after efforts to achieve adequate alpha blockade 
then beta blockade 
 
 
4.2.5. Psychiatric illness/social situations that would limit compliance with study 
requirements including returning for scans, taking oral medication, home monitoring of 
blood pressure and heart rate, recording side effects in a self-report diary, or becoming 
pregnant while on study drug 
 
 
4.2.6. Pregnant and breast-feeding subjects.  
 
 
4.2.7. Patients with prolactinomas 
 
 
4.3 
Inclusion of Women and Minorities  

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Men, women, and members of all races and ethnic groups are eligible for this trial. 
 
5.0 
Registration 
 
All subjects who have been consented are to be registered in the OnCore™ Database and also an 
IND compliant database (RedCap Cloud) All subjects will be registered through Cleveland Clinic 
and will be provided a study number by contacting study coordination 
or research nurse 
 
 
6.0  
Treatment Plan 
 
6.1 
Treatment Regimen: 625 mg po d1 d2 weekly (each week can begin +/- 1 day) 
  
 
Tumor size and/or metabolic activity will be evaluated at study entry before initial ONC201 at 6 
weeks and 3 months. ONC201 will be administered at 625 mg orally day1, day 2 weekly. Patients 
without progression at 3 months will continue oral ONC201 until progression occurs with imaging 
and clinical evaluations at approximately 3 month intervals.   
 
6.2 
Logistics of ONC201 Dosing  
 
ONC201 dosing will be orally on two consecutive days weekly (each week +/- 1 day) and must 
start within 3 weeks of registration and study enrollment.  PC-PG  subjects are to have be on an 
alpha blocker (e.g. doxazosin) and a beta blocker (e.g. metoprolol or atenolol).  These 
recommendations are adapted from Endocrine Society clinical practice guidelines for pre-surgical 
Medical preparation of PC-PG patients (table 9 page 1929 ref [102]).  
 
 
If a subject has nausea or illness causing potential difficulty taking oral drugs, waiting for next day 
is advised so there is no loss of study drug. If nausea or illness is severe for longer than 2 days, 
contact study chair. ONC201 will be given until progression as determined appearance of new 
metastatic disease or lesion progression by RECIST.  Patients with clinical benefit may continue 
to be treated with regular 3 month follow-up.. 
 
 
 
Dose modifications for ONC201:  
 
If any subject has unacceptable grade 3 or greater drug-related AE or SAE with dose #1 other than 
hypertension that is controlled with additional medication (e.g. persisting, affecting quality of life, 
or not ameliorated with medical intervention), the patient will be off study.  If 2 or more patients 
experience the same grade 3 or greater study drug-related AE or study drug related SAE the study 
will temporarily stop enrollment and will be analyzed for potential means to prevent or ameliorate 
the side effect and consent form revised.  
 

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Oncoceutics will be contacted regarding approaches to drug-related AE and/or SAE including 
control of episodes of grade 3 or greater hypertension from catecholamine release with additional 
medications. The consent form will be revised to inform future subjects of anticipated new 
potential side effects and patients on study will be informed by telephone or email and re-consented 
at next study visit.  
 
At the present time, no grade ≥ 2 drug-related AEs have been reported in human studies with 
ONC201. For additional information see also ONC201 Investigators Brochure [98]. 
. 
 General Concomitant Medications and Supportive Care Guidelines 
 
Concomitant prescribed medicines will be recorded at study entry and follow-up visits. Any 
history or current anti-hypertension medication within 3 months of study entry will be recorded. 
 
Supportive care with over-the-counter agents are allowed as clinically indicated (e.g. medicine for 
pain and headaches, GI side effects such as nausea, diarrhea, and constipation). If used regularly, 
effort should be made to record such meds as a concomitant medication.  
 
Because of the unknown potential for interaction with ONC201 and dopamine receptor agonist 
medications decreasing efficacy against PC-PG dopamine agonist psychotropic drugs, L-DOPA, 
bromocriptine, metoclopramide are prohibited while on study.  
 
Table 3 lists drugs to be avoided in PC-PG patients (and those using an agent such as ONC201 
that acts via DRD2 to avoid potential interactions or false elevation of normetanepherine or 
metanepherines plasma or urine tests) [102]. 
 
Table 4.   Potential ONC201:DRD2 Medication and Biomarker Test Interactions 
(Reference [102]) 
 
 
 
 
 
Adverse 
    Possible False Elevation#  
Drug class/Medication 
 
Reactions 
Normetanepherine Metanepherines 
Dopamine D2 agonists a 
 
Yes 
 
 
+ 
 
+ 
Norepinepherine reuptake inhibitors b Yes 
 
 
++ 
 
- 
Monoamine Oxidase Inhibitors c  
Yes 
 
 
++ 
 
++ 
Serotonin reuptake inhibitors d 
rare 
 
 
- 
 
- 
Neuromuscular blockere 
 
Yes 
 
 
- 
 
- 
Busipirone 
 
 
 
No 
 
 
- 
 
++ 
Acetaminophen 
 
 
No 
 
 
++ 
 
- 
 
#False elevation: ++ clear increase; + mild increase; - no increase 
a examples: metoclopromide, chloropromazine, prochlorperazine, droperidol 
b tricyclics including amitryptaline, imipramine 
c examples: tranciproamine, moclobemide, phenelzine 
dexamples paroexetine, fluoxetine 
eexamples: succinylcholine, tubocurarine, atacurium 
 
 
 

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6.3. Other therapy while on study  
 
6.3.1 Radiotherapy 
 
Radiation oncology consultation is suggested to facilitate treatment of progressive pain and/or 
neurologic dysfunction in non-target lesions before therapy starts or during treatment. The 
radiation oncologist should also assist in determining whether AE or SAE are radiation-related, 
drug-related, prior-treatment-related, or disease-related. To maintain function and quality of life 
(QOL) all patients will be permitted to have clinically indicated (e.g. pain) radiotherapy of 
indicator and non-indicator lesions after week 6 and continue ONC201 if there are no new 
metastases.   
  
6.3.2 Surgery or Thermal Ablation 
If major surgery or thermal ablation are  done before starting oral ONC201, all side effects should 
have decreased to grade 2 or less before starting therapy and the surgical specialist  or 
interventional radiologist should also assist in determining whether subsequent AE or SAE are 
related to prior surgery or thermal ablation , drug-related, or disease-related.  Similarly, after week 
6 if surgery or ablation of a non-indicator lesion can maintain or improve quality of life, this is 
allowed. 
 
6.3.3. Chemotherapy 
 
Any investigational agents or commercially available chemotherapy agents other than 
corticosteroids should not be administered with the intent to treat the subject's malignancy while 
on ONC201 study drug. Octreotide and zoledronic acid are permitted for treatment of 
neuroendocrine side effects and bone metastases, respectively.  If a patient has persistent and active 
disease> 6 months after starting d1d2 weekly ONC201 dosing and has clinical benefit, then 
rational combination therapy on a case-by-case basis after discussion with PI, and written 
permission from Oncoceutics (study drug supplier), FDA and Cleveland Clinic IRB may be 
considered. Examples of potential additive or synergy include ONC201 with an mTOR inhibitor, 
gemcitabine + bavituximab, or NK cellular therapy to allow a patient to get additional ONC201 
and additional therapy which may improve efficacy. 
 
6.4 
Criteria for Removal from Study 
 
Treatment may continue until one of the following criteria applies: 
 Disease progression with documentation of new metastases, 
 Intercurrent illness that prevents further administration of treatment, 
 The investigator considers it, for safety reasons, to be in the best interest of the subject.  
 Unacceptable quality of life or adverse event(s) such as decline in performance from metastatic 
cancer, seizures, pain, or effects of prior therapy 
 Unacceptable treatment related toxicity, NCI CTC AE version 4.0 Grade 3 or 4 that fails to 
recover to baseline or < Grade 3 in the absence of treatment within 3 weeks  
 Any toxicity or other issue that causes a delay of study drug administration by more than 4 
weeks (i.e. 7 weeks from last dose) 
 Subject decision to withdraw from treatment (partial consent) or from the study (full consent) 

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 Pregnancy during the course of the study for a child-bearing participant 
 Death 
 Principal Investigator temporarily suspends or prematurely discontinues study participation. 
The date and reason for discontinuation must be documented (e.g. non-compliance). Every 
effort should be made to complete the appropriate assessments.  
 
Principal Investigator and Oncoceutics reserve the right to temporarily suspend or prematurely 
discontinue this study. The date and reason for discontinuation must be documented. Every effort 
should be made to complete the appropriate assessments.  
 
6.5 
Duration of Follow Up 
 
Subjects will be followed for toxicity for 30 days after treatment has been discontinued or until 
death, whichever occurs first.  
 
The clinical course of each event will be followed until resolution, stabilization, or until it has been 
determined that the study treatment or participation is not the cause for a maximum of 3 months. 
In other words if attribution is “not ONC201 related”, follow-up of the AE is not needed 
indefinitely for study purposes.  
 
Any unexpected SAE that occurs and is considered to be definite, probable, or possibly ONC201 
related will be recorded and reported within 3 business days to Cleveland Clinic IRB and 
Oncoceutics. Serious adverse events (SAE) that are definite, probable, or possibly ONC201 related 
and still ongoing at the end of the study period will necessitate additional follow-up to determine 
the final outcome. 
 
Serious adverse events that are still ongoing at the end of the study period will necessitate follow-
up to determine the final outcome. Any serious adverse event that occurs after the study period 
and is considered to be possibly related to the study treatment or study participation will be 
recorded and reported immediately. 
 
Subjects will be followed for progression-free survival, and b) overall survival. If a subject decides 
to discontinue ONC201 without progression, contact with subject will be by phone, e-mail, and 
notes from referring physician every 3 months for year 2 of the study, then yearly for a maximum 
of 4 years after completion of ONC 201.  Overall survival will be captured by searching for 
obituaries and/or utilizing the social security death index annually.  
 
 
7.0  
Dose Delays/Dose Modifications and evaluation windows 
 
ONC201 (625 mg po) will be administered Day1, Day 2 weekly (start of week +/- 1 day). 
 
 If ONC201 cannot be taken orally because of illness, supply problems (for example, lost or 
damaged pills), a delay up to 3 weeks until restoration of enteral nutrition and/or obtaining new 
study drug will be considered acceptable.  
 

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If patient is still unable to take oral medication(s) after 3 weeks, the study chair should be 
contacted. If >4week delay, patient will be considered off-study and should get end-of-study 
evaluations.  
 
Evaluation windows: 6week, 3 month and approximately every 3 months after should be within 
10 working days of anticipated date. 
 
8.0 
Adverse Events and Potential Risks  
 
8.1 
ONC201  
 
The following are potential adverse events as detailed in the ONC201 Investigator’s Brochure, 
version 6 (11-2019). 
 
Table 5. Adverse Events I ONC201 Potential  Risks of ONC201 in informed consent form 
based on IB Version 6 dated November 2019. 
 
Frequent (in 100 people receiving ONC201 20 to 35 may have): 
 Fatigue 
 Nausea 
 Headache 
 Vomiting 
Occasional (In 100 people receiving ONC201 10 to 20 may have): 
 Low white blood cells (Leukopenia) 
 Abnormal walking (Gait disturbance) 
 Trouble speaking (Dysarthria) 
 Insomnia  
 High blood sugar (Hyperglycemia) 
 Weakness on one side of the body (Hemiparesis) 
 Low red blood cells (Anemia) 
 Dizziness 
 Muscular weakness 
 Low phosphorous in the blood (Hypophosphatemia) 
 Seizures 
 Diarrhea 
 High liver enzymes (ALT and AST) 
Rare but serious adverse events that were considered related to ONC201(In 100 people 
receiving ONC201, 3 or fewer may have): 
 Encephalopathy 
 Lung Infection (Pneumonia) 

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 Bleeding (Hemorrhage) 
 Blood infection (Sepsis) 
 Tumor Lysis syndrome, a disease caused by cancer cells dying 
 Stroke 
 Trouble breathing (Dyspnea) 
 Respiratory distress 
 Blockage in the intestines (Small bowel obstruction) 
 Death 
Adverse events that have been observed in previous clinical trials of ONC201 that were 
attributed by the investigator as possibly-related or probably-related to ONC201 include, but are 
not limited to fatigue, nausea, headache, vomiting, high blood sugar and low red blood cells. 
 
 
No induction of cell death in normal tissues has been documented in animal studies with ONC201- 
even at exaggerated dosing levels.  This is consistent at early as well as late observation time 
points, suggesting that pro-apoptotic signaling in response to ONC201 is highly selective for tumor 
cells but not normal cells [98].  Clinical pharmacodynamic and preclinical studies in animals show 
that activity of the study drug outlives its systemic exposure (t ½ about 6 hr in mice and 12 hr in 
humans (Figures 3 and 4) [87].  
 
The safety margin (ratio of therapeutic dose to lowest dose with a mild adverse event) of ONC201 
is at least 10-fold in rats and dogs  in GLP toxicology studies[98]. In general, GLP studies with 
oral ONC201 revealed that adverse events associated with exaggerated doses of ONC201 were 
mild and reversible. The only findings that were observed in both rats and dogs were decreased 
activity and decreased food consumption. Weight loss was seen in rats, but not dogs. When (dogs) 
received very large doses of ONC201 intravenously over 30 minutes (30-50 times the RP2D in 
humans), some had vomiting and decreased activity. No observed were seen in dogs that were 
given 25 times the RP2D; no side effects were seen at 50 times the RP2D dose as a 2 hour 
intravenous infusion. These safety data are consistent with the experience in non-GLP studies as 
well as in various experiments in mice and also human cells (bone marrow as well as fibroblasts).  
 
Human experience.  The first-in man trial of ONC201 was completed in fall 2015 and has been 
reported in abstract/poster (AACR-EORTC Nov 8, 2015; table 4)  [93]. In this trial fever was seen 
in 1 patient (table 4). There were no grade 2-4 adverse events at the RP2D.There is 1 report of a 
rash in 2016 in the GBM trial.   
 
8.2 
Definitions  
 
8.2.1 
Adverse Event  
  
An adverse event (AE) is any unfavorable or unintended event, physical or psychological, 
associated with a research study, which causes harm or injury to a research participant as a result 
of the participant’s involvement in a research study. The event can include abnormal laboratory 
findings, symptoms, or disease associated with the research study. The event does not necessarily 

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have to have a causal relationship with the research, any risk associated with the research, the 
research intervention, or the research assessments.  
 
Adverse events may be the result of the interventions and interactions used in the research; the 
collection of identifiable private information in the research; an underlying disease, disorder, or 
condition of the subject; and/or other circumstances unrelated to the research or any underlying 
disease, disorder, or condition of the subject.  
 
8.2.2   Serious Adverse Events  
A serious adverse event (SAE) is any adverse experience occurring at any dose that results in any 
of the following outcomes:  
 Results in death.  
 Is a life-threatening adverse experience.  The term life-threatening in the definition of 
serious refers to an adverse event in which the subject was at risk of death at the time 
of the event.  It does not refer to an adverse event which hypothetically might have 
caused death if it were more severe.  
 Requires inpatient hospitalization or prolongation of existing hospitalization.  Any 
adverse event leading to hospitalization or prolongation of hospitalization will be 
considered as Serious, UNLESS at least one of the following expectations is met: 
o The admission results in a hospital stay of less than 24 hours OR 
o The admission is pre-planned (e.g., elective or scheduled surgery arranged 
prior to the start of the study) OR 
o The admission is not associated with an adverse event (e.g., social 
hospitalization for purposes of respite care. 
However it should be noted that invasive treatment during any hospitalization may fulfill 
the criteria of “medically important” and as such may be reportable as a serious adverse 
event dependent on clinical judgment.  In addition where local regulatory authorities 
specifically require a more stringent definition, the local regulation takes precedent.  
 Results in persistent or significant disability/incapacity.  The definition of disability 
is a substantial disruption of a person’s ability to conduct normal life’s functions. 
 Is a congenital anomaly/birth defect.  
 Is an important medical event.  Important medical events that may not result death, 
be life-threatening, or require hospitalization may be considered a serious adverse 
experience when, based upon appropriate medical judgment, they may jeopardize the 
subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
disease or disorders, or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. The development of a new cancer is 
always considered an important medical event. 
 
 
 
8.2.3 Adverse Event Evaluation  
 

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The investigator or designee is responsible for ensuring that all adverse events (both serious and 
non-serious) observed by the clinical team or reported by the subject which occur after the subject 
has signed the informed consent are fully recorded in the subject’s medical records. Source 
documentation must be available to support all adverse events.  
 
A laboratory test abnormality considered clinically relevant should be reported as an adverse event.   
 
The investigator or sub-investigator (treating physician if applicable) will provide the following 
for all adverse events (both serious and non-serious): 
 Event term (as per CTCAE) 
 Description of the event 
 Date of onset and resolution 
 Expectedness of the toxicity 
 Grade of toxicity  
 Attribution of relatedness to the investigational agent- (this must be assigned by an 
investigator, sub-investigator, or treating physician) 
 Action taken as a result of the event, including but not limited to; no changes, dose 
interrupted, reduced, discontinued, etc. or action taken with regard to the event, i.e. no 
action, received medication or other intervention, etc. 
 Outcome of event 
 
Descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 4 will be utilized for AE reporting.  
 
An expected adverse event is an event previously known or anticipated to result from 
participation in the research study or any underlying disease, disorder, or condition of the subject. 
The event is usually listed in the Investigator Brochure, consent form or research protocol.  
 
An unexpected adverse event is an adverse event not previously known or anticipated to result 
from the research study or any underlying disease, disorder, or condition of the subject.  
 
Attribution is the relationship between an adverse event or serious adverse event and the study 
drug.  Attribution will be assigned as follows: 
 Definite – The AE is clearly related to the study drug. 
 Probable – The AE is likely related to the study drug. 
 Possible – The AE may be related to the study drug. 
 Unlikely – The AE is doubtfully related to the study drug. 
 Unrelated – The AE is clearly NOT related to the study drug. 
 
Protocol must specify if attribution is required for individual components of the treatment regimen 
or the treatment regimen as a whole. 
 
8.3  
SAE Report Form 
SAEs will be recorded on the FDA Form 3500A (MedWatch) but should only be reported as 
instructed below.  The electronic FDA SAE reporting forms should not be used.   
 

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8.4  
Reporting Procedures for Serious Adverse Events 
For the purposes of safety reporting, all adverse events will be reported that occur through 30 days 
after the final dose of study drug. Adverse events, both serious and non-serious, and deaths that 
occur during this period will be recorded in the source documents.  
 
All SAEs should be monitored until they are resolved or are clearly determined to be due to a 
subject’s stable or chronic condition or intercurrent illness(es). Related AEs will be followed until 
resolution to baseline or grade 1 or stabilization.  
 
8.4.1 SAE Reporting Requirements 
 
Participating investigators must report all grade 2 serious adverse events to the Principal 
Investigator within 24 hours of discovery or notification of the event. The participating 
investigator must also provide follow-up information on the SAE until final resolution. 
  
 
Peter M. Anderson MD, PhD   Principal Investigator 
Cleveland Clinic, Pediatric Hematology/Oncology and Bone Marrow Transplant 
9500 Euclid Ave, Cleveland OH 44195 
 
  
 
 
  
 
 
 
 
 
.  
The Principal Investigator will review the SAE and report the event to the Cleveland Clinic IRB, 
Oncoceutics, and FDA as applicable. It is the PI responsibility to ensure that grade ≥2 AE and SAE 
are reported to the Cleveland Clinic IRB according to the local IRB’s policies and procedures in 
reporting adverse events.  
 
Although this is an investigator-initiated IND study, the PI will provide information to Oncoceutics 
in a timely manner (3-5 working days) which may impact analysis of safety and/or efficacy in 
other concurrent clinical trials of ONC201.  
 
 
Institutional Review Board Reporting Requirements: 
 
 The principal investigator or designate will report adverse events to the Cleveland Clinic 
IRB according to policies and procedures for reporting adverse events.  
 
8.5 
SAEs and OnCore 

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 All SAEs will be entered into OnCore and into an IND compliant database  
 A copy of the SAE form(s) submitted to the sponsor-investigator is also uploaded into 
OnCore and the IND compliant database (REDCap). 
 
8.6  
Data Safety and Toxicity Committee (DSCT) 
 
It is the responsibility of the PI to ensure that ALL SAEs occurring on this trial are reported to the 
Case Comprehensive Cancer Center’s DSCT. This submission is simultaneous with their 
submission to the sponsor and/or other regulatory bodies.  
 
The sponsor-investigator is responsible for submitting an annual report to the DSTC as per CCCC 
Data and Safety Monitoring Plan. 
  
8.7 
Data and Safety Monitoring Plan (DSMP) 
This protocol will adhere to the policies of the Case Comprehensive Cancer Center Data and 
Safety Monitoring Plan in accordance with NCI guidelines.   
 
9.0 
PHARMACEUTICAL INFORMATION 
  
Investigational Agent:  ONC201; Other Name: TIC10 
 
Product description: 125 mg capsules 
The investigational drug product is a hydroxypropyl methylcellulose (HPMC) capsule filled with 
ONC201 dihydrochloride, intended for oral administration.  Excipients can include 
microcrystalline cellulose. Each capsule of drug product contains the equivalent 125mg of 
anhydrous ONC201 free base. This corresponds to ~150mg of drug substance that corrects for the 
ONC201 dihydrochloride salt and moisture. 
 
Storage requirements: ONC201 is stable at room temperature as capsules.  
 
Stability: The ONC201 drug product capsules are stored in a multi-dose container. Capsules are 
packaged in high-density polyethylene (HDPE) white opaque bottles, with an induction seal and 
capped with a white ribbed SecuRx® polypropylene (PPE) cap.  
 
Route of administration: oral  
 
Drug Procurement: ONC201 will be supplied for this study by Oncoceutics (610-613-4891). 
 
Packaging and labeling: The ONC201 drug product capsules are 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.  
 
Drug Accountability: The investigator or designated study personnel are responsible for 
maintaining accurate dispensing records of the study drug. All study drugs must be accounted for, 
including study drug accidentally or deliberately destroyed. Under no circumstances will the 

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investigator allow the investigational drug to be used other than as directed by the protocol. 
Cleveland Clinic Investigational Pharmacies will be responsible for drug storage, dispensing 
ONC201 for study use and compound preparation and dispensing of solution, and drug 
accountability of patients enrolled at Cleveland Clinic.  
 
Drug Destruction: At the completion of the study, there will be a final reconciliation of drug 
shipped, drug consumed, and drug remaining. This reconciliation will be logged on the drug 
reconciliation form, signed and dated. Any discrepancies noted will be investigated, resolved, and 
documented prior to return or destruction of unused study drug. Drug destroyed on site will be 
documented in the study files. 
 
Other Information:  
Drug containers will be labeled “ONC201 Study Drug- for Investigational Use ONLY” 
 Initial supply of ONC201 will be supplied by Cleveland Clinic investigational pharmacy 
Doses will be supplied (capsules) and study personnel will provide a calendar with 
recommended dates of d1, d2 administration until next scheduled follow-up at 6 weeks (60 
pills). 
 Subsequent ONC201 doses Patients with stable disease and responding patients (SD, PR, 
or CR) will be supplied with 140 pills for 4 cycles of 625 mg (10 capsules weekly with a 
calendar and drug /symptom diary for a total of 140 capsules before next imaging time 
point). The additional study drug supplies will be given after review of study radiologic 
evaluations at study visits and determination of continuing SD, PR or CR status.   
 
Because of interval growth between initial on study scan and 6 weeks, patients with new RECIST 
progression or new metastases at 6 weeks and are asymptomatic may elect to remain on study. 
However, interval increase in sum of longest diameters of existing or new lesions between week 
6 and 3 months using RECIST will be considered progressive disease.   If imaging is stable or PR 
or CR, continuation supply may be sent to the patient by investigational pharmacy via express 
courier with tracking information and study personnel will review drug accountability log sent by 
patient to PI or research nurse with the patient by phone or virtual (video) visit.  
 
10.0 
EXPLORATORY STUDY 
 
10.1 
Exploratory Study: Neuroendocrine biomarkers and PK/PD 
Biomarkers expressed by individual patient’s neuroendocrine tumors will be determined at time 
of study entry.  
 
10.1.2   Rationale for Analysis 
Analysis will provide clinical experience, including neuroendocrine biomarkers and efficacy, that 
may possibly be useful future clinical trials with ONC201. 
 
10.1.3 Collection of Specimens 
Most specimens are routine clinical care and are analyzed in Cleveland Clinic Laboratory 
Medicine facilities (cbc, chemistries, urine VMA/HVA, dopamine, normetanepherine, 
metanepherines, bombesin, etc.).  
 

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10.1.4 Handling of Specimens 
Biomarker specimens are routine clinical care. 
 
10.1.5 Analytical Laboratory:  
Biomarker specimens are routine clinical care 
. 
  
10.2  
Correlative Study: Banking of plasma for future studies 
Plasma will be banked for future correlative studies to include potential genetic and epigenetic 
biomarker analysis, ctDNA analysis, TRAIL, and DR family expression.  
 
10.2.1 Rationale for Analysis 
Analysis to identify novel molecular classifiers and circulating biomarkers to inform future clinical 
trials with ONC201. 
 
10.2.3 Collection of Specimens 
1. Obtain 10 ml venous blood by standard phlebotomy technique from a peripheral access 
point or from a central line by trained study personnel into BD Vacutainer EDTA tubes, 
Cat# 366643. 
2. Invert tube gently after collection several times after collection. 
 
 
3. Transport the tube immediately to M3-029 (Mian) laboratory. Time between draw and 
start of laboratory processing should not exceed 1 h. Note: Total processing time not to 
exceed 3 hours. (if anticipating longer processing, blood should be collected in Streck 
cfDNA preservative tubes [Cell-Free DNA BCT 6-Tube Pack (RUO) 
218961]) 
 
10.2.4 Handling and Storage of Specimens 
1. Upon arrival in the laboratory, spin tubes at 900 x g  for 10 min at room temperature. 
2. Transfer supernatant to a 15 ml or 50 ml or tube without disturbing the cellular layer 
using a 10 ml pipette. 
3. An optional second 900 g spin in a new 15 ml conical tube is preferred for removal of 
residual erythrocytes and mononuclear cells. 
4.  
5. Aliquot ~1.05 ml plasma form the large tube to a 1.5 ml tubes.  
6. Spin tubes at 16,000 g (~13,500 rpm) for 10 min at room temperature.  
 
 

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7. Transfer two times 1 ml of plasma from the 1.5 ml tube to a fresh 1.5-2 ml cryovial 
(Fisher) tube without disturbing the pellet. 
 
 
Labeling of tubes  
Tubes for plasma collection are labeled as follows: 
Patient ID, Tube Number, e.g. 1..n; Date, e.g. Sept 1, 2016;Volume e.g. 1.0 ml  
Storage: Plasma vials are stored at  -80ºC in a 81 well freezer storage box.  
 
10.2.5 Research and Analytical Laboratory 
Translational Hematology and Oncology (THOR) Lab : Omar Y. Mian, MD, PhD 
9500 Euclid Ave - 
Cleveland, OH 44195 
 
11.0  STUDY PARAMETERS AND CALENDAR  
 
11.1 
Study Parameters. 
 
11.1.1 Screening Evaluation  
This will be done by the subject’s primary oncologist or principal investigator or co-investigator. 
 
The screening evaluation should be done within 4 weeks of anticipated first dose of ONC201 (if 
eligible). See Table 5 (next page).  
 
Information to be obtained for eligible patients includes: 
 CBC with differential 
 LFT (bilirubin, ALT, AST, total alkaline phosphatase) 
 BUN and creatinine 
 PC-PG: normetanepherine, metanepherines, chromogranin 
 Other clinically indicated markers depending on neuroendocrine tumor type (for example 
urine VMA/HVA, plasma dopamine, or bombesin)   
 Measurement of least one detectable lesion (CT or MRI, or PET-CT or PET-MRI) 
 Determination of Karnofsky performance status 
 Review of prior hypertension medication and eligibility criteria with study coordinator 
 
If there are questions of whether a patient is eligible, the oncologist should discuss with Dr. Peter 
Anderson (
)  
 
11.1.2 Treatment Period 
ONC201 administration should begin within 3 weeks of registration. Labs and imaging windows 
once enrolled are +/- 2 weeks. Weekly ONC201 study drug dosing +/- 1 day.  
On study tumor measurements should be within 3 weeks of registration. 

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11.2 
Study Calendar  
 
Table 6. ++Observations to be Reviewed at Study Entry and Time Points 
 
Study Entry Observation        wk6 
 
3mo 
every 3 months 
Off therapy  
*KPS, bp* 
 
 
x 
 
x 
x 
 
 
*Labs and biomarkers^ 
x 
 
x 
x 
 
 
AE# and SAE  
 
x 
 
x 
x 
 
 
x 
 
Imaging Response**  
x 
 
x 
x 
 
 
Symptom + Drug diary 
x 
 
x 
x 
 
Clinical benefit assessment 
x 
 
x 
x 
 
Survival (PFS and OS)## 
x 
 
x 
x 
 
 
x 
 
++face-to-face review is strongly encouraged. However, because COVID-19 causing travel and 
lodging difficulties, after discussion with PI on a case-by-case basis, written informed consent (see 
section 13.2.1) , clinical AE, scan measurement review, and lab review can be done using virtual 
visits and documented in EPIC in prior to study entry and at week 6, 12 and every 3 months prior 
to ordering ONC201 drug dispensing by investigational pharmacy using express courier with 
tracking. 
 
*Karnofsky performance status (KPS), blood pressure (bp): if PC-PG, use of wireless cuff to EPIC 
via MyChart encouraged (order as “connected bp” in EPIC).  Labs: cbc with differential, chemistry 
panel 
 ^biomarkers: as clinically indicated depending on tumor type may include plasma free 
normetanepherine, metanepherines, chromogranin; if neuroblastoma urine VMA/HVA, dopamine, 
serotonin, 5-HIAA 
 
 BCT tube/plasma for ccfDNA  and ccfRNA storage pre, Week 6, and 3 months 
#Grade ≥2 AE; any SAE**Tumor measurements (see section 12) 
 sum of longest axis diameters of solid tumors 
sum short axis of involved lymph nodes 
sum of products of perpendicular diameters for brain tumors  
 
CT or MRI as per RECIST criteria [120].  
 
PET-CT or PET-MRI:  change in SUV on PET.CT or PET-MRI compared to baseline at 6 weeks, 
months 3,12 months and then yearly.   
 
Clinical benefit: Karnofsky performance status ≥60%, and no new metastases (mixed response 
continued SD, PR, or CR) 

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## PFS: progression-free survival as per RECIST; OS: overall survival- year 2-5 by phone, email 
or notes from referring physician.  
 
 
12.0  MEASUREMENT OF EFFECT  
 
Antitumor Effect – Solid Tumors 
For the purposes of this study, subjects should be re-evaluated for imaging response at 6 weeks 
and every 3 months +/- 2 week (maximum 10 working days).  
 
Imaging responses and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guidelines (version 1.1, ref [120]) [Eur J Ca 45:228-247, 2009]. Changes in the largest diameter 
(unidimensional measurement) of the tumor lesions and the shortest diameter in the case of 
malignant lymph nodes are used in the RECIST criteria (table 6).  
 
 
Definitions 
Evaluable for toxicity (Grade ≥2 AE and SAE): All subjects will be evaluable for toxicity from 
the time of their first treatment with ONC201. 
 
Evaluable for objective response: Only those subjects who have measurable disease present at 
baseline, have received at least 6 doses of ONC201, and have had their disease evaluated at weeks 
6 and 3 months will be considered evaluable for response. These subjects will have their response 
classified according to the definitions stated below. Patients with mixed responses and/or 
documented progression at week 6 and thereafter will be allowed to stay on study after discussion 
of indications, risks, and alternatives with their treating oncologist. 
 
Evaluable Non-Target Disease Response: Subjects who have lesions present at baseline that are 
evaluable, but do not meet the definitions of measurable disease, have received at least 6 doses of 
ONC201, 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 for non-nodal lesions and short axis for nodal lesions 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). Bone lesions are considered measurable if there is corresponding 18FDG uptake on 
PET-CT or PET-MRI with SUV ≥5 and size is ≥10mm. Tumor lesions that are situated in a 
previously irradiated area are considered to be considered measurable if there is recent change in 
size of character of the lesion and/or there is 18FDG uptake on PET-CT or PET-MR consistent 
with active disease (e.g. SUV≥5).  
 

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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. Clinical correlation with 18FDG-PET-CT or PET MRI is highly recommended.  
 
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. Leptomeningeal disease, ascites, pleural or pericardial effusions, 
lymphangitis cutis, pneumonitis, 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. ‘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 subject, these are preferred for selection as target lesions. 
 
Target /indicator 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 or indicator 
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 reproducible 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: Other lesions (or sites of disease) including any measurable lesions over and 
above the 5 target lesions should may identified as additional non-target lesions and 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 at 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. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and > 10 mm diameter as assessed using calipers 

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(e.g., skin nodules). In the case of skin lesions, documentation by color photography including a 
ruler to estimate the size of the lesion is recommended. 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable. Conventional 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). 
 
Use of MRI remains a complex issue. 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 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-holding 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 is not routine 
or serially performed. 
 
Ultrasound: Ultrasound is not reproducibly useful in assessment of lesion size and should not be 
used a method of measurement. If there is concern about radiation exposure at CT, MRI may be 
used instead of CT in selected instances. 
 
Tumor markers: Tumor markers trends alone cannot be used to assess response.  
FDG-PET: While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in assessment 
of progression (particularly possible ‘new’ disease and/or appearance of new metastases). New 
lesions on the basis of FDG-PET imaging can be identified according to the following algorithm:  
 
a. Negative FDG-PET at baseline with a positive FDG-PET at follow-up is often evidence of 
progressive disease (PD) based on a new lesion. If possibly a false positive, biopsy or resection 
may be required for confirmation of new metastatic disease. 
 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive FDG-

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PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up CT or MRI 
scans are needed to determine if there is truly progression occurring at that site (if so, the date of 
PD will be the date of the initial abnormal FGD-PET scan). If the positive FDG-PET at follow-up 
corresponds to a pre-existing site of disease on CT that is not progressing on the basis of the 
anatomic images, this is not PD. 
 
c. FDG-PET may be used to upgrade a response to a complete response (CR) in 
a manner similar to a biopsy in cases where a residual radiographic abnormality is thought to 
represent fibrosis or scarring. Note: A ‘positive’ FDG-PET scan lesion means one which is FDG 
avid with an initial uptake greater than twice that of the surrounding tissue on the attenuation 
corrected image. 
 
Table 7.  Response Criteria and Evaluation of Solid Tumor Target Lesions (RECIST) 
Measurements: Longest Diameters in Target Lesions* + SUV 
 
Response                
 
Evaluation of Effect in Target Lesion  
Complete Response (CR) 
Disappearance or fibrosis of all target lesions. Any pathologic 
lymph nodes must have reduction in short axis to <10mm and have 
SUV is <4. 
  
Partial Response (PR) 
At least 30% decrease in sum of longest diameters of target lesions 
(compared to initial on study baseline) and any decrease in SUV in 
18FDG imaging 
 
Stable disease (SD) 
0-29% decrease in sum of longest diameters of target lesions 
(compared to initial on study baseline) or 
 
0-19% increase in sum of longest diameters of target lesions 
(compared to initial on study baseline). SUV may increase or 
decrease 
 
Progressive disease 
20% or more increase of sum of longest diameters of target lesions 
(compared to initial on study baseline). The sum must also be at an 
increase of at least 5mm   or one or more new lesions that are 
considered metastatic disease (e.g. high SUV) in the setting of 
rising biomarkers   
 
*At study entry identify 5 or fewer target lesions and sum the longest diameters. This is the 
number to be used.  Lymph nodes: shortest dimension 
 
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 subject’s best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
 

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13.0 
DATA REPORTING / REGULATORY CONSIDERATIONS  
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 8.0 
(Adverse Events: List and Reporting Requirements). 
 
13.1 
Data Reporting  
The OnCore™ Database will be utilized, as required by the Case Comprehensive Cancer Center, 
to provide data collection for both accrual entry and trial data management. OnCore™ is a Clinical 
Trials Management System housed on secure servers maintained at Case Western Reserve 
University. OnCore™. Access to data through OnCore™ is restricted by user accounts and 
assigned roles. Once logged into the OnCore™ system with a user ID and password, OnCore™ 
defines roles for each user which limits access to appropriate data. User information and password 
can be obtained by contacting the OnCore™ Administrator at OnCore-registration@case.edu. 
 
OnCore™ is designed with the capability for study setup, activation, tracking, reporting, data 
monitoring and review, and eligibility verification. This study will utilize electronic Case Report 
Form completion in the OnCore™ database. A calendar of events and required forms are available 
in OnCore™. 
 
An IND compliant database (REDCap) similar to other Oncoceutics ONC201 trials also be used. 
 
13.2 
Regulatory Considerations 
The study will be conducted in compliance with ICH guidelines and with all applicable federal 
(including 21 CFR parts 56 & 50), state or local laws. 
13.2.1 Written Informed consent 
Provision of written informed consent must be obtained prior to any study-related procedures. The 
Principal Investigator will ensure that the subject is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study as well as the 
subject’s financial responsibility. Subjects must also be notified that they are free to discontinue 
from the study at any time. The subject should be given the opportunity to ask questions and be 
allowed time to consider the information provided. The original, signed written Informed Consent 
Form must be kept with the Research Chart in conformance with the institution’s standard 
operating procedures. A copy of the signed written Informed Consent Form must be given to the 
subject. Additionally, documentation of the consenting process should be located in the research 
chart. The informed consent discussion may be done virtually with the subject and PI having the 
same version of printed consent form and signing the signature page during the discussion. The PI 
and subject will exchange electronic versions of the signature page (JPEG or pdf via email) and 
printed versions of signature pages containing both signatures will be retained for study records. 
The consent discussion will be documented in EPIC. 
13.2.2 Subject Data Protection 
In accordance with the Health Information Portability and Accountability Act (HIPAA), a subject 
must sign an authorization to release medical information to the sponsor and/or allow the sponsor, 
a regulatory authority, or Institutional Review Board access to subject’s medical information that 
includes all hospital records relevant to the study, including subjects’ medical history.  

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13.2.3  Retention of records 
The Principal Investigator of The Case Comprehensive Cancer Center supervises the retention of 
all documentation of adverse events, records of study drug receipt and dispensation, and all IRB 
correspondence for as long as needed to comply with local, national and international regulations. 
No records will be destroyed until the Principal Investigator confirms destruction is permitted.  
 
13.2.4  Audits and inspections  
Authorized representatives of the sponsor, a regulatory authority, an Independent Ethics 
Committee (IEC) or an Institutional Review Board (IRB) may visit the site to perform audits or 
inspections, including source data verification. The purpose of an audit or inspection is to 
systematically and independently examine all study-related activities and documents to determine 
whether these activities were conducted, and data were recorded, analysed, and accurately reported 
according to the protocol, Good Clinical Practice (GCP), guidelines of the International 
Conference on Harmonization (ICH), and any applicable regulatory requirements.   
 
14.0  STATISTICAL CONSIDERATIONS  
 
This study is a phase 2 trial of ONC201 in patients 14years and older who have neuroendocrine 
tumors.  Cohort C will have had 2x drug exposure as the initial cohorts A and B.  
 
The study population will include neuroendocrine cancers including PC-PG because this group 
has the highest expression or DRD2 of all tumors in the TCGA data set. If DRD2 receptor 
binding is important we would expect to see clinical benefit (CR + PR + stable disease at 6 
weeks and 3 months or longer plus maintenance of Karnofsky performance status >60). Data 
will be presented as not only numbers of CR + PR + stable disease at time points, but also 
duration of lack of progression (clinical benefit). Objective responses will be defined using CT 
or MRI and RECIST criteria. PET-CT, and/or PET-MRI will be used to assess metabolic 
responses. Changes in sum of longest diameters and SUV of indicator lesions identified using 
CT or MRI will be determined. Clinical (therapeutic) benefit is a non-linear quality (yes or no) 
that requires a) maintenance of performance (≥60% Karnofsky), and b) no new metastases 
(SD+PR+CR).  Because of possibility of responses in subsets of patients, this trial may provide 
the first positive indication of efficacy in rare tumors  but is not powered for subset analysis.   
 
Cohorts A+B have met initial efficacy endpoints for both PC-PG and “other neuroendocrine”, 
respectively; a clinical benefit rate of 25% (3/12 or more CR+PR+SD at 3 months was seen - 
see table 3 . However additional efficacy with more PR and longer SD are desired. Therefore, 
because of safety in other trials, the day1d2 weekly dosing of ONC201 is worthy of additional 
study in neuroendocrine tumor patients including current stable patients with continued 
metastases as well as additional patients with neuroendocrine tumors. 
 
A secondary goal of the trial is to evaluate the clinical effectiveness of ONC201 in patients with 
PC-PC and other neuroendocrine tumors by assessing PFS and OS. Results will be depicted in 
tabular form and as Kaplan-Meier survival curves.  
 
 

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ONC201 Toxicity Monitoring:  Stopping Rule Guidelines  
 
Although ONC201 is expected to be safe and tolerable, toxicity will be monitored continuously 
and the following guidelines will be used to trigger consideration of early closure due to toxicity. 
If any patient has any grade 3 or greater AE including hypertension or symptoms related to 
catecholamine excess subsequently controlled with increase of alpha+ beta blockade, the study 
PI is to be notified and if this is drug-related toxicity the circumstances will investigated and 
analysis of methods and means to prevent/reduce toxicity will be discussed and implemented.  
 
If 2 or more patients experience unanticipated drug-related grade 3 or greater toxicity except 
hypertension, Oncoceutics, IRB, and FDA will be notified and consent form changed to reflect 
potential for this new side effect.  
 
Biomarker exploratory objective: blood biomarkers will include clinically relevant biomarkers. 
Analysis will be done as a) descriptive tables at pre, week 6, 3 months and subsequent time 
points b) for biomarkers of 3 or more mean, median and SSD pre vs time points, and most 
importantly, c)  within group comparison (patients as their own control) comparing biomarker 
change from before treatment as a function of time.  Percentage change from pre-therapy will 
be determined and significance of change pre vs at 6 weeks and 3 months, and longer will be 
compared as well as patients with both once/week and d1D2 weekly dosing.   
 
Results of objective responses (CR, PR + stable disease), AE/SAE, hypertension medicine 
tapering, and biomarker trends will be shared as tables with Case Comprehensive Cancer 
Center Protocol Research Monitoring Committee and Oncoceutics on a quarterly basis and 
FDA on a yearly basis. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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