Clinical trial NCT02863991
Conditions: Multiple Myeloma
Sponsor: Chimerix
Start date: 2017-04-19; Completion date: 2019-12-16
Enrollment: 17 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This was a Phase 1/2 open-label study of ONC201 administered orally once every week in combination with dexamethasone in adults with relapsed/refractory multiple myeloma. The primary objective of this study was to evaluate the antitumor efficacy of ONC201.

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

Detailed description:
In Phase 1 of the study, patients were to receive 375 or 625 mg ONC201 once every week in combination with dexamethasone using a 3+3 dose escalation design to evaluate up to 625 mg ONC201 weekly with 20 mg dexamethasone. In Phase 2 of the study, patients were to receive 625 mg ONC201 once every week. Dexamethasone was to be administered at a dose determined in Phase 1.

A treatment cycle was defined as 3 weeks. The dose-limiting toxicity window was defined as the first 3 weeks of treatment (i.e., 1 cycle). Patients may have continued treatment with ONC201 until disease progression, occurrence of an unacceptable adverse event, intercurrent illness or changes in the patient's condition rendered the patient unacceptable to continue, patient decision to withdraw from the study, or discontinuation of the study by the Sponsor.

Assessments of tumor response were conducted using the International Myeloma Working Group response criteria. Safety was assessed through the reporting of adverse events, measurement of vital signs, electrocardiograms, and clinical laboratory results.

Before the study was terminated, a total of 17 patients were enrolled and treated with ONC201: 2 patients received 375 mg ONC201 and 15 patients received 625 mg ONC201.

Arms: arm 1: Patients received 375 mg ONC201 once every week in combination with dexamethasone. arm 2: Patients received 625 mg ONC201 once every week in combination with dexamethasone.
Interventions: intervention 1: ONC201 intervention 2: Dexamethasone
Intervention descriptions: intervention 1: 375 mg or 625 mg ONC201 intervention 2: 20 mg dexamethasone

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Title: Oral ONC201 in Relapsed/Refractory Multiple Myeloma 
Protocol Number: ONC007 (NCT02863991) 
Protocol Date: 12 February 2018 (Version 7.0) 


Oncoceutics, Inc. 
Protocol ONC007 
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Protocol Title: Oral ONC201 in Relapsed/Refractory Multiple Myeloma 
 
 
Protocol Number: 
ONC007 
Protocol Version/Date: 
Version 07 / 02-12-2018 
Sponsor: 
Oncoceutics, Inc. 
3624 Market Street, Suite 5E 
Philadelphia, PA 19104 
 
 
Principal Investigator: 
Carolyn Tan, MD 
Fox Chase Cancer Center 
Philadelphia, PA 
 
Sub Investigator: 
Ajai Chari, MD 
Mt Sinai Medical Center 
New York, NY 
 
 
 
CAUTION: Investigational New Drug 
 
 
This document is a protocol for a human research study. This study is to be conducted 
according to the protocol, and applicable government regulations and Institutional research 
policies and procedures. No deviation from the protocol will be implemented without the prior 
review and approval of the IRB except where it may be necessary to eliminate an immediate 
hazard to a research subject. In such case, the deviation will be reported to the IRB according to 
its policies and procedures. 
 
 
Limited by Federal (or United States) Law to Investigational Use 
 
 
The information contained in this protocol is the confidential property of the Sponsor. It is 
intended solely for the recipient clinical investigator(s) for the purposes of conducting the clinical 
study, and may not be reproduced or disclosed to third parties without proper authorization from 
the Sponsor. 


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Protocol Synopsis 
 
Proposed Indication: 
Oral ONC201 is intended for treatment of adult patients with relapsed/refractory multiple 
myeloma for whom no standard therapy is available. 
 
Rationale: 
ONC201 is an orally bioavailable first-in-class small molecule with demonstrated antitumor 
activity in preclinical models of difficult-to-treat solid and liquid tumors without imparting 
significant toxicity. Multiple myeloma has been selected for evaluation in this trial based on 
preclinical efficacy as well as the mechanism of action of ONC201 that involves engagement of 
the integrated stress response that leads to downstream inactivation of Ras signaling and 
induction of the TRAIL pathway. 
 
Objectives and endpoints 
 
Primary Objective 
• 
Determine the antitumor efficacy of ONC201 in combination with dexamethasone. 
 
Secondary Objectives 
• 
Evaluate the overall safety profile of ONC201 in combination with dexamethasone. 
• 
Assess the pharmacodynamic (PD) effects of ONC201 in combination with 
dexamethasone. 
• 
Assess effect of ONC201 in combination with dexamethasone on survival endpoints. 
 
 
Primary Endpoint 
• 
Overall response rate (ORR) using the International Myeloma Working Group response 
criteria. 
 
Secondary Endpoints 
• 
Overall safety profile of ONC201 as characterized by type, frequency, severity, timing 
and relationship to study therapy of adverse events and laboratory abnormalities. 
• 
Effects of ONC201 on pharmacodynamic (PD) markers. 
• 
Effects of ONC201 on survival endpoints (i.e., progression-free survival, time to 
progression, and duration of response). 
 
Study design 
This is a Phase 1/2 open-label study of ONC201 administered orally once every week in 
combination with dexamethasone to patients with relapsed/refractory multiple myeloma. 
 
In Phase 1 of the study, patients will receive 625 mg ONC201 once every week in combination 
with dexamethasone using a 3+3 dose escalation design that will evaluate up to 625mg 
ONC201 weekly with 20mg dexamethasone. Three weeks is defined as a treatment cycle. 


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Phase 1 of the study will involve a safety cohort of at least 6 relapsed/refractory multiple 
myeloma patients who will receive ONC201 and dexamethasone. 
 
In Phase 2 of the study, patients will receive 625mg ONC201 once every week. 
Dexamethasone will be administered at a dose determined in Phase 1. Patients may not cross 
over from Phase 1. Tumor assessments will be conducted using the International Myeloma 
Working Group response criteria. The study plans to enroll 42 patients over a period of 2 years. 
 
 
Eligibility criteria 
Inclusion 
1. Patients must be refractory to, or not a candidate for, established therapy known to 
provide clinical benefit for their malignancy. 
2. Measurable disease M protein component in serum (at least 0.5 g/dL) and/or urine (if 
present) (>=0.2 g excreted in a 24 hour collection sample), or serum free light chain level 
≥10 mg/dL, provided the serum free light chain ratio was abnormal. 
3. Able to swallow and retain oral medication. 
4. All previous therapies for cancer, including radiotherapy, major surgery and 
investigational therapies discontinued for ≥ 14 days (≥ 28 days for mitomycin C or 
nitrosoureas) before study entry, and all acute effects of any prior therapy resolved to 
baseline severity or Grade ≤ 1 Common Terminology Criteria for Adverse Events 
(CTCAE v4.03), except alopecia or parameters defined in this eligibility list. 
5. Age ≥ 18 years. 
6. ECOG performance status ≤ 1. 
7. Adequate organ and marrow function as defined below: 
a. Absolute neutrophil count 
≥1,000/mm3 without growth factor use ≤ 7 days 
prior to treatment (cycle 1 day 1, C1D1) 
b. Platelets 
≥50,000/mm3 without platelet transfusion ≤ 3 
days prior to C1D1 
c. Hemoglobin 
>8.0 mg/dL without red blood cell transfusion ≤ 3 
days prior to C1D1 
d. Total serum bilirubin 
<1.5 X upper limit of normal (ULN); subjects  with 
>1.5X upper limit of normal require approval of medical monitor. 
e. AST (SGOT)/ALT (SGPT) 
≤2 X ULN; ≤ 5 X ULN if there is liver involvement 
secondary to tumor 
f. 
Serum creatinine 
≤ 1.5 X ULN (OR creatinine clearance ≥ 30 
mL/min/1.73 m2) 
g. Serum or urine pregnancy test (for females of childbearing potential) negative 
≤7 days of starting treatment 
8. Ability to understand and the willingness to sign a written informed consent document 
and comply with the study scheduled visits, treatment  plans,  laboratory  tests  and 
other procedures. 
9. Female patients must be surgically sterile or be postmenopausal, or must agree to   
use effective contraception during the period of the trial and for at least 90 days after 
completion of treatment. Male patients must be surgically sterile or must agree to use 
effective contraception during the period of the trial and for at least 90 days after 


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completion of treatment. The decision of effective contraception will be based on the 
judgment of the principal investigator or a designated associate. 
 
 
Exclusion 
1. Active inflammatory gastrointestinal disease, chronic diarrhea (unless related to 
underlying malignancy or prior related treatment) or history of abdominal fistula, 
gastrointestinal perforation, peptic ulcer disease, or intra-abdominal abscess within 6 
months prior to study enrollment. Gastroesophageal reflux disease under treatment with 
proton pump inhibitors is allowed. 
2. Pregnancy or breast feeding. 
3. Current active treatment in another clinical study. 
4. Active bacterial, fungal or viral infection including hepatitis B (HBV), hepatitis C (HCV) 
5. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome 
(AIDS)-related illness that is not well controlled. 
6. Active or prior plasma cell leukemia (defined as either 20% of peripheral WBC 
comprised of plasma/CD138+ cells or an absolute count of 2 x 10^9/L). 
7. Solitary bone or solitary extramedullary plasmacytoma as the only evidence of plasma 
cell dyscrasia. 
8. Subjects with serum calcium (corrected for albumin) ≥ 12 mg/dL 
9. Any of the following in the previous 6 months: myocardial infarction, severe/unstable 
angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, 
cerebrovascular accident, transient ischemic attack or symptomatic pulmonary 
embolism. 
10. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality 
that may increase the risk associated with study participation or study drug 
administration, or may interfere with the interpretation of study results, or in the judgment 
of the investigator would make the patient inappropriate for entry into the study. 
11. Actively receiving medications that have the risk of Torsades de Pointes or are string 
cytochrome P450 inhibitors or inducers. 
 
Statistical methods 
Overall response rate (ORR) will be determined with the corresponding 95% exact confidence 
interval. Descriptive statistics will be provided for selected demographic, safety, PD and 
biomarker data by dose, dose schedule and time, response rate, and time to progression as 
appropriate. Descriptive statistics on continuous data will include means, medians, standard 
deviations, and ranges, while categorical data will be summarized using frequency counts and 
percentages. 


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SCHEDULE OF ACTIVITIES 
 
Table 1: Schedule of Activities 
 
Examination1 
Baseline 
Cycle 1 
Cycle 
2 
Cycle 
3+ 
Follow 
up2 
Day 
-28 
1 
2& 
3 
8 
15 
1 
1 
1 
Informed Consent 
X 
Medical History 
X 
Inclusion/Exclusion 
Criteria 
X 
X 
Concurrent meds 
X 
X 
X 
X 
X 
Physical exam3 
X 
X 
X 
X 
X 
Performance Status 
(ECOG) 
X 
X 
Vital signs4 
X 
X 
X 
X 
X 
Pregnancy Test 
X 
Urinalysis 
X 
X 
X 
X 
Toxicity Assessment5 
X 
X 
X 
X 
X 
X 
X 
12-Lead EKG6 
X 
X 
X 
X 
Bone Marrow 
Aspiration/Biopsy7 
X 
X 
X7 
X7 
Serum Protein 
Electrophoresis 
X 
X 
X 
X 
X 
 
1 All assessments have a ± 2 business day window, except where specified. 
2 4 weeks (28 days) after off study visit. 
3 Height (baseline only) and weight included. 
4 Blood pressure, HR, temperature and respiratory rate. 
5 Toxicity assessments will be performed at each patient encounter. Baseline signs and symptoms prior to C1D1 
must also be assessed. 
6 EKG assessment performed in triplicate. Cycle 1 day 1 and cycle 2 day 1 will be obtained at 2 hours (+15 minutes) 
post-dose. Cycle 1 day 15 and cycle 2 day 15 will be taken pre-dose 
7 Bone marrow biopsy will be performed within 45 days of cycle 1 day 1. Bone marrow biopsy to be repeated at 
relapse. If possible, repeat bone marrow biopsy 6 hours after the second dose is administered (C1D8). If bone 
marrow biopsy cannot be carried out at any time point, an aspirate will be needed. Restaging should be performed 
within 7 days prior to the scheduled visit date. Bone marrow biopsy will also be performed for suspected complete 
response as per IMWG criteria. 


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Examination1 
Baseline 
Cycle 1 
Cycle 
2 
Cycle 
3+ 
Follow 
up2 
Serum Quantitative 
Immunoglobulins8 
X 
X 
X8 
X8 
X8 
Serum β2-Microglobulin8 
X 
X 
X8 
X8 
X8 
Serum free light chains 
(kappa and lambda) with 
ratio8 
X 
X 
X8 
X8 
X8 
Serum and Urine 
Immunoelectrophoresis8 
X 
X 
X8 
X8 
X8 
24-Hour Urine M-protein 
electrophoresis9 
X 
X 
X9 
X9 
X9 
Urine collection10 
X 
X 
Skeletal X-rays11 
X 
X 
X 
Hematology12 
X 
X 
X 
X 
X 
X 
X 
Serum Chemistry13 
X 
X 
X 
X 
X 
X 
X 
Coagulation Profile14 
X 
X 
X 
X 
Blood draws for PK/PD15 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
8 As needed to evaluate response. In patients with IgD myeloma, IgD levels must be followed if available. 
9 Repeat 24-hour urine M-protein determination monthly in patients who initially had measurable urinary M- 
protein and for whom this is being used in response criteria. Patients who initially lack urine M-protein, or in whom 
the M-protein disappears, must have the 24-hour urine M-protein obtained every 12 weeks. 
Immunoelectrophoresis or immunofixation of serum and urine do not need to be repeated unless the M-spike 
disappears on electrophoresis. 
10 Urine collection: A 24 hour urine will be collected when the patient visits the clinic 24 hours after first dose of 
ONC201 on Cycle 1 Day 2. Spot urine collection will be carried out on Cycle 1 Day 2 and Day 3.. 
11 Including lateral skull, axial skeleton, and long bones. 
12  WBC plus differential, Hgb, PLT. 
13Glucose, BUN, Creatinine, Albumin, AST, ALT, Total bilirubin, Alkaline phosphatase , LDH, Na+, K+, Ca++, 
Phosphate, Uric acid, Magnesium. Eligibility parameters must be met at baseline, but not necessary to meet 
criteria after treatment initiation. 
14 PT/PTT, INR. 
15 Blood draws for PK/PD evaluations: will be collected at baseline and 2 hours, 24 hours, 48 hours, and 72 hours 
after the first dose of ONC201; Cycle 1 Day 8, Cycle 1 Day 15; pre-dose for the first day of cycle 2, cycle 3 and every 
odd cycle beyond cycle 3. Blood will also be collected at the follow-up visit at the end of treatment. 


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Table of Contents 
1 
INTRODUCTION................................................................................................................... 11 
1.1 
Proposed Indication ...................................................................................................................... 11 
1.2 
Background on Study Agent .......................................................................................................... 11 
1.2.1 
Preclinical Efficacy .................................................................................................................. 11 
1.2.2 
Mechanism of Action ............................................................................................................. 15 
1.2.3 
Nonclinical Safety/Toxicology Studies in Animals .................................................................. 16 
1.2.4 
Pharmacokinetic Studies ........................................................................................................ 19 
1.3 
Clinical Studies ............................................................................................................................... 21 
1.4 
Rationale ........................................................................................................................................ 23 
2 
OBJECTIVES AND ENDPOINTS ......................................................................................... 25 
2.1 
Objectives ...................................................................................................................................... 25 
2.1.1 
Primary Objective ................................................................................................................... 25 
2.1.2 
Secondary Objectives ............................................................................................................. 25 
2.2 
Endpoints ....................................................................................................................................... 25 
2.2.1 
Primary Endpoint .................................................................................................................... 25 
2.2.2 
Secondary Endpoints .............................................................................................................. 25 
3 
STUDY DESIGN ................................................................................................................... 26 
3.1 
Overview........................................................................................................................................ 26 
3.2 
Number of Patients ....................................................................................................................... 26 
3.3 
Dose and Planned Scheme ............................................................................................................ 26 
4 
ELIGIBILITY CRITERIA ........................................................................................................ 27 
4.1 
Inclusion ........................................................................................................................................ 27 
4.2 
Exclusion ........................................................................................................................................ 28 
4.3 
Contraception ................................................................................................................................ 28 
5 
STUDY TREATMENTS ......................................................................................................... 29 
5.1 
Drug Supply ................................................................................................................................... 29 


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5.1.1 
Formulation, Packaging and Storage ...................................................................................... 29 
5.1.2 
Drug Accountability ................................................................................................................ 29 
5.2 
ONC201 Administration ................................................................................................................ 30 
5.3 
General Concomitant Medication and Supportive Care Guidelines ............................................. 30 
5.4 
Duration of Therapy ...................................................................................................................... 30 
5.5 
Criteria for Removal from Study .................................................................................................... 31 
5.6 
Dose Limiting Toxicity (DLT) definition .......................................................................................... 32 
6 
DOSING DELAYS/DOSE MODIFICATIONS ........................................................................ 32 
6.1 
Concomitant Medications ............................................................................................................. 34 
6.1.1 
Drug Interactions .................................................................................................................... 34 
6.1.2 
Corticosteroids ....................................................................................................................... 34 
6.1.3 
Anti-emetic Therapy ............................................................................................................... 34 
6.1.4 
Other Anticancer or Experimental Drugs ............................................................................... 34 
6.1.5 
Hematopoietic Growth Factors .............................................................................................. 34 
6.2 
Palliative and Supportive Care ...................................................................................................... 35 
7 
STUDY PROCEDURES........................................................................................................ 35 
7.1 
Baseline ......................................................................................................................................... 35 
7.2 
Trials Period ................................................................................................................................... 36 
7.3 
Treatment ...................................................................................................................................... 36 
7.4 
End of Treatment Visit ................................................................................................................... 36 
7.5 
Follow-up Visit ............................................................................................................................... 37 
7.6 
Patient Withdrawal ....................................................................................................................... 37 
8 
ASSESSMENTS ................................................................................................................... 37 
8.1 
Safety Evaluations ......................................................................................................................... 37 
8.2 
Efficacy Evaluations ....................................................................................................................... 38 
8.3 
Correlative studies ......................................................................................................................... 39 
8.3.1 
Background ............................................................................................................................. 39 
8.3.2 
Biomarkers ............................................................................................................................. 39 
8.3.3 
ONC201 Plasma Concentration .............................................................................................. 39 


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8.3.4 
Blood for immune cell studies ................................................................................................ 39 
8.3.5 
ONC201 urine collection ........................................................................................................ 40 
8.4 
EKG Assessments ........................................................................................................................... 40 
8.5 
Concomitant Medications ............................................................................................................. 40 
9 
ADVERSE EVENT REPORTING.......................................................................................... 41 
9.1 
Adverse Events .............................................................................................................................. 41 
9.2 
Reporting Period............................................................................................................................ 42 
9.3 
Definition of an Adverse Event ...................................................................................................... 42 
9.4 
Abnormal Test Findings ................................................................................................................. 42 
9.5 
Serious Adverse Events ................................................................................................................. 43 
9.6 
Hospitalization ............................................................................................................................... 44 
9.7 
Severity Assessment ...................................................................................................................... 45 
9.8 
Causality Assessment .................................................................................................................... 46 
9.9 
Exposure in utero........................................................................................................................... 46 
9.10 
Withdrawal Due to Adverse Events ............................................................................................ 47 
9.11 
Eliciting Adverse Event Information ............................................................................................ 47 
9.12 
Reporting Requirements ............................................................................................................. 47 
9.12.1 
Serious Adverse Event Reporting Requirements ................................................................. 47 
9.12.2 
Potential Cases of Drug-Induced Liver Injury ....................................................................... 48 
9.12.3 
Non-Serious Adverse Event Reporting Requirements ......................................................... 49 
10 DATA ANALYSIS/STATISTICAL METHODS ....................................................................... 49 
10.1 
Efficacy Evaluation ...................................................................................................................... 49 
10.2 
Futility Analysis ............................................................................................................................ 49 
10.3 
Early Stopping Rules for Safety/adverse events ......................................................................... 50 
11 QUALITY CONTROL AND QUALITY ASSURANCE ............................................................ 50 
12 DATA HANDLING AND RECORD KEEPING ....................................................................... 51 
12.1 
Case Report Forms/Electronic Data Record ................................................................................ 51 
12.2 
Record Retention ........................................................................................................................ 51 
13 ETHICS ................................................................................................................................. 51 


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13.1 
Institutional Review Board (IRB) ................................................................................................. 51 
13.2 
Ethical Conduct of the Trial ......................................................................................................... 51 
13.3 
Patient Information and Consent ................................................................................................ 52 
14 DEFINITION OF END OF TRIAL .......................................................................................... 52 
15 DISCONTINUATION CRITERIA ........................................................................................... 52 
16 PUBLICATION OF TRIAL RESULTS ................................................................................... 52 
17 REFERENCES ..................................................................................................................... 54 
18 APPENDIX ............................................................................................................................ 57 
18.1 
Appendix A: List of Abbreviations ............................................................................................... 57 
18.2 
Appendix B: Performance Status ................................................................................................ 58 
18.3 
Appendix C: Multiple Myeloma Disease Tracking ....................................................................... 59 


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1 
INTRODUCTION 
This study will evaluate the efficacy of ONC201 administered in combination with 
dexamethasone to patients with relapsed/refractory multiple myeloma. The study plans to enroll 
42 patients who will receive ONC201 once every week and will have tumor assessment using 
International 
Myeloma Working Group response criteria. 
1.1 
Proposed Indication 
ONC201 is intended for treatment of adult patients with relapsed/refractory multiple myeloma for 
whom no standard therapy is available. 
1.2 
Background on Study Agent 
ONC201 (TIC10) is an orally bioavailable first-in-class small molecule that directly antagonizes 
DRD2 to activate the integrated stress response (ISR) in tumors cells that leads to downstream 
anticancer effects that include inactivation of prosurvival Akt and ERK signaling along with 
induction and activation of the TRAIL apoptosis pathway (Allen et al., 2013). The efficacy of 
ONC201 has been consistently demonstrated in numerous in vitro and in vivo experiments 
(subcutaneous, orthotopic, and transgenic) by multiple institutions. Despite its strong cytotoxicity 
in tumor cells, ONC201 does not induce cell death in normal cells. In vivo studies indicate that 
the safety margin (ratio of therapeutic dose to lowest dose with a mild adverse event) of 
ONC201 is at least 10-fold in rats and dogs in GLP toxicology studies. The profile of ONC201 is 
well suited for an oncology product: preclinical efficacy with infrequent administration, broad- 
spectrum activity independent of mutations or disease type, orally active, compelling safety 
profile, combines synergistically and safely with many approved therapies, highly active by 
employing a combination of established anti-tumor/pro-apoptotic pathways, highly stable, water 
soluble, and penetrates the blood-brain barrier. In summary, preclinical studies suggest that 
ONC201 is an orally active antitumor agent with a favorable safety profile given its broad- 
spectrum activity demonstrated in a variety of aggressive cancer models. 
1.2.1 
Preclinical Efficacy 
ONC201 induces broad-spectrum cell death in tumor cells harboring diverse mutations in genes 
such as p53, KRAS, Raf, EGFR and others that render resistance to chemotherapies and 
targeted agents. ONC201 induces caspase-mediated apoptosis in cancer cell lines and exhibits 
broad-spectrum cytotoxicity in vitro. ONC201 has demonstrated single agent anti-tumor effects 
in several solid tumor models that include subcutaneous (Figure 1.1), orthotopic, and transgenic 
models in a wide range of malignancies in preclinical models (e.g. glioblastoma multiforme, 
triple-negative breast cancer, colorectal cancer and non-small cell lung cancer). 


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Figure 1.1 ONC201 antitumor activity in subcutaneous xenografts. Subcutaneous 
xenografts in athymic nude mice receiving a single dose of ONC201 (100 mg/kg, IP). Data 
shown is approximately 1 week following single dose administration and is relative to the tumor 
size on the day of administration. 
Beyond solid tumors, ONC201 has also demonstrated striking efficacy in liquid tumors that 
include leukemia, multiple myeloma, and B-cell lymphoma (Figure 1.2). Multiple myeloma is 
highly sensitive to agents such as proteasome inhibitors that induce the ER stress response, the 
same pathway triggered by ONC201 treatment by a unique mechanism. Furthermore, multiple 
myeloma cell lines are particularly sensitive to ONC201 compared to other tumor types (Figure 
1.3-1.4). In accordance with its unique mechanism, ONC201 is effective despite evolved 
resistance to the proteasome inhibitor bortezomib in multiple myeloma cell lines. Thus, the 
mechanism of action and preclinical efficacy results for ONC201 indicate that multiple myeloma 
is a highly sensitive tumor type that warrants clinical investigation of its monoagent antitumor 
activity. 


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Figure 1.2 ONC201 prolongs the survival of transgenic mice with lymphoma. Overall 
survival of Eμ-myc treated once a week during weeks 9-12 with ONC201 (PO, qwk). P=.00789 
determined by log-rank test. 
 
 
 
 
Figure 1.3 ONC201 broad-spectrum activity in cancer cell lines with high sensitivity in 
multiple myeloma. Cancer cell lines EC50 extrapolated from by the ATP-dependent Cell Titer 
Glo assay (72 hrs, n=2). 


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Figure 1.4 ONC201 causes a dose-dependent eradication of multiple myeloma cell 
culture. RPMI8226 cells were incubated with indicated concentrations of ONC201 (72 hrs, 
n=3). 
Preclinical efficacy studies revealed that ONC201 has peak efficacy when administered at 25 
mg/kg orally once every two weeks. Administering doses more frequent than every 2 weeks or 
at doses higher than 25 mg/kg did not yield additional efficacy in the preclinical model. To begin 
to estimate the safety margin of ONC201 in vivo, exploratory exaggerated dosing studies were 
conducted in mice. ONC201 was administered IP to cohorts of mice as a single dose either as 
an IP bolus or fractionated IP dose. The single bolus dose was well tolerated up to 220 mg/kg. 
At 250 mg/kg, single rapidly administered IP doses of ONC201 caused labored breathing, 
dyspnea, and death. A dose of 250 mg/kg ONC201 administered IP and divided into four 
equivalent doses was well-tolerated. The preclinical efficacy of ONC201 in mice was achieved 
at doses as low as 12.5 mg/kg with maximal efficacy observed in at least one model at 25 
mg/kg. Administering ONC201 twice a week in nude mice at 25 mg/kg caused a mild reversible 
skin rash following two weeks of administration that was not observed with weekly 
administration. 


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1.2.2 
Mechanism of Action 
ONC201 was identified through a phenotypic screen as a small molecule that induces p53- 
independent upregulation of TRAIL gene transcription in tumor cells. A series of gene 
expression profiling and cell signaling investigations have unraveled signaling pathways that are 
engaged in tumor cells following ONC201 treatment. 
ONC201 appears to activate the integrated stress response (ISR), which is the same signaling 
pathway activated by ER stress-inducing compounds such as proteasome inhibitors (e.g. 
bortezomib). When the ISR is activated by ER stress-inducing compounds, the pathway is often 
referred to as the ER stress response. ONC201 causes an early-stage increase in the 
phosphorylation of eIF2-alpha at serine 51, which results in attenuation of protein translation 
and upregulation of the transcription 
factor ATF4 (Figure 1.5). ATF4 up 
regulates CHOP, which is also a 
transcription factor that regulates 
several 
apoptosis-related 
genes 
such as the TRAIL-receptor DR5. 
ATF4 
and 
CHOP 
upregulate 
expression of TRB3, which interacts 
directly with Akt to decrease its 
kinase activity. TRB3 also serves as 
a scaffold protein in the MAPK 
signaling 
pathway 
that 
can 
negatively regulate this pathway. 
Decreased levels of phospho-MEK, - 
 
ERK, 
and 
–Akt  have 
been 
documented 
 in 
response  
to 
Figure 1.5 Proposed model of ONC201 MOA in tumor cells 
ONC201. The decreased ERK and Akt kinase activity results in less phosphorylated Foxo3a, 
which is a transcription factor that regulates both the TRAIL and DR5 genes. Dephosphorylated 
Foxo3a undergoes nuclear translocation and activation in response to ONC201. 
In summary, ONC201 appears to activate the ISR that attenuates protein translation and 
activates ATF4, which causes induction of genes that lead to apoptosis. ATF4 and CHOP also 
downregulate Akt and ERK activity that cooperatively induce complementary downstream 
apoptotic effects. Preliminary evidence suggests that ONC201 may not activate eIF2-alpha 
through PERK. This distinct mechanism may explain the lack of cross-resistance between 
ONC201 and other ER stress-inducing agents such as bortezomib. In addition, ONC201 has 
enhanced antitumor efficacy in combination with bortezomib that may be explained by engaging 
parallel stimuli that lead to an enhanced activation of the ISR in tumor cells. 


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1.2.3 
Nonclinical Safety/Toxicology Studies in Animals 
In rats and dogs ONC201 was better tolerated when administered orally compared to 
intravenously. In rat non-GLP studies, the No-Observed Adverse Effect Level (NOAEL) was 225 
mg/kg with oral administration compared to 100 mg/kg with a 2 hour infusion and 50 mg/kg with 
a 30 minutes infusion. Non-GLP clinical observations in rodents included decreased activity, 
altered gait, and mortality. In dog non-GLP studies, the NOAEL in doses was at least 120 mg/kg 
with oral administration and clinical observations were limited to emesis and changes in fecal 
consistency. The non-GLP studies only evaluated at clinical observations, weight gain, food 
consumption and gross findings at necropsy. In general the toxicology/safety studies indicate 
that the acute toxicities associated with ONC201 are limited to the day of administration and are 
reversible. 
In GLP dog studies, the NOAEL was at least 42 mg/kg. Observations were limited to decreased 
activity, decreased food consumption, emesis, salivation, and/or soft, loose or mucous feces. In 
rat GLP studies, the NOAEL was at least 125 mg/kg. Observations included decreased activity, 
decreased food consumption, decreased body weight, and abnormal stance and gait. Minor 
changes in serum chemistries were noted, largely in the 225 mg/kg rat cohort, which included 
slight increases in cholesterol and chloride. The significance of these findings is unknown as 
other clinical chemistry and histology did not corroborate this observation (e.g. liver findings). 
Rats receiving 125 or 225 mg/kg ONC201 had mild edema and inflammation that was primarily 
submucosal in the stomach and was completely resolved by day 19. 
1.2.3.1 Non-GLP Safety Studies 
Non-GLP studies were conducted in rats and dogs to assess clinical observations and body 
weight with ONC201. 
Non-GLP toxicology studies in rats 
 
The ability of rats to tolerate ONC201 by intravenous administration was explored as a function 
of infusion time. Clinical observations with intravenous administration included decreased 
activity, salivation, abnormal gait and stance, labored respiration, pale skin, nasal discharge, 
prostration during the dose, mild body twitching, and red discharge from the mouth. 
The NOAEL following administration of ONC201 to Sprague-Dawley rats by a 30-minute 
intravenous infusion was 50 mg/kg. The NOAEL following administration of ONC201 to 
Sprague-Dawley rats by a 2-hour intravenous infusion was 100 mg/kg. Administration of 100 
mg/kg ONC201 by intravenous infusion over 30 minutes resulted in the death of one male rat. 
Administration of 200 mg/kg ONC201 by a 2-hour infusion resulted in the death of both animals 
during the infusion period. Following these observations, the tolerance of oral ONC201 was 
explored given the potential to lower acute toxicity by lowering the maximal concentration 
(Cmax). Clinical observations with oral exaggerated doses of ONC201 included decreased 
activity, abnormal gait and stance, prostration, irregular respiration, moderate twitching, red 


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discharge on the muzzle, scant feces, hunched posture, not eating, piloerection, and skin cold 
to touch. The NOAEL following administration of ONC201 to Sprague-Dawley rats by oral 
gavage was 225 mg/kg. 
Non-GLP toxicology studies in dogs 
 
In parallel to non-GLP toxicology studies in rats, the ability of beagle dogs to tolerate ONC201 
was explored. No deaths were observed at any doses in dogs. The NOAEL following the 30- 
minute intravenous infusion of ONC201 to beagle dogs is considered to be at least 33.3 mg/kg. 
The 2 hour-intravenous infusion of 16.7 mg/kg ONC201 was not associated with any clinical 
signs of toxicity. Therefore the NOAEL following a 2 hour-intravenous infusion of ONC201 to 
beagle dogs is considered to be greater than 16.7 mg/kg, though higher doses were not 
explored as the oral route was selected for further development based on observations in rats. 
The NOAEL with oral ONC201 was considered to be at least 120 mg/kg in dogs. Clinical 
observations at doses of 66.7 to 120 mg/kg were limited to emesis and changes in fecal 
consistency. 
1.2.3.2 GLP Toxicology and Safety Studies 
Single Dose Oral Toxicity Study in Dogs (GLP) 
 
A GLP study was performed to evaluate the toxicity and toxicokinetics of ONC201 following a 
single oral dose to Beagle dogs followed by a 2-day or an 18-day recovery period. Dogs 
received a single dose of 0, 4.2, 42, or 120 mg/kg by oral gavage. There was no mortality 
observed in this study. There were no definitive ONC201-related effects on group mean body 
weight or body weight gain, EKG rhythm or morphology, mean heart rate or arterial blood 
pressure, urinalysis, hematology parameters, coagulation parameters, clinical chemistry 
parameters, erythrocyte morphology, gross findings on necropsy, changes in absolute or organ 
to body or organ to brain weights. 
Although not statistically significant, there were some dose-related decreases in group mean 
food consumption for the first week following dosing. The 120 mg/kg females had statistically 
significantly decreased group mean food consumption compared to the vehicle control group on 
Days 14, 15 and 18. There were no clinical signs of toxicity noted following a single dose of 4.2 
mg/kg ONC201. At a dose of 42 mg/kg and 120 mg/kg, some dogs had clinical observations at 
approximately 1 hour post-dose including decreased activity, emesis, salivation, and/or soft, 
loose or mucous feces. Of uncertain relationship to ONC201 administration was the unusual 
finding of mononuclear cell inflammation in the blood vessels of the brain, which was multifocal 
and mild in one high dose female at Day 3, multifocal and minimal in one high dose female at 
Day 19, and minimal and focal in one control female at Day 19. Similar findings were not noted 
in any male animal. 
Based on the results of this study, the NOAEL following oral administration of ONC201 at single 
doses of 4.2, 42 or 120 mg/kg to Beagle dogs is considered to be at least 42 mg/kg. 


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Single Dose Oral Toxicity and Toxicokinetic Study in Rats with a 19-Day Recovery and a 30- 
Minute Intravenous Infusion Toxicokinetic Arm (GLP) 
 
A GLP study was performed to evaluate the toxicity of ONC201 following a single oral dose in 
Sprague-Dawley rats with necropsy after a 2-day or an 18-day recovery period. Rats received 0, 
12.5, 125, or 125 mg/kg ONC201 by oral gavage. 
There was no mortality observed in this study. There were no definitive ONC201-related effects 
on coagulation parameters, clinical chemistry parameters, gross findings at necropsy. There 
were no clinical signs of toxicity noted at single doses up to 125 mg/kg ONC201. There were no 
ONC201-related statistically significant changes in hematology parameters or clinical 
chemistries outside of the historical control range for these values. 
At a dose of 225 mg/kg, clinical signs of toxicity were limited on the day of dose administration 
to one out of twenty males and one out of twenty females that showed signs of decreased 
activity and abnormal gait and stance. The male was also noted to have increased respiration. 
All were normal by Day 2. No ONC201 related changes were noted during the functional 
observational battery (CNS activity) performed on Day 1 between 1 and 2 hr post-dose with the 
exception of one 225 mg/kg female noted as having decreased activity. A statistically significant 
decrease in group mean body weight gain was noted on Day 7 for the 225 mg/kg males. A 
statistically significant decrease in group mean food consumption was noted on Day 7 for the 
225 mg/kg males. 
On Day 3 the 225 mg/kg females also had increased glucose, cholesterol, sodium and chloride. 
Sodium and chloride were statistically significantly increased for the 125 mg/kg females. Only 
cholesterol and chloride were outside historical control ranges for this laboratory on day 19. As 
the increase in cholesterol was only noted for the females and no corresponding liver findings 
were observed, the significance of this finding is unknown. Though within normal historical 
control values for these laboratories, chloride remained increased for the 225 mg/kg males while 
cholesterol remained increased for the 225 mg/kg females. 
Changes in brain and liver weights were noted but did not occur in a dose-dependent manner 
and no microscopic changes were noted for in these organs for the high dose females. These 
changes were considered incidental and unrelated to treatment. At the Day 3 necropsy, 
ONC201-related minimal to mild edema and/or mixed cell inflammation was present in the non- 
glandular stomach of 225 mg/kg males and females. This edema and inflammation was 
primarily submucosal, although in some animals the inflammation involved the serosa or 
mesentery. Two males and one female had minimal focal ulceration of the overlying squamous 
epithelium. Similar stomach findings were seen in 125 mg/kg animals, with a lower incidence 
than in 225 mg/kg. There was complete resolution of all stomach lesions at the Day 19 
necropsy, indicating full recovery. 


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Based on the results of this study, the NOAEL following oral administration of ONC201 at single 
doses of 12.5, 125 or 225 mg/kg to Sprague-Dawley rats is considered to be at least 125 mg/kg. 
Evaluation of the Effect of ONC201 Dihydrochloride on Respiratory Function Following Single- 
Dose Administration in Rats (GLP) 
 
A GLP study was performed to determine the potential effects of ONC201 dihydrochloride on 
respiratory function in rats following a single oral gavage administration. Twenty four (6/group) 
male rats received 0, 12.5, 125, or 225 mg/kg ONC201 by oral gavage and were monitored in 
plethysmographic chambers. The oral administration of ONC201 dihydrochloride at 12.5 and 
125 mg/kg did not induce any biologically relevant effects on respiratory rate, tidal volume or 
minute volume in conscious male rats. A marginal to moderate transient decrease in respiratory 
rate and minute volume was observed following the oral administration of ONC201 
dihydrochloride at 225 mg/kg, which resolved by 2 hours. 
 
 
1.2.4 
Pharmacokinetic Studies 
 
1.2.4.1 Pharmacokinetic Studies in Animals 
The measured half-life of ONC201 in mice is ~6 hours with intravenous administration as 
measured by an HPLC-UV assay. In rats, exposure to ONC201 was dose-dependent and 
approximately dose-proportional. Exposure to ONC201 was slightly greater in female rats after 
a single oral gavage dose. Plasma t1/2 ranged from 2.3 to 8.4 hours in 7 of 8 profiles. Clearance 
ranged from 7.5 to 23.5 L/hr/kg in 7 of 8 profiles. Volume of distribution ranged from ~49 to 
~103 L/kg in 6 of 8 profiles. 
 
In dogs, exposure to ONC201 following oral gavage dosing at 4.2, 42, and 120 mg/kg ONC201 
was dose-dependent and increased with greater ONC201 dose levels (Figure 1.6). Exposure to 
ONC201 was similar in male and female dogs with the observation that all mean male Cmax and 
AUC values were slightly greater than those corresponding female values. Elimination of 
ONC201 from plasma was similar between the mid and high dose levels; mean t1/2 ranged from 
4.6 to 7.8 hours. Mean t1/2 following the low dose of 4.2 mg/kg was ~1 hour [the half-life 
determined for dogs in the low dose group may represent more of a distribution phase half-life 
rather than the terminal plasma elimination half-life]. Overall elimination of ONC201 was greater 
following the low dose. 


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Figure 1.6 Dog Plasma Concentrations (Mean ± SD) of ONC201 Plotted as a Function of 
Time Following a Single Oral Gavage Dose to Male and Female Beagle Dogs. 
1.2.4.2 Pharmacokinetic Studies in Humans 
In a Phase I dose escalation clinical trial of ONC201 in advanced solid tumors, the 
pharmacokinetics of single agent ONC201 was determined by LC-MS-MS analysis of plasma 
collected in the first cycle of therapy within 21 days of drug administration (Fig 1.7; Table 1.1). 
Trends of increasing exposure with dose were consistent with dose proportionality. Patients 
receiving 625mg ONC201 exhibited a mean half-life of 11.3 hours and achieved a Cmax of 
3.6 ug/mL (~9.3 uM), which occurred at 1.8 hours following administration (Tmax). The mean 
volume of distribution was 369 L, consistent with a large distributive volume. 
Mean AUC was 37.7 h.μg/mL and mean CL/F was 25.2 L/h. Generally, CL/F was observed to 
be variable but consistent across all dose groups. There were no apparent relationships 
between drug CL/F and patient sex and age. Noticeable, shallow trends were observed with 
patient weight and BSA. An overall increase in CL/F was observed as weight and BSA 
increased. Although a slight upward trend was observed, there was no strong correlation 
between CL/F and CLCR. 
Stronger correlations were observed with the distributive volume estimate and patient weight 
and BSA. A increase in volume of distribution was observed with increasing patient weight or 
BSA, as expected. Trends of decreasing exposure with increasing weight were observed in 
plots of Cmax/Dose and AUC/Dose versus patient weight. Weight normalized CL/F was plotted 
versus Dose, showing a similar trend to un-normalized CL/F. 


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Figure 1.7: Mean ONC201 plasma concentrations versus time following 
the first dose of ONC201. Concentrations are shown as (A) A mean for 
each dose cohort, or (B) for individuals treated at 625 mg. 
Table 
ONC201 
1.1 
 
 
 
 
 
 
pharmacokinetic parameters determined in patients receiving 625 mg ONC201 
(n=24). 
 
 
 
 
 
 
 
 
1.3 
Clinical Studies 
The clinical safety of ONC201 has been evaluated in a phase I clinical trial. The design was an 
open-label, dose-escalation phase I trial of monoagent ONC201 in patients with advanced, 
refractory tumors who had exhausted or refused standard treatment options for their respective 
indications. The primary objective of this study was to determine the recommended phase 2 
dose (RP2D) of ONC201 administered orally in patients with advanced cancers, as well as to 
evaluate the safety and tolerability of the drug. Secondary objectives included pharmacokinetics 


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and pharmacodynamics evaluation of ONC201 and preliminary assessment of anti-tumor 
efficacy. 
An accelerated dose escalation design was employed to reduce the number of patients treated 
at potentially sub-therapeutic dose and to accelerate the determination of the recommended 
phase 2 dose. Ten evaluable patients (aged 47-80 years) received oral ONC201 once every 3 
weeks at five dose levels ranging from 125 to 625 mg. The study design included only one 
patient per cohort until any patient experiences a grade 2 adverse event during the first cycle of 
treatment, defined as 21 days. Five dose levels (125 mg, 250 mg, 375 mg, 500 mg, 625 mg) 
were selected for the study. Enrollment at each subsequent dose level required that all patients 
enrolled at the prior dose level completed Cycle 1 dosing and were evaluated 21 days later to 
assess safety. 
On average, patients received 2.9 doses of ONC201. Nine out of ten patients completed at least 
2 cycles, 4 patients completed at least four cycles, and one patient received six cycles and 
remains on therapy. 625 mg was the highest dose administered and was determined to be the 
RP2D. Dyspnea and fatigue was observed in a few patients, which was attributed to their 
underlying disease. No drug-related toxicities Grade >1 were observed in any patients in this 
study. 
Clinical and laboratory results indicated that the drug possessed biologically activity in the 
treated patients. Patient #3, a 72 year old with advanced clear cell endometrial (uterine) cancer 
had a mixed objective response with >50% decrease in lymphadenopathy (10/11 afflicted lymph 
nodes responded) after 2 doses. Patient #4, a 62-year-old male with renal cancer and bone 
metastasis with debilitating pain in the clavicle experienced relief from his clavicular pain. 
Patient #6, a 69-year-old patient with prostate adenocarcinoma, has received 8 doses of 
ONC201 and has stable disease. Patient #8, a 71-year old colon cancer patient had stable 
disease for at least 12 weeks with 4 doses of ONC201. 
A 47-year-old male with appendiceal cancer (patient #2) had CA27.29 tumor biomarker of 30 
units that was in the abnormal range, which decreased to 20 units (normal range) after 4 doses 
of ONC201. Given the heterogeneity of the tumor types in the enrolled patients, no widely used 
biomarker was available to uniformly assay all patient samples. Since most solid tumors 
express cytokeratin-18, the serum M30 assay was selected to detect a caspase-cleaved form of 
cytokeratin-18 that occurs during apoptosis. Clinical studies have demonstrated the M30 assay 
to be predictive of clinical response (Demiray et al; 2006) in solid tumors. Induction of the M30 
assay for apoptosis was noted in 67% of patients treated at the RP2D with a range of 1.25- to 4- 
fold increase. 
An expansion phase of this Phase I trial with ONC201 enrolled 18 additional patients with 
advanced solid tumors to confirm the tolerability of the 625mg ONC201 RP2D. The only 
adverse events among the 18 patients enrolled in the expansion phase that were attributed as 
possibly-related to ONC201 were: nausea (1 patient), emesis (2 patients), and increased level 


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of serum amylase (2 patients). All of these adverse events were Grade 1 and reversed rapidly. 
Laboratory studies and physical exams did not reveal any drug-related abnormalities. Similarly, 
cardiovascular assessments revealed no drug-related effects. 
 
Another arm of this study has been opened to evaluate weekly dosing. Three patients have 
been treated with 375mg ONC201 on a weekly basis and six patients have been treated with 
625mg on a weekly basis. As of September 8, 2016, there have been no reports of drug- 
related adverse events in any of these patients. All three 375mg and six of the 625mg patients 
have successfully completed the DLT window (21 days). Based on these findings, the 
recommended administration schedule of ONC201 is 625mg once every week. 
Additional clinical studies of ONC201 are enrolling, including a Phase I clinical trial in advanced 
solid tumors and multiple myeloma, a Phase I/II clinical trial in relapsed/refractory acute 
leukemias and high-risk myelodysplastic syndrome (MDS), a Phase I/II clinical trial in 
relapsed/refractory Non-Hodgkin’s lymphoma (NHL) and a Phase II clinical trial in bevacizumab- 
naïve glioblastoma multiforme (GBM). 
1.4 
Rationale 
ONC201 is a first-in-class small molecule with consistent antitumor activity in difficult-to-treat 
cancers as demonstrated using in vitro, ex vivo, and in vivo models. The mechanism of action of 
ONC201 appears to involve the activation of the integrated stress response (ISR) that causes a 
downstream inactivation Akt and ERK signaling as well as induction of the pro-apoptotic TRAIL 
pathway. Multiple myeloma is highly sensitive to ER stress-inducing agents that trigger the ISR 
such as proteasome inhibitors used to treat multiple myeloma. The efficacy of ONC201 has 
been demonstrated in numerous solid and liquid tumor cell lines and patient sample that are 
refractory to chemotherapy and targeted therapies, including bortezomib refractory multiple 
myeloma. ONC201 is effective in tumor cells harboring diverse mutations in genes such as p53, 
KRAS, Raf, EGFR and others that render resistance to chemotherapy and targeted therapies. 
Multiple myeloma have been selected for evaluation in this trial based on preclinical efficacy as 
well as the mechanism of action of ONC201 that involves engagement of the ISR, inactivation of 
Ras signaling, and induction of the TRAIL pathway that should be effective in these tumors 
based on preclinical and clinical evidence. Administration of ONC201 with dexamethasone in 
this study is based on preclinical evidence that ONC201 synergizes with dexamethasone in 
multiple myeloma cell lines (Figure 1.8). 


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Figure 1.8 ONC201 synergizes with dexamethasone in multiple myeloma. Combination 
indices (left) and exemplary combination results (right) for cell viability of RPMI-8226 cells 
treated with ONC201 and/or dexamethasone (72 hrs, n=2). 
 
 
ONC201 will be administered once every week. This infrequent dosing schedule was selected 
based on the preclinical findings that these schedules are effective and well tolerated in mouse 
models. This observation is rationalized by the sustained intratumoral activity of the molecule for 
several days to weeks following a single dose of the drug. 
In preclinical studies, ONC201 acute toxicity is transient and generally resolves within several 
hours of administration. Preclinical data with ONC201 suggests saturation of efficacy at a 
human equivalent of 125mg. A dose of 625 mg is expected to exceed the dose (and associated 
Cmax) with maximal efficacy by 5-fold and thus higher doses may not be explored. 
The frequency of once a week dosing is being evaluated based on the excellent clinical safety 
and PK observations in the first-in-human study. 


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2 
OBJECTIVES AND ENDPOINTS 
 
2.1 
Objectives 
 
2.1.1 
Primary Objective 
• 
Determine the antitumor efficacy of ONC201 in combination with dexamethasone. 
2.1.2 
Secondary Objectives 
• 
Evaluate the overall safety profile of ONC201 in combination with dexamethasone. 
• 
Assess the pharmacodynamic (PD) effects of ONC201 in combination with 
dexamethasone. 
• 
Assess effect of ONC201 in combination with dexamethasone on survival endpoints. 
2.2 
Endpoints 
 
2.2.1 
Primary Endpoint 
• 
Overall response rate (ORR) using the International Myeloma Working Group response 
criteria. 
2.2.2 
Secondary Endpoints 
• 
Overall safety profile of ONC201 as characterized by type, frequency, severity, timing 
and relationship to study therapy of adverse events and laboratory abnormalities. 
• 
Effects of ONC201 on pharmacodynamic (PD) markers. 
• 
Effects of ONC201 on survival endpoints (i.e., progression-free survival, time to 
progression, and duration of response) 


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3 
STUDY DESIGN 
 
3.1 
Overview 
This is a Phase 1/2, open-label study of ONC201 in combination with dexamtheasone in adult 
patients with relapsed/refractory multiple myeloma. This trial intends to explore the antitumor 
efficacy of orally administered ONC201 at 625 mg weekly in patients receiving concomitant 
dexamethasone, using the International Myeloma Working Group response criteria. 
Throughout the study, AEs, SAEs, laboratory values, vital signs, physical examination findings, 
ECOG performance status, and EKGs will be obtained. Toxicity will be evaluated according to 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), 
version 4.03. Study drug may be discontinued if a patient experiences study treatment-related 
toxicity. 
Serial blood samples to measure relevant biomarkers will be collected at prespecified time 
points as indicated in Section 7. 
3.2 
Number of Patients 
Phase 1 is expected to enroll up to 12 patients and Phase 2 will enroll up to 30 evaluable 
patients over the course of 2 years. The actual sample size will depend on the clinical results. 
3.3 
Dose and Planned Scheme 
In Phase I, ONC201 is inteneded to be administered once every week at 375mg or 625mg. 
Dexamethasone will be administered same day of each ONC201 administration. One cycle is 
defined as 21 days (three weeks), which is also the dose-limiting toxicity (DLT) window. 
Phase 1 of the study involves a 3 + 3 dose escalation with a starting dose of 375mg 
ONC201 followed by an escalation to 625mg ONC201. This will allow assessment of 
the safety, tolerability, pharmacodynamic effects, and efficacy of two doses of weekly 
ONC201 in combination with dexamethasone. Dexamethasone will be administered at 
20mg weekly. In the unexpected event that >1/6 patients in the first cohort experience  
a DLT, dose de-escalation will proceed by a 3 + 3 design using 8mg dexamethasone 
and 375mg ONC201. Further dose de-escalation would involve step-wise decreasing 
125mg increments of ONC201. Dose de-escalation below 125mg ONC201 and 8 mg 
dexamethasone will not be permitted. 
Once a recommended phase 2 dose (RP2D) has been determined in Phase I based 
on a favorable benefit/risk ratio (anticipated to be 625mg ONC201 with 20mg 
dexamethasone), the study will progress to Phase 2 of the study. 


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4 
ELIGIBILITY CRITERIA 
The following eligibility criteria are designed to select subjects for whom protocol treatment is 
considered appropriate. All relevant medical and non-medical conditions should be taken into 
consideration when deciding whether this protocol is suitable for a particular subject. 
4.1 
Inclusion 
1. Patients must be refractory to, or not a candidate for, established therapy known to 
provide clinical benefit for their malignancy. 
2. Measurable disease M protein component in serum (at least 0.5 g/dL) and/or urine (if 
present) (>=0.2 g excreted in a 24 hour collection sample), or serum free light chain level 
≥10 mg/dL, provided the serum free light chain ratio was abnormal. 
3. Able to swallow and retain oral medication. 
4. All previous therapies for cancer, including radiotherapy, major surgery and 
investigational therapies must be discontinued for ≥ 14 days (≥ 28 days for mitomycin C 
or nitrosoureas) before study entry, and all acute effects of any prior therapy must have 
resolved to baseline severity or Grade ≤ 1 Common Terminology Criteria for Adverse 
Events (CTCAE v4.03), except alopecia or parameters defined in this eligibility list. 
5. Age ≥ 18 years 
6. ECOG performance status ≤ 1 
7. Adequate organ and marrow function as defined below: 
h. Absolute neutrophil count 
≥1,000/mm3 without growth factor use ≤ 7 days 
prior to treatment (cycle 1 day 1, C1D1) 
i. 
Platelets 
≥50,000/mm3 without platelet transfusion ≤ 3 
days prior to C1D1 
j. 
Hemoglobin 
>8.0 mg/dL without red blood cell transfusion ≤ 3 
days prior to C1D1 
k. Total serum bilirubin 
<1.5 X upper limit of normal (ULN) ; subjects with 
>1.5X upper limit of normal require approval of medical monitor. 
l. 
AST (SGOT)/ALT (SGPT) 
≤2 X ULN; ≤ 5 X ULN if liver dysfunction is felt to 
be secondary to tumor burden 
m. Serum creatinine 
≤ 1.5 X ULN (OR creatinine clearance ≥ 30 
mL/min/1.73 m2) 
n. Serum or urine pregnancy test (for females of childbearing potential) negative 
≤7 days of starting treatment 
8. Ability to understand and the willingness to sign a written informed consent document 
and comply with the study scheduled visits, treatment  plans,  laboratory  tests  and 
other procedures. 
9. Female patients must be surgically sterile or be postmenopausal, or must agree to   
use effective contraception during the period of the trial and for at least 90 days after 
completion of treatment. Male patients must be surgically sterile or must agree to use 
effective contraception during the period of the trial and for at least 90 days after 
completion of treatment. The decision of effective contraception will be based on the 
judgment of the principal investigator or a designated associate. 


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4.2 
Exclusion 
1. Active inflammatory gastrointestinal disease such as chronic diarrhea (unless related to 
underlying malignancy or prior related treatment) or history of abdominal fistula, 
gastrointestinal perforation, peptic ulcer disease, or intra-abdominal abscess within 6 
months prior to study enrollment. Gastroesophageal reflux disease under treatment with 
proton pump inhibitors is allowed. 
2. Pregnancy or breast feeding 
3. Current active treatment in another clinical study 
4. Active bacterial, fungal or viral infection including hepatitis B (HBV), hepatitis C (HCV) 
5. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome 
(AIDS)-related illness that is not well controlled. 
6. Active or prior plasma cell leukemia (defined as either 20% of peripheral WBC 
comprised of plasma/CD138+ cells or an absolute count of 2 x 10^9/L) 
7. Solitary bone or solitary extramedullary plasmacytoma as the only evidence of plasma 
cell dyscrasia. 
8. Subjects with serum calcium (corrected for albumin) ≥ 12 mg/dL 
9. Any of the following in the previous 6 months: myocardial infarction, severe/unstable 
angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, 
cerebrovascular accident, transient ischemic attack or symptomatic pulmonary 
embolism. 
10. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality 
that may increase the risk associated with study participation or study drug 
administration, or may interfere with the interpretation of study results, or in the judgment 
of the investigator would make the patient inappropriate for entry into the study. 
11. Actively receiving medications that have risk of Torsades de Pointes or are strong 
cytochrome P450 inhibitors or inducers. 
 
4.3 
Contraception 
During the study, fertile female patients must take precautions to prevent pregnancy since the 
effects of the study medication on the fetus are unknown. Male patients with partners of 
childbearing potential must take precautions to prevent pregnancy of the partner since the 
effects of this drug on sperm are unknown. These restrictions should remain in force for 90 days 
from the last dose of investigational agent. Drug interaction studies with oral contraceptives 
have not been performed, so barrier methods of contraception or abstinence should be 
considered. The definition of effective contraception should be in agreement with local 
regulation and based on the judgment of the principal investigator or a designated associate. A 
suggested definition of adequate contraception is the use of double barrier contraception (e.g., 
condom plus spermicide in combination with a female condom, diaphragm, cervical cap or 
intrauterine device). 


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Mfg date: XX-XXXX 
Batch # xxx-xxx-xxxx-xx 
ONC201 Capsules, 125mg 
For Oral Use Only 
Caution: New Drug--Limited by Federal (or United States) law to investigational use. 
Storage: Preserve in original tightly closed containers at room temperature (15 to 30°C) 
Sponsor: Oncoceutics, Inc. 
5 
STUDY TREATMENTS 
 
5.1 
Drug Supply 
 
5.1.1 
Formulation, Packaging and Storage 
The study drug ONC201 is provided as a dihydrochloride salt (125 mg free base; ~150mg 
disalt), along with microcrystalline cellulose, filled into hydroxypropyl methylcellulose (HPMC) 
capsule shells. 
The ONC201 drug product capsules are intended for oral administration. The product is stored 
in a multi-dose container. The capsules are packaged in high-density polyethylene (HDPE) 
white opaque bottles, closed with an induction seal and capped with a white ribbed SecuRx® 
polypropylene (PPE) cap. The capsules are to be stored in the original closed container at room 
temperature (15 to 30°C). 
The study drug bottle label bears the following information: 
 
Figure 3.1: Investigational drug label 
5.1.2 
Drug Accountability 
Upon receipt at the investigative site, study drug product must be stored at room temperature in 
the original packaging. The drug should be protected from light and excessive humidity in a 
monitored, locked, secure area with limited access. Storage area temperature conditions must 
be monitored and recorded daily. All temperature excursions will be reported to the sponsor for 
assessment and authorization for continued use. Study site staff must instruct patients on how 
to store and administer oral study drug agents that are dispensed for at-home administration. 
Accountability for study drug product is the responsibility of the investigator. The study site must 
maintain accurate records demonstrating dates and amount of study treatment received, to 
whom dispensed (patient-by-patient accounting), and accounts of any study treatment 
accidentally or deliberately destroyed. A written explanation must be provided for any 
discrepancies. Patients are to be instructed on proper accountability of the take-home study 


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drugs and will be instructed to return any unused drug in the original packaging along with their 
completed diary cards at the appropriate clinic visits. The investigator must destroy or return all 
unused drug product provided. 
5.2 
ONC201 Administration 
Patients will receive 625 mg of ONC201 on an outpatient basis. The study drug, ONC201, will 
be supplied in capsule form for oral dosing. Patients should take designated capsules of 
ONC201 at approximately the same time on each day of drug administration. Patients will be 
instructed to not eat for 2 hours pre and 2 hours post dosing. If the patient vomits after taking 
ONC201, they should not retake the dose. Missed doses will not be made up. 
ONC201 should be taken with a glass of water and consumed over as short a time as possible. 
Patients should swallow the capsules as a whole and not chew them. Do not crush or empty  
the capsule. If vomiting occurs during the course of treatment, no re-dosing of the patient is 
allowed before the next scheduled dose. The occurrence and frequency of any vomiting during 
a treatment cycle must be noted as an adverse event. In addition, on the days of drug 
administration the exact time of any episodes of vomiting within the first 4 hours post-dosing on 
that day must be noted whenever possible. 
Dexamethasone will be obtained and administered per standard of care guidelines for multiple 
myeloma patients. Administration of dexamethasone is recommended approximately 6 hours (+ 
2 hours) after ONC201. 
5.3 
General Concomitant Medication and Supportive Care Guidelines 
Because there is a potential for interaction of ONC201 with other concomitantly administered 
drugs through the cytochrome P450 system, the case report form will capture the concurrent 
use of all other drugs, over-the-counter medications, and/or alternative therapies. Concomitant 
medications that have risk of Torsades de Pointes, or are strong cytochrome P450 inhibitors or 
inducers, are not allowed. 
Any medication taken by a subject during the course of the study and the reason for its use will 
be documented in the source documents and case report form (CRF) that will be provided by 
the Sponsor. 
5.4 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue once 
every weeks until one of the following criteria applies: 
• Disease progression 
• Intercurrent illness that prevents further administration of treatment 
• Unacceptable adverse event(s) 
• Patient decides to withdraw from the study 
• General or specific changes in the patient's condition that render the patient unacceptable 
for further treatment in the judgment of the investigator. 


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• The Sponsor chooses to discontinue the study: for example if severe or life threatening 
toxicities are encountered by other enrolled patients in the clinical trial or the dose to 
pharmacokinetics or pharmacodynamics relationship plateaus. 
Patients will be followed for three years after removal from study or until death, whichever 
occurs first. Patients removed from study for unacceptable adverse event(s) will be followed 
until resolution or stabilization of the adverse event. 
5.5 
Criteria for Removal from Study 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
the following criteria applies: 
• 
Disease progression 
• 
Intercurrent illness that prevents further administration of treatment ≥ 14 days or specific 
changes in the patient's condition that render the patient unacceptable for further 
treatment in the judgment of the investigator 
• 
Patient non-compliance with protocol requirements (determined via meeting with PI, 
applicable Sub-I, clinical research coordinator, and patient) 
• 
Unacceptable adverse event(s). Note, a DLT in and of itself may not be an unacceptable 
adverse event. However, any grade 4 study-drug related AE is unacceptable and will 
lead to withdraw. The investigator will use his/her opinion, in consultation with the PI, to 
determine if a study-drug related AE is unacceptable, acceptable, or clinically 
insignificant (also acceptable). 
• 
Withdrawal of consent (attempts should be made to clarify, with the patient, if withdrawal 
is specific to study participation, or if it applies to data collection as well). Note: patients 
lost to follow up (defined as no contact > 60 days after last on-study contact and at least 
3 attempts) are considered to have withdrawn study participation consent. Data 
collection is permissible. Date of last contact will be recorded as the withdrawal date. 
• 
Pregnancy 
• 
Oncoceutics’ decision to forgo further drug development of ONC201 
 
The reason for study removal and the date the patient was removed must be documented in 
the CRF. 
Severe adverse events, availability of new adverse toxicology in animals, and financial 
difficulties due to withdrawal of funds may result in stopping the trial. An  investigator, 
Sponsor, or IRB may take such actions. If the trial is terminated for safety reasons, subjects 
will be notified immediately and assured that appropriate treatment and follow-up will be 
available. If an investigator terminates the trial he will inform the Sponsor, subjects, and IRB 
about the reason for such action. Similarly if the Sponsor terminates the trial, it will inform the 
investigators, the IRB, and the subjects of the reason for such an action. Similar notifications 
will be sent by the IRB if it takes such an action. 


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5.6 
Dose Limiting Toxicity (DLT) definition 
Toxicity will be evaluated according to the NCI CTCAE, version 4.03. The DLT safety 
observation window is defined as the first 3 weeks (one cycle). A DLT will be defined as any of 
the following AEs, occurring within the first 21 days of dosing and considered possibly related 
(except where defined) to ONC201: 
Hematologic: 
 
• Grade 4 neutropenia that persists for >7 consecutive days 
 
• Febrile neutropenia (defined as neutropenia ≥ Grade 3 and a body temperature 38.5°C) 
 
• Grade ≥ 3 neutropenic infection 
 
• Grade 4 thrombocytopenia (platelets <25,000 cells/mm3) or Grade ≥ 3 thrombocytopenia 
with bleeding 
Nonhematologic: 
 
• Any other Grade ≥ 3 toxicity not classified under CTCAE blood or bone marrow with the 
exception of nausea, vomiting, or diarrhea. Grade 3 nausea or vomiting that persists for 5 
days and is not controlled with standard antiemetic therapy will be considered a DLT. 
• Alopecia is not a DLT 
 
• Any AE leading to inability to complete planned study drug during the DLT window should 
be considered a DLT 
Although toxicities may be observed at any point during treatment, only those occurring during 
the defined DLT observation window of treatment (1 cycle) that are considered DLTs will 
guide dose escalation decisions, expansion of a dose level, or evaluation of intermediate dose 
levels. Patients will be monitored through all cycles of therapy for treatment-related toxicities, 
and all toxicities, including those occurring in beyond the DLT observation window will be 
monitored. 
 
 
6 
DOSING DELAYS/DOSE MODIFICATIONS 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for dose delays and dose modifications. 
Below are dose modifications (Table 6.1) for adverse events that are attributable to study drug, 
including: nausea, vomiting, diarrhea, neutropenia, and thrombocytopenia. If a patient 


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experiences other adverse events, or several adverse events and there are conflicting 
recommendations based on Grade, the investigator will use the recommended dose adjustment 
that reduces the dose. Dose modifications will be made based on an adverse event that occurs 
during any time during a cycle. 
Criteria for disrupting treatment, dose modification, or discontinuation are listed in Table 6.1. 
Dose modifications are per the clinical judgment of the investigator and agreement of the 
subject, the treatment will be resumed according to the table below. Dose modification may not 
be required for adverse events that are clinically manageable. 
Table 6.1 Dose adjustment rules for Adverse Events (AEs), including Nausea, Diarrhea, 
Neutropenia, Thrombocytopenia, and Other AEs. Alopecia does not require dose 
adjustments. 
 
CTCAE Grade 
Management/Next Dose for ONC201 
≤ Grade 2 
No change in dose 
Grade 3 or 4* 
Hold until < Grade 2. 
For first instance, if resolved to < Grade 2 within 21 days resume 
dosing at 500mg ONC201 and 8mg dexamethasone. 
For second instance, if resolved to < Grade 2 within 21 days 
resume dosing at 8mg dexamethasone and 375mg ONC201.** 
*Patients requiring a delay of >21 days weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
 
Participants who experience an adverse event that requires a treatment delay or dose reduction 
should be monitored with appropriate laboratory testing or other clinical evaluation at least 
weekly until resolution; if the adverse event does not resolve within 21 days, the interval for 
testing may be reduced after consultation and written approval by the Overall Principal 
Investigator (or his designee). 
For holds for reasons other than treatment related toxicities, if the participant does not meet 
criteria to resume treatment within 6 weeks of the event precipitating the hold, the study 


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agent(s) may be restarted with approval from the overall Principal Investigator or designee, as 
long as there has been no significant evidence of disease progression (e.g., by clinical findings, 
symptoms, tumor markers) during the treatment interruption. 
 
 
6.1 
Concomitant Medications 
 
6.1.1 
Drug Interactions 
No formal metabolic or drug-drug interactions with ONC201 or any metabolites have been 
performed. These studies will be performed later in the development of this agent. A literature 
search revealed that ONC201 was inactive in a CYP450 screen. Strong inducers and inhibitors 
of the cytochrome P450 system should not be used on study. Concomitant medications that 
have risk of Torsades de Pointes are also not allowed. 
6.1.2 
Corticosteroids 
Dexamethasone will be given to all patients per study protocol. Additional steroids will be 
restricted to physiologic replacement or less for those in which it is clinically indicated. 
Use of non-systemic steroid use is permitted (e.g. cream, lotion, inhalers). 
 
 
6.1.3 
Anti-emetic Therapy 
There are no restrictions on use of antiemetic therapy for this trial. Premedications to prevent 
emerging toxicities are permitted as long as their use does not conflict with other guidelines in 
this protocol. 
 
 
6.1.4 
Other Anticancer or Experimental Drugs 
Treatment with other anticancer or experimental drugs is not permitted for patients treated on 
this protocol. Exceptions include use of LHRH, and octreotide. 
6.1.5 
Hematopoietic Growth Factors 
The use of any growth factor is not permitted for patients during the DLT window, unless it’s use 
is deemed medically necessary by the treating physician secondary to an emerging toxicity. In 
this situation, only G-CSF is permitted for neutropenic fever or grade 4 neutropenia > 7 days 
duration, if the investigator feels such treatment would be in the patient’s best interest. Use of 
growth factors outside of the DLT window must follow institutional and ASCO guidelines. In 
situations where G-CSF is felt to be warranted, pegylated G-CSF should only be used if the 
study drug dosing interval is 2 weeks or greater. G-CSF must be used if the study drug dosing 
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The use of erythropoietin growth factor is generally discouraged. Use of erythropoietin must 
follow institutional and ASCO guidelines. The use of a thrombopoietin agonist is not permitted. 
6.2 
Palliative and Supportive Care 
All palliative care necessary for optimal care of the patient should be provided. Investigational 
drug must be held during radiotherapy and for 1 week afterwards. If possible, the investigational 
drug should be held for 1 week prior to the administration of palliative radiotherapy if possible. It 
is not known if ONC201 acts as a radiosensitizer or if this would lead to increased toxicity. 
However, the potential for ONC201 to act as a radiosensitizer exists. ONC201 should be held 
for at least one week prior to any elective surgery. 
 
7 
STUDY PROCEDURES 
Note that hematology, blood chemistry, and urinalysis, below, refers to any biologic sampling 
done for safety or efficacy testing, as detailed in the Schedule of Activities. For example, 
patients with multiple myeloma may undergo a 24-hour urine collection but this is not explicitly 
defined in the text below. The Schedule of Activities take precedence over text in this section. 
7.1 
Baseline 
The following procedures/assessments must be performed within 28 days prior to the first dose 
of ONC201. 
• 
Patient signature on informed consent form 
• 
Medical history, including tumor history, history of other disease processes (active or 
resolved), concomitant illnesses, and demographics. 
• 
Tumor assessment. 
 
The following procedures/assessments must be performed within 28 days prior to the first dose 
of ONC201. 
• 
Baseline signs and symptoms 
• 
Vital signs 
• 
Height 
• 
Weight 
• 
Physical exam 
• 
ECOG performance status 
• 
Hematology, blood chemistry, coagulation, urinalysis and per SoA 
• 
Pregnancy test (serum or urine), if applicable 
• 
Triplicate EKG (12 leads) 
• 
Concomitant medications 
 
Following successful completion of the baseline assessments and confirmation of eligibility 
patients may be enrolled. 


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7.2 
Trials Period 
The following procedures/assessments will be performed on the days specified in the Schedule 
of Activities: 
• 
Vital signs 
• 
Weight 
• 
ECOG performance status 
• 
Physical exam 
• 
Hematology, blood chemistry, coagulation, urinalysis, and per SoA 
• 
Triplicate EKG (12 leads) 
• 
Study drug compliance 
• 
Adverse events 
• 
Drug compliance 
• 
Concomitant medications 
• 
Tumor assessment: at the end of every even cycle (e.g., Cycles 2, 4, 6) 
• 
Blood draws for PK/PD 
• 
Urine collection 
 
7.3 
Treatment 
ONC201 will be orally administered at 625mg weekly day 1, day 8, and day 15 of each 
treatment cycle (21 days). Dexamethasone will be administered at the indicated dose on each 
day that ONC201 is administered in each treatment cycle (day 1, day 8, and day 15). 
Administration of dexamethasone is recommended approximately 6 hours (+ 2 hours) after 
ONC201. 
7.4 
End of Treatment Visit 
A final visit (“Follow Up”) will occur for all patients when disease progression is documented 
or subsequent anticancer therapy is initiated or the patient is withdrawn from treatment for 
any other reason. 
The following procedures/assessments will be carried out as described in the Schedule of 
Activities table and unless performed in the previous week. Every effort should be made to have 
a final tumor assessment. 
• 
Vital signs 
• 
Weight 
• 
ECOG performance status 
• 
Triplicate EKG (12 leads) 
• 
Hematology, blood chemistry, coagulation, urinalysis and per SoA 
• 
Tumor assessment, unless carried out in the previous 6 weeks 
• 
Adverse events 
• 
Concomitant medications 


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7.5 
Follow-up Visit 
Safety follow up will continue in all patients for 28 days after the last dose of treatment. For 
those patients who have discontinued study treatment for reasons other than disease 
progression, all tumor assessments should be repeated every 6 weeks until disease 
progression or another antitumor therapy is initiated. 
7.6 
Patient Withdrawal 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
the following criteria applies: 
• 
Disease progression 
• 
Intercurrent illness that prevents further administration of treatment ≥ 14 days or specific 
changes in the patient's condition that render the patient unacceptable for further 
treatment in the judgment of the investigator 
• 
Patient non-compliance with protocol requirements (determined via meeting with PI, 
applicable Sub-I, clinical research coordinator, and patient) 
• 
Unacceptable adverse event(s). Note, a DLT in and of itself may not be an unacceptable 
adverse event. However, any grade 4 study-drug related AE is unacceptable and will 
lead to withdraw. The investigator will use his/her opinion, in consultation with the PI, to 
determine if a study-drug related AE is unacceptable, acceptable, or clinically 
insignificant (also acceptable). 
• 
Withdrawal of consent (attempts should be made to clarify, with the patient, if withdrawal 
is specific to study participation, or if it applies to data collection as well). Note: patients 
lost to follow up (defined as no contact > 60 days after last on-study contact and at least 
3 attempts) are considered to have withdrawn study participation consent. Data 
collection is permissible. Date of last contact will be recorded as the withdrawal date. 
• 
Pregnancy 
• 
Oncoceutics’ decision to forgo further drug development of ONC201 
 
 
8 
ASSESSMENTS 
 
8.1 
Safety Evaluations 
Safety assessments include collection of AEs, SAEs, and safety laboratory. Assessment of 
adverse events will include the type, incidence, severity (graded by the National Cancer Institute 
Common Terminology Criteria for Adverse Events [NCI CTCAE] version 4.03), timing, 
seriousness, and relatedness. 
Baseline signs and symptoms will be recorded at baseline and then reported as adverse events 
during the trial if they worsen in severity or increase in frequency. 
The minimum requested lab data includes: 


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Table 7.1: Laboratory Tests Required (All patients) 
 
Hematology 
Blood Chemistry 
Urinalysis 
Coagulation tests 
White Blood Cell 
Count (WBC) 
Glucose 
pH 
Activated partial 
thromboplastin time 
(APTT) 
Absolute Neutrophil 
Count (ANC) 
BUN 
Specific gravity 
Prothrombin time 
Platelet count 
Creatinine 
Protein 
Hemoglobin 
Albumin 
Glucose 
WBC differential 
count 
AST/ALT 
Ketones 
Total Bilirubin 
Blood 
Alkaline phosphatase 
Leukocyte esterase 
LDH 
Nitrates 
Sodium 
Magnesium 
Potassium 
Calcium 
Phosphate 
Uric Acid 
Investigators may order additional blood tests for planning treatment administrations, dose 
modification, or further evaluation of adverse events. 
 
Additional assessments are defined in the Schedule of Activities table. 
 
8.2 
Efficacy Evaluations 
Assessment of response will be made using the International 
Myeloma 
Working 
Group response criteria (Palumbo et al, 2014). All patients’ files and radiologic images must be 
available for source verification. 
Imaging may include chest, abdomen and pelvis CT or MRI or PET/CT scans (when applicable); 
brain CT or MRI scan for patients with known CNS involvement; bone scan and/or bone x-rays 
for patients with lytic bone lesions, if applicable. 


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Tumor assessments conducted at baseline, at the end of every other cycle, whenever disease 
progression is suspected (e.g., symptomatic deterioration), and at the time of withdrawal from 
the study (if not done in the previous 6 weeks). 
The same imaging technique used to characterize each identified and reported lesion at 
baseline will be employed in the following tumor assessments. 
 
Assuming a background ORR of 10%, if the ORR on the current study for patients receiving 
ONC201 were 30% or higher there would be interest in further investigation of this treatment 
regimen. Therefore, this study will be used to detect a difference of 20% using a one- sided 
binomial test. Statistically, the hypothesis that will be tested is: 
 
H0: p<=0.1 versus H1: p>0.3 
where p is the proportion of patients achieving an objective response. Enrollment of 30 patients 
will yield 84% power to detect a 20% difference at an alpha level of 0.05 (one-sided). 
 
 
8.3 
Correlative studies 
 
8.3.1 
Background 
Molecular markers involved in the molecular mechanism of ONC201 will be assessed on 
available tumor and serum specimens. Urine samples may be used to evaluate the excretion of 
ONC201 or its metabolites. 
8.3.2 
Biomarkers 
Prolactin and other proteins will be measured in serum as pharmacodynamic markers. One red- 
top tube (without anti-coagulant) of blood will be collected at the following time points: Baseline 
and 2 hours, 24 hours, 48 hours, and 72 hours after the first dose of ONC201; Cycle 1 Day 8; 
Cycle 1 Day 15. An additional 1 tube of 5mL of blood will also be collected on the day of drug 
administration (pre-dose) on cycles 2, cycle 3 and every odd cycle beyond cycle 3 (day 1 of 
each cycle). For patients with archival specimens, genomic analysis may also be investigated to 
determine if a mutation signature profile can help predict safety and/or efficacy 
8.3.3 
ONC201 Plasma Concentration 
The plasma obtained prior to the isolation of PBMCs (see Section 8.3.4) will be used to 
determine the concentration of ONC201. No additional blood samples will be collected from the 
patient for these studies. These samples will be used to approximate the Cmax of ONC201 
based on its pharmacokinetic profile. 
8.3.4 
Blood for Immune Cell Studies 
Peripheral blood mononuclear cells (PBMCs) will be harvested and investigated for effects of 
ONC201 on the immune system. One EDTA tube of blood will be collected at the same time 
points as the red-top tubes are collected: Baseline and 2 hours, 24 hours, 48 hours, and 72 
hours after the first dose of ONC201; Cycle 1 Day 8; Cycle 1 Day 15; pre-dose for the first day 


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of cycle 2 and beyond (day 1 of each cycle). Blood will also be collected at the follow-up visit at 
the end of treatment, for correlative studies. 
Immune cytokines and effectors will be assessed on serum samples obtained for 
pharmacodynamic analyses. No additional blood samples will be collected from the patient for 
these studies. 
8.3.5 
Urine Collection for ONC201 metabolism Studies 
An aliquot of the 24 hour baseline urine collection will be needed. The Cycle 1 Day 1 - 24 hour 
urine collection will be moved to Cycle 1 Day 2. The patients will collect urine in the clinic on 
Cycle 1 Day 1, starting after taking the first dose of ONC201. The urine will be stored at the site, 
and the number of hours for this portion of the collection and the volume will be recorded. The 
patients need to remain in the clinic until the 6 hour PK sample is drawn. The patients will go 
home with empty bottles provided by the site to finish collecting the 24 hour urine sample and 
the patient will be told the time of completion and will return the next day. The number of hours 
for this portion of the collection and the volume will be recorded as well, and 100mL aliquots 
from both samples will be frozen and transported to Biorepository.  On Cycle 1 Day 2 and Day 
3, there will be a spot urine. 
 
 
8.4 
EKG Assessments 
Triplicate 12-lead EKGs will be performed per the Schedule of Activities and include baseline, 
cycle 1 day 1, cycle 1 day 15 and cycle 2 day 1, and cycle 2 day 15. Cycle 1 day 1 and cycle 2 
day 1 will be obtained at 2 hours (+15 minutes) post-dose. Cycle 1 day 15 and cycle 2 day 15 
will be taken pre-dose. Electrocardiogram assessments are to be performed after the 
measurement of vital signs, with the patient supine and rested for 5 minutes, and before any 
closely timed blood collection. Two – 5 minutes should lapse between each EKG assessment. 
The dates and exact times of EKG recordings will be recorded. Any findings from EKGs 
collected after initiation of study treatment will be captured as AEs if, in the opinion of the 
investigator, there has been a clinically significant change from baseline. 
8.5 
Concomitant Medications 
Medications used by the patient and therapeutic procedures completed by the patient will be 
recorded in the CRF from screening through 28 days after the last dose of study drug or the 
start of subsequent antineoplastic therapy, whichever occurs first. 


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9 
ADVERSE EVENT REPORTING 
 
9.1 
Adverse Events 
All observed or volunteered adverse events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections. 
For all adverse events, the investigator must pursue and obtain information adequate both to 
determine the outcome of the adverse event and to assess whether it meets the criteria for 
classification as a serious adverse event requiring immediate notification to Oncoceutics. For all 
adverse events, sufficient information should be obtained by the investigator to determine the 
causality of the adverse event. The investigator is required to assess causality. For adverse 
events with a causal relationship to the investigational product, follow-up by the investigator is 
required until the event or its sequalae resolve or stabilize at a level acceptable to the 
investigator, and Oncoceutics concurs with that assessment. 
All “unexpected” (defined below) and/or “serious” (defined below) adverse events occurring 
during the active portion of therapy, or up to 30 days after the last dose of treatment, will be 
reported. Events will be promptly reported, in writing, to the local IRB in accordance with IRB 
policy. If a death occurs the IRB will be notified within 24-hours of initial receipt of 
information. All other SAEs must be reported to the IRB within three to ten days of initial 
receipt of information. Written follow-up reports are required when additional information is 
needed to fully characterize the event. Copies of each report sent to the IRB will be kept in 
the study regulatory file. 
The principal investigator has the obligation to report all serious adverse events to 
Oncoceutics (the Sponsor). 
This includes serious, related, labeled (expected) and serious, related, unlabeled 
(unexpected) adverse experiences. All deaths during treatment or within 30 days following 
completion of active protocol therapy must be reported within 5 working days. 
Any serious adverse event occurring after the patient has provided informed consent and 
until 4 weeks after the patient has stopped study participation must be reported. This 
includes the period in which the study protocol interferes with the standard medical 
treatment given to a patient (e.g. treatment withdrawal during washout period, change in 
treatment to a fixed dose of concomitant medication). 
Serious adverse events occurring more than 4 weeks after study discontinuation need only 
be reported if a relationship to ONC201 study drug (or therapy) is suspected. 
For Comparator Drugs/Secondary Suspects (Concomitant Medications), all serious adverse 
experiences will be forwarded to the product manufacturer by the investigator. 


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9.2 
Reporting Period 
Serious adverse events require immediate notification to Oncoceutics beginning from the time 
that the patient provides informed consent, which is obtained prior to the patient’s participation 
in the clinical trial, i.e., prior to undergoing any trial-related procedure and/or receiving 
investigational product, through and including 28 calendar days after the last administration of 
the investigational product. Any serious adverse event occurring any time after the reporting 
period must be promptly reported if a causal relationship to investigational product is suspected. 
Adverse events (serious and non-serious) should be recorded on the CRF from the time the 
patient has taken at least one dose of trial treatment through last patient visit. 
If a subject begins a new anticancer therapy, the adverse event reporting period for non-serious 
adverse events ends at the time the new treatment is started. Death must be reported if it 
occurs during the serious adverse event reporting period after the last dose of investigational 
product, irrespective of any intervening treatment. 
9.3 
Definition of an Adverse Event 
An adverse event is any untoward medical occurrence in a clinical investigation patient 
administered a product or medical device; the event need not necessarily have a causal 
relationship with the treatment or usage. Examples of adverse events include but are not limited 
to: 
 
• 
Abnormal test findings; 
• 
Clinically significant symptoms and signs; 
• 
Changes in physical examination findings; 
• 
Hypersensitivity. 
 
Additionally, they may include the signs or symptoms resulting from: 
• 
Drug overdose; 
• 
Drug withdrawal; 
• 
Drug abuse; 
• 
Drug misuse; 
• 
Drug interactions; 
• 
Drug dependency; 
• 
Exposure in utero; 
• 
Exposure during breast feeding. 
 
Worsening of signs and symptoms of the malignancy under trial should be reported as adverse 
events in the appropriate section of the CRF. Disease progression assessed by measurement 
of malignant lesions on radiographs or other methods should not be reported as adverse events 
9.4 
Abnormal Test Findings 
The criteria for determining whether an abnormal objective test finding should be reported as an 
adverse event are as follows: 


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• 
Test result is associated with accompanying symptoms, and/or 
• 
Test result requires additional diagnostic testing or medical/surgical intervention, and/or 
• 
Test result leads to a change in trial dosing (outside of protocol-stipulated dose 
adjustments) or discontinuation from the trial, significant additional concomitant drug 
treatment, or other therapy, and/or 
• 
Test result is considered to be an adverse event by the investigator or sponsor. 
 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an adverse event. Any abnormal test result that is determined to be an error does not 
require reporting as an adverse event. 
9.5 
Serious Adverse Events 
A serious adverse event is any untoward medical occurrence at any dose that: 
 
• 
Results in death; 
• 
Is life-threatening (immediate risk of death); 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization; 
• 
Results in persistent or significant disability/incapacity; 
• 
Results in congenital anomaly/birth defect. 
 
Progression of the malignancy under trial (including signs and symptoms of progression) should 
not be reported as a serious adverse event unless the outcome is fatal within the safety 
reporting period. Hospitalization due to signs and symptoms of disease progression should not 
be reported as serious adverse event. If the malignancy has a fatal outcome during the trial or 
within the safety reporting period, then the event leading to death must be recorded as an 
adverse event and as a serious adverse event with CTC grade 5 (see Section 9.7, Severity 
Assessment). 
 
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event. An important medical event may not be immediately life-threatening and/or result 
in death or hospitalization. However, if it is determined that the event may jeopardize the patient 
or may require intervention to prevent one of the other outcomes listed in the definition above, 
the important medical event should be reported as serious. 
 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse. 
 
The Sponsor will notify the FDA of any adverse experience associated with the use of the 
drug that is both serious and unexpected, as soon as possible and in no event later than 15 
calendar days after the PI’s discovery of the event. Notification may be submitted to the 
Sponsor on a MedWatch Form FDA 3500A http://www.fda.gov/medwatch/safety/3500a.pdf. 


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The PI shall also notify the Sponsor of any unexpected fatal or life-threatening experiences 
associated with the use of the drug, as soon as possible but no later than 7 calendar days 
from the PI’s discovery of the event information. 
The serious adverse event report must include, but need not be limited to: (1) the date of the 
event; (2) designation of the report as an initial report or a follow-up report, (3) identification 
of all safety reports previously filed for the clinical protocol concerning a similar adverse 
event, and an analysis of the significance of the adverse event in light of previous similar 
reports; (4) clinical site; (5) the Principal Investigator; (6) NIH Protocol number; (7) FDA’s 
Investigational New Drug (IND) Application number; (8) vector type , e.g., adenovirus; (9) 
vector subtype, e.g., type 5, relevant deletions; (10) gene delivery method, e.g., in vivo, ex 
vivo transduction; (11) route of administration, e.g., intratumoral, intravenous; (12) dosing 
schedule; (13) a complete description of the event; (14) relevant clinical observations; (15) 
relevant clinical history; (16) relevant tests that were or are planned to be conducted; (17) 
date of any treatment of the event; and (18) the suspected cause of the event. These items 
may be reported by using the recommended Adverse Event Reporting Template available 
on NIH OBA’s web site at: http://www4.od.nih.gov/oba/rac/documents1.htm, or you can use 
a MedWatch form. 
9.6 
Hospitalization 
Adverse events reported from clinical trials associated with hospitalization or prolongation of 
hospitalization is considered serious. Any initial admission (even if less than 24 hours) to a 
healthcare facility meets these criteria. Admission also includes transfer within the hospital to an 
acute/intensive care unit (e.g., from the psychiatric wing to a medical floor, medical floor to a 
coronary care unit, neurological floor to a tuberculosis unit). 
Hospitalization does not include the following: 
 
• 
Rehabilitation facilities; 
• 
Hospice facilities; 
• 
Respite care (e.g., caregiver relief); 
• 
Skilled nursing facilities; 
• 
Nursing homes; 
• 
Routine emergency room admissions; 
• 
Same day surgeries (as outpatient/same day/ambulatory procedures). 
 
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
adverse event is not in itself a serious adverse event. Examples include: 
• 
Admission for treatment of a preexisting condition not associated with the development 
of a new adverse event or with a worsening of the preexisting condition (e.g., for work-up 
of persistent pre-treatment lab abnormality); 


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• 
Social admission (e.g., patient has no place to sleep); 
• 
Administrative admission (e.g., for yearly physical exam); 
• 
Protocol-specified admission during a clinical trial (e.g., for a procedure required by 
• 
the trial protocol); 
• 
Optional admission not associated with a precipitating clinical adverse event (e.g., for 
elective cosmetic surgery); 
• 
Hospitalization for observation without a medical AE; 
• 
Pre-planned treatments or surgical procedures should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient; 
• 
Admission exclusively for the administration of blood products. 
 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as adverse events. However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an adverse event. For example, an 
acute appendicitis that begins during the adverse event reporting period should be reported as 
the adverse event, and the resulting appendectomy should be recorded as treatment of the 
adverse event. 
9.7 
Severity Assessment 
If required on the adverse event case report forms, the investigator will use the following 
definitions of Severity in accordance with Cancer Therapy Evaluation Program, Common 
Terminology Criteria for Adverse Events (Version 4.03) to describe the maximum intensity of the 
adverse event. If the event is serious, the CTC grade reported in the adverse event CRF must 
be consistent with the description of CTC grade included in the narrative section of the serious 
adverse event report. 
Table 8.1: General AE Grading Assessment 
 
Grade 
Clinical Description of Severity 
0 
No change from normal or reference range 
(This grade is not included in CTCAE but may 
be used in certain circumstances) 
1 
MILD adverse event 
2 
MODERATE adverse events 
3 
SEVERE adverse events 
4 
LIFE-THREATENING OR DISABLING 
adverse events 
5 
DEATH RELATED TO adverse events 
Note the distinction between the severity and the seriousness of an adverse event. A severe 
event is not necessarily a serious event. For example, a headache may be severe (interferes 
significantly with patient's usual function) but would not be classified as serious unless it met 
one of the criteria for serious adverse events, listed above. 


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9.8 
Causality Assessment 
The investigator’s assessment of causality must be provided for all adverse events (serious and 
non-serious). An investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to an 
adverse event. If the investigator’s final determination of causality is unknown and the 
investigator does not know whether or not investigational product caused the event, then the 
event will be handled as “related to investigational product” for reporting purposes. If the 
investigator's causality assessment is "unknown but not related to investigational product", this 
should be clearly documented on trial records. 
In addition, if the investigator determines a serious adverse event is associated with trial 
procedures, the investigator must record this causal relationship in the source documents and 
CRF, as appropriate, and report such an assessment in accordance with the serious adverse 
event reporting requirements, if applicable. 
9.9 
Exposure in utero 
An exposure in-utero (EIU) occurs if: 
 
1. A female becomes, or is found to be, pregnant either while receiving or having been 
directly exposed to (e.g., environmental exposure) the investigational product, or the 
female becomes, or is found to be, pregnant after discontinuing and/or being directly 
exposed to the investigational product (maternal exposure); 
2. A male has been exposed, either due to treatment or environmental, to the 
investigational product prior to or around the time of conception and/or is exposed during 
the partner pregnancy (paternal exposure). 
 
If a woman becomes pregnant or suspects that she is pregnant while participating in this study, 
she must inform the investigator immediately and permanently discontinue study drug. 
Oncoceutics must be immediately (with 24 hours of awareness) be contacted. The pregnancy 
must be followed for the final pregnancy outcome. 
 
If any trial patient or trial patient’s partner becomes or is found to be pregnant during the trial 
patient’s treatment with the investigational product, the investigator must submit this information 
to Oncoceutics. In addition, the investigator must submit information regarding environmental 
exposure to this study drug in a pregnant woman (e.g., a nurse reports that she is pregnant and 
has been exposed to a cytotoxic product by inhalation or spillage). This must be done 
irrespective of whether an adverse event has occurred and within 24 hours of awareness of the 
pregnancy. The information submitted should include the anticipated date of delivery (see below 
for information related to induced termination of pregnancy). 
 
Follow-up is conducted to obtain pregnancy outcome information on all Exposure in Utero 
reports with an unknown outcome. The investigator will follow the pregnancy until completion or 
until pregnancy termination (i.e., induced abortion) and then notify Oncoceutics of the outcome. 
The reason(s) for an induced abortion should be specified. A serious adverse event case is 
created with the event of ectopic pregnancy. 


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9.10 Withdrawal Due to Adverse Events 
Withdrawal due to adverse event should be distinguished from withdrawal due to insufficient 
response, according to the definition of adverse event noted earlier, and recorded on the 
appropriate adverse event CRF page. When a patient withdraws due to a serious adverse 
event, the serious adverse event must be reported in accordance with the reporting 
requirements defined below. 
9.11 Eliciting Adverse Event Information 
The investigator is to report all directly observed adverse events and all adverse events 
spontaneously reported by the trial patient. In addition, each trial patient will be questioned 
about adverse events. 
9.12 Reporting Requirements 
Each adverse event is to be assessed to determine if it meets the criteria for serious adverse 
event. If a serious adverse event occurs, expedited reporting will follow local and international 
regulations, as appropriate. 
All adverse events will be reported on the adverse event page(s) of the CRF. It should be noted 
that the form for collection of serious adverse event information is not the same as the adverse 
event CRF. Where the same data are collected, the forms must be completed in a consistent 
manner. For example, the same adverse event term should be used on both forms. Adverse 
events should be reported using concise medical terminology on the CRFs as well as on the 
form for collection of serious adverse event information. 
9.12.1 Serious Adverse Event Reporting Requirements 
If a serious adverse event occurs, Oncoceutics is to be notified within 24 hours of awareness of 
the event by the investigator. In particular, if the serious adverse event is fatal or life- 
threatening, notification to Oncoceutics must be made immediately, irrespective of the extent of 
available adverse event information. This timeframe also applies to additional new information 
(follow-up) on previously forwarded serious adverse event reports as well as to the initial and 
follow-up reporting of Exposure in Utero and exposure during breast feeding cases. 
In the rare event that the investigator does not become aware of the occurrence of a serious 
adverse event immediately (e.g., if an outpatient trial patient initially seeks treatment 
elsewhere), the investigator is to report the event within 24 hours after learning of it and 
document the time of his/her first awareness of the adverse event. For all serious adverse 
events, the investigator is obligated to pursue and provide information to Oncoceutics in 
accordance with the timeframes for reporting specified above. In addition, an investigator may 
be requested by Oncoceutics to obtain specific additional follow-up information in an expedited 
fashion. This information collected for serious adverse events is more detailed than that 
captured on the adverse event case report form. In general, this will include a description of the 
adverse event in sufficient detail to allow for a complete medical assessment of the case and 


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independent determination of possible causality. Information on other possible causes of the 
event, such as concomitant medications and illnesses must be provided. In the case of a patient 
death, a summary of available autopsy findings must be submitted as soon as possible to 
Oncoceutics or its designated representative. 
9.12.2 Potential Cases of Drug-Induced Liver Injury 
While ONC201 is not expected to cause significant elevations in liver enzymes, such 
occurrence is of special interest to regulatory agencies. Abnormal values in aspartate 
transaminase (AST) and/or alanine transaminase (ALT) concurrent with abnormal elevations in 
total bilirubin that meet the criteria outlined below in the absence of other causes of liver injury 
are considered potential cases of drug-induced liver injury (potential Hy’s Law cases) and 
should always be considered important medical events. 
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the subject’s individual baseline values and underlying conditions. Subjects who 
present with the following laboratory abnormalities should be evaluated further to definitively 
determine the etiology of the abnormal laboratory values: 
A. Subjects with AST or ALT baseline values within the normal range who subsequently 
present with AST or ALT ≥3 times the upper limit of normal concurrent with a total 
bilirubin ≥2 times the upper limit of normal with no evidence of hemolysis and an alkaline 
phosphatase 
2 times the upper limit of normal or not available. 
B. Subjects with pre-existing AST or ALT baseline values above the normal range who 
subsequently present with AST or ALT ≥2 times the baseline values and ≥3 times the 
upper limit of normal, or ≥8 times the upper limit of normal (whichever is smaller) 
concurrent with a total bilirubin of ≥2 times the upper limit of normal and increased by 
one upper limit of normal over baseline or >3 times the upper limit of normal (whichever 
is smaller) with no evidence of hemolysis and an alkaline phosphatase 
2 times the 
upper limit of normal or not available. 
 
The subject should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results. This evaluation should 
include laboratory tests, detailed history and physical assessment and the possibility of hepatic 
neoplasia (primary or secondary) should be considered. In addition to repeating AST and ALT, 
laboratory tests should include albumin, creatine kinase, total bilirubin, direct and indirect 
bilirubin, gamma-glutamyl transferase (GGT), international normalized ratio (INR) and alkaline 
phosphatase. A detailed history, including relevant information, such as review of ethanol, 
recreational drug and supplement consumption, family history, sexual history, travel history, 
history of contact with a jaundiced subject, surgery, blood transfusion, history of liver or allergic 
disease, and work exposure, should be collected. Further testing for acute hepatitis A, B, or C 
infection and liver imaging (e.g., biliary tract) may be warranted. All cases confirmed on repeat 
testing as meeting criteria A or B, with no other cause for LFT abnormalities identified at the 


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time should be considered potential Hy’s Law cases irrespective of availability of all the results 
of the investigations performed to determine etiology of the abnormal LFTs. Such potential Hy’s 
Law cases should be reported as serious adverse events. 
9.12.3 Non-Serious Adverse Event Reporting Requirements 
Non-serious adverse events are to be reported on the adverse event CRF. 
 
 
10 DATA ANALYSIS/STATISTICAL METHODS 
 
 
10.1 Efficacy Evaluation 
All patients who have received a minimum of 2 cycles of study treatment had baseline 
assessments and at least one on-study tumor assessment following treatment will be 
considered evaluable for response. 
Objective Response Rate (ORR) is defined as the proportion of patients with a Complete (CR) 
or Partial Response (PR) relative to the total number of evaluable patients. Responses will be 
defined according to the International Myeloma Working Group response criteria (see Appendix 
C: Multiple Myeloma Disease Tracking for Myeloma Worksheet). 
The best overall response is the best response recorded from the start of treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started) or the withdrawal from the study. Stable 
disease will be considered the best response when observed at least after two months from 
baseline. 
Tumor responses will be analyzed in a descriptive manner. The number and percentage of 
objective response (CR+PR) will be tabulated by dose level. An ORR may be summarized for 
the RP2D expansion cohort with the corresponding 95% exact confidence interval. 
10.2 Futility Analysis 
A Bayesian method by Thall et al (1995) will be used for futility monitoring in Phase 2 of the 
study. The trial will be stopped early if Pr (ORR < 0.1 |data)>0.95. That is, the trial will be 
stopped early if there is more than a 95% probability that the ORR is lower than 10%. We 
assume that ORR follows a prior distribution of beta (0.1, 0.9). 
The futility rules will be implemented once the first 12 patients have been enrolled in Phase 2. 
The corresponding stopping boundaries are listed in the following table 10.1. For example, if 
there are no responses in the first 12 patients enrolled in Phase 2, the trial will be terminated 
early due to futility. Multc Lean software V2.1 was used for the design. If the trial continues until 
20 additional patients are evaluated, and 3 responses are observed among the 26 patients, then 
the 95% credible interval for the response rate would be (2.6%, 25.7%). 


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Table 10.1: Stopping boundaries for futility monitoring 
 
# Patients 
(inclusive) 
Stop the trial if there are this many responses 
total: 
# responders (inclusive) 
1-11 
Never stop with this many patients 
12-23 
0 
24-25 
0-1 
26 
Reach maximum number of patients, always stop 
 
 
10.3 Early Stopping Rules for Safety/adverse events: 
Adverse events will be assessed continuously throughout the study. During evaluation of the 
first cohort of 12 eligible patients, if 4 patients have to discontinue the study drug due to 
treatment-related adverse events, the study will be interrupted for consideration of dose 
reduction or termination. If 6 of a total of 26 eligible patients have to discontinue the study drug 
due to treatment-related adverse events the study will be suspended and early termination for 
excess toxicity will be considered after careful investigation of the causes of the higher than 
expected toxicities. Once the cause of the higher than anticipated toxicities has been 
determined, the study team will confer with the FCCC DSMC and IRB to make a determination 
whether accrual can be resumed or the study will be terminated early. The chance of early 
termination with a true toxicity of 30% is 51%. The chance of early termination in error (when 
true toxicity is 5%) is 0.2%. The overall study power is 85% (for detection of overly toxic 
treatment) and has type I error of 0.3%. 
 
11 QUALITY CONTROL AND QUALITY ASSURANCE 
During study conduct, Oncoceutics (or its representatives) will conduct periodic monitoring visits 
to ensure that the protocol and GCPs are being followed. The monitors will also review source 
documents to confirm that the data recorded on CRFs is accurate. Direct access to source 
documents to perform this verification will be provided. 


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12 DATA HANDLING AND RECORD KEEPING 
 
12.1 Case Report Forms/Electronic Data Record 
As used in this protocol, the term case report form (CRF) should be understood to refer to either 
a paper form or an electronic data record or both, depending on the data collection method used 
in this trial. 
A CRF is required and should be completed for each enrolled patient. The completed original 
CRFs are the sole property of FCCC and Oncoceutics, and are subject to review by appropriate 
regulatory authorities. 
It is the investigator's responsibility to ensure completion and to review and approve all CRFs. 
CRFs must be signed by the investigator or by an authorized staff member. These signatures 
serve to attest that the information contained on the CRFs is true. At all times, the investigator 
has final personal responsibility for the accuracy and authenticity of all clinical and laboratory 
data entered on the CRFs. Patient source documents are the physician's patient records 
maintained at the trial site. 
12.2 Record Retention 
To enable evaluations and/or audits from regulatory authorities, the investigator agrees to keep 
records, including the identity of all participating patients (sufficient information to link records, 
e.g., CRFs and hospital records), all original signed informed consent forms, copies of all CRFs, 
serious adverse event forms, source documents, and detailed records of treatment disposition. 
The records will be retained by the investigator according to ICH and local regulations. 
If the investigator relocates, retires, or for any reason withdraws from the trial, the trial records 
must be transferred to an acceptable designee, such as another investigator or another 
institution. 
 
13 ETHICS 
 
13.1 Institutional Review Board (IRB) 
It is the responsibility of the investigator to have prospective approval of the trial protocol, 
protocol amendments, informed consent forms, and other relevant documents, from the IRB. 
The only circumstance in which an amendment may be initiated prior to IRB approval is where 
the change is necessary to eliminate apparent immediate hazards to the patients. In that event, 
the investigator must notify the IRB in writing within 5 working days after the implementation. 
13.2 Ethical Conduct of the Trial 
The trial will be performed in accordance with the protocol, International Conference on 
Harmonization (ICH) Good Clinical Practice guidelines, and applicable local regulatory 
requirements and laws. 


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13.3 Patient Information and Consent 
All parties will ensure protection of patient personal data and will not include patient names on 
any sponsor forms, reports, publications, or in any other disclosures. High standards of 
confidentiality and protection of patient personal data. 
The informed consent form (ICF) must be approved by the IRB and must be in compliance with 
ICH GCP, local regulatory requirements, and legal requirements. 
The investigator must ensure that each trial patient, or his/her legally acceptable representative, 
is fully informed about the nature and objectives of the trial and possible risks associated with 
participation. The investigator, or a person designated by the investigator, will obtain written 
informed consent from each patient or the patient's legally acceptable representative before any 
trial-specific activity is performed. The informed consent form used in this trial, and any changes 
made during the course of the trial, must be prospectively approved by the IRB before use. The 
investigator will retain the original of each patient's signed consent form. 
 
14 DEFINITION OF END OF TRIAL 
The end of trial is defined as the time when enrollment is completed according to protocol 
planned sample size, and assessment and requirements are completed as per protocol, and the 
stated objectives of the trial are achieved. 
 
15 DISCONTINUATION CRITERIA 
Premature termination of this clinical trial may occur because of a regulatory authority decision, 
change in opinion of the IRB/IEC, drug safety problems, or at the discretion of Oncoceutics. In 
addition, Oncoceutics retains the right to discontinue development of ONC201 at any time. 
 
16 PUBLICATION OF TRIAL RESULTS 
All information regarding ONC201 supplied by Oncoceutics to the investigator is privileged and 
confidential information. The investigator agrees to use this information to accomplish the study 
and will not use it for other purposes without consent from Oncoceutics. It is understood that 
there is an obligation to provide Oncoceutics with complete data obtained during the study. The 
information obtained from the clinical study will be used toward the development of ONC201 
and may be disclosed to regulatory authority(ies), other investigators, corporate partners, or 
consultants as required. Upon completion of the clinical study and evaluation of results by 
Oncoceutics, the hospital or institution and/or investigator may publish or disclose the clinical 
trial results pursuant to the terms contained in the applicable Clinical Trial Agreement. 
It is anticipated that the results of this study will be presented at scientific meetings and/or 
published in a peer-reviewed scientific or medical journal. A Publications Group comprising 


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Oncoceutics employees and study investigators will be formed to oversee the publication of the 
study results, which will reflect the experience gained during the conduct of the study. 
A prepublication manuscript or abstract is to be provided to Oncoceutics a minimum of 30 days 
before the intended submission date of the manuscript or abstract to a publisher. Within 30 days 
after receipt by Oncoceutics of the notification, Oncoceutics shall inform the study center 
whether it has objections to the publication for reasons including, but not limited to, those 
defined below: 
• 
If patentable subject matter is disclosed, the publication shall be delayed for a period not 
to exceed 90 days from Oncoceutics’ receipt of the proposed publication to allow time for 
the filing of patent applications covering patentable subject matter. 
• 
If confidential information is contained in any proposed publication or public disclosure, 
such confidential information will be removed at Oncoceutics’ request. 
The overall principal investigator will be the last author on abstracts and publications of the data 
generated from this study. Other authors will be listed according to number of patients enrolled 
to the study. If the principal investigator has the highest enrollment, he/she may choose to be 
either first or last author. This policy may be changed with the agreement of both the 
investigators and Oncoceutics. 


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18 APPENDIX: 
 
18.1 Appendix A: List of Abbreviations 
Abbreviation 
Term 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
CNS 
Central Nervous System 
Cmax 
Maximum plasma Concentration 
CRA 
Clinical Research Associate 
CRC 
Clinical Research Coordinator 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECOG 
Eastern Cooperative Oncology Group 
FCCC 
Fox Chase Cancer Center 
H&P 
History and Physical 
ITP 
Investigational Therapeutic Protocol 
ITT 
Intention to Treat 
LDH 
Lactate Dehydrogenase 
MAD 
Maximally Administered Dose 
MTD 
Maximum Tolerated Dose 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
ORR 
Overall Response Rate 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PS 
Performance Status 
RP2D 
Recommended Phase 2 Dose 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic-Pyruvic Transaminase 
SoA 
Schedule of Activities 
ULN 
Upper Limit of Normal 
WOCBP 
Women of Child Bearing Potential 


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18.2 Appendix B: Performance Status 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time. 
Ambulatory and capable of all self- 
care, but unable to carry out any 
work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any 
self-care. Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 


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18.3 Appendix C: Multiple Myeloma Disease Tracking 
  Multiple Myeloma Disease Status Tracking 
 
Monoclonal 
Protein: 
IgA 
IgD 
IgE 
IgG 
IgM 
Light Chain: 
Kappa(κ) 
Lambda(λ) 
Values 
Yes/No 
Date 
Immuno- 
fixation 
(Serum) 
Immuno 
-fixation 
(Urine) 
SPEP 
UPEP 
24-Hour 
Urine 
κ/λ 
ratio 
% 
Plasm 
a Cells 
in BM 
Plasma- 
cytomas? 
Lytic 
Lesions?