Clinical trial NCT03394027
Conditions: Triple Negative Breast Cancer Endometrial Cancer Hormone Receptor Positive, HER2 Negative Breast Cancer
Keywords: Imipridones TNBC Metastatic Male Breast Cancer
Sponsor: National Cancer Institute (NCI)
Start date: 2018-01-17; Completion date: 2021-10-07
Enrollment: 30 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

The new drug ONC201 have been shown to kill breast cancer and endometrial cancer cells in the laboratory. The exact mechanism of action is not completely clear yet, but the ONC201 destroys the mitochondria inside the cells. Blocking mitochondrial activity may kill tumor cells, which would shrink tumors. Researchers want to see if ONC201 helps shrink tumors of certain breast or endometrial cancers and if that effect is maintained.

Objective:

To see if ONC201 shrinks tumors with a lasting effect.

Eligibility:

Adults ages 18 and older who have metastatic breast cancer (hormone-positive or triple-negative) or metastatic endometrial cancers.

Design:

Participants will be screened with:

* Medical history
* Physical exam
* Heart, blood, and urine tests
* Computed tomography (CT) and bone scans
* Review of medical report and tumor sample
* Participants will have a tumor biopsy before starting treatment and after 5 weeks taking the study drug. A scan or ultrasound may be used to guide the biopsy. Patients will receive local anesthetic and a needle will remove a small piece of tumor.
* The study will be done in 28-day cycles. Every day 1 of each cycle participants will repeat most screening tests, will be seen by the physician and receive a supply of the study drug.
* Participants will take the study drug by mouth once every 7 days. They will keep a diary of when they take the drug and any side effects. During cycle 1, participants will get weekly calls to discuss their health and symptoms. Images will be repeated every 2 cycles to evaluate response to the treatment.

Detailed description:
Background:

* Advanced breast cancer and endometrial cancer have limited treatment options. Current treatments provide a modest improvement in progression free survival, but no treatments improve survival.
* ONC201 is the founding member of a novel class of anticancer drugs called imipridones. The exact mechanism of ONC201 is unknown at this time, but preclinical data suggests that it causes global downregulation of mitochondrial genes leading to mitochondrial damage and ultimately non-apoptotic cell death.
* Preclinical studies have demonstrated that ONC201 selectively kills various cancer cells, including breast cancer cells (hormone-receptor positive cell lines, human epidermal growth factor receptor 2 (HER2+) cell line as well as triple negative breast cancer cell lines) and endometrial cancer cells, while having little effect on normal cells.
* An on-going phase I study of ONC201 has demonstrated clinical benefit in some solid tumors, including endometrial cancer.

Objectives:

* Cohort 1: To determine the progression free survival (PFS) at 8 months of ONC201 in metastatic hormone receptor positive breast cancer (HR+BC)
* Cohort 2: To determine the overall response rate (ORR) of ONC201 in metastatic triple negative breast cancer (TNBC)
* Cohort 3: To determine the overall response rate (ORR) of ONC201 in advanced endometrial cancer (EC)

Eligibility:

Selected Inclusion Criteria

* Histologically confirmed metastatic breast cancer or endometrial cancer with appropriate immunohistochemistry (IHC) testing and confirmation of HER2 non-amplification required for the breast cancer cohorts (cohorts 1 and 2)
* Age 18 years or older
* Female and male breast cancer patients are eligible for the breast cancer cohorts
* Eastern Cooperative Oncology Group (ECOG) 0 or 1
* Measurable metastatic disease with greater than or equal to 1 biopsiable lesion with willingness to undergo a biopsy
* Cohort 1 Hormone receptor + breast cancer (HR+BC) requires prior treatment with greater than or equal to 2 lines of hormonal treatment. No prior treatment required for cohorts 2/3 (TNBC and EC).
* Adequate hematopoietic, hepatic and renal function

Selected Exclusion Criteria

* Patients who have received chemotherapy in the previous 3 weeks (6 weeks for nitrosoureas or mitomycin); other investigational agents within 3 weeks or a programmed cell death protein 1 (PD1)/programmed death-ligand 1 (PDL1) agent within 4 weeks prior to first dose of study treatment.
* Radiotherapy less than or equal to 4 weeks before first dose of study treatment.
* Symptomatic central nervous system (CNS) metastases. Asymptomatic or brain metastases treated greater than 4 weeks from first dose of study treatment are allowed.
* History of invasive malignancy less than or equal to 3 years
* Known history of cardiac arrhythmias including uncontrolled atrial fibrillation, tachyarrhythmias or bradycardia.
* History of congestive heart failure (CHF), or myocardial infarction (MI) or stroke in the previous 3 months will be excluded.
* Started denosumab or bisphosphonate therapy within 28 days prior to Cycle 1 Day 1
* Human immunodeficiency virus (HIV), Hepatitis B, or Hepatitis C infection

Design:

* This is a phase II single arm study of ONC201 divided in three cohorts, each cohort with different type of metastatic, advanced disease:
* Cohort 1: HR+ breast cancer (male and female)
* Cohort 2: Triple negative breast cancer (male and female)
* Cohort 3: Endometrial cancer (female only)
* All patients will receive ONC201 at the recommended phase 2 dose (RP2D) of 625mg by mouth every 7 days with each cycle being 28 days long. Patients will receive ONC201 as long as they derive clinical benefit or toxicity becomes impeditive
* Patients will be evaluated for toxicity every 4 weeks by Common Terminology Criteria for Adverse Events (CTCAE) v5.0 and for response every two cycles (8 weeks) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

Arms: arm 1: Single arm divided in three cohorts, each cohort with a different type of metastatic disease: estrogen receptor (ER) + breast cancer, triple negative breast cancer, and endometrial cancer
Interventions: intervention 1: ONC201
Intervention descriptions: intervention 1: 625 mg by mouth every 7 days; each cycle = 28 days. Patients will receive ONC201 as long as they derive clinical benefit or toxicity becomes impeditive.

Protocol documents:
Prot_SAP_000.pdf: 
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Abbreviated Title: ONC201 in advanced cancers 
Version Date: 06/17/2020 
 
Abbreviated Title: ONC201 in advanced cancers 
CC Protocol #: 18-C-0034 
Amendment:  E 
Version Date: 06/17/2020 
NCT Number: NCT03394027 
 
Title: A Phase 2 Study of ONC201 in recurrent/refractory metastatic breast cancer and advanced 
endometrial carcinoma   
 
NCI Principal Investigator: 
Alexandra Zimmer, MD 
 
Women’s Malignancies Branch (WMB), CCR, NCI  
National Cancer Institute  
Building 10, Room 2B50A  
9000 Rockville Pike  
Bethesda, MD 20892  
Phone: 240-760-6132 
Email: alexandra.zimmer@nih.gov 
 
 
Investigational Agents:     
Drug Name: 
ONC201 
IND Number: 
136939 
Sponsor: 
Center for Cancer Research 
Manufacturer: 
Oncoceutics, Inc 


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PRÉCIS  
Background: 
• Advanced breast cancer and endometrial cancer have limited treatment options. Current 
treatments provide a modest improvement in progression free survival but no treatments 
improve survival.  
• ONC201 is the founding member of a novel class of anticancer drugs called imipridones. 
The exact mechanism of ONC201 is unknown at this time, but preclinical data suggests 
that it causes global downregulation of mitochondrial genes leading to mitochondrial 
damage and ultimately non-apoptotic cell death.  
• Preclinical studies have demonstrated that ONC201 selectively kills various cancer cells, 
including breast cancer cells (hormone-receptor positive cell lines, HER2+ cell line as 
well as triple negative breast cancer cell lines) and endometrial cancer cells, while having 
little effect on normal cells. 
• An on-going phase I study of ONC201 has demonstrated clinical benefit in some solid 
tumors, including endometrial cancer.  
Objectives: 
• Cohort 1: To determine the progression free survival (PFS) at 8 months of ONC201 in 
metastatic hormone receptor positive breast cancer (HR+BC) 
• Cohort 2: To determine the overall response rate (ORR) of ONC201 in metastatic triple 
negative breast cancer (TNBC)  
• Cohort 3: To determine the ORR of ONC201 in advanced endometrial cancer (EC) 
 
Eligibility:  
Selected Inclusion Criteria  
• Histologically confirmed metastatic breast cancer or endometrial cancer with appropriate 
IHC testing and confirmation of HER2 non-amplification required for the breast cancer 
cohorts (cohorts 1 and 2) 
• Age 18 years or older  
• Female and male breast cancer patients are eligible for the breast cancer cohorts 
• ECOG 0 or 1 
• Measurable metastatic disease with  >1 biopsiable lesion with willingness to undergo a 
biopsy 
• Cohort 1 (HR+BC) requires prior treatment with >2 lines of hormonal treatment. No 
prior treatment required for cohorts 2/3 (TNBC and EC).  
• Adequate hematopoietic, hepatic and renal function 
 
Selected Exclusion Criteria   
• Patients who have received chemotherapy in the previous 3 weeks (6 weeks for 
nitrosoureas or mitomycin); other investigational agents within 3 weeks or a PD1/PDL1 
agent within 4 weeks prior to first dose of study treatment.  


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• Radiotherapy < 4 weeks before first dose of study treatment 
• Symptomatic CNS metastases. Asymptomatic or brain metastases treated > 4 weeks from 
first dose of study treatment are allowed.  
• History of invasive malignancy < 3 years 
• Known history of cardiac arrhythmias including uncontrolled atrial fibrillation, 
tachyarrhythmias or bradycardia.  
• History of CHF, or MI or stroke in the previous 3 months will be excluded. 
• Started denosumab or bisphosphonate therapy within 28 days prior to Cycle 1 Day 1 
• HIV, Hepatitis B, or Hepatitis C infection 
 
Design: 
• This is a phase II single arm study of ONC201 divided in three cohorts, each cohort with 
a different type of metastatic, advanced disease:  
o Cohort 1: HR+ breast cancer (male and female) 
o Cohort 2: Triple negative breast cancer (male and female) 
o Cohort 3: Endometrial cancer (female only) 
• All patients will receive ONC201 at the recommended phase 2 dose (RP2D) of 625mg by 
mouth every 7 days with each cycle being 28 days long. Patients will receive ONC201 as 
long as they derive clinical benefit or toxicity becomes impeditive 
• Patients will be evaluated for toxicity every 4 weeks by CTCAE v5.0 and for response 
every two cycles (8 weeks) by RECIST 1.1.  
 
 
 
 


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STUDY SCHEMA 
 
 
 
Study Schema Figure  
 
*See Table 1 for dose reductions  
 
 
 
Table 1: ONC201 Dose Reduction Schedule  
 
Dose Level  
(DL) 
ONC201  
(by mouth) 
1 (Starting Dose) 
625mg every 7 days 
-1 
500mg every 7 days 
-2 
375mg every 7 days 
-3 
250mg every 7 days 
Cohort 1: HR+BC   
Cohort 2: TNBC   
Cohort 3: EC
ONC201 625mg* by 
mouth every 7 days. 
A cycle is 28 days
Disease progression, 
patient withdraw or 
toxicities 


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TABLE OF CONTENTS  
PRÉCIS ........................................................................................................................................... 2 
TABLE OF CONTENTS ................................................................................................................ 5 
1 
INTRODUCTION ................................................................................................................ 10 
1.1 
Study Objectives ............................................................................................................ 10 
1.1.1 
Primary Objective ................................................................................................... 10 
1.1.2 
Secondary Objectives .............................................................................................. 10 
1.1.3 
Exporatory Studies: ................................................................................................. 10 
1.2 
Background and Rationale ............................................................................................. 10 
1.2.1 
Current Standards of Care for Recurrent/Refractory Invasive Breast Cancer ........ 10 
1.2.2 
Current Standards of Care for Endometrial Cancer ................................................ 11 
1.2.3 
Development of ONC201 ....................................................................................... 12 
1.2.4 
Pharmaceutical Manufacturer Updates ................................................................... 16 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT ....................................................... 17 
2.1 
Eligibility Criteria for Cohort 1: Hormone Receptor Positive Breast Cancer ................ 17 
2.1.1 
Inclusion Criteria .................................................................................................... 17 
2.1.2 
Exclusion Criteria ................................................................................................... 18 
2.2 
Eligibility Criteria for Cohort 2: Triple Negative Breast Cancer ................................... 19 
2.2.1 
Inclusion Criteria .................................................................................................... 19 
2.2.2 
Exclusion Criteria ................................................................................................... 21 
2.3 
Eligibility Criteria for Cohort 3: Endometrial Cancer ................................................... 22 
2.3.1 
Inclusion Criteria .................................................................................................... 22 
2.3.2 
Exclusion Criteria ................................................................................................... 23 
2.4 
Recruitment Strategies ................................................................................................... 23 
2.5 
Screening Evaluation ...................................................................................................... 24 
2.5.1 
Screening activities performed prior to obtaining informed consent ...................... 24 
2.5.2 
Screening activities performed after a consent for screening has been signed ....... 24 
2.6 
Participant Registration and Status Update Procedures ................................................. 26 
2.7 
Screen Failures ............................................................................................................... 26 
2.8 
Treatment Assignment and Randomization/Stratification Procedures .......................... 26 
2.9 
Baseline Evaluation ........................................................................................................ 27 
3 
STUDY IMPLEMENTATION ............................................................................................ 28 


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3.1 
Study Design .................................................................................................................. 28 
3.2 
Drug Administration ...................................................................................................... 28 
3.2.1 
Self-Administered Study Drugs: ............................................................................. 28 
3.3 
Dose Modifications/Delays and Management of Toxicities .......................................... 29 
3.3.1 
Modifications and Toxicity Management ............................................................... 29 
3.3.2 
Medication Delay .................................................................................................... 30 
3.3.3 
Instructions on Missed Doses ................................................................................. 31 
3.4 
Study Calendar ............................................................................................................... 32 
3.5 
Criteria for Removal from Protocol Therapy and Off Study Criteria ............................ 35 
3.5.1 
Criteria for removal from protocol therapy ............................................................ 35 
3.5.2 
Off-Study Criteria ................................................................................................... 35 
4 
CONCOMITANT MEDICATIONS/MEASURES .............................................................. 35 
4.1 
Restrictions ..................................................................................................................... 36 
4.2 
Contraception ................................................................................................................. 36 
5 
BIOSPECIMEN COLLECTION .......................................................................................... 36 
5.1 
Correlative Studies for Research/Pharmacokinetic Studies ........................................... 36 
5.2 
Genomic Alterations in Breast and Endometrial Cancers .............................................. 38 
5.3 
Tumor biopsies ............................................................................................................... 39 
5.3.1 
Timing* ................................................................................................................... 39 
5.3.2 
Tissue Sampling and Handling ............................................................................... 39 
5.4 
Blood samples ................................................................................................................ 40 
5.4.1 
Timing ..................................................................................................................... 40 
5.4.2 
Sampling and Handling ........................................................................................... 40 
5.5 
Table 5: Specimen Collection and Storage .................................................................... 42 
5.6 
Sample Storage, Tracking and Disposition .................................................................... 49 
5.6.1 
Patient sample protections ...................................................................................... 49 
5.6.2 
Sample Storage, Tracking and Disposition (CPC) ................................................. 49 
5.6.3 
Laboratory of Jane Trepel ....................................................................................... 50 
5.6.4 
Procedures for storage of tissue specimens in the Laboratory of Pathology .......... 51 
5.6.5 
End of Study ........................................................................................................... 51 
5.7 
Samples for Genetic/Genomic Analysis ........................................................................ 51 
5.7.1 
Certificate of Confidentiality .................................................................................. 52 


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6 
DATA COLLECTION AND EVALUATION ..................................................................... 52 
6.1 
Data Collection ............................................................................................................... 52 
6.1.1 
Source Documents .................................................................................................. 53 
6.1.2 
Case Report Forms .................................................................................................. 53 
6.2 
Data Sharing Plans ......................................................................................................... 53 
6.2.1 
Human Data Sharing Plan ....................................................................................... 53 
6.2.2 
Genomic Data Sharing Plan .................................................................................... 54 
6.3 
Response Criteria ........................................................................................................... 54 
6.3.1 
Disease Parameters ................................................................................................. 54 
6.3.2 
Methods for Evaluation of Measurable Disease ..................................................... 55 
6.3.3 
Response Criteria .................................................................................................... 57 
6.3.4 
Duration of Response .............................................................................................. 59 
6.3.5 
Progression-Free Survival ....................................................................................... 59 
6.4 
Toxicity Criteria ............................................................................................................. 59 
7 
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN .... 60 
7.1 
Definitions ...................................................................................................................... 60 
7.2 
OHSRP Office of Compliance and Training / IRB Reporting ....................................... 60 
7.2.1 
Expedited Reporting ............................................................................................... 60 
7.2.2 
IRB Requirements for PI Reporting at Continuing Review ................................... 60 
7.3 
NCI CLINICAL DIRECTOR REPORTING ................................................................. 60 
7.4 
NIH Required Data and Safety Monitoring Plan ........................................................... 60 
7.4.1 
Principal Investigator/Research Team .................................................................... 60 
8 
SPONSOR SAFETY REPORTING ..................................................................................... 61 
8.1 
Definitions ...................................................................................................................... 61 
8.1.1 
Adverse Event ......................................................................................................... 61 
8.1.2 
Serious Adverse Event (SAE) ................................................................................. 61 
8.1.3 
Life-threatening....................................................................................................... 61 
8.1.4 
Severity ................................................................................................................... 62 
8.1.5 
Relationship to Study Product ................................................................................ 62 
8.2 
Assessment of Safety Events .......................................................................................... 62 
8.3 
Reporting of Serious Adverse Events ............................................................................ 62 
8.4 
Safety Reporting Criteria To The Pharmaceutical Collaborators .................................. 63 


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8.5 
Reporting Pregnancy ...................................................................................................... 64 
8.5.1 
Maternal exposure ................................................................................................. 64 
8.5.2 
Paternal exposure .................................................................................................... 64 
8.6 
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND .................. 64 
9 
Clinical Monitoring ............................................................................................................... 64 
10 STATISTICAL CONSIDERATIONS.................................................................................. 65 
10.1 
Statistical Hypothesis ................................................................................................. 65 
10.2 
Sample Size Determination ........................................................................................ 65 
10.3 
Populations for Analyses ............................................................................................ 67 
10.4 
Statistical Analyses ..................................................................................................... 67 
10.4.1 General Approach ................................................................................................... 67 
10.4.2 Analysis of the Primary Endpoints ......................................................................... 67 
10.4.3 Analysis of the Secondary Endpoints ..................................................................... 67 
10.4.4 Safety Analyses ....................................................................................................... 68 
10.4.5 Baseline Descriptive Statistics ................................................................................ 68 
10.4.6 Planned Interim Analyses ....................................................................................... 68 
10.4.7 Sub-Group Analyses ............................................................................................... 68 
10.4.8 Tabulation of individual Participant Data ............................................................... 68 
10.4.9 Exploratory Analyses .............................................................................................. 68 
11 COLLABORATIVE AGREEMENTS ................................................................................. 69 
11.1 
Clinical Trial Agreement ............................................................................................ 69 
12 HUMAN SUBJECTS PROTECTIONS ............................................................................... 69 
12.1 
Rationale For Subject Selection ................................................................................. 69 
12.2 
Participation of Children ............................................................................................ 69 
12.3 
Participation of Subjects Unable to Give Consent ..................................................... 69 
12.4 
Evaluation of Benefits and Risks/Discomforts ........................................................... 69 
12.5 
Risks/Benefits Analysis .............................................................................................. 70 
12.5.1 Benefits ................................................................................................................... 70 
12.5.2 Risks ........................................................................................................................ 70 
12.5.3 Risks/Benefits Analysis .......................................................................................... 71 
12.6 
Consent Process and Documentation ......................................................................... 71 
12.6.1 Request for Waiver of Consent for Screening Activities ........................................ 71 


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13 PHARMACEUTICAL INFORMATION ............................................................................. 72 
13.1 
Drug ONC201 (IND # 136939) .................................................................................. 72 
13.1.1 Source ..................................................................................................................... 72 
13.1.2 Toxicity ................................................................................................................... 72 
13.1.3 Formulation and preparation ................................................................................... 74 
13.1.4 Stability and Storage ............................................................................................... 74 
13.1.5 Incompatibilities ..................................................................................................... 75 
14 REFERENCES ..................................................................................................................... 76 
15 APPENDICES ...................................................................................................................... 81 
15.1 
Appendix A-Performance Status Criteria ................................................................... 81 
15.2 
Appendix B- Method for Preparing PBMC Samples from Blood For 
Pharmacodynamic (PD) Studies ............................................................................................... 82 
15.3 
Appendix C – SOP for Cytokine Collection .............................................................. 83 
15.4 
Appendix D- Standard Operating Procedure for Plasma and Buffy coat collection for 
circulating tumor DNA ............................................................................................................. 85 
15.5 
Appendix E- Oral Medication Diary .......................................................................... 87 
15.6 
Appendix F- Oncoceutics Specimen Collection, Processing, Storage and Shipping . 89 
15.6.1 Serum Sample Supplies .......................................................................................... 90 
15.6.2 Plasma Processing ................................................................................................... 91 
15.6.3 Serum Processing .................................................................................................... 92 
15.6.4 Arranging for Shipments......................................................................................... 94 
15.6.5 Oncoceutics Specimen Shipping Form ................................................................... 99 
 
 
 


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1 
INTRODUCTION 
1.1 
STUDY OBJECTIVES 
1.1.1 Primary Objective 
• Cohort 1 HR+BC - To determine the progression free survival  at 8 months (PFS by 
RECIST) of ONC201 in patients with refractory, metastatic hormone receptor positive 
breast cancer  
• Cohort 2 TNBC - To determine the overall response rate (ORR; CR + PR by RECIST) of 
ONC201 in patients with metastatic triple negative breast cancer  
• Cohort 3 Endometrial Cancer - To determine the ORR of ONC201 in patients with 
advanced or metastatic endometrial cancer  
1.1.2 Secondary Objectives 
• Cohort 1 HR+BC – Safety, ORR, clinical benefit rate (CBR; CR + PR + SD by RECIST)  
• Cohort 2 TNBC – Safety, CBR, PFS  
• Cohort 3 Endometrial Cancer – Safety, CBR, PFS  
1.1.3 Exporatory Studies:  
The primary goal of the exploratory studies is to identify potential predictive biomarkers of 
response as well as additional evidence of the mechanism of action of and resistance to ONC201. 
These will be performed in an exploratory fashion on select patients if there are adequate 
samples for analysis.  
 
1.2 
BACKGROUND AND RATIONALE 
This is a phase II study of ONC201 for the treatment of metastatic hormone receptor positive 
breast cancer, metastatic triple negative breast cancer, and endometrial cancer. At this time, there 
is no clear benefit to the combination of ONC201 plus anti-HER2 therapies. However, we plan 
to develop preclinical data for ONC201 in combination with HER2 targeted drugs (e.g., 
trastuzumab, trastuzumab emtansine, and lapatinib) and we anticipate initiating a Phase I run-in 
study at a later date.  
 
1.2.1 Current Standards of Care for Recurrent/Refractory Invasive Breast Cancer  
Invasive breast cancer remains the most common malignancy in women in the United States with 
an annual incidence of 123.1 cases per 100,000 women (5). Treatment of invasive breast cancer 
involves local control with surgery and/or radiation where appropriate, as well as systemic 
control with endocrine therapy, HER2 targeted therapy, and chemotherapy. Despite advances in 
early detection and effective treatments, breast cancer is the second most common cause of US 
cancer deaths in women with an annual rate of 21.9 deaths per 100,000 women (5). It is 
estimated that in 2017, there will be 252,710 new cases of breast cancer with 40,610 deaths (6). 


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1.2.1.1 Hormone Receptor Positive Breast Cancer  
Hormone receptor positive breast cancer (HR+BC) accounts for approximately 75% of all breast 
cancers and is defined by immunohistochemical (IHC) staining of at least  1% of tumor cells 
with estrogen receptors and/or  1% with progesterone receptors. Despite optimal treatment, up 
to 30% of women with node-negative breast cancer recur after their initial diagnosis. While the 
risk is greatest within the first two years of diagnosis, women with HR+BC have an increased 
risk for recurrence up to 25 years after diagnosis (7, 8). Recurrence can be loco-regional or 
metastatic. Once metastatic, there are limited effective treatments and overall prognosis is poor.  
Generally, patients with metastatic or recurred disease are first treated with endocrine therapy 
alone (e.g. tamoxifen, aromatase inhibitors, or fulvestrant) or, more recently, endocrine therapy 
in combination with CDK 4/6 inhibitors or mTOR inhibitors (9). However, once the cancer is 
determined to be hormone refractory, chemotherapy is the next treatment option.  
Combination chemotherapy regimens have higher response rates and longer progression free 
survival (PFS), but with higher toxicity profiles and no added survival benefit when compared to 
single agent chemotherapy regimens (10). Therefore, the use of sequential single agents is the 
favored regimen once the cancer is refractory to endocrine therapy. Preferred single agents, like 
paclitaxel or capecitabine, carry a PFS of 5.7 to 8.0 months (11, 12). Both endocrine therapy and 
chemotherapy in this setting have been shown to have palliative benefit but no curative therapies 
exist.  
 
1.2.1.2 Triple Negative Breast Cancer  
Triple-negative breast cancer (TNBC) accounts for 10-20% of all breast cancers, and is defined 
by the absence of estrogen and progesterone receptors (ER, PR) and the absence of HER2 
amplification or over-expression (13). Thus, patients with TNBC do not benefit from known 
targeted therapies to ER or HER2 (14). Standard therapy for metastatic TNBC is single agent 
chemotherapy and, in metastatic patients, ORRs are around 30-35%, with median PFS 4.5-6 
months, and median OS around 12 months (15).  Clearly, new approaches to the treatment of 
TNBC are needed to improve outcomes.   
 
1.2.2 Current Standards of Care for Endometrial Cancer  
Endometrial adenocarcinoma is the most common malignancy of the female genital tract with an 
estimated 61,380 new cases and 10,920 deaths in 2017 (6). While endometrial cancer is often 
found in early stages due to irregular vaginal bleeding in a predominantly postmenopausal 
population, there has been a recent increase in cancer-related mortality (16). This is suspected to 
be due to an increase in advanced-stage cancers, high risk histologies (e.g., serous carcinomas or 
clear cell carcinomas) and patients being diagnosed at an older age (16). In addition, there is an 
increased risk of endometrial cancer in patients with Lynch Syndrome (17). 
Multi-agent chemotherapy regimens are preferred in the relapsed or advanced/metastatic setting. 
Current first line chemotherapy regimens have response rates ranging from 21% to 81%. These 


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responses are of short duration with median progression free survival of approximately one year 
(18, 19). Due to a relatively low toxicity profile and multiple studies demonstrating improved 
survival, carboplatin and paclitaxel is the preferred regimen for advanced/metastatic or recurrent 
endometrial cancer with response rates of 40 to 62% and overall survival from 13 to 29 months 
(20). If a multi-drug regimen cannot be tolerated, single agent treatment with paclitaxel (most 
active), cisplatin, carboplatin, doxorubicin, liposomal doxorubicin, topotecan, or docetaxel can 
be used. However, response rates with single agents are lower (first-line treatment response rate 
21% to 36%; second line treatment response rates 4% to 27%) (21). None of these therapies are 
curative and second line therapies have not been shown to improve survival (21). New therapies 
are needed to improve outcomes in patients with advanced stage endometrial cancers. 
 
1.2.3 Development of ONC201 
1.2.3.1 Preclinical Development of ONC201 
ONC201 (also known as TIC10 and NSC350625) is the founding member of a novel class of 
anti-cancer compounds called imipridones (22). It is an orally active small molecule that was 
initially identified by a screen for small molecules that could induce tumor necrosis factor (TNF) 
–related apoptosis-inducing ligand (TRAIL) on colon cancer cells, and activate the TRAIL death 
receptors on those cells inducing an autocrine apoptotic death.  


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TRAIL is a type II transmembrane 
protein that is expressed in various 
tissues and cells including the surface 
of Natural Killer (NK) and T cells, macrophages and dendritic cells (23, 24). On immune cells, 
the expression of TRAIL plays a role in immune surveillance in the prevention of tumors and 
metastasis (25). Humans have five distinct TRAIL receptors (26, 27). Death receptor 4 (DR4) 
and DR5 contain intracellular death 
domains and are capable of signaling 
apoptosis. There are two membrane-
bound decoy receptors called DcR1 
and DcR2 which lack a functional 
death domain and while unable to 
activate apoptosis, are able to inhibit 
TRAIL signaling. Osteoprotogerin is 
the fifth TRAIL-binding receptor 
which also functions as a 
decoy/inhibitor by sequestering 
TRAIL extracellularly. TRAIL is 
attractive as an anti-tumor agent 
because of its capability to induce 
apoptosis in cancer cells by activating 
DR4 and DR5 with little toxicity 
against normal cells (23, 28).  In our 
preclinical work, we have shown that 
TRAIL receptor agonists are most 
active against triple negative breast 
cancer and in particular those with 
mesenchymal features (29, 30).   
Despite their robust cell killing of 
tumor cells in vitro and in animal 
models in vivo, efficacy of TRAIL 
receptor agonists has been limited in 
clinical trials.  The limited activity is 
thought to be due to lack of reliable 
predictive biomarkers of sensitivity 
and drug properties that limit efficacy 
such as short serum half-life, stability, and bio-distribution (25, 28, 31). There is a need to find 
alternative approaches to activating the DR pathways.  ONC201 induces sustained up-regulation 
of TRAIL in tumor cell lines, which activates DR through autocrine and paracrine mechanisms.  
Several alternative mechanisms have also been proposed for the anticancer activity of ONC201, 
including inhibition of the dopamine receptor D2 (DRD2), and activation of an atypical 
integrated stress response in tumor cells (32, 33). 
Figure 1: Structure and mechanism of action of ONC201. In 
the TRAIL-dependent pathway, ONC201 inhibits both AKT and 
MEK, resulting in the dephosphorylation of the transcription 
factor FOXO3a. This enables its translocation from the 
cytoplasm into the nucleus where it binds to the TRAIL 
promoter and upregulates gene transcription of TRAIL. 
Apoptosis occurs through activation of TRAIL-DR receptors. In 
the TRAIL-independent pathway, ONC201 induces a stress 
response through an unknown mechanism which differs 
between solid tumors and hematologic malignancies. The 
mechanism of ONC201 appears to be different in breast cancer 
cell lines, where ONC201 demonstrates caspase-independent, 
DR4/5 independent mechanisms distinct from TRAIL-induced 
apoptosis. Instead it induces mitochondrial dysfunction and 
ATP depletion.  Image adapted from Greer and Lipkowitz, 
2016: (3). 


14 
Abbreviated Title: ONC201 in advanced cancers 
Version Date: 06/17/2020 
 
ONC201 has been extensively 
investigated in the Lipkowitz 
lab as a promising means to 
kill tumor cells. Rather than a 
simple induction of TRAIL 
and induction or DR receptor-
dependent apoptosis, both the 
Lipkowitz lab and independent 
labs have shown that ONC201 
has both TRAIL-dependent 
and TRAIL-independent 
pathways of inducing death 
(Figure 1– two right sided 
pathways).  
 
We have investigated the 
mechanism by which ONC201 
kills breast cancer cells. 
Unexpectedly, ONC201 did 
not induce caspase 3 or PARP 
cleavage, and its toxicity was 
not inhibited by Z-VAD-
FMK, nor by siRNA 
knockdown of DR4 or DR5.  By contrast GST-TRAIL induced caspase 3 and PARP cleavage 
and GST-TRAIL-induced cell death was inhibited by Z-VAD- FMK and by siRNA knockdown 
of DR5.  Live cell imaging revealed ONC201 induces cell membrane ballooning followed by 
rupture consistent with necrosis, whereas GST-TRAIL induced classic apoptosis morphology. 
Together these results suggest that ONC201 kills breast cancer cells via a caspase-independent, 
DR4/5-independent mechanism distinct from TRAIL-induced apoptosis. ONC201 does induce 
ATF4 and CHOP, consistent with the recently published observations of another group (32, 33).   
Further mechanistic studies in the Lipkowitz lab showed that ONC201 induced transcriptional 
down regulation of multiple nuclear encoded mitochondrial genes, resulting in decreased 
mitochondrial oxidative phosphorylation and ATP production (Figure 1– right pathway). Our 
data suggest that in addition to the published mechanisms, ONC201 can kill breast cancer cells 
by a novel mechanism involving inhibition of mitochondrial respiration. In breast cancer cells 
this appears to be the dominant mechanism. One of the reasons for conducting this trial in the 
Intramural program is to validate and expand our understanding of ONC201’s mechanism of 
action in the human. Such data will translate back to the bench, enabling the development of 
combination therapies and plans for overcoming resistance.  
We have tested ONC201 across a range of breast cancer cell lines and have found that all 
subtypes are inhibited by ONC201, and the IC50s for the cell lines range from 0.8-5µM (Figure 
2).  This is within the achievable concentrations that were seen in pharmacokinetic studies from 
phase I studies (2). 
20160422
ER+
HER2+
TNBC
(BaA)
TNBC
(BaB)
Colon 
cancer
T47D 
MCF7
BT474
SKBR3
HCC1954
AU565
HCC1937
MB468
HCC1187
BT20
MDAMB231
Hs578T
MDAMB436
HCC38
hTERT-HME1
HCT116
0
2
4
6
(uM)
n=8
n=3
n=4
n=10
n=3
n=3
n=4
n=8
n=4
n=3
n=17
n=4
n=3
n=3
n=3
n=3
IC50 of ONC201 in various cell lines
(5 days treatment)
T47D
MCF7
BT474
SKBR3
HCC1954
AU565
HCC1937
MB468
HCC1187
BT20
MDAMB231
Hs578T
MDAMB436
HCC38
hTERT-HME1
HCT116
3.6940
2.4000
1.8870
1.3160
1.1150
0.7908
2.1550
1.2920
0.7898
0.8858
2.0190
0.6431
4.8270
1.9120
1.5420
1.8400
(uM)
IC50
Figure 2:  IC50 for breast cancer cell lines treated with ONC201.  Cells 
were treated with a dose curve of ONC201 for 5 days and viability 
measured by MTS assay.  The data represent the mean IC50 for each cell 
line (Greer and Lipkowitz, unpublished observations). 


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Abbreviated Title: ONC201 in advanced cancers 
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ONC201 has been evaluated as a 
therapeutic agent in vitro as well 
as in vivo in various cell lines. 
Single-dose experiments in 
HCT116 wild-type (human colon 
cancer) xenograft–bearing mice 
corroborated the antitumor 
activity of ONC201 (TIC10) 
(Figure 3). In vivo experiments 
have shown promising anti-tumor 
effects in 12 subcutaneous 
xenographs (including triple 
negative breast cancer, non-small 
cell lung cancer, hepatocellular 
carcinoma, glioblastoma, colon 
cancer and head and neck 
squamous cell carcinoma), one 
orthotopic xenograph 
(glioblastoma) and one transgenic (lymphoma) model. Dr. El-Deiry’s group has demonstrated 
that ONC201 inhibits xenografts of the triple negative breast cancer cell line MDA-MB-231 (1).  
 
1.2.3.2 Clinical Development of ONC201 
Due to preclinical results, ONC201 is currently being investigated in phase I and II trials in 
patients with refractory solid tumors including glioblastoma as well as in patients with 
relapsed/refractory non-Hodgkin’s lymphoma, relapsed/refractory acute leukemias and high-risk 
myelodysplastic syndromes. Many of these trials are ongoing, but results from the first-in-human 
phase I trial of ONC201 in patients with refractory solid tumors are promising (2, 4). The trial 
enrolled 28 patients with 15 different types of tumors including prostate cancer, endometrial 
cancer, ovarian cancer, colon cancer, gallbladder cancer and sarcoma. In this heavily treated 
population (average of 5-6 prior treatments), researchers found prolonged stable disease in many 
patients, as well as disease reduction in others patients, most notably in those with endometrial or 
prostate cancer. This trial also evaluated the safety and tolerability of ONC201. The 
recommended phase 2 dose (RP2D) was determined to be 625mg by mouth q3 weeks and dosing 
was subsequently adjusted to weekly dosing due to pharmacokinetic studies. 
There have been no deaths attributed to study drug. There have been no SAEs assessed by the 
investigators as “probably” or “definitely” related to study drug, and no discontinuation of 
ONC201 due to toxicity has been reported.The most common AEs reported as possibly related to 
ONC201 were mild/moderate nausea, vomiting, anorexia, pyrexia and fatigue.  
More than 70 patients with advanced solid tumors and hematological malignancies were 
evaluated in phase I clinical trials and no serious side effects were found attributable to 
ONC201. Grade I adverse events that have been observed and reported include fever, 
nausea, vomiting, fatigue, and elevated serum amylase that were attributed as possibly-
related to ONC201. One Grade II allergic reaction occurred that was managed with standard 
Figure 3: Bioluminescence imaging of luciferase-
expressing HCT116 p53−/− xenografts that received a 
single intraperitoneal injection of ONC201 (TIC10) or 
vehicle (n = 6). Image from Allen et al, 2013 (1).    


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Abbreviated Title: ONC201 in advanced cancers 
Version Date: 06/17/2020 
 
medications. One Grade III event neutropenia was transiently observed. No other Grade III 
or IV events were reported so far. 
 
 
 
The lesion-by-
lesion results of 
this phase 1 
study were 
recently reported 
(Figure 4) (2, 4).  
In this phase I 
study, 3 of 5 
patients with 
endometrial 
cancer had stable 
disease by 
RECIST criteria 
(> 4 months in 2 
and >10 months 
in one). The 
Lipkowitz lab 
has also 
confirmed that 
ONC201 had a 
similar effect on 
the killing of 
various 
endometrial cancer cell lines (data not shown) as it did on breast cancer cell lines. Based on these 
result we propose to include a cohort of patients with endometrial cancer in our trial. 
Only one triple negative breast cancer patient was recruited for the phase 1 study, and 
unfortunately had disease progression while on ONC201. Nevertheless, the preclinical data on 
breast cancer cell lines performed by the drug developer and confirmed by the Lipkowitz lab is 
encouraging that women with breast cancer may derive clinical benefit from ONC201.  
1.2.4 Pharmaceutical Manufacturer Updates 
1.2.4.1 ONC201 Investigator Brochure v6 November 2019 
As of October 31, 2019, the majority of adverse events (AEs) experienced by participants on 
clinical trials who received ONC201 were mild or moderate in severity. The most frequently 
reported AEs of any grade (in greater than 25% of patients) were fatigue, nausea, headache and 
vomiting. These AEs were generally Grade 1/2, with fatigue being the only Grade 3/4 AE that 
occurred in more than one patient on the ONC013 study (17.4%). 
Figure 4: Waterfall plot of best fractional change in tumor size relative 
to baseline on a lesion-by-lesion basis. Best change in lesion size is 
defined as maximal reduction or minimal increase in sum of longest 
dimensions of target lesions relatively to pretreatment assessment. 
Image from Stein et al, 2017(4).  


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Abbreviated Title: ONC201 in advanced cancers 
Version Date: 06/17/2020 
 
Eleven patients experienced serious adverse events (SAEs) that were considered possibly related 
to ONC201. The list of SAEs reported by investigators that were attributed as possibly-related to 
ONC201 by the investigator are: 
• Grade 1: Fatigue, vomiting 
• Grade 3:  Encephalopathy, cognitive impairment, neutropenia, upper respiratory 
infection, respiratory distress, pneumonia, stroke, tremor, fatigue, bone pain, anorexia, 
weakness 
• Grade 4 Dysphagia, dyspnea 
Two suspected unexpected serious adverse (SUSAR) events occurred at a dose of 625mg daily. 
Both events were encephalitis that occurred on the investigator-initiated trial NCT02392572 in 
patients with MDS or AML and are considered dose-limiting toxicities(DLT). No other DLTs 
occurred in other indications or at lower doses both as monotherapy or in combination with other 
agents. Only one dose reduction (625mg to 500mg) occurred in one patient with a Grade 3 
neutropenia assessed by the PI as possibly related to ONC201. However, upon re-challenge 
neutropenia did not recur. 
Based on the clinical safety data summarized above, ONC201 administered at the doses and 
schedules below 625mg daily appears to be well tolerated in adults and children. 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT  
2.1 
ELIGIBILITY CRITERIA FOR COHORT 1: HORMONE RECEPTOR POSITIVE BREAST CANCER  
2.1.1 Inclusion Criteria 
2.1.1.1 Patients must have histologically confirmed persistent or recurrent invasive metastatic 
hormone receptor positive, HER2 normal breast cancer for which standard curative 
measures do not exist or are no longer effective. Hormone receptor positive is defined 
as estrogen receptor (ER) positive  10% by immunohistochemistry (IHC) and/or 
progesterone receptor (PR) positive  10% by IHC.HER2 will be considered negative 
per ASCO-CAP guidelines (HER2 test result as negative if a single test (or both tests) 
performed show: 1) IHC 1+ as defined by incomplete membrane staining that is 
faint/barely perceptible and within >10% of the invasive tumor cells; 2) IHC 0 as 
defined by no staining observed or membrane staining that is incomplete and is 
faint/barely perceptible and within ≤10% of the invasive tumor cells; or 3) ISH negative 
based on: a) Single-probe average HER2 copy number <4.0 signals/cell or b) Dual-
probe HER2/CEP17 ratio <2.0 with an average HER2 copy number <4.0 
signals/cell)and HER2 testing must have been performed in a laboratory accredited by 
the College of American Pathologists (CAP) or another accrediting entity. 
2.1.1.2 Patients must have measurable disease, per RECIST 1.1. See Section 6.3.1 for the 
evaluation of measurable disease. 
2.1.1.3 Patients must have at least one lesion deemed safe to biopsy and be willing to undergo 
mandatory biopsies. 
2.1.1.4 HR+BC patients must have received prior treatment with at least 2 lines of hormonal 
treatment (SERM, AI, or fulvestrant) and deemed ineligible for further hormonal 


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Abbreviated Title: ONC201 in advanced cancers 
Version Date: 06/17/2020 
 
therapy . Patients may have received prior chemotherapy and there is no limit to the 
number of prior chemotherapy.  
2.1.1.5 Age >18 years.  
2.1.1.6 ECOG performance status 0 or 1  
2.1.1.7 Adequate renal function, defined as serum creatinine ≤ 1.5 X upper limit of normal 
(ULN), or measured creatinine clearance ≥ 60 mL/min/1. 
2.1.1.8 Adequate hepatic function, defined as AST and ALT levels ≤ 3 X ULN and total 
bilirubin < 1.5 X ULN, unless known diagnosis of Gilbert’s syndrome, where bilirubin 
≤ 5 mg/dL will be permitted. Gilbert’s syndrome will be defined as elevated 
unconjugated bilirubin, with conjugated (direct) bilirubin within the normal range and 
less than 20% of the total. Total bilirubin will be permitted up to 5 mg/dL, if patients 
have historical readings consistent with the definition of Gilbert’s syndrome prior to 
entering study.  
2.1.1.9 Adequate bone marrow function, defined as absolute neutrophil (ANC) ≥ 1,500/mm3 
(≥1.5 X106/L), platelet count ≥ 75,000/mm3 (≥ 75 X106/L), and hemoglobin ≥ 9 mg/dL 
(transfusion to obtain hemoglobin ≥ 9 mg/dL within 24 hours prior to dosing is 
allowed).  
2.1.1.10 Patients must be able to swallow oral medications (capsules) without chewing, 
breaking, crushing, opening or otherwise altering the product formulation.  
2.1.1.11 The effects of ONC201 on the developing human fetus are unknown.  For this reason 
and because imipridone agents are known to be teratogenic, female patients must either 
be of non-reproductive potential (i.e., post-menopausal by history: ≥60 years old and no 
menses for ≥1 year without an alternative medical cause; OR history of hysterectomy, 
OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must 
have a negative serum pregnancy test upon study entry and agree to use contraception 
or abstinence during the study and for and for at least 4 weeks after the final dose of any 
study-related medications. Male patients must use at least two forms of contraception 
during the study and for at least 4 weeks after the final dose of any study-related 
medications or have a partner who is not of reproductive potential.  (See Section 4.2)  
2.1.1.12 Ability of subject to understand and the willingness to sign a written informed consent 
document.  
2.1.2 Exclusion Criteria 
2.1.2.1 Patients who have received chemotherapy in the previous 3 weeks (6 weeks for 
nitrosoureas or mitomycin); other investigational agents within 3 weeks or a PD1/PDL1 
agent within 4 weeks prior to first dose of study treatment.  
2.1.2.2 Patients who have undergone radiotherapy within 4 weeks of first dose of study 
treatment. 
2.1.2.3 Patients with a history of another invasive malignancy within the last 3 years. 
2.1.2.4 Patients with symptomatic brain metastases or leptomeningeal involvement. Patients 
with asymptomatic or brain metastases that have been treated with radiation at least 4 
weeks prior to first dose of study treatment are allowed.  


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Abbreviated Title: ONC201 in advanced cancers 
Version Date: 06/17/2020 
 
2.1.2.5 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to imipridones or other agents used in study. 
2.1.2.6 Patients with a mean QTcF interval of > 500 msec or receiving therapeutic agents 
known to prolong the QT interval  
2.1.2.7 Known history of cardiac arrhythmias including uncontrolled atrial fibrillation, 
tachyarrhythmias or bradycardia, history of congestive heart failure, or myocardial 
infarction or stroke in the previous 3 months will be excluded. 
2.1.2.8 Known history of gastrointestinal illnesses that would preclude the absorption of 
ONC201, which is an oral agent 
2.1.2.9 Patients with bone metastases who have initiated denosumab or bisphosphonate therapy 
within 28 days prior to Cycle 1 Day 1. 
2.1.2.10 Pregnant women are excluded from this study because ONC201 has the potential for 
teratogenic or abortifacient effects.  Because there is an unknown but potential risk for 
adverse events in nursing infants secondary to treatment of the mother with ONC201, 
breastfeeding should be discontinued if the mother is treated with ONC201.  These 
potential risks may also apply to other agents used in this study. 
2.1.2.11 HIV-positive patients on combination antiretroviral therapy are ineligible because of the 
potential for pharmacokinetic interactions with ONC201.  
2.1.2.12 Patients who have known active Hepatitis B, or Hepatitis C infections. 
 
2.2 
ELIGIBILITY CRITERIA FOR COHORT 2: TRIPLE NEGATIVE BREAST CANCER  
2.2.1 Inclusion Criteria 
 Patients must have histologically or cytologically confirmed persistent or recurrent 
invasive, metastatic triple negative breast cancer (TNBC) for which standard curative 
measures do not exist or are no longer effective. TNBC, defined as ER negative (ER < 
10%), PR negative (PR <10%).  HER2 will be considered negative per ASCO-CAP 
guidelines (HER2 test result as negative if a single test (or both tests) performed show: 
1) IHC 1+ as defined by incomplete membrane staining that is faint/barely perceptible 
and within >10% of the invasive tumor cells; 2) IHC 0 as defined by no staining 
observed or membrane staining that is incomplete and is faint/barely perceptible and 
within ≤10% of the invasive tumor cells; or 3) ISH negative based on: a) Single-probe 
average HER2 copy number <4.0 signals/cell or b) Dual-probe HER2/CEP17 ratio <2.0 
with an average HER2 copy number <4.0 signals/cell) and HER2 testing must have 


20 
Abbreviated Title: ONC201 in advanced cancers 
Version Date: 06/17/2020 
 
been performed in a laboratory accredited by the College of American Pathologists 
(CAP) or another accrediting entity. 
 Patients must have received at least one line of prior chemotherapy in the metastatic 
setting. 
2.2.1.1 Patients must have measurable disease, per RECIST 1.1. See Section 6.3.1 for the 
evaluation of measurable disease. 
2.2.1.2 Patients must have at least one lesion deemed safe to biopsy and be willing to undergo 
mandatory biopsies. 
2.2.1.3 Eligible patients may or may not have received prior chemotherapy and there is no limit 
to the number of prior chemotherapy. Patients are also eligible if they have received 
treatment with immunotherapy, such PD-1 inhibitors, PD-L1 inhibitors or CTLA4 
inhibitors.   
2.2.1.4 Age >18 years.  
2.2.1.5 ECOG performance status 0 or 1  
2.2.1.6 Adequate renal function, defined as serum creatinine ≤ 1.5 X upper limit of normal 
(ULN), or measured creatinine clearance ≥ 60 mL/min/1. 
2.2.1.7 Adequate hepatic function, defined as AST and ALT levels ≤ 3 X ULN and total 
bilirubin < 1.5 X ULN, unless known diagnosis of Gilbert’s syndrome, where bilirubin 
≤ 5 mg/dL will be permitted. Gilbert’s syndrome will be defined as elevated 
unconjugated bilirubin, with conjugated (direct) bilirubin within the normal range and 
less than 20% of the total. Total bilirubin will be permitted up to 5 mg/dL, if patients 
have historical readings consistent with the definition of Gilbert’s syndrome prior to 
entering study.  
2.2.1.8 Adequate bone marrow function, defined as absolute neutrophil (ANC) ≥ 1,500/mm3 
(≥1.5 X106/L), platelet count ≥ 75,000/mm3 (≥ 75 X106/L), and hemoglobin ≥ 9 mg/dL 
(transfusion to obtain hemoglobin ≥ 9 mg/dL within 24 hours prior to dosing is 
allowed).  
2.2.1.9 Patients must be able to swallow oral medications (capsules) without chewing, breaking, 
crushing, opening or otherwise altering the product formulation.  
2.2.1.10 The effects of ONC201 on the developing human fetus are unknown.  For this reason 
and because imipridone agents as well as other therapeutic agents used in this trial are 
known to be teratogenic. Female patients must either be of non-reproductive potential 
(i.e., post-menopausal by history: ≥60 years old and no menses for ≥1 year without an 
alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal 
ligation, OR history of bilateral oophorectomy) or must have a negative serum 
pregnancy test upon study entry and agree to use contraception or abstinence during the 
study and for and for at least 4 weeks after the final dose of any study-related 
medications. Male patients must use at least two forms of contraception during the 


21 
Abbreviated Title: ONC201 in advanced cancers 
Version Date: 06/17/2020 
 
study and for and for at least 4 weeks after the final dose of any study-related 
medications or have a partner who is not of reproductive potential. (See Section 4.2).  
2.2.1.11 Ability of subject to understand and the willingness to sign a written informed consent 
document.  
2.2.2 Exclusion Criteria 
2.2.2.1 Patients who have received chemotherapy in the previous 3 weeks (6 weeks for 
nitrosoureas or mitomycin); other investigational agents within 3 weeks or a PD1/PDL1 
agent within 4 weeks prior to study enrollment.  
2.2.2.2 Patients who have undergone radiotherapy within 4 weeks of first dose of study 
treatment. 
2.2.2.3 Patients with a history of another invasive malignancy within the last 3 years. 
2.2.2.4 Patients with symptomatic brain metastases or leptomeningeal involvement. Patients 
with asymptomatic or brain metastases that have been treated with radiation at least 4 
weeks prior to first dose of study treatment are allowed. 
2.2.2.5 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to imipridones or other agents used in study. 
2.2.2.6 Patients with a mean QTcF interval of > 500 msec or receiving therapeutic agents 
known to prolong the QT interval  
2.2.2.7 Known history of cardiac arrhythmias including uncontrolled atrial fibrillation, 
tachyarrhythmias or bradycardia, history of congestive heart failure, or myocardial 
infarction or stroke in the previous 3 months will be excluded. 
2.2.2.8 Known history of gastrointestinal illnesses that would preclude the absorption of 
ONC201, which is an oral agent 
2.2.2.9 Patients with bone metastases who have initiated denosumab or bisphosphonate therapy 
within 28 days prior to Cycle 1 Day 1. 
2.2.2.10 Pregnant women are excluded from this study because ONC201 has the potential for 
teratogenic or abortifacient effects.  Because there is an unknown but potential risk for 
adverse events in nursing infants secondary to treatment of the mother with ONC201, 
breastfeeding should be discontinued if the mother is treated with ONC201.  These 
potential risks may also apply to other agents used in this study. 
2.2.2.11 HIV-positive patients on combination antiretroviral therapy are ineligible because of the 
potential for pharmacokinetic interactions with ONC201.  
2.2.2.12 Patients who have known active Hepatitis B, or Hepatitis C infections. 
 


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Abbreviated Title: ONC201 in advanced cancers 
Version Date: 06/17/2020 
 
2.3 
ELIGIBILITY CRITERIA FOR COHORT 3: ENDOMETRIAL CANCER  
2.3.1 Inclusion Criteria 
2.3.1.1 Patients must have histologically or cytologically confirmed persistent or recurrent 
advanced or metastatic invasive endometrial cancer (EC) for which standard curative 
measures do not exist or are no longer effective.  
2.3.1.2 Patients must have measurable disease, per RECIST 1.1..  See Section 6.3.1 for the 
evaluation of measurable disease. 
2.3.1.3 Patients must have at least one lesion deemed safe to biopsy and be willing to undergo 
mandatory biopsies. 
2.3.1.4 Women with endometrial cancer must have had at least one prior line of therapy in the 
metastatic/recurrent setting but there is no limit to the number of prior chemotherapy 
lines. Patients are eligible if they have received treatment with immunotherapy, such 
PD-1 inhibitors, PD-L1 inhibitors or CTLA4 inhibitors.   
2.3.1.5 Age >18 years.  
2.3.1.6 ECOG performance status 0 or 1  
2.3.1.7 Adequate renal function, defined as serum creatinine ≤ 1.5 X upper limit of normal 
(ULN), or measured creatinine clearance ≥ 60 mL/min/1. 
2.3.1.8 Adequate hepatic function, defined as AST and ALT levels ≤ 3 X ULN and total 
bilirubin < 1.5 X ULN, unless known diagnosis of Gilbert’s syndrome, where bilirubin 
≤ 5 mg/dl will be permitted. Gilbert’s syndrome will be defined as elevated 
unconjugated bilirubin, with conjugated (direct) bilirubin within the normal range and 
less than 20% of the total. Total bilirubin will be permitted up to 5 mg/dL, if patients 
have historical readings consistent with the definition of Gilbert’s syndrome prior to 
entering study.  
2.3.1.9 Adequate bone marrow function, defined as absolute neutrophil (ANC) ≥ 1,500/mm3 
(≥1.5 X106/L), platelet count ≥ 75,000/mm3 (≥ 75 X106/L), and hemoglobin ≥ 9 mg/dL 
(transfusion to obtain hemoglobin ≥ 9 mg/dL within 24 hours prior to dosing is 
allowed). 
2.3.1.10 Patients must be able to swallow oral medications (capsules) without chewing, 
breaking, crushing, opening or otherwise altering the product formulation.  
2.3.1.11 The effects of ONC201 on the developing human fetus are unknown.  For this reason 
and because imipridone agents as well as other therapeutic agents used in this trial are 
known to be teratogenic. Female patients must either be of non-reproductive potential 
(i.e., post-menopausal by history: ≥60 years old and no menses for ≥1 year without an 
alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal 
ligation, OR history of bilateral oophorectomy) or must have a negative serum 
pregnancy test upon study entry and agree to use contraception or abstinence during the 
study and for and for at least 4 weeks after the final dose of any study-related 
medications. Male patients must use at least two forms of contraception during the 


23 
Abbreviated Title: ONC201 in advanced cancers 
Version Date: 06/17/2020 
 
study and for and for at least 4 weeks after the final dose of any study-related 
medications or have a partner who is not of reproductive potential. (See Section 4.2). 
2.3.1.12 Ability of subject to understand and the willingness to sign a written informed consent 
document.  
2.3.2 Exclusion Criteria 
2.3.2.1 Patients who have received chemotherapy in the previous 3 weeks (6 weeks for 
nitrosoureas or mitomycin); other investigational agents within 3 weeks or a PD1/PDL1 
agent within 4 weeks prior to study enrollment.  
2.3.2.2 Patients who have undergone radiotherapy within 4 weeks of first dose of study 
treatment. 
2.3.2.3 Patients with a history of another invasive malignancy within the last 3 years. 
2.3.2.4 Patients with symptomatic brain metastases or leptomeningeal involvement. Patients 
with asymptomatic or brain metastases that have been treated with radiation at least 4 
weeks prior to first dose of study treatment are allowed. 
2.3.2.5 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to imipridones or other agents used in study. 
2.3.2.6 Patients with a mean QTc interval of > 500 msec or receiving therapeutic agents known 
to prolong the QT interval  
2.3.2.7 Known history of cardiac arrhythmias including uncontrolled atrial fibrillation, 
tachyarrhythmias or bradycardia, history of congestive heart failure, or myocardial 
infarction or stroke in the previous 3 months will be excluded. 
2.3.2.8 Known history of gastrointestinal illnesses that would preclude the absorption of 
ONC201, which is an oral agent 
2.3.2.9 Patients with bone metastases who have initiated denosumab or bisphosphonate therapy 
within 28 days prior to Cycle 1 Day 1. 
 
2.3.2.10 Pregnant women are excluded from this study because ONC201 has the potential for 
teratogenic or abortifacient effects.  Because there is an unknown but potential risk for 
adverse events in nursing infants secondary to treatment of the mother with ONC201, 
breastfeeding should be discontinued if the mother is treated with ONC201.  These 
potential risks may also apply to other agents used in this study. 
2.3.2.11 HIV-positive patients on combination antiretroviral therapy are ineligible because of the 
potential for pharmacokinetic interactions with ONC201.  
2.3.2.12 Patients who have known active Hepatitis B, or Hepatitis C infections. 
 
2.4 
RECRUITMENT STRATEGIES 
This protocol may be abstracted into a plain language announcement posted on NIH websites 
(e.g. clinicaltrials.gov) and on NIH social media platforms.  Participants may also be identified 
through referrals from physicians, or from populations in NIH Clinics. 
 


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2.5 
SCREENING EVALUATION 
2.5.1 Screening activities performed prior to obtaining informed consent 
Minimal risk activities that may be performed before the subject has signed a consent include the 
following:  
• Email, written, in person or telephone communications with prospective subjects 
regarding their medical issues and possible eligibility to the clinical trial 
• Review of existing medical records to include H&P, laboratory studies, etc.   
• Review of existing MRI, x-ray, or CT images 
• Review of existing photographs or videos 
• Review of existing pathology specimens/reports from a specimen obtained for diagnostic 
purposes 
A waiver of consent for these activities has been requested in section 12.6.1. 
2.5.2 Screening activities performed after a consent for screening has been signed 
The following activities will be performed only after the subject has signed the study consent OR 
the consent for study 01-C-0129 (provided the procedure is permitted on that study) on which 
screening activities may also be performed. Assessments performed at outside facilities or on 
another NIH protocol within the timeframes below may also be used to determine eligibility once 
a patient has signed the consent. 
The screening evaluations or tests will be conducted as described below and in the Study 
Calendar (Section 3.4) after the participant has signed the consent document. 
For baseline evaluations, please see section 2.9. 
2.5.2.1 Pathologic Confirmation 
Confirmation of tumor histology in NCI Laboratory of Pathology (archival tumor samples will 
be requested; if unavailable, the subject may choose to undergo fresh biopsy). Pathological 
confirmation of diagnosis of breast cancer or endometrial cancer in the Laboratory of Pathology 
at NIH Clinical Center or Walter Reed National Military Medical Center at Bethesda. However, 
if no pathologic specimen is available, patients may enroll with a pathologist’s report showing a 
histologic diagnosis of HR+BC, TNBC or Endometrial Cancer in a College of American 
Pathologists (CAP) accredited laboratory and a clinical course consistent with the disease. 
 
2.5.2.2 History and Physical, Vital Signs, Height, Weight, and Concomitant Medications 
Medical history and physical examination, including vitals signs and concomitant medications, 
will be conducted at screening and at subsequent visits as indicated in the schedule of 
assessments. Results of the physical examination including any abnormalities will be 
documented and can be used for the baseline examination if conducted within 17 days prior to 
enrolling on trial. Abnormal findings will be reassessed at subsequent visits. On subsequent 
visits, any newly diagnosed or worsening conditions, signs and symptoms, whether related or 
unrelated to the trial, will be reported as adverse events.  


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2.5.2.3 Performance Status  
The ECOG performance status (Appendix A) will be assessed at screening and at subsequent 
visits as indicated in the schedule of assessments and documented in the clinical record.  
2.5.2.4 Scans for disease evaluation at screening.  
 
• CT of chest/abdomen /pelvis (MRI may be substituted at investigator’s discretion)  
• Bone scan may be done at the investigator’s discretion is there is concern for bone 
disease  
• Brain MRI (preferred) or head CT with contrast may be done at the investigator’s 
discretion if there is concern for CNS metastasis 
If the screening scan has been obtained within 17 days prior to first dose of study treatment , it 
may be used for baseline evaluation.  
2.5.2.5 Laboratory Studies 
 
Screening laboratory studies to include:  
• CBC with differential, PT/INR/PTT, Biochemical profile for Screening: 14 
comprehensive metabolic panel (sodium, potassium, chloride, carbon dioxide, BUN, 
creatinine or measured creatinine clearance, glucose, AST (SGOT), ALT (SGPT), total 
bilirubin, serum creatinine.  If the labs have been obtained within 10 days prior to 
initiation of therapy, they may be used for baseline evaluation.  
• Anti-HIV, anti-HCV, Hepatitis B surface Ag: viral titers will be obtained within 28 days 
prior to enrollment. 
 
2.5.2.6 Pregnancy Testing  
 
For female subjects of childbearing potential, urine or serum HCG will be performed on initial 
screening.  
• 
A urine beta-HCG will be performed before each administration of ONC201 during 
the treatment phase, at the end-of-treatment visit, and at the post-treatment follow-up 
visit.  
• 
Patients who are postmenopausal (age-related amenorrhea for 12 or more consecutive 
months, or documented FSH > 40 mIU/mL) / Estradiol < 20mIU/mL), or who had 
undergone hysterectomy or bilateral oophorectomy are exempt from pregnancy 
testing.  


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2.5.2.7 Tumor Block 
A primary tumor paraffin block will be requested to perform comparative genomic analysis as 
part of correlative studies planned for this clinical trial. 
2.5.2.8 Tumor Biopsy 
A biopsy of fresh frozen tissue will be planned after consent but prior to the first dose of 
ONC201. 
2.5.2.9 Research Blood Samples 
Peripheral blood samples for the correlative studies will be collected after consent but prior to 
the first dose of ONC201, per Section 5 Biospecimen Collection. 
2.6 
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES 
Registration and status updates (e.g., when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration & Status Updates found here. 
2.7 
SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently assigned to the study intervention or entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any serious adverse event 
(SAE). 
2.8 
TREATMENT ASSIGNMENT AND RANDOMIZATION/STRATIFICATION PROCEDURES 
Cohorts 
Number 
Name 
Description 
1 
HR+ breast cancer 
HR+ breast cancer (male and female) 
2 
TNBC 
Triple negative breast cancer (male and female) 
3 
Endometrial cancer 
Endometrial cancer (female only) 
 
Arms 
Number 
Name 
Description 
1 
ONC201 
All patients from all 3 cohorts will receive ONC201 at the 
recommended phase 2 dose (RP2D) of 625mg by mouth every 7 
days with each cycle being 28 days long. 


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Randomization/Stratification Procedures 
Randomization and stratification procedures are not applicable to this study. 
• All patients from Cohort 1 will be assigned to Arm 1. 
• All patients from Cohort 2 will be assigned to Arm 1. 
• All patients from Cohort 3 will be assigned to Arm 1. 
 
2.9 
BASELINE EVALUATION 
Scans and x-rays must be done within 17 days prior to the initiation of study therapy. All other 
studies should be performed within 10 days prior to initiation of study therapy, unless otherwise 
specified. If the tests were performed within these timeframes at screening, they do not need to 
be repeated at start of treatment. 
• Start the process for documentation of germline BRCA mutation status (Cohort 1 and 2). 
• Start the process for documentation of Lynch syndrome (germline evaluation) or MSI 
status of tumor (somatic evaluation by genomics, IHC or demonstration of Microsatellite 
instability of the tumor). (Cohort 3 only) 
• History and physical examination with ECOG evaluation (Appendix A), history of prior 
therapy, review of concurrent medications, and review of baseline symptoms.   
• Assessment of disease by imaging (may include CT chest, abdomen and pelvis or MRI)  
• EKG obtained within 7 days of initiating therapy  
• Laboratory evaluations  
o CBC with differential and platelet count  
o Sodium, potassium, chloride, CO2, creatinine or measured creatinine clearance, 
glucose, BUN 
o Mineral panel (magnesium, calcium, albumin, phosphorus), lactic acid and a lipid 
panel   
o Hepatic panel (alkaline phosphatase, AST/ALT/total bilirubin) with total protein 
o PT/INR/PTT 
o β-HCG in women of childbearing potential  
o Hormone panel: Prolactin, Estrogen 
o Lymphocyte phenotyping – TBNK 
o Tumor Markers: Breast cancer (cohorts 1 and 2) – CEA, CA15-3, CA 27.29; 
Endometrial cancer (cohort 3) – CA-125 
o Urinalysis 
o Germline mutation analysis of BRCA or Lynch Syndrome (germline evaluation) 
or MSI status of tumor (somatic evaluation by genomics, IHC or demonstration of 
Microsatellite instability of the tumor) (if not previously documented) 
 
• Correlative Tests (Refer to the tables in section 5.5 for additional information) 
o Tumor biopsy  
o Blood sampling  


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3 
STUDY IMPLEMENTATION 
3.1 
STUDY DESIGN 
This is an open label, phase II single arm study of ONC201 divided in three cohorts, each cohort 
with a different type of metastatic, advanced disease: ER+ BC, TNBC and endometrial cancer. 
All proposed cohorts require measurable disease based on RECIST criteria and disease that can 
be biopsied safely. The study will specify a required biopsy prior to treatment and a biopsy 
during the second cycle after drug treatment. There will also be an optional biopsy at the time of 
progression. Participants will receive ONC201 starting at the RP2D of 625mg q7 days. Each 
cycle is 28 days long. ONC201 can be given +/- 1 day due to holidays, inclement weather, 
conflicts, or similar reasons.  
During Cycle 1, patients will receive weekly phone calls by research staff to ask about changes 
to health and any potential side effects. 
While the drug has activity against HER2 amplified breast cancer cells in vitro, we would not 
initiate a single agent HER2+ cohort at this time because of the clear benefit to HER2 targeted 
therapies in this subset of breast cancer.  We will develop preclinical data for ONC201 in 
combination with HER2 targeted drugs (e.g., trastuzumab, trastuzumab emtansine, and lapatinib) 
and plan to initiate a phase I run-in trial at a later date. 
 
3.2 
DRUG ADMINISTRATION 
 
At the start of each cycle, enough study drug for one complete cycle will be dispensed by the 
pharmacy. Patients will be given a medication diary (see Appendix E) to record dates of 
administration as well as side effects. Patients in all cohorts will self-administer five capsules 
(each capsule 125mg x 5 = 625mg) of ONC201 by mouth every 7 days with each cycle being 28 
days in duration. The capsules may be taken one hour before or two hours after eating, according 
to patient preference.  If patients are unable to tolerate this dose, they can have three dose 
reductions before being removed from the study (see Table 2). Patients will receive ONC201 as 
long as they derive clinical benefit or toxicity becomes impeditive.  
 
3.2.1 Self-Administered Study Drugs:  
The ONC201 used in this study is a self-administered investigational agent. Such agents are 
dispensed from the pharmacy to a participant or to a Patient Care Unit for self-medication and a 
record of the dispensed investigational agent is generated and kept by the dispensing pharmacy.  
As indicated above, patients will be asked to keep a medication diary and bring it with them on 
each study visit (See Appendix E). Patients will also bring any remaining pills to each study 
visit. The research nurse will review and validate the completeness and accuracy of the 
participant’s diary with the participant.  


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If a participant goes off study while at home, the research nurse will ensure and document the 
return of the unused oral investigational agents from the participant. Unused investigational 
agent will be destroyed per dispensing pharmacy procedure.  
 
3.3 
DOSE MODIFICATIONS/DELAYS AND MANAGEMENT OF TOXICITIES 
• In the case of toxicity, appropriate medical treatment should be used (including anti-emetics, 
anti-diarrheals, etc.).  
• Once a patient has a dose reduction for toxicity, the dose will not be increased.  
• Participants continuing to experience toxicity at the off treatment visit will be contacted for 
additional assessments until the toxicity has resolved or is deemed irreversible. Patients must 
remain on the study to have additional assessments completed.  
• For AEs that are unrelated to the study drugs, study drug may be held for up to 14 days at the 
discretion of the PI.  
3.3.1 Modifications and Toxicity Management 
Table 2: ONC201 Dose Reduction Schedule  
Dose Level  
(DL) 
ONC201  
(by mouth) 
Number of Capsules*  
1 (Starting Dose) 
625mg every 7 days 
5 capsules  
-1 
500mg every 7 days 
4 capsules  
-2 
375mg every 7 days 
3 capsules  
-3 
250mg every 7 days 
2 capsules 
 * Each ONC201 capsule is 125mg 
Summary of Dose Modifications or Discontinuation for ONC201-Related Adverse Events  
Worst Treatment-Related Non-Hematologic AE (except for controlled nausea and vomiting) 
During the Previous Cycles 
 
Grade 
Dose modification 
0-2 
No dose modifications for non-hematologic AEs.  
3 
Reduce by one dose level (except controlled nausea, and vomiting).  
4 
Stop (except controlled nausea and vomiting).  
 
Worst Treatment-Related Hematologic AE During the Previous Cycle  
Worst AE 
Platelets 


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≥75 x 109 /L  
50 – 75 x 109 /L  
< 50 x 109 /L  
ANC 
≥ 1.5 x 109 /L  
Dose unchanged 
Dose unchanged 
Reduce 1 dose 
level 
≥1 to 1.5 x 109 /L 
Dose unchanged 
Dose unchanged 
Reduce 1 dose 
level 
< 1 x 109 /L  
Reduce 1 dose 
level 
Reduce 1 dose 
level 
Reduce 1 dose 
level 
 
Dose reductions: If any treatment related non-hematologic AE observed was grade > 2 (except 
controlled nausea and vomiting) and/or if platelets < 50 x 109 /L and/or ANC < 1 x 109 /L, then 
the dose should be reduced by one dose level. Patients who require more than three dose 
reductions will have treatment stopped. If any treatment-related non-hematologic AE observed 
was grade 4 (except controlled nausea and vomiting) then ONC201 treatment should be stopped.  
Any dose reductions of ONC201 will be determined according to: (1) non-hematologic AE 
during the preceding treatment cycle, as well as (2) the lowest ANC and platelets observed. No 
dose escalation should be attempted.  
Important: If the dose was reduced or delayed for AEs, there will be no dose re-escalation in 
subsequent treatment cycles.  
 
3.3.2 Medication Delay  
 
Hematologic AE on Day 1 of Each Cycle  
AE 
Delay 
ANC< 1.0 x 109 /L and/or  
Platelet count < 75 x 109 /L 
Delay up to 4 weeks until all resolved. If not 
resolved after 4 weeks, then remove from study 
regimen.  
 
 
Non-Hematologic AE (except for controlled nausea, and vomiting) on Day 1 of Each Cycle (within the 
prior 72 hours) 
Grade 
Delay 


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2-4 
Delay by 1 week up to 4 consecutive weeks until 
all resolved (to grade ≤ 1). If not resolved after 4 
weeks, then remove from study regimen.  
 
On day 1 of each cycle, patients must have adequate hematopoietic function (i.e., ANC ≥ 1.0 x 
109 /L, platelet count ≥ 75 x 109 /L) and all grade 2, 3 or 4 non-hematologic AEs (except for 
controlled nausea, and vomiting) must have resolved to grade ≤ 1.  
If AEs persists, treatment should be delayed by 1 week for up to 4 consecutive weeks. If, after 4 
weeks of delay, all treatment related AEs have still not resolved (to grade ≤ 1): then any further 
treatment with ONC201 should be stopped.  
 
3.3.3 Instructions on Missed Doses 
ONC201 can be given +/- 1 day due to holidays, inclement weather, conflicts, or similar reasons. 
If the first dose of the 4-week cycle not taken within 1 day of day 1 of the cycle, the cycle will be 
delayed one week. If a mid-cycle dose (i.e., D8, D15, D22) is more than 1 day late, the weekly 
dose will be skipped and the next dose will be resumed in accordance with the planned 
administration day. 
 
 


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3.4 
STUDY CALENDAR 
Procedure 
Screening/ 
Baseline 
Cycle 1 
Cycle 2 
Subsequent 
Odd 
numbered 
cycles 
Subsequent 
Even 
numbered 
cycles 
End of 
treatment 
visit 
(~ 30 
days 
from last 
dose) 
Day 1 
(±3days) 
Day 1 
(±3days) 
Day 1 
(±3days) 
Day 1 
(±3days) 
 
Informed consent 
X 
 
 
 
 
 
History and PE2 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
Performance Score 
X 
X 
X 
X 
X 
X 
Labs  
X3 
X4 (< 10 
days) 
X4 
X4 
X4 
X4 
Pathology 
confirmation5 
X 
 
 
 
 
 
Tumor block 
X6 
 
 
 
 
 
Fresh frozen tissue 
(tumor biopsy)7 
X 
 
X 
 
 
X 
(optional) 
Correlative 
Research Studies 
(blood samples)  
X 
X 
X 
X 
X 
X 
PK/PD  
 
X 
 
 
 
 
NIH Advance 
Directives Form 
X 
(optional) 
 
 
 
 
 
Radiological 
Assessments8 
 
X (< 17 
days) 
 
X 
 
 
Response 
Evaluation 
 
 
 
X 
 
 


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Procedure 
Screening/ 
Baseline 
Cycle 1 
Cycle 2 
Subsequent 
Odd 
numbered 
cycles 
Subsequent 
Even 
numbered 
cycles 
End of 
treatment 
visit 
(~ 30 
days 
from last 
dose) 
Day 1 
(±3days) 
Day 1 
(±3days) 
Day 1 
(±3days) 
Day 1 
(±3days) 
 
Adverse Events 
 
X 
X 
X 
X 
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
Electrocardiogram9  
 
X1 
X 
 
 
 
 
1 Up to 7 days before enrolling the trial 
2 History including prior treatments and review of baseline adverse events and concurrent 
medications. Physical examination includes neurological exam. Height (at screening only) and 
weight are also included. 
3 CBC with differential, PT/INR/PTT, AST (SGOT), ALT (SGPT), total protein, total bilirubin, 
serum creatinine.Urine or serum HCG on day of screening for women of childbearing potential. 
Anti-HIV, anti-HCV, Hepatitis B Surface Ag (within 28 days prior to first dose of study 
treatment).  
4 Labs must be obtained <10 days of initiating treatment: CBC with differential, PT/INR/PTT,  
sodium, potassium, chloride, carbon dioxide, BUN, creatinine or measured creatinine clearance, 
glucose, AST, ALT, bilirubin, calcium, total protein, albumin, alkaline phosphatase, phosphorus, 
magnesium, urinalysis, prolactin, estrogen, lactic acid and lipid panel. Lymphocyte phenotyping 
(TBNK). Urine or serum HCG for women of childbearing potential. Tumor Markers (CEA, 
CA15-3, CA27.29 for breast cancer and CA125 for endometrial cancer). Evaluation of germline 
BRCA1/2 (cohorts 1 and 2) or Lynch syndrome (germline evaluation) or MSI status of tumor 
(somatic evaluation by genomics, IHC or demonstration of Microsatellite instability of the 
tumor) (cohort 3) if no documentation of mutational analysis provided.  
5 Pathological confirmation of diagnosis (plus ER, PR and HER2 expression for breast cancer 
patients) in the Laboratory of Pathology at NIH Clinical Center or Walter Reed National Military 
Medical Center at Bethesda. However, if no pathologic specimen is available, patients may 
enroll with a pathologist’s report showing a histologic diagnosis of HR+BC, TNBC or 
Endometrial Cancer in a College of American Pathologists (CAP) accredited laboratory and a 
clinical course consistent with the disease. 
6 Primary tumor paraffin block will be requested at enrollment to perform comparative genomic 
analysis as part of correlative studies planned for this clinical trial. 


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7 Planned biopsy after consent but prior to first dose of ONC201 as well as a planned biopsy on 
C2D2 after the 5th dose of ONC201. There is also an optional biopsy at the time of progression.  
8Baseline images within 17 days prior to initiation of therapy: CT of chest/abdomen /pelvis (MRI 
may be substituted at investigator’s discretion), Bone scan only at baseline. Brain MRI may be 
ordered at the discretion of the investigator if there is concern for CNS metastasis. CT of 
chest/abdomen/pelvis to be repeated every 8 weeks +/- 4 days after start of treatment (odd 
numbered cycles). Additional imaging to be performed at the investigator’s discretion. 
9 12-lead EKG within 7 days prior to initiation of therapy and on C2D1, with monthly repeats 
only for abnormal baseline EKGs or if patient is symptomatic.  
 
Note:  Allowance for scheduling changes: Brief interruption and delay in the 28-day cycle may 
occasionally be required due to travel delays, airport closure, inclement weather, family 
responsibilities, security alerts and government holidays, etc., for scheduling convenience. This 
can also extend to complications of disease not attributable to disease progression or protocol 
therapy.  These delays will not be considered protocol deviation.


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3.5 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
Prior to removal from study, effort must be made to have all subjects complete a safety visit 
approximately 30 days following the last dose of study therapy. 
3.5.1 Criteria for removal from protocol therapy 
• Progressive disease 
• Participant requests to be withdrawn from active therapy 
• Unacceptable Toxicity as defined in section 3.3. 
• Investigator discretion 
• Positive pregnancy test 
3.5.2 Off-Study Criteria 
• Screen Failure 
• Completed study follow-up period 
• Study closure 
• Participant requests to be withdrawn from study 
• Death 
 
4 
CONCOMITANT MEDICATIONS/MEASURES 
The investigator’s brochure for ONC201 by Oncoceutics does not describe any known drug-drug 
interactions with ONC201. In vitro cytochrome P450 assays were conducted in human 
hepatocytes. In these studies, ONC201 is not an inducer of the CYP450 system (CYP1A2, 2B6, 
and 3A4). ONC201 was observed to be a mild inhibitor of the CYP450 enzymes (1A2, 2B6, 
2C8, 2C9, 2C19, 2D6, 3A4) at 35-429 uM, i.e., at least 3.5-fold above the Cmax observed in the 
first-in-human trial.  
 
Drugs that antagonize DRD2 are commonly used as antipsychotics. However, comparison 
between ONC201 and other typical antipsychotics (such as haloperidol and risperidone) reveal 
substantial differences in anti-tumor activity, therapeutic window, specificity and receptor 
pharmacology. Moreover, the current administration schedule of ONC201 dosing is atypical for 
antipsychotic drugs. Taken together, there is no clear expectation that side effects that are 
commonly observed with antipsychotic drugs will be observed with ONC201 in the current 
schedule. Nevertheless, it is possible that side effects associated with antipsychotics could be 
observed with ONC201including weight gain, diabetes, metabolic disorders, dystonia, akinesia, 
akathisia, tremors, muscle rigidity, insomnia, blurry vision, Parkinsonian symptoms, cognitive 
impairment, sexual dysfunction, osteoporosis, sedation, behavioral changes, and cardiac 
disorders.  


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4.1 
RESTRICTIONS 
As a general precaution, the use of metformin and similars are prohibited due to potential 
similarities in mechanisms and mitochondrial damage. Patients will also be prohibited from 
using herbs and magic potions.  
Breast feeding 
It is not known whether ONC201 is excreted in breast milk. It is recommended that women do 
not breastfeed during treatment with ONC201 and for at least 2 months after the last dose.  
Blood Donation 
Patients should not donate blood while participating in this study or for 90 days following the 
dose of ONC201.  
4.2 
CONTRACEPTION 
The effects of ONC201 on the developing human fetus are unknown. For this reason, women of 
childbearing potential and men must agree to use two methods of adequate contraception (see 
Table 3) prior to study entry, for the duration of study participation and for at least 4 weeks after 
the final dose of any study-related medications. Cessation of birth control after this point should 
be discussed with a responsible physician. Periodic abstinence, the rhythm method and the 
withdrawal method are not acceptable methods of birth control.  
 
Table 3: Effective methods of contraception (two methods must be used) 
Barrier Methods 
Intrauterine Device Methods 
Hormonal Methods 
Male condom plus spermicide 
Copper T 
Implants 
Cap plus spermicide 
Progesterone Ta 
Hormone shot or injection 
Diaphragm plus spermicide 
Levonorgestrel-releasing 
intrauterine system           
(e.g., Mirena) 
Combined pill 
 
 
Minipill 
 
 
Patch 
aThis is also considered a hormonal method of birth control  
 
5 
BIOSPECIMEN COLLECTION 
5.1 
CORRELATIVE STUDIES FOR RESEARCH/PHARMACOKINETIC STUDIES 
The primary goal of the correlative studies is to identify potential predictive biomarkers as well 
as additional evidence of the mechanism of action of and resistance to ONC201. Other 
correlative study aims include investigation of proof-of-concept biomarkers. These will be 


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performed in an exploratory fashion on select patients if there are adequate samples for analysis. 
(Table 4; Table 5)  
While the exact mechanism of ONC201 is unclear at this time, preclinical data as well as the 
phase I data have identified multiple potential mechanisms of action. As mentioned above, 
ONC201 is thought to have both TRAIL-dependent and TRAIL-independent mechanisms of 
killing. ONC201 has been identified as a selective antagonist of DRD2 that activates the 
integrated stress response in tumor cells leading to TRAIL activation. Serum prolactin will be 
evaluated as a surrogate marker for target engagement, which is induced by DRD2 antagonism in 
the pituitary gland (34). In the solid tumor phase I study, prolactin was found to increase in 
patients taking ONC201 and was loosely associated with response in the small trial. However, 
there is no evidence that DRD2 is present on tumors. In addition to serum prolactin levels, we 
will also evaluate select biopsy samples for the presence of DRD2.    
ONC201 has shown TRAIL-dependent apoptosis as well as caspase-independent, DR4/5-
independent, TRAIL-independent induction of the integrated stress response through inhibition 
of mitochondrial respiration. Due to these conflicting mechanisms, we will evaluate select tissue 
biopsy samples for markers of apoptosis including cleaved caspase-3, cleaved poly(ADP ribose) 
polymerase (PARP), cleaved terminal deoxynucleotidyl transferase dUPT nick end labeling 
(TUNEL), ATF4 expression, CHOP expression, phospho-AMPK levels, annexin-V, TRAIL 
receptor and TRAIL expression. We will also evaluate markers of apoptosis in the serum 
including TRAIL expression, M30 assays, and M65 assays. We also plan to evaluate serum 
cytokine levels including IL6, L24, IL32, IL1RAP, which were found to be increased after 
ONC201 administration on RNAseq.   
Like Metformin, ONC201 induces inhibition of mitochondrial respiration. Metformin induces 
mitochondrial stress which in turn initiates the integrated stress response through AFT4 which 
increases fibroblast growth factor 21 (FGF21). Due to similarities between these two drugs, we 
will evaluate the lipid profile and serum lactic levels due to known effects of Metformin on these 
labs (38).  
Recent data from the El-Deiry lab suggests that ONC201 increases NK cell numbers and that this 
may contribute to the anti-tumor activity.(39)  If sufficient PBMCs are available, PBMCs will be 
processed and stored at Trepel Lab according to SOP (Table 5), and will be assessed using multi-
parameter flow cytometry for immune subsets including but not necessarily limited to Tregs, 
myeloid-derived suppressor cells, effector CD4+ and CD8+ T-cells, NK cells and monocyte 
subsets. Assessment will include functional markers, i.e. PD-1, Tim-3, CTLA-4, CD40, HLA-
DR and PD-L1. This study will be done in collaboration with Jane Trepel of Developmental 
Therapeutics Branch/CCR/NCI.  
Peripheral blood will be collected at baseline and post-therapy to enumerate circulating tumor 
cell (CTC) levels at baseline and post-therapy, and analyze for correlation with clinical response 
or survival. CTCs will be assessed using ferrofluidic enrichment and multiparameter flow 
cytometric detection. CTCs will be identified as viable, nucleated cells, that positively express 
one or more epithelial or tumor markers and are negative for expression of hematopoietic 
markers. Cell free DNA (cfDNA) and mitochondrial DNA will also be evaluated.  


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Finally, due to impressive preclinical data involving mitochondrial stress following by 
ballooning after exposure to ONC201, tumor biopsy samples will be evaluated by electron 
microscopy to evaluate the impact of ONC201 on mitochondrial and cellular morphology.   
All samples will be barcoded, with data entered and stored in Labmatrix, the patient sample data 
management system utilized by the NCI Clinical Pharmacology Core (CPC). This is a secure 
program, with access to the Labmatrix system limited to defined CPC personnel who are issued 
individual user accounts. The program creates a unique barcode ID for every sample and sample 
box, which cannot be traced back to patients without Labmatrix access. The data recorded for 
each sample includes the patient ID, name, trial name/protocol number, sample collection time, 
cycle time point, dose, material type, as well as box and freezer locations. Patient demographics 
associated with the clinical center patient number are provided in the system. Samples will be 
stored until requested by the PI. All requests are monitored and tracked in Labmatrix.  
Table 4: Correlative Studies* 
PMBC 
Plasma/Whole Blood 
Archived Tissue 
Samples 
Tumor and/or  
Effusion Cells 
Immune phenotyping 
Dendritic cell 
maturation 
TRAIL levels 
Serum M30 assay 
Serum M65 assay 
Cytokines 
Circulating Tumor 
Cells  
Cell free DNA 
Cell free Mitochondrial 
DNA 
Whole exome 
sequencing 
RNASeq 
Markers of 
Apoptosis 
TRAIL expression 
TRAIL receptor 
expression 
Dopamine Receptor 
D2 
Whole exome 
sequencing 
RNASeq 
Dopamine Receptor 
D2 
Electron Microscopy 
 
* Correlative studies will include but are not limited to the studies listed above. Correlative 
studies will be performed if adequate samples are collected and on select patients.  
 
5.2 
GENOMIC ALTERATIONS IN BREAST AND ENDOMETRIAL CANCERS  
Patients with breast or endometrial cancer who are being evaluated for treatment may have tumor 
tissue obtained through the course of work-up, diagnosis or staging of their disease. This tissue 
may be submitted from outside (i.e. FFPE tissue) or obtained during tests at the Clinical Center. 
This tumor tissue will be submitted to Frederick for next-generation DNA sequencing using 
comprehensive cancer gene panel testing. This tumor sequencing is exploratory and will not be 
reported to the patient. Germline testing will be performed with the sole purpose to help identify 
the somatic mutations. As many as 20 patient tumor samples will be sent for molecular profiling 
per year of the protocol. No exploratory germline testing will be performed on this protocol.  


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Patients with endometrial cancer and associated malignant peritoneal cytology that is obtained at 
the time of staging laparoscopy will have that peritoneal fluid submitted for clinical diagnostic 
cytopathologic analysis in the Laboratory of Pathology. In addition, any peritoneal or pleural 
fluid collected during enrollment on the study will be examined for malignant cells in the 
Laboratory of Pathology’s Cytopathology section.  
 
5.3 
TUMOR BIOPSIES  
5.3.1 Timing*  
 
Biopsies will be performed at the following times: 
• 
Mandatory – after consent, prior to treatment on cycle 1 day 1 
• 
Mandatory - cycle 2 day 2 (< 24 hours of ONC201 dose) 
• 
Optional - at the time of progression  
 
*Biopsies may be not performed on the specific dates and times due to the following reasons, 
including but not limited to, delayed recovery of hematologic toxicities, delayed clinic schedule, 
or national holidays. 
 
5.3.2 Tissue Sampling and Handling 
 
1. Attempts will be made to obtain up to four cores if safe and feasible. These tumor core 
biopsies will be obtained percutaneously or per vagina through interventional radiology (for 
endometrial cancer cohort) as long as considered minimal surgical risk. Two 3-millimeter 
punch biopsies of skin will be acceptable in lieu of 18-gauge core biopsies for patients with 
skin involvement. Inability to get tissue with a reasonable attempt will not preclude treatment 
and the patient will remain eligible for all other translational components. 
a. Core 1: Electron Microscopy  
b. Core 2: RNA later buffer 
c. Cores 3: FFPE 
d. Cores 4 and 5: OCT 
 
2. The use of imaging to facilitate biopsies will be decided upon by members of the 
interventional radiology team. Should CT scans be needed for biopsy, a limit of 10 scans for 
each procedure will be observed to minimize radiation exposure to the patient. 
 
3. The schedule for the biopsies will be made with Special Procedures (Dr. Elliott Levy). 
Members of the WMB lab will be on call to receive and embed biopsies:  ozakimk@nih.gov, 
Phone 410-522-5661, beeper 102-11155. 


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4. All cores will be stored, barcoded, in the WMB lab at -80oC on site until use according to our 
laboratory SOP. See Table 5 for information about specimen collection and storage.  
 
5.4 
BLOOD SAMPLES  
The following tests will be performed on selected patients’ peripheral blood samples. If collected 
samples are not sufficient, the correlative studies will be performed in order of priority as 
detailed below. These correlative studies will be done in an exploratory fashion.  
5.4.1 Timing 
Research blood samples will be performed at the following times: 
• 
C1D1: after consent, prior to treatment on cycle 1 day 1 
• 
C1D1: 6 hours after ONC201 administration (blood for PK only) 
• 
On Day 1 of each cycle starting with cycle 2: Prior to treatment on day 1 
• 
Optional - at the time of progression  
 
5.4.2 Sampling and Handling 
 
5. We will collect no more than 40ml of research blood at each time point specified. If there is 
an issue obtaining blood from a participant, samples will be prioritized as follows:  
a. 8ml of blood for immune assays (citrate blue/black tiger top) 
b. 10 ml of blood for circulating tumor cells, cell free DNA and cell free 
mitochondrial DNA (cell save preservative) 
c. 10ml of blood for germline DNA analysis for correlative studies (Streck tube; 
C1D1 only) 
d. 4ml of blood for cytokine analysis (lavender top tube) 
e. 6ml of blood each for serum M30/M65 and Trail expression (red top tube) 
f. 6ml of blood for Pharmacokinetics (lavender top tube; C1D1 only but prior to 
drug ingestion and then 6 hours after) 
 
6. Members of the WMB lab will be on call to receive patient samples: ozakimk@nih.gov, 
Phone 410-522-5661, beeper 102-11155. 
 
7. See Table 5 for information about specimen collection and storage.  
 
8. As soon as possible after the patient is scheduled please send an email notification to the 
Trepel Lab, Developmental Therapeutics Branch, NCI: Jane Trepel at 
trepel@helix.nih.gov; Sunmin Lee at leesun@mail.nih.gov; Min-Jung Lee at min-


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jung.lee@nih.gov and Akira Yuno at akira.yuno@nih.gov that the sample is scheduled. 
After the samples are drawn please call the Trepel lab at 240-760-6330 to communicate 
that the sample is ready. Keep the sample on the unit at room temperature. The sample 
will be picked up by a lab member, entered in a secure patient database and processed for 
CTC assessment and immune subset analysis. 
  
 


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5.5 
TABLE 5: SPECIMEN COLLECTION AND STORAGE   
Tumor Biopsy*  
Correlative 
Study  
Collection 
Point(s) 
SOP for collection 
Contact 
SOP after collection  
Electron 
Microscopy 
C1D1 prior to 
treatment 
 
C2D2 
 
Optional at 
time of 
progression 
Preserve the biopsy tissue sample is to 
fix the tissue without delay 
1. Prepare Eppendorf microfuge tube 
(~1.5ml) or conical centrifuge tube 
(15ml) fill with EM fixative (4% 
formaldehyde + 2% glutaraldehyde 
in 0.1M cacodylate buffer, ambient 
temperature) and drop the tissue 
into the fixative.  
2. Fix for 2hrs at room temperature, 
then store in 4C.  
3. Obtain barcode 
 
 
Members of the WMB labs 
will be on call to receive 
and embed biopsies:  
ozakimk@nih.gov, Phone  
410-522-5661, beeper 102-
11155. 
Fix for 2hrs at room temperature, then store in 
4C.  
 
Will be shipped in batches to Kunio Nagashima 
for processing/embedding for the EM analysis.  
Kunio Nagashima  
8560 Progress Drive 
Wing D, Room D2018, 2nd floor 
Frederick Maryland 21701 
Phone: 301-846-1594 
FAX: 301-846-6716 
EMAIL: nagashimak@mail.nih.gov 
 
Dopamine 
Receptor D2 
  
And  
 
Death 
Receptors  
 
C1D1 prior to 
treatment 
 
C2D2 
 
Optional at 
time of 
progression 
a) Prepare two or three Eppendorf 
tubes which contain 1 ml of 4% 
formalin and leave tubes at room 
temperature.  
b) Quickly make your way to 
Interventional Radiology (IR) on 
the floor. Ask one of the techs or 
nurses where your patient is and 
prepare to receive the sample.  
c) Lay a paper towel next to your 
bucket.  
d) Take out the forceps and rinse/dry 
them thoroughly before placing 
them on the paper towel.  
e) Put on a mask, hair net and gloves.  
 
Members of the WMB  labs 
will be on call to receive 
and embed biopsies:  
ozakimk@nih.gov, Phone 
213-703-2032 / 410-522-
5661, beeper 102-11155.. 
Oncoceutics requests: 5 unstained slides (FFPE) 
from each time point 
 
Will later be shipped to Oncoceutics: 
John Coolidge 
Biorespiratory Manager- Boston 
SciSafe, Inc 
35 Dunham Road 
Billerica, MA 01821  
Tel. 404-242-1578 


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f) 
When the radiologist is ready, take 
the slide with the sample on it 
while being CAREFUL NOT TO 
TOUCH THE DOCTOR’S 
GLOVE.  
g) Use the forceps to gently pickup 
and place the sample in the 
Eppendorf tube.  
h) Leave the Eppendorf tube at room 
temperature overnight.  
i) 
Next day carefully remove 4% 
formalin from the Eppendorf tube 
and replace 1 ml of 70% ethanol. 
Leave the tube at room 
temperature.  
j) 
Call AmericanHistolab (Tel: 301-
330-1200) to pick up the sample.  
k) Cost for paraffin embedding and 
H&E staining: $7.95/block. 
Catalogue Number: 1001  
l) The sample labelling with a 
random code and barcoding should 
be same as OTC preserved 
samples collected at the same day  
Email: jfc@scisafe.com   
  
At the time of shipment, the laboratory must 
complete the Specimen Shipping Form ( section 
15.6.5) and email it to the following: 
1. Rohinton.tarapore@oncoceutics.com 
a) jfc@scisafe.com   
Whole Exome 
Sequencing and 
RNAseq done  
 
C1D1 prior to 
treatment 
 
C2D2 
 
Optional at 
time of 
progression  
• Perform core needle biopsy. 
• Pick the core from the biopsy 
needle onto a sterile glass slide. 
• Fill cryomold about 1/3 full with 
OCT. Place the cryomold in dry ice 
to partially freeze the optimal 
cutting temperature (OCT). The 
OCT should be jelly-like, not 
completely frozen. 
• Carefully lift the core biopsy by 
both ends with sterile forceps. Do 
not stretch the biopsy or it will 
break. 
 
Members of the WMB labs 
will be on call to receive 
and embed biopsies:  
ozakimk@nih.gov, Phone 
410-522-5661, beeper 102-
11155.  
3 
Frozen sections should be cut at 5-8um on 
plain, uncoated glass  microscope slides. 
4 
The tissue section should be placed as 
close as possible to the center of the slide. 
Do not place the frozen section at the end 
of the slide. 
5 
Two tissue sections from the same biopsy 
may be placed on the same glass slide if 
space permits. 
6 
Do not allow the tissue section to air on 
the slide. Freeze immediately on dry ice or 


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*Biopsies may be not performed on the specific dates and times due to the following reasons, including but not limited to, delayed 
recovery of hematologic toxicities, delayed clinic schedule, or national holidays. 
 
Plasma/Serum 
Correlative 
Study  
Collection 
Point(s) 
SOP for collection 
Contact 
SOP after collection  
Pharmacokinetics 
C1D1 prior to 
treatment 
 
C1D1 6hr 
after drug 
 
 
Optional at 
time of 
progression 
1. Collect 6ml of blood into a 
Lavender top, vacutainer tube 
2. Obtain barcode  
Blood must be centrifuged, separated 
and frozen within 2 hours of 
collection. Specimens must be stored 
frozen at -70ºC (preferred) or -20ºC 
(acceptable) at each study site until 
shipped on dry ice to the designated 
analytical laboratory. 
 
Members of the WMB labs 
will be on call to receive 
study samples:   
ozakimk@nih.gov, Phone 
410-522-5661, beeper 102-
11155. 
1. Centrifuge the filled lavender top tube at 
1500 g (3000 rpm) for 15 minutes until the 
plasma and the cells are well separated.  
2. Label 2 blue cap transfer vials lengthwise 
with the appropriate barcode labels 
indicating “plasma (blue)”.  
3. Clearly print the study number “Study 
XXX”, patient ID number, date and time of 
the blood draw.  
4. Transfer ~1.5 mL of plasma into each of the 
2 blue top transfer vials labeled “plasma 
(blue)” 
5. Store sample in a freezer with a minimum     
-20ºC or preferable -70ºC 
• Lay the biopsy as straight as 
possible in the OCT. Once the 
sample touches the OCT, you 
cannot reposition it or the sample 
will break apart. 
• Quickly add OCT on top of the 
biopsy, completely covering the 
sample. 
• Ensure the sample is level and 
freeze immediately in dry ice. 
• Obtain barcode  
Store wrapped in aluminum foil or in a 
50ml Falcon tube at 70 degrees C. 
at– 
80 degrees C.  
 


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Correlative 
Study  
Collection 
Point(s) 
SOP for collection 
Contact 
SOP after collection  
 
Will later be shipped to Oncoceutics: 
Sample Receiving Officer 
XenoBiotic Laboratories, Inc 
107 Morgan Lane 
Plainsboro, NJ 08536 
Tel. 609-799-2295 x252 
Email: sro@xbl.com  
  
At the time of shipment, the laboratory must 
complete the Specimen Shipping Form (15.6.5 
Appendix E) and email it to the following: 
m) Rohinton.tarapore@oncoceutics.com 
n) sro@xbl.com  
 
Serum M30 and 
M65 
C1D1 prior to 
treatment 
 
Day 1 of each 
subsequent 
cycle 
 
Optional at 
time of 
progression 
4. Collect 6ml of blood into a Red 
top, vacutainer tube 
5. Obtain barcode  
 
Blood must be centrifuged, separated 
and frozen within 2 hours of 
collection. Specimens must be stored 
frozen at -70ºC (preferred) or -20ºC 
(acceptable) at each study site until 
shipped on dry ice to the designated 
analytical laboratory. 
 
Members of the WMB labs 
will be on call to receive 
study samples:   
ozakimk@nih.gov, Phone  
410-522-5661, beeper 102-
11155. 
 
1. Centrifuge the filled red top tube at 1500 g 
(3000 rpm) for 15 minutes until the plasma 
and the cells are well separated.  
2. Label 2 yellow cap transfer vials lengthwise 
with the appropriate barcode labels 
indicating “serum (red)”.  
3. Clearly print the study number “Study 
XXX”, patient ID number, date and time of 
the blood draw.  
4. Transfer ~1.5 mL of serum into each of the 
2 yelloq top transfer vials labeled “serum 
(red)” 
5. Store sample in a freezer with a minimum     
-20ºC or preferable -70ºC 


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Correlative 
Study  
Collection 
Point(s) 
SOP for collection 
Contact 
SOP after collection  
 
See above Pharmocokinetics section for 
shipping information to Oncoceutics.  
 
TRAIL 
Expression 
C1D1 prior to 
treatment 
 
Day 1 of each 
subsequent 
cycle 
 
Optional at 
time of 
progression 
1. Collect 6ml of blood into a Red 
top, vacutainer tube 
2. Obtain barcode  
 
Blood must be centrifuged, separated 
and frozen within 2 hours of 
collection. Specimens must be stored 
frozen at -70ºC (preferred) or -20ºC 
(acceptable) at each study site until 
shipped on dry ice to the designated 
analytical laboratory. 
 
Members of the WMB labs 
will be on call to receive 
study samples:  
ozakimk@nih.gov, Phone 
410-522-5661, beeper 102-
11155. 
2. Centrifuge the filled red top tube at 1500 g 
(3000 rpm) for 15 minutes until the plasma 
and the cells are well separated.  
3. Label 2 yellow cap transfer vials lengthwise 
with the appropriate barcode labels 
indicating “serum (red)”.  
4. Clearly print the study number “Study 
XXX”, patient ID number, date and time of 
the blood draw.  
5. Transfer ~1.5 mL of serum into each of the 
2 yelloq top transfer vials labeled “serum 
(red)” 
6. Store sample in a freezer with a minimum     
-20ºC or preferable -70ºC 
 
See above Pharmocokinetics section for 
shipping information to Oncoceutics.  
 
Germline gDNA 
C1D1 
1. Collect 10mL of blood into BCT 
Streck tubes ( Label the tube with 
appropriate Study/Patient Number 
Identifiers. Record the time of 
collection and whether the blood 
was drawn using a peripheral 
venous access device (eg. cannula 
Members of the WMB labs 
will be on call to receive 
study samples:  
ozakimk@nih.gov, Phone 
410-522-5661, beeper 102-
11155. 
See Appendix D for full SOP 


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Correlative 
Study  
Collection 
Point(s) 
SOP for collection 
Contact 
SOP after collection  
or butterfly) or a central venous 
access device (CVAD).  
2. After collection, gently invert 
tubes 8-10 times to mix and leave 
tubes upright prior to 
centrifugation. 
3. Obtain barcode 
Circulating 
Tumor Cells, Cell 
free DNA, and 
Cell free 
mitochondrial 
DNA 
C1D1 prior to 
treatment 
 
Day 1 of each 
subsequent 
cycle 
  
Optional at 
time of 
progression 
1. Either one 10-mL CellSave 
Preservative Tube OR a 10-mL 
Streck tube, PLUS one 10-mL 
CPT tube for each time point will 
be collected from each patient. 
Please, make sure tubes are full. 
2. Immediately after collection, 
invert the blood tubes 3-4 times. 
3. Plasma from these samples will be 
stored at Trepel lab after CTCs are 
harvested. 
4. Obtain barcode  
As soon as possible after the patient is scheduled please send email notification 
to the Trepel lab: Jane Trepel at trepel@helix.nih.gov; Sunmin Lee at 
leesun@mail.nih.gov; Min-Jung Lee at min-jung.lee@nih.gov; Akira Yuno at 
akira.yuno@nih.gov that the sample is scheduled.  
As soon as the sample is drawn, please call the Trepel lab at 240-760-6330 to 
communicate that the sample is ready. Keep the sample on the unit at room 
temperature. The sample will be picked up by the lab and processed for CTC 
enumeration. 
Cytokine 
Analysis  
C1D1 prior to 
treatment 
 
Day 1 of each 
subsequent 
cycle 
 
Optional at 
time of 
progression 
3. Collect 4ml of venous blood in a 
venous blood BD Vacutainer 
spray-coated K2EDTA (lavender 
top) tube.  
4. Gently invert 10 times to mix 
blood and anticoagulant.  
5. Store tubes at room temperature 
until centrifugation.  
 
As soon as possible after the patient is scheduled please send email notification 
to the Blood Processing Core for processing and stoage of the blood sampled 
(EDTA plasma) at NCIBloodcore@mail.nih.gov -  at least 24 hours before 
transporting samples (the Friday before is preferred). For sample pickup, page 
102-11964.  
 
For immediate help, call 240-760-6180 (main blood processing core number) 
or, if no answer, 240-760-6190 (main clinical pharmacology lab number). For 
questions regarding sample processing, contact NCIBloodcore@mail.nih.gov 
As soon as the sample is drawn, please call the BPC to communicate that the 
sample is ready. Keep the sample on the unit at room temperature.  


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Correlative 
Study  
Collection 
Point(s) 
SOP for collection 
Contact 
SOP after collection  
It is generally preferred and often 
necessary to process the samples 
within 5 hours of collection. 
 
Plasma will be separated and aliquoted according to the BPC SOPs and stored, 
barcoded, in the CPC repository until use (See Section 15.6.5).  
 
Peripheral Blood Mononuclear Cells (PBMCs) 
Correlative 
Study  
Collection 
Point(s) 
SOP for collection 
Contact 
SOP after collection  
Immune Assays   
C1D1 prior to 
treatment 
 
Day 1 of each 
subsequent 
cycle 
  
Optional at 
time of 
progression 
6. One 8-ml BD Vacutainer Cell 
Preparation Tubes (CPT citrate 
blue/black tiger top) will be collected 
from each patient. 
7. Immediately after collection, mix the 
blood sample by gentle inversion 
several times. The date and exact time 
of each blood draw should be recorded 
on the tube.   
 
As soon as possible after the patient is scheduled please send email 
notification to the Trepel lab at trepel@helix.nih.gov; Sunmin Lee at 
leesun@mail.nih.gov; Min-Jung Lee at min-jung.lee@nih.gov; Akira 
Yuno at akira.yuno@nih.gov and call the Trepel lab at 240-760-6330 to 
arrange for immediate pick-up when the sample is drawn.  
 
 
 
 


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5.6 
SAMPLE STORAGE, TRACKING AND DISPOSITION 
Samples collected at NCI will be ordered in CRIS and tracked through a Clinical Trial Data 
Management system. Should a CRIS screen not be available, the CRIS downtime procedures will 
be completed and will accompany the specimen and be filed in the medical record. Samples will 
not be sent outside NIH without appropriate approvals and/or agreements, if required.  
 
At the end of the protocol, samples will be stored for potential further analysis as new information 
becomes available (only for those subjects who consented to future optional studies). Any new use 
of identified or coded samples, specimens, or data will undergo prospective and continuing IRB 
review and approval.   
5.6.1 Patient sample protections 
Each patient sample set will be coded with a unique patient identifier. No patient specific 
information is encoded in this identifier. The protocol scientific investigators handling samples will 
be blinded as to as to the patient identification, patient data and outcome. Tissue and blood samples 
obtained by and stored through WMB will be labeled with unique barcodes. 
Blood samples obtained by and stored through the Clinical Pharmacology Core and Trepel Lab will 
be labeled with unique barcodes obtained by Dr. Figg’s laboratory barcode system. 
The amount of blood that may be drawn from adult patients (i.e., those persons 18 years of age or 
older) for research purposes shall not exceed 10.5 mL/kg or 550 mL, whichever is smaller, over 
any eight week period.  
If a patient needs to have a malignant effusion or ascites tapped for diagnostic or therapeutic 
purposes, a sample will be collected for research.  
5.6.2 Sample Storage, Tracking and Disposition (CPC)  
Sample Data Collection: 
All samples sent to the Clinical Pharmacology Core (CPC) will be barcoded, with data entered and 
stored in the Labmatrix system utilized by the CPC. This is a secure program, with access to 
Labmatrix limited to defined Figg lab personnel, who are issued individual user accounts. 
Installation of Labmatrix is limited to computers specified by Dr. Figg. These computers all have a 
password restricted login screen.  
Labmatrix creates a unique barcode ID for every sample and sample box, which cannot be traced 
back to patients without Labmatrix access. The data recorded for each sample includes the patient 
ID, name, trial name/protocol number, time drawn, cycle time point, dose, material type, as well as 
box and freezer location. Patient demographics associated with the clinical center patient number 
are provided in the system. For each sample, there are notes associated with the processing method 
(delay in sample processing, storage conditions on the ward, etc.).  
Sample Storage and Destruction:  


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Barcoded samples are stored in barcoded boxes in a locked freezer at either -20° or -80° C 
according to stability requirements. These freezers are located onsite in the BPC and offsite at NCI 
Frederick Central Repository Services in Frederick, MD. Visitors to the laboratory are required to 
be accompanied by laboratory staff at all times.  
Access to stored clinical samples is restricted. Samples will be stored until requested by a 
researcher named on the protocol. All requests are monitored and tracked in Labmatrix. All 
researchers are required to sign a form stating that the samples are only to be used for research 
purposes associated with this trial (as per the IRB approved protocol) and that any unused samples 
must be returned to the BPC. It is the responsibility of the NCI Principal Investigator to ensure that 
the samples requested are being used in a manner consistent with IRB approval.  
Following completion of this study, samples will remain in storage as detailed above. Access to 
these samples will only be granted following IRB approval of an additional protocol, granting the 
rights to use the material.  
If, at any time, a patient withdraws from the study and does not wish for their existing samples to 
be utilized, the individual must provide a written request. Following receipt of this request, the 
samples will be destroyed (or returned to the patient, if so requested) The PI will record any loss or 
unanticipated destruction of samples as a deviation. Reports will be made per the requirements of 
section 7.2. 
Sample barcodes are linked to patient demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use of the 
Labmatrix. It is critical that the sample remains linked to patient information such as race, age, 
dates of diagnosis and death, and histological information about the tumor, in order to correlate 
genotype with these variables. 
5.6.3  Laboratory of Jane Trepel  
Samples will be processed immediately by the Trepel laboratory.  Biospecimens will be collected 
and processed using validated SOPs that will ensure both specimen quality and patient 
confidentiality. Using a computerized inventory system and a backup hardcopy process, all specimen 
collection and processing steps will be documented and the specific location of each specimen will 
be tracked. Each new specimen collected will be assigned a unique barcode identifier that can be 
linked to the original specimen collected and other relevant information within the inventory system.  
Specimen labels will indicate: protocol number, order in which the patient enrolled on the trial, type 
of sample, collection time, and total volume collected, as appropriate.  The inventory process 
contains other security provisions sufficient to safeguard patient privacy and confidentiality. Access 
to the inventory system and associated documents will be restricted to appropriate individuals. 
Requests to use specimens stored in the repository must be approved. SOPs ensure that any changes 
in informed consent made by a patient and relayed to the PI will be reflected in the inventory system 
to ensure that specimens are destroyed as appropriate. All laboratory personnel will be trained to 
adhere to SOPs and will be monitored for high-quality performance. 


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5.6.4 Procedures for storage of tissue specimens in the Laboratory of Pathology 
Tissues designated for clinical diagnostics are transported to the Laboratory of Pathology (LP) 
where they are examined grossly and relevant portions are fixed, embedded in paraffin and 
sectioned and stained for diagnostic interpretation.  Unutilized excess tissue that is not placed in 
paraffin blocks  is stored in formalin for up to three months, in accordance with College of 
American Pathologists/Joint Commission on Accreditation of Healthcare Organizations 
(CAP/JCAHO) guidelines, and then discarded.  Following completion of the diagnostic workup, 
the slides and tissue blocks are stored indefinitely in the LP’s clinical archives.  All specimens are 
catalogued and retrieved utilizing the clinical laboratory information systems, in accordance with 
CAP/JCAHO regulations.  The use of any stored specimens for research purposes is only allowed 
when the appropriate IRB approval has been obtained.  In some cases, this approval has been 
obtained via the original protocol on which the patient was enrolled.  
5.6.5 End of Study  
At the end of the protocol, samples will be stored for potential further analysis as new information 
becomes available (only for those subjects who consented to future optional studies). Any new use 
of identified or coded samples, specimens, or data will undergo prospective and continuing IRB 
review and approval.  
The study will remain open so long as sample or data analysis continues. Samples, and associated 
data, will be stored in the locations listed above until they are no longer of scientific value, or 
unless the patient withdraws consent for their continued use. If researchers have samples remaining 
once they have completed all studies associated with the protocol, they must be returned to the 
WMB laboratory or to the BPC repository. Samples can only be saved at the completion of the 
study for future use if subjects consented. Access to these samples will only be granted following 
IRB approval of an additional protocol, granting the rights to use the material. 
 
5.7 
SAMPLES FOR GENETIC/GENOMIC ANALYSIS 
If not previously evaluated for germline mutations in BRCA1/2 or Lynch syndrome, patients will 
undergo evaluation upon enrollment on trial. If the research findings are verified in the CLIA 
certified lab, the subject will be offered the opportunity to come to NIH (at our expense) to have 
genetic education and counseling with the NCI Genetics Branch to explain this result.  If the 
subject does not want to come to NIH, a referral to a local genetic healthcare provider will be 
provided (at their expense). This is the only time during the course of the study that incidental 
findings will be returned. No interrogations regarding clinically actionable findings will be made 
after the primary analysis. 
Subjects will be contacted if a clinically actionable gene variant is discovered. Clinically actionable 
findings for the purpose of this study are defined as disorders appearing in the American College of 
Medical Genetics and Genomics recommendations for the return of incidental findings that is 
current at the time of primary analysis. (A list of current guidelines is maintained on the CCR 
intranet: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Incidental+Findings+Lists).  Subjects will 


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be contacted at this time with a request to provide a blood sample to be sent to a CLIA certified 
laboratory which has an FDA approved test for that mutation. If the research findings are verified 
in the CLIA certified lab, the subject will be referred to the NIH Genetics counseling service for 
the disclosure of the results.   
This is the only time during the course of the study that incidental findings will be returned. No 
interrogations regarding clinically actionable findings will be made after the primary analysis. 
5.7.1 Certificate of Confidentiality 
As part of study efforts to provide confidentiality of subject information, this study will obtain a 
Certificate of Confidentiality which helps to protect personally identifiable research information.  
The Certificate of Confidentiality allows investigators on this trial to refuse to disclose identifying 
information related to the research participants, should such disclosure have adverse consequences 
for subjects or damage their financial standing, employability, insurability or reputation.  The 
informed consent includes the appropriate coverage and restrictions of the Certificate of 
Confidentiality. 
 
6 
DATA COLLECTION AND EVALUATION  
6.1 
DATA COLLECTION 
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system (C3D) and ensuring data accuracy, consistency and timeliness. The principal 
investigator, associate investigators/research nurses and/or a contracted data manager will assist 
with the data management efforts.  All data obtained during the conduct of the protocol will be kept 
in secure network drives or in approved alternative sites that comply with NIH security standards. 
Primary and final analyzed data will have identifiers so that research data can be attributed to an 
individual human subject participant. 
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event.  
Document AEs from the first study intervention, Study Day 1, through 30 days after the study 
treatment was last administered.  Beyond 30 days after the last intervention, only adverse events 
which are serious and related to the study intervention need to be recorded. 
An abnormal laboratory value will be considered an AE if the laboratory abnormality is 
characterized by any of the following: 
• 
Results in discontinuation from the study 
• 
Is associated with clinical signs or symptoms  
• 
Requires treatment or any other therapeutic intervention 
• 
Is associated with death or another serious adverse event, including hospitalization.  
• 
Is judged by the Investigator to be of significant clinical impact 
• 
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
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End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable.  
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in section 7.2.1.  
6.1.1 Source Documents  
Source documents are defined as original documents, data and records. This may include hospital 
records, clinical and office charts, laboratory data/information, patients' diaries or evaluation 
checklists, pharmacy dispensing and other records, recorded data from automated instruments, 
microfiches, photographic negatives, microfilm or magnetic media, X-rays. The investigator will 
permit trial-related monitoring, audits, IRB review, and regulatory inspection(s), providing direct 
access to source documents.  
 
6.1.2 Case Report Forms  
Data may be entered from the source documents directly into eCRFs in C3D for each patient 
enrolled in this study. The principal investigator or research nurse will review the eCRFs for 
completeness and accuracy. Independent audits may also be conducted by NCI personnel to ensure 
completeness and accuracy of data in C3D. 
 
6.2 
DATA SHARING PLANS 
6.2.1 Human Data Sharing Plan 
I will share human data generated in this research for future research as follows: 
1. Coded, linked data in an NIH-funded or approved public repository.   
2. Coded, linked data in BTRIS (automatic for activities in the Clinical Center) 
3. Identified or coded, linked data with approved outside collaborators under appropriate 
agreements. 
Data will be shared through: 
1. An NIH-funded or approved public repository.  Insert name or names:_clinicaltrials.gov, 
dbGaP. 
2. BTRIS (automatic for activities in the Clinical Center) 
3. Approved outside collaborators under appropriate individual agreements. 
4. Publication and/or public presentations. 
Data will be shared:  
a) Before publication. 
b) At the time of publication or shortly thereafter. 
 


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6.2.2 Genomic Data Sharing Plan 
Unlinked genomic data will be deposited in public genomic databases such as dbGaP in 
compliance with the NIH Genomic Data Sharing Policy. 
6.3 
RESPONSE CRITERIA 
For the purposes of this study, patients should be re-evaluated for response every 8 weeks +/- 4 
days with imaging modalities determined appropriate by the investigators.  In addition to a baseline 
scan, confirmatory scans should also be obtained 4 weeks +/- 4 days following initial 
documentation of objective response. 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1).(40) Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST 
criteria. 
6.3.1 Disease Parameters 
Measurable disease:  Measurable lesions are defined as those that can be accurately measured in at 
least one dimension (longest diameter to be recorded) as: 
1. By chest x-ray: >20 mm; 
2. By CT scan: 
1. 
Scan slice thickness 5 mm or under: as >10 mm  
2. 
Scan slic thickness > 5 mm: double the slice thickness 
3. With calipers on clinical exam: >10 mm. 
All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph node 
must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to 
be no greater than 5 mm).  At baseline and in follow-up, only the short axis will be measured and 
followed. 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable. 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if 
they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline.  Target lesions should be selected on the basis of their size (lesions with the 


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longest diameter), be representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements.  It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion which can be measured reproducibly should be selected.  A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated 
and reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, then 
only the short axis is added into the sum.  The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the disease. 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence, absence, or 
in rare cases unequivocal progression of each should be noted throughout follow-up.  
 
6.3.2 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical lesions:  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed using calipers 
(e.g., skin nodules).  In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
Conventional CT and MRI:  This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice thickness greater 
than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  MRI is 
also acceptable in certain situations (e.g. for body scans).   
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal resolution; 
however, there are many image acquisition variables involved in MRI, which greatly impact image 
quality, lesion conspicuity, and measurement.  Furthermore, the availability of MRI is variable 
globally.  As with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of disease.  Furthermore, 
as with CT, the modality used at follow-up should be the same as was used at baseline and the 
lesions should be measured/assessed on the same pulse sequence.  It is beyond the scope of the 
RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image acquisition 


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protocol should be followed as closely as possible to prior scans.  Body scans should be performed 
with breath-hold scanning techniques, if possible. 
PET-CT:  At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements.  However, if the 
site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to a 
diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for 
RECIST measurements and can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time.  Note, however, that the PET portion of the CT introduces 
additional data which may bias an investigator if it is not routinely or serially performed.   
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next.  If new lesions are identified by ultrasound in the course of the study, confirmation by CT or 
MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used instead of 
CT in selected instances. 
Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor evaluation is not 
advised.  However, such techniques may be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials where recurrence following complete 
response (CR) or surgical resection is an endpoint. 
 
Cytology, Histology:  These techniques can be used to differentiate between partial responses (PR) 
and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell 
tumors, where known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
 
FDG-PET:  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in assessment 
of progression (particularly possible 'new' disease).  New lesions on the basis of FDG-PET imaging 
can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not 


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PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively described 
in the protocol and supported by disease-specific medical literature for the indication.  
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
6.3.3 Response Criteria 
6.3.3.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking 
as reference the baseline sum of diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest 
on study).  In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.  (Note:  the appearance of one or more new lesions is also considered 
progressions). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum of diameters while on study. 
6.3.3.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis). 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression 
of existing non-target lesions.  Unequivocal progression should not normally trump target lesion 
status.  It must be representative of overall disease status change, not a single lesion increase.     
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed at a 
later time by the review panel (or Principal Investigator). 


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6.3.3.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started).  The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-
CR/Non-PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not 
evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
Note: 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
 


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For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
6.3.4 Duration of Response 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  
6.3.5 Progression-Free Survival 
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first. 
6.4 
TOXICITY CRITERIA 
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study.  The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 
5.0.  A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm ).  
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used 
as an endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be 
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7 
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN 
7.1 
DEFINITIONS 
Please refer to definitions provided in Policy 801: Reporting Research Events found here. 
 
7.2 
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING 
7.2.1 Expedited Reporting 
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 802 
Non-Compliance Human Subjects Research found here. Note: Only IND Safety Reports that meet 
the definition of an unanticipated problem will need to be reported per these policies. 
 
7.2.2 IRB Requirements for PI Reporting at Continuing Review 
Please refer to the reporting requirements in Policy 801: Reporting Research Events found here..  
. 
7.3 
NCI CLINICAL DIRECTOR REPORTING  
Problems expeditiously reported to the OHSRP in iRIS will also be reported to the NCI Clinical 
Director.  A separate submission is not necessary as reports in iRIS will be available to the Clinical 
Director. 
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email to the Clinical Director unless they are due to progressive 
disease.   
To report these deaths, please send an email describing the circumstances of the death to Dr. Dahut 
at NCICCRQA@mail.nih.gov within one business day of learning of the death. 
 
7.4 
NIH REQUIRED DATA AND SAFETY MONITORING PLAN    
7.4.1 Principal Investigator/Research Team  
The clinical research team will meet on a regular basis weekly when patients are being actively 
treated on the trial to discuss each patient. Decisions about dose level enrollment and dose 
escalation if applicable will be made based on the toxicity data from prior patients.  
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Events meeting requirements for expedited reporting as described in section 
7.2.1 will be submitted within the appropriate timelines.  
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 


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investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.  
8 
SPONSOR SAFETY REPORTING 
8.1 
DEFINITIONS 
8.1.1 Adverse Event  
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product (ICH E6 (R2)) 
8.1.2 Serious Adverse Event (SAE) 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
• 
Death, 
• 
A life-threatening adverse event (see section 8.1.3) 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
o A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery 
arranged prior to the start of the study), a planned hospitalization for pre-existing 
condition, or a procedure required by the protocol, without a serious deterioration in 
health, is not considered a serious adverse event. 
o A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for patient convenience) is not considered a serious adverse event.  
o Emergency room visits or stays in observation units that do not result in admission to 
the hospital would not be considered a serious adverse event. The reason for seeking 
medical care should be evaluated for meeting one of the other serious criteria. 
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions 
• 
A congenital anomaly/birth defect. 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
8.1.3 Life-threatening  
An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of 


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death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death. (21CFR312.32) 
8.1.4 Severity 
The severity of each Adverse Event will be assessed utilizing the CTCAE version v5.0. 
8.1.5 Relationship to Study Product 
All AEs will have their relationship to study product assessed using the terms:  related or not 
related.   
• Related – There is a reasonable possibility that the study product caused the adverse event. 
Reasonable possibility means that there is evidence to suggest a causal relationship between 
the study product and the adverse event. 
• Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event. 
8.2 
ASSESSMENT OF SAFETY EVENTS 
AE information collected will include event description, date of onset, assessment of severity and 
relationship to study product and alternate etiology (if not related to study product), date of 
resolution of the event, seriousness and outcome. The assessment of severity and relationship to the 
study product will be done only by those with the training and authority to make a diagnosis and 
listed on the Form FDA 1572 as the site principal investigator or sub-investigator.  AEs occurring 
during the collection and reporting period will be documented appropriately regardless of 
relationship.  AEs will be followed through resolution. 
SAEs will be: 
• 
Assessed for severity and relationship to study product and alternate etiology (if not related 
to study product) by a licensed study physician listed on the Form FDA 1572 as the site 
principal investigator or sub-investigator. 
• 
Recorded on the appropriate SAE report form, the medical record and captured in the 
clinical database. 
• 
Followed through resolution by a licensed study physician listed on the Form FDA 1572 as 
the site principal investigator or sub-investigator. 
For timeframe of recording adverse events, please refer to section 6.1. All serious adverse events 
recorded from the time of first investigational product administration must be reported to the 
sponsor.  
.  
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS 
Any AE that meets  protocol-defined serious criteria or meets the definition of Adverse Event of 
Special Interest that require expedited reporting must be submitted immediately (within 24 hours of 
awareness) to OSRO Safety using the CCR SAE report form.  


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All SAE reporting must include the elements described in section 8.2. 
SAE reports will be submitted to the Center for Cancer Research (CCR) at: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  CCR SAE report form and 
instructions can be found at: 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=157942842 
Following the assessment of the SAE by OSRO, other supporting documentation of the event may 
be requested by the OSRO Safety and should be provided as soon as possible. 
 
8.4 
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS 
All events listed below must be reported in the defined timelines to CCRsafety@mail.nih.gov.  
The CCR Office of Regulatory Affairs will send all reports to the manufacturer as described below. 
Serious Adverse Event and Suspected Unexpected Serious Adverse Reaction, Medical Device 
Event, Potential Incident, Device Deficiency or Incident Reporting:  Principal Investigator shall 
forward to Oncoceutics Inc, any SAE, SUSAR, Medical Device Event, Device Deficiency or 
Incident information, including, but not limited to, all initial and follow-up information involving 
any Study subject in the Study.  Notification shall be in the form of a completed CIOMS 
I/MedWatch (or other mutually agreed upon format) within two (2) business days of learning of the 
information.  This information shall be transmitted to Oncoceutics using the contact information 
provided below or such other modified contact information as provided by Oncoceutics in 
writing.  All information shall be transmitted in the English language and contain the reporter’s 
name and the Study subject identifier code.   SUSAR information will be reported unblinded if the 
Study Drug has been blinded in the Study.  Randomization codes for all other SAEs will be 
provided to Oncoceutics at end of Study if the Study Drug has been blinded in the Study. 
Oncoceutics may define certain Non-Serious Events of Interest.  If any Non-Serious Events of 
Interest are defined, Oncoceutics will provide such information in writing to Principal Investigator 
at the time of Protocol approval, execution of the CTA or anytime thereafter.  Reporting of any 
defined Non-Serious Events of Interest will be handled in the same manner as SAEs unless 
mutually agreed otherwise in writing by the parties.  
All reports of Study Drug exposure during pregnancy or lactation (including a female partner of a 
male Study subject using the Study Drug), whether associated with an AE or not, must be reported 
to Oncoceutics in accordance with the timelines and contact information for an SAE.  Principal 
Investigator shall follow pregnancies to term to obtain the outcome of the pregnancy.  The outcome 
of the pregnancy shall be forwarded to Oncoceutics.  
Institution and Principal Investigator shall fully comply with all of their respective reporting 
obligations to the applicable regulatory authorities with respect to any AE, SAE or SUSAR that 
arises from the Study. 
SAE reports and any other relevant safety information are to be forwarded to Josh Allen, PhD of 
Oncoceutics via email (josh.allen@oncoceutics.com) and/or facsimile number: 1-844-245-7650.  
 
 


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 A MedWatch form is available at http://www.fda.gov/medwatch/   
 
8.5 
REPORTING PREGNANCY 
8.5.1 Maternal exposure 
If a patient becomes pregnant during the course of the study, the study treatment should be 
discontinued immediately, and the pregnancy reported to the Sponsor no later than 24 hours of 
when the Investigator becomes aware of it. The Investigator should notify the Sponsor no later than 
24 hours of when the outcome of the pregnancy becomes known, 
Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects and 
spontaneous miscarriages that meet serious criteria (section 8.1.2) should be reported as SAEs.  
The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth, or congenital abnormality) should be followed up and documented. 
8.5.2 Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for 28 
days after the last dose of ONC201. 
Pregnancy of the patient’s partner is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring from the date of the first dose until 28 days after the last dose 
should, if possible, be followed up and documented. 
8.6 
REGULATORY REPORTING FOR STUDIES CONDUCTED UNDER CCR-SPONSORED IND 
Following notification from the investigator, CCR, the IND sponsor, will report any suspected 
adverse reaction that is both serious and unexpected.  CCR will report an AE as a suspected 
adverse reaction only if there is evidence to suggest a causal relationship between the study product 
and the adverse event.  CCR will notify FDA and all participating investigators (i.e., all 
investigators to whom the sponsor is providing drug under its INDs or under any investigator’s 
IND) in an IND safety report of potential serious risks from clinical trials or any other source, as 
soon as possible, in accordance to 21 CFR Part 312.32.  
All serious events will be reported to the FDA at least annually in a summary format. 
 
9 
CLINICAL MONITORING 
As a sponsor for clinical trials, FDA regulations require the CCR to maintain a monitoring 
program. The CCR’s program allows for confirmation of: study data, specifically data that could 
affect the interpretation of primary and secondary study endpoints; adherence to the protocol, 
regulations, ICH E6, and SOPs; and human subjects protection. This is done through independent 
verification of study data with source documentation focusing on: 
• 
Informed consent process 
• 
Eligibility confirmation 


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• 
Drug administration and accountability 
• 
Adverse events monitoring 
• 
Response assessment. 
The monitoring program also extends to multi-site research when the CCR is the coordinating 
center. 
This trial will be monitored by personnel employed by a CCR contractor. Monitors are qualified by 
training and experience to monitor the progress of clinical trials. Personnel monitoring this study 
will not be affiliated in any way with the trial conduct. 
 
10 STATISTICAL CONSIDERATIONS   
10.1  STATISTICAL HYPOTHESIS 
The primary objectives of this trial are to determine whether ONC201 is able to be associated with 
1) potential improvement in the PFS probability of patients with refractory/recurrent metastatic 
HR+ breast cancer, 2) an improvement in overall response rate in patients with metastatic TNBC, 
or 3) an improvement in overall response rate in patients with advanced endometrial cancer.  
Primary Endpoints: 
• Cohort 1: To determine the progression free survival (PFS) at 8 months of ONC201 in 
metastatic hormone receptor positive breast cancer (HR+BC) 
• Cohort 2: To determine the overall response rate (ORR) of ONC201 in metastatic triple 
negative breast cancer (TNBC)  
• Cohort 3: To determine the ORR of ONC201 in advanced endometrial cancer (EC) 
 
Secondary Endpoints for all cohorts will include safety of ONC201, clinical benefit rate (defined as 
partial response + complete response + stable disease).  
 
10.2 SAMPLE SIZE DETERMINATION 
Cohort 1: Refractory/recurrent metastatic HR+ breast cancer 
Data from published trials indicate that the median PFS in patients with refractory/recurrent 
metastatic HR+ breast cancer is approximately 4 months. In this cohort, the goal is to determine if 
use of ONC201 is able to be associated with an 8-month median PFS probability (7, 8). With 24 
evaluable patients receiving the proposed therapy, assuming accrual would take place over 
approximately 2 years, and that there would be at least 1 year of additional potential follow-up after 
the last patient has begun the therapy, there would be 80% power to determine whether there is a 
difference between a 4 month median PFS and an improved 8-month median PFS, with a one sided 
0.10 alpha level test, using the method of Brookmeyer and Crowley (41). In practice, Kaplan-Meier 
curves and appropriate confidence intervals at selected time points will be provided to help 
interpret results relative to the expected results.  As an early stopping rule, if 0 of the first 5 patients 
is able to be progression-free at 8 months, then no further patients will be accrued into this cohort 
as soon as that is able to be determined since the upper 95% one-sided confidence bound on 0/5 is 


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45%, and thus this indicates inconsistency with an 8-month median PFS. The study may need to 
pause accrual to evaluate if PFS in any of the first 5 patients is ≥ 8 months. 
 
Cohort 2:  Metastatic TNBC 
Data which have been published suggest that a response rate (PR+CR) for treatment of recurrent or 
metastatic TNBC is approximately 30-35% (13-15).  In order to establish the efficacy of this 
treatment in patients with metastatic TNBC, the primary objective in this cohort would be to 
determine if using ONC201 would rule out a 25% response rate and result in a response rate 
consistent with 45%. As such, this cohort will be evaluated using a single stage design in order to 
rule out an unacceptably low PR+CR rate of 25% (p0=0.25) in favor of an improved response rate 
of 45% (p1=0.45). Based on a one-sided exact binomial test, 29 patients would have 82% power to 
rule out 25% and result in findings consistent with a 45% PR + CR rate. At the end of the study, we 
would form the two-sided 80% and 95% CI about the observed percentages of both response 
(PR+CR) and clinical benefit (SD+PR+CR). 11 responses (PR+CR) in 29 patients (37.9%) has a 
two-sided 80% CI of 25.7-51.5%, which would be sufficiently interesting for further evaluation. As 
an early stopping rule, after 10 evaluable patients have been enrolled, if there are 0 or 1 with 
clinical benefit (SD+PR+CR), then the cohort would end accrual as soon as this would be 
determined since the 90% one-sided upper CI bound on 1/10 is 33.7%, which would be marginally 
too low for further interest. Both the PR+CR and SD+PR+CR rates can be formed at the interim 
time for descriptive purposes as well as for evaluation for early stopping. The study may need to 
pause accrual to evaluate if clinical benefit in the first 10 patients exceeds the early stopping rule. 
Cohort 3: Advanced endometrial cancer 
Published data from several trials report response rates of 8 to 15% for second line treatment in 
patients with advanced endometrial cancer (18-21). As such, it would be desirable if new 
treatments are associated with at least a 12-15% response rate for further consideration.  In patients 
with advanced endometrial cancer, the primary objective of this study would be to determine if 
using ONC201 would rule out a 5% response rate and result in a response rate consistent with 25%. 
As such, the trial will be conducted using a single stage design (42) in order to rule out an 
unacceptably low PR+CR rate of 5% (p0=0.05) in favor of an improved response rate of 25% 
(p1=0.25). Based on a one-sided exact binomial test, 25 patients would have 90% power to rule out 
5% and result in findings consistent with a 25% PR + CR rate. At the end of the study, we would 
form the two-sided 80% and 95% CI about the observed percentages of both response (PR+CR) 
and clinical benefit (SD+PR+CR). 3 responses (PR + CR) in 25 patients (12.0%) has a two-sided 
80% CI of 4.5-24.8%, which is potentially worthy of further consideration, while 4 responses in 25 
(16.0%) has a two-sided 80% CI of 7.2-29.5%, which would be sufficiently interesting for further 
evaluation. As an early stopping rule, after 13 evaluable patients have been enrolled, if there are 0 
patients with clinical benefit (SD+PR+CR), then the cohort would end accrual since the 90% one-
sided upper CI bound on 0/13 is 16.2%, which would be marginally too low for further interest. 
Both the PR+CR and SD+PR+CR rates can be formed at the interim time for descriptive purposes 
as well as for evaluation for early stopping.  The study may need to pause accrual to evaluate if 
clinical benefit in the first 13 patients exceeds the early stopping rule. 
Any secondary evaluations performed will be done in an exploratory fashion, with results 
presented without any formal adjustment for multiple comparisons.  


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It is expected that approximately 1 patient per month may enroll onto this trial in the ER+ breast 
cancer cohort, and that 6 to 8 patients per year may enroll in each of the other two cohorts. Thus, it 
is expected that 3 to 4 years may be required in order to enroll up to 24+29+25=78 evaluable 
patients. In order to allow for a small number of unevaluable patients, the accrual ceiling will be set 
at 90 patients. 
10.3 POPULATIONS FOR ANALYSES 
Evaluable for toxicity:  All patients will be evaluable for toxicity from the time of their first 
treatment with ONC201. 
Evaluable for objective response: Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will 
be considered evaluable for response.  These patients will have their response classified according 
to the definitions stated below.  (Note:  Patients who exhibit objective disease progression prior to 
the end of cycle 1 will also be considered evaluable.) 
Evaluable Non-Target Disease Response:  Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle of 
therapy, and have had their disease re-evaluated will be considered evaluable for non-target 
disease.  The response assessment is based on the presence, absence, or unequivocal progression of 
the lesions.  
Evaluable for Progression Free Survival: In all three cohorts, all participants who took at least one 
cycle of study drug and have adequate follow-up to be included in a PFS analysis (cohort 1) or to 
have response and clinical benefit evaluated (cohorts 2 and 3) will be included in the analyses. 
10.4 STATISTICAL ANALYSES 
10.4.1 General Approach 
Analyses performed will be descriptive, reporting the outcome measure indicated along with two-
tailed 80% and 95% confidence intervals for PFS (cohort 1), and 80% and 95% confidence 
intervals about the response rate and clinical benefit rate in cohorts 2 and 3.  
10.4.2 Analysis of the Primary Endpoints 
 
Cohort 1: Kaplan-Meier curves for PFS using all patients who receive treatment and are eligible for 
evaluation will be included, and appropriate confidence intervals (80% and 95% two sided 
confidence intervals) at selected time points will be provided to help interpret results relative to the 
expected results.   
 
Cohort 2 and 3: At the end of the trial we will form the two-sided 80% and 95% CI about the 
observed percentages of both response (PR+CR) and clinical benefit (SD+PR+CR). 
10.4.3 Analysis of the Secondary Endpoints 
 
• Cohort 1 HR+BC – Safety—AEs will be tabulated, ORR—response rate will be reported 
along with 95% two-sided confidence interval, clinical benefit rate (CBR; CR + PR + SD 


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by RECIST) clinical benefit rate will be reported along with 95% two-sided confidence 
interval  
• Cohort 2 TNBC – Safety-AEs will be tabulated CBR, clinical benefit rate will be reported 
along with 95% two-sided confidence interval; PFS by Kaplan-Meier analysis   
• Cohort 3 Endometrial Cancer – Safety, CBR clinical benefit rate will be reported along with 
95% two-sided confidence interval, PFS by Kaplan-Meier analyses 
 
10.4.4 Safety Analyses 
The safety of ONC201 tabulations be evaluated by descriptive statistics of each adverse event type 
and grade. 
 
10.4.5 Baseline Descriptive Statistics 
No formal analysis of baseline statistics will be performed. 
 
10.4.6 Planned Interim Analyses 
The interim analyses are described for each cohort in the sample size determination paragraph. 
 
10.4.7 Sub-Group Analyses 
No subgroup analyses are planned. 
 
10.4.8 Tabulation of individual Participant Data 
No individual participant data will be provided. 
 
10.4.9 Exploratory Analyses 
 
Blood samples at baseline and Day 1 of each subsequent cycle, as well as biopsy specimens at 
baseline and cycle 2 will yield a set of biomarkers, such as markers of apoptosis, indications of 
mitochondrial damage and immune subsets. The difference of the values at cycle 1 vs. baseline and 
cycle 2 vs. baseline will be determined, and these differences will be used as a covariate for 
analysis of PFS in each cohort to see if the level of change in biomarkers may be associated with 
PFS. These analyses will be done in an exploratory fashion using Kaplan-Meier curves and log 
rank tests. The changes in the biomarkers will also be compared between responders and non-
responders in the three cohorts using an exact form of a Wilcoxon rank sum test. All of these 
explorations will be done only if adequate patient data are available. Results will be presented 
without adjustment for multiple comparisons. 


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11 COLLABORATIVE AGREEMENTS  
11.1 CLINICAL TRIAL AGREEMENT 
The study agent, ONC201 is provided by Oncoceutics., Inc. under a Clinical Trial Agreement (NCI 
CTA #1035). Results or study data may be communicated to CTA partner, according to the terms 
of the NIH- Advanced Accelerator Applications SA CTA. 
12 HUMAN SUBJECTS PROTECTIONS  
12.1 RATIONALE FOR SUBJECT SELECTION 
Subjects from all racial and ethnic groups are eligible for this trial if they meet the eligibility 
criteria. Efforts will be made to extend the accrual to a representative population. If differences in 
outcome that correlate to racial or ethnic identity are noted, accrual may be expanded or additional 
studies may be performed to investigate those differences more fully. 
12.2 PARTICIPATION OF CHILDREN 
The age group for enrollment on this trial is 18 or more years of age. Because no dosing or adverse 
event data are currently available on the use of ONC201 in participants < 18 years of age, children 
are excluded from this study. 
12.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT 
Adults unable to give consent are excluded from enrolling in the protocol.  However, re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (section 12.5), all subjects will be offered the opportunity to fill in their 
wishes for research and care, and assign a substitute decision maker on the “NIH Advance 
Directive for Health Care and Medical Research Participation” form so that another person can 
make decisions about their medical care in the event that they become incapacitated or cognitively 
impaired during the course of the study. Note: The PI or AI will contact the NIH Ability to Consent 
Assessment Team (ACAT) for evaluation as needed for the following: an independent assessment 
of whether an individual has the capacity to provide consent; assistance in identifying and 
assessing an appropriate surrogate when indicated; and/or an assessment of the capacity to appoint 
a surrogate.  For those subjects that become incapacitated and do not have pre-determined 
substitute decision maker, the procedures described in NIH HRPP SOP 14E for appointing a 
surrogate decision maker for adult subjects who are (a) decisionally impaired, and (b) who do not 
have a legal guardian or durable power of attorney, will be followed. 
12.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
ONC201 is an investigational agent for use in metastatic breast cancer and in advanced endometrial 
cancer. The protocol provides for detailed and careful monitoring of all patients to assess for 
toxicity. Toxicity data will be collected and reviewed to ensure that there were no severe toxicities 
that would preclude further patient enrollment. Patients will be treated with therapeutic intent and 
response to the therapy will be closely monitored.  


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12.5 RISKS/BENEFITS ANALYSIS 
12.5.1 Benefits  
The potential benefit to a patient on this study is a reduction or stability in breast cancer or 
endometrial cancer, as well as potentially the prevention or delay in development of new metastatic 
lesions, which may or may not have favorable impact on symptoms and/or survival.  
12.5.2 Risks  
12.5.2.1 Study Drug Risks 
Risks include the possible occurrence of any of a range of side effects which are listed in the 
Consent Document or in section 13.1.2 of this protocol document. Frequent monitoring for adverse 
effects will help to minimize the risks associated with administration of the study agents.  
12.5.2.2 Radiation Risks 
The study will involve radiation from the following sources: 
• Up to 3 CT scans for the collection of biopsies 
• Up to 8 CT scans per year for disease assessment  
• 1 technetium-99 bone scan for disease assessment 
Subjects may be exposed to approximately 11.59 rem. This amount is more than would be expected 
from everyday background radiation. Being exposed to excess radiation can increase the risk of 
cancer. The risk of getting cancer from the radiation exposure in this study is 1.2 out of 100 (1.2 %) 
and of getting a fatal cancer is 0.6 out of 100 (0.6%).  
12.5.2.3 Risks from Blood Draws: 
Side effects of blood draws include pain and bruising, lightheadedness, and rarely, fainting. 
12.5.2.4 Risks of CT Scans: 
In addition to the radiation risks discussed above, risks associated with CT scans are allergic 
reaction to and kidney damage from the contrast dye, nausea, vomiting, and anxiety. 
12.5.2.5 Risks of Technetium-99 Bone Scans: 
In addition to the radiation risks described above, risks associated with technetium-99 bone scans 
are pain, bruising, injection site infection, and allergic reaction to the contrast agent. 
12.5.2.6 Specimen Collection Risks 
Risks include those associated with specimen collection including pain, bleeding and the possibility 
of infection at the sampling site. All care will be taken to minimize risks that may be incurred by 
tumor sampling. However, there are procedure-related risks (such as bleeding, infection and 
visceral injury) that will be explained fully during informed consent. If patients suffer any physical 
injury as a result of the biopsy, immediate medical treatment is available at the NIH’s Clinical 
Center in Bethesda, Maryland. Although no compensation is available, any injury will be fully 


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evaluated and treated in keeping with the benefits or care to which patients are entitled under 
applicable regulations. 
 
12.5.3 Risks/Benefits Analysis  
The potential benefits from this therapy are stabilization or shrinkage of the tumor and a reduction 
in chances of developing new lesions, with decrease of symptoms caused be progressive disease. 
Given the efforts to minimize risk with the administration of this combination, this protocol 
involves greater than minimal risk, but presents the potential for direct benefit to individual 
subjects. 
 
12.6 CONSENT PROCESS AND DOCUMENTATION 
The informed consent document will be provided to the participant or consent designee(s) (e.g., the 
legally authorized representative [LAR] if participant is an adult unable to consent) for review prior 
to consenting.  A designated study investigator will carefully explain the procedures and tests 
involved in this study, and the associated risks, discomforts and benefits. In order to minimize 
potential coercion, as much time as is needed to review the document will be given, including an 
opportunity to discuss it with friends, family members and/or other advisors, and to ask questions 
of any designated study investigator. A signed informed consent document will be obtained prior to 
entry onto the study. 
The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other NIH approved remote platforms) per discretion of the 
designated study investigator and with the agreement of the participant/consent designee(s).  
Whether in person or remote, the privacy of the subject will be maintained. Consenting 
investigators (and participant/consent designee, when in person) will be located in a private area 
(e.g., clinic consult room). When consent is conducted remotely, the participant/consent designee 
will be informed of the private nature of the discussion and will be encouraged to relocate to a 
more private setting if needed.   
For the optional biopsy in the protocol, the patient will consent at the time of the procedure.  If the 
patient refuses the optional biopsy at that time, the refusal will be documented in the medical 
record and in the research record. 
12.6.1 Request for Waiver of Consent for Screening Activities 
Prior to the subject signing the consent for this study pre-screening activities listed in section 2.5.1 
may be performed.  
We request a waiver of consent for these activities as they involve only minimal risk to the 
subjects.  A waiver will not adversely affect the rights and welfare of the subjects given that the 
activities are only intended to determine suitability for screening for participation in research 
protocols.  These activities could not practicably be carried out without the wavier as central 
recruiting services, utilized in the NIH Clinical Center, perform pre-screening activities for 
multiple studies and obtaining consent for each one is beyond their resources.  The subjects will be 


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provided with additional pertinent information after participation as they will be informed whether 
or not they are eligible to sign a consent for additional screening. 
13 PHARMACEUTICAL INFORMATION   
13.1 DRUG ONC201 (IND # 136939) 
13.1.1 Source  
ONC201 is an investigational drug supplied under a Clinical Trials Agreement by Oncoceutics 
INC.  
13.1.2 Toxicity  
Generally, ONC201 is well tolerated at all of the tested dose levels. To date, over 70 patients have 
taken at least one dose of ONC201 and no Grade IV events have been reported. One grade II 
allergic reaction occurred after the 5th dose of ONC201 625mg (q3 week schedule) that was 
managed by standard over the counter medications. One grade III neutropenia was transiently 
observed after the 5th dose of ONC201. The dose was reduced to 500mg q3weeks without 
recurrence of the neutropenia (Table 6).(2, 4) 
 
Table 6: All Grade I AEs attributed (possibly related) to ONC201 on every 3-week dosing schedule 
for the Phase I trial.  
ONC201 Dose  
   No. of Patients 
125mg 
1 
250mg 
1 
375mg 
1 
500mg 
1 
625mg 
24 
Pyrexia 
1 
0 
0 
0 
0 
Fatigue 
1 
0 
0 
0 
0 
Elevated Amylase 
0 
0 
0 
0 
2 
Emesis 
0 
0 
0 
0 
1 
Nausea 
0 
0 
0 
0 
1 
* Note: No drug-related AE > Grade 1 reported on the Phase I solid tumor trial  
 
While human exposure to ONC201 is still somewhat limited at this time, side effects seen in 
animals included the following:  
▪ Nausea 
▪ Salivation 
▪ Vomiting 
▪ Abnormal breathing 
▪ Twitching 


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▪ Abnormal walking or standing 
 
While side effects are minimal, based on pharmacokinetic data, it would be reasonable to dose 
reduce if more significant side effects did occur. Based on the mean AUC and Cmax data from the 
phase I study, a dose reduction to 500mg weekly with two further reduction to 375mg weekly and 
then 250mg weekly would be reasonable and would likely not significantly affect clinical benefit 
(Figure 5).  
 
 
 
 
The metabolism and excretion of ONC201 is still unknown at this time. However, it is suspected to 
be excreted by the kidneys. This is supported by preliminary observations in rats (unpublished 
data, communication with Oncoceutics, Inc).  
 
The effects of ONC201 on the developing human fetus are unknown. For this reason, women 
of childbearing potential and men must agree to use adequate contraception (hormonal or 
barrier method of birth control; abstinence) prior to study entry and for the duration of study 
participation. Should a woman become pregnant or suspect she is pregnant while she or her 
partner is participating in this study, she should inform her treating physician immediately. An 
assessment should be made to ensure the potential benefit would justify a potential risk to the 
fetus. 
 
It is not known whether ONC201 is excreted in breast milk. It is recommended that women do 
not breastfeed during treatment with ONC201 and for 2 months after the last dose. 
Figure 5: Mean AUC and Cmax for each dose cohort following first dose of ONC201. Image 
adapted from Stein et al, 2015 (2).  


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13.1.3 Formulation and preparation  
The investigational drug product is a hydroxypropyl methylcellulose (HPMC) capsule filled with 
ONC201 dihydrochloride, intended for oral administration. Each capsule of drug product 
contains the equivalent 125mg of anhydrous ONC201 free base with or without microcrystalline 
cellulose. This corresponds to ~150mg of drug substance that corrects. 
 
 
13.1.4 Stability and Storage  
The capsules are to be stored in a closed container at room temperature (15 to 30°C). 
Based on the current stability data room temperature (25°C/60%RH) will be used for the drug 
product storage. No shelf life has been established for this product at this point. However, 
representative clinical trial batches will be placed on stability. Any batches that are out of 
specifications will be removed from use. 
 
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).  
 
Administration procedures 
ONC201 is taken by mouth every 7 days by the patient. Pharmacy can dispense the exact number 
of capsules needed for cycle, as prescribed by the physician, by transferring them to a white, 


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opaque, HDPE container with child-proof closures. This type of container is the same as the one 
the drug is initially supplied in. Remaining capsules will be kept in the original bottle and will be 
dispensed for the subsequent prescription/subject. 
 
13.1.5 Incompatibilities   
The investigator’s brochure for ONC201 by Oncoceutics does not describe any known drug-drug 
interactions with ONC201. In vitro cytochrome P450 assays were conducted in human hepatocytes. 
In these studies, ONC201 is not an induced of the CYP450 system (CYP1A2, 2B6, 2B6, and 3A4). 
ONC201 was observed to be a mild inhibitor of the CYP450 enzymes (1A2, 2B6, 2C8, 2C9, 2C19, 
3A4) at 35-429 uM, i.e., at least 3.5 fold above the Cmax observed in the first-in-human trial.  
 
Drugs that antagonize DRD2 are commonly used as antipsychotics. However, comparison between 
ONC201 and other typical antipsychotics (such as haloperidol and risperidone) reveal substantial 
differences in anti-tumor activity, therapeutic window, specificity and receptor pharmacology. 
Moreover, the current administration schedule of ONC201 dosing is atypical for antipsychotic 
drugs. Taken together, there is no clear expectation that side effects that are commonly observed 
with antipsychotic drugs will be observed with ONC201 in the current schedule. Nevertheless, it is 
possible that side effects associated with antipsychotics could be observed with ONC201; weight 
gain, diabetes, metabolic disorders, dystonia, akinesia, akathisia, tremors, muscle rigidity, 
insomnia, blurry vision, Parkinsonian symptoms, cognitive impairment, sexual dysfunction, 
osteoporosis, sedation, behavioral changes, and cardiac disorders.  
 
 
 


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and 5. Immunity. 2000;12(6):611-20. PubMed PMID: 10894161. 
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superfamily. Nat Rev Cancer. 2002;2(6):420-30. doi: 10.1038/nrc821. PubMed PMID: 12189384. 
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TRAIL receptor agonist drozitumab targets basal B triple-negative breast cancer cells that express 
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induces apoptosis in triple-negative breast cancer cells with a mesenchymal phenotype. Breast 


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Zeng Z, Tabe Y, Allen JE, Wang Z, Ma W, Lee HC, Orlowski R, Sarbassov dD, Lorenzi PL, 
Huang X, Neelapu SS, McDonnell T, Miranda RN, Wang M, Kantarjian H, Konopleva M, Davis 
RE, Andreeff M. ATF4 induction through an atypical integrated stress response to ONC201 
triggers p53-independent apoptosis in hematological malignancies. Sci Signal. 2016;9(415):ra17. 
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33. 
Kline CL, Van den Heuvel AP, Allen JE, Prabhu VV, Dicker DT, El-Deiry WS. ONC201 
kills solid tumor cells by triggering an integrated stress response dependent on ATF4 activation by 
specific eIF2α kinases. Sci Signal. 2016;9(415):ra18. doi: 10.1126/scisignal.aac4374. PubMed 
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P, Cam M, Lang M, Voeller D, Reinhold WC, Rajapakse V, Pommier Y, Weigert R, Linehan WM, 
Lipkowitz S. ONC201 kills breast cancer cells in vitro by targeting mitochondria. Oncotarget. 
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Stein M, El-Deiry W, editors. Imipridone ONC201promotes intra-tumoral accumulation of 
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15 APPENDICES 
15.1 APPENDIX A-PERFORMANCE STATUS CRITERIA 
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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15.2 APPENDIX B- METHOD FOR PREPARING PBMC SAMPLES FROM BLOOD FOR 
PHARMACODYNAMIC (PD) STUDIES  
1. Using a BD Vacutainer CPT, draw the blood sample. Assure that the anticoagulant being 
used (sodium citrate or sodium heparin) is correct for the intended use of the specimen and 
that the tube size is correct for the blood draw volume required by the protocol.  
2. Mix the sample by inverting the tube for 5-8 times and centrifuge the sample at 1500 g for 
30min at 18-25°C, without break.  
3. After centrifuge, remove two thirds of plasma and transfer whitish PBMC layer into the 
labeled 15-ml conical tube using a 3-ml Falcon transfer pipet.  
4. Discard the Vacutainer CPT tube in biohazard waste container.  
5. Add Plasma-Lyte A USP to the 15-ml tube to bring total volume to 14 ml, cap and mix by 
gentle inversion 5-8 times.  
6. Centrifuge the sample at 430 g for 10 min at 18-25°C, without break.  
7. Using a new transfer pipet, aspirate as much supernatant as possible without disturbing the 
cell pellet and discard the supernatant into biohazardous liquid waste.  
8. Re-suspend the cell pellet in 2 ml of Plasma-Lyte A USP by gently flicking the bottom of 
the tube with the index finger and then gently pipet up and down a few times.  
9. Immediately after resuspending the cell pellet, transfer 10 ul of sample into a cell count to 
count the number of cells.  
10. The calculated volume required to make a suspension /ml. 
Transfer 1 mL aliquots of the PBMC cell suspension into individual 1.5-ml cryovials. 
Centrifuge the cryovials in Eppendorf centrifuge at 10000 rpm for 10 minutes at 4-10°C. 
Remove and discard as much supernatant as possible without disturbing the cell pellet.  
11. For viable cells storage, the cell pellet should be suspended in FBS with 10% DMSO at this 
stage and then stored at -80°C until use.  
 
 
 


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15.3 APPENDIX C – SOP FOR CYTOKINE COLLECTION  
Appendix C - 
Time points of the sampling  
• Venous blood should be collected from all patients enrolled in the protocols at the 
beginning of therapy, prior to the administration of the investigational agent. The 
pre-cycle 1 samples will serve as the baseline sample. Additional time points should 
be defined in the clinical protocol.  
 
Blood collection 
• Collect 4 mL of blood in a venous blood BD Vacutainer® spray-coated K2EDTA 
tube (example BD Cat# 367861; http://www.bd.com/us/contact/).  Gently invert 10 
times to mix blood and anticoagulant.   
• Store the tubes at room temperature until centrifugation.  It is generally preferred 
and often necessary to process the samples within 5 hours.  
 
Blood sample processing 
• Centrifuge at 1300 RCF for 10 min in a swing-head centrifuge, or 15 min in a fixed 
angle centrifuge (balance the tube in the centrifuge). Do not use brake to stop 
centrifuge. 
• Carefully aspirate the supernatant (plasma) into a new centrifuge tube.   
• Inspect serum for turbidity.  Turbid samples should be centrifuged and aspirated 
again to remove insoluble matter.  
 
Sample storage 
• Carefully aliquot each sample into two cryovials with printed labels with a sample 
identifier and store them at -80oC. 
 
Shipping information  
• One of the two sets of plasma samples should be sent to Dr. Liang Cao at the 
National Cancer Institute at the end of the study on dry ice.  A separate sample sheet 
with at least a patient number and a sample identifier for each sample should be 
provided via secured electronic mail.  A separate email with tracking information 
should be sent to the recipient at the time of shipping to ensure the receiving of the 
samples package on time. See Storage Instructions  in Section 15.6 Appendix F for 
information regarding the second set of plasma samples. 
 
• Ship information is as follows: 
Liang Cao, Ph.D. 
Genetics Branch  


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Center for Cancer Research  
National Cancer Institute 
37 Convent Dr. MSC 4265 
Bldg 37, Rm 6134 
Bethesda, MD 20892-1906 
Phone: (301) 435-9039  
E-mail: caoli@mail.nih.gov 
 
Data collection and transmission  
• Data will be generated in a table format. 
• Data will be transmitted via email to the PI of the studies in an Excel document. 
 
 


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15.4 APPENDIX D- STANDARD OPERATING PROCEDURE FOR PLASMA AND BUFFY COAT COLLECTION 
FOR CIRCULATING TUMOR DNA 
 
Ref 1: Plasma protocol from Brenton Laboratory SOP at Cancer Research UK Cambridge Institute. 
Ref2: Manual for cell free DNA BCT® tubes from Streck labs for buffy coat isolation.  
 
Required consumables  
- Streck tubes (Cell free DNA BCT tubes, Streck Inc) with freshly drawn patient blood..   
- 2ml screw-capped micro-tubes (Sarstedt: 72.694.006), Dnase/Rnase free.  
- 2ml non-screw-capped Non-Stick DNase/RNase-free Microfuge Tubes (Applied Biosystems: 
AM12475)  
- Transfer pipette (Fisher Scientific: 2655116) 
 
Procedure 1:  Recommended procedure for the Plasma collection, processing, storage and transport 
of plasma for ctDNA and/or circulating nucleic acid studies  
 
IMPORTANT: Blood samples should be centrifuged as soon as possible after collection to avoid 
fragmentation, degradation and leukocyte lysis. Samples should be spun within 1 hour of 
collection.  
 
1. Collect blood into BCT Streck tubes ( Label the tube with appropriate Study/Patient 
Number Identifiers. Record the time of collection and whether the blood was drawn using a 
peripheral venous access device (eg. cannula or butterfly) or a central venous access device 
(CVAD).  
2. After collection, gently invert tubes 8-10 times to mix and leave tubes upright prior to 
centrifugation. 
3. Within 1 hour of collection, centrifuge samples at 1600g for 10 minutes at room 
temperature using a “swing out” rotor. (NB. Centrifuge with the brake off).  Record the 
time of centrifugation.   
Note: If adapters are not available, place the streck tubes into 50 mL conical tubes and then 
spin  
4. Transfer 1ml aliquots of plasma to sterile 2ml Microfuge tubes (DNase/RNase-free tubes 
can be used at this stage) and leave about 0.5 ml over the buffy coat (Refer figure on next 
page).  
Take care to avoid any buffy coat layer in this step. See Procedur 2 below for separate 
collection of buffy coat for genomic DNA 


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5. Centrifuge the plasma aliquots in a bench top centrifuge at 14,000rpm (10,000 xg) for 10 
minutes to pellet any remaining cellular debris.  
6. Carefully transfer 1ml aliquots of supernatant to sterile 2ml screw-capped micro-tubes, and 
discard the pellet.  
7. Label tubes with appropriate barcode labels as required by the Study. Freeze aliquots in a -
800C freezer in appropriately labeled storage boxes.  
 
Procedure 2.  Preparation of buffy coat isolate from blood sample for isolation of total genomic 
DNA (gDNA).   
1. Following Step 4 in the plasma collection protocol 1 above, carefully transfer the buffy coat 
layer into a separate sterile screw capped tube using a transfer pipette or standard pipette. It 
may help to use a gentle swirling action with the tip to remove the buffy coat layer, taking 
care to avoid plasma and the red blood cell layer wherever possible.  Volume should not 
exceed 0.5 -1 ml.  
2. Label tubes with appropriate barcode labels as required by the Study. Freeze tubes in a -
800C freezer in appropriately labelled storage boxes. 
 
Note: The buffy coat is going to contain erythrocytes and some plasma.  This may be frozen 
directly in -80C freezer for months before being used for gDNA preparation.  Qiagen blood DNA 
mini  kits may be used and this requires about 200 ul of buffy coat.  
 
**  Electronically record all appropriate collection details (study and anonymized patient 
identifier), collection date, sample volume, and sample/biorepository identifiers into study log 
records, as defined by study requirements. Record box number/row/column position, and if there 
were any sample handling or quality issues (e.g. if samples were hemolyzed).  
 
 
 
 
 
 
 
 
Figure 1. Streck tubes after centrifugation (step 3) 
 
 


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15.5 APPENDIX E- ORAL MEDICATION DIARY 
Oral Medication Diary for ONC201 
Patient’s Name: __________________________________  
Date: __________________ 
Patient Study ID: _________________________________  
Cycle #: ________________ 
INSTRUCTIONS TO THE PATIENT:  
1. Complete one form for each cycle (28 days). 
2. You will take ___ (number) ____ mg (dosage) capsules each Tuesday Morning (white spaces) +/- 1 day (light gray 
space). You may take the capsules one hour before or two hours after eating, as you prefer. If you forget to take the 
pills on your assigned day, you can take the missed dose up to 1 day after (light gray space). Do not take the weekly 
dose if more than 1 day late after scheduled dose (dark gray spaces).   
3. Record the date, the number of pills you took, and when you took them. 
4. If you have any comments or notice any side effects, please record them in the Comments column. 
5. Please bring your pill bottle and this form to your physician when you go for your next appointment.  
General Comments: 
_______________________________________________________________________________
_____________________________________________________________________________  
Day 
# pills and when taken: 
ONC201 
 
Comments 
Day 
# pills and when taken: 
ONC201 
 
Comments 
 Date  # Capsules 
Time  
 Date  # Capsules 
Time  
1  
 
 
 
 
15   
 
 
 
2  
 
 
 
 
16   
 
 
 
3  
 
 
 
 
17   
 
 
 
4  
 
 
 
 
18   
 
 
 
5  
 
 
 
 
19   
 
 
 
6  
 
 
 
 
20   
 
 
 
7  
 
 
 
 
21   
 
 
 
8  
 
 
 
 
22   
 
 
 
9  
 
 
 
 
23   
 
 
 
10   
 
 
 
24   
 
 
 
11   
 
 
 
25   
 
 
 
12   
 
 
 
26   
 
 
 
13   
 
 
 
27   
 
 
 
14   
 
 
 
28   
 
 
 
Patient’s Signature: ___________________________________Date: ____________________ 
 


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Study Team will complete this section:  
6. Date patient started protocol treatment_____________________  
7. Date patient was removed from study _____________________  
8. Patient’s planned daily dose______________________________  
9. Total number of pills taken this month ______________________  
Physician/Nurse’s Signature ____________________________________________________________________   
 
 
 
 
 


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15.6 APPENDIX F- ONCOCEUTICS SPECIMEN COLLECTION, PROCESSING, STORAGE AND SHIPPING 
 
 
 
 
3624 MARKET STREET; SUITE 5E 
UNIVERSITY CITY SCIENCE CENTER 
PHILADELPHIA, PA 19104 
 
SPONSOR CONTACT: 
ROHINTON TARAPORE, PHD 
TELEPHONE: 215-966-6115 
E-MAIL:  ROHINTON.TARAPORE@ONCOCEUTICS.COM 
 
 
Summary of Laboratory Studies  
Laboratory studies on specimens obtained from patients receiving ONC201 treatment will be 
performed to characterize ONC201 exposure and its biological activity in advanced cancer patients. 
Blood for laboratory analysis will be drawn to assess plasma ONC201 drug concentration and 
serum tumor biomarkers.   
 
If available, as described in the protocol, archival tumor tissue will be accessed at the time of 
enrollment for subjects enrolled in this study to conduct future correlative assays to measure 
biomarkers of therapeutic response to ONC201 including molecular markers involved in the 
mechanism of action of ONC201.   
 
All blood and tissue specimens will be collected and prepared for shipping by the clinical sites. 


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Blood Sample Collection and Processing 
At the specified time points, approximately 6 mL of blood will be collected in the specified tube 
type(s), to be processed, aliquoted into duplicate transfer vials and frozen, to be shipped to the 
designated analytical laboratory.  Refer to the study protocol for blood sample collection time 
points.  
Blood must be centrifuged, separated and frozen within 2 hours of collection. Specimens must be 
stored frozen at -70ºC (preferred) or -20ºC (acceptable) at each study site until shipped on dry ice 
to the designated analytical laboratory. 
Supplies for Collection of Blood Samples 
 
Plasma Sample Supplies 
Plasma samples are to be collected and aliquoted using the following commercially available 
tubes.  
 
For plasma blood collection  
Becton-Dickinson Plastic Whole Blood tube with spray-coated K2EDTA  
Lavender top, Vacutainer  
Catalogue 367525 
Tube Size: 16x100 
Draw Volume: 10mL  
 
For plasma aliquots 
Wheaton 2mL Ext FS CryoElite 
Blue Cap Patch Sterile  
Catalogue W985868 
 
15.6.1 Serum Sample Supplies 
Serum samples are to be collected and aliquoted using the following commercially available 
tubes.   
 
For serum blood collection 
Serum Tube, Increased Silica Act Clot Activator, Silicone-Coated Interior  
Red Top Vacutainer 
BD Catalogue 366430 


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Abbreviated Title: ONC201 in advanced cancers 
Version Date: 06/17/2020 
 
 
Tube Size: 16 X 100  
Draw Volume: 10mL  
 
For serum aliquot storage  
Wheaton 2mL Ext FS CryoElite 
Yellow Cap Patch Sterile  
Wheaton Catalogue W985866 
 
Collection of Blood  
Check the expiration dates on the vacutainer tubes before collecting blood. If the tubes have 
expired, discard them. Do not substitute another brand of collection tube. Prepare the blood 
collection tubes by affixing the barcode labels to each tube before collecting specimens from the 
subject. 
 
Using standard aseptic venipuncture techniques, draw the blood sample into the specified 
collection tube. For time points requiring both plasma and serum blood draws, the plasma sample 
should be drawn first. Remove tourniquet as soon as blood flow into the first vacutainer tube is 
established; excessive use of tourniquets can lead to hemoconcentration and falsely elevated 
results.  Ensure each vacutainer is full to provide accurate blood:additive ratios.  Mix blood tubes 
by gently inverting each tube 5 times. On the barcode label, clearly print with a black permanent 
marking pen the study number “XXX”, patient ID number, the date and time of the blood draw 
(hours and minutes).  Enter the information on the Patient-Specific Specimen Collection Log and 
maintain the log in the Patient source records. 
 
Place the full blood collection tube(s) into a resealable clear biohazard bag. Arrange prompt pick 
up by, or delivery to, the local laboratory since blood must be processed and frozen within 2 
hours of collection. 
 
Processing of Blood Specimens  
15.6.2 Plasma Processing  
Centrifuge the filled lavender top tube at 1500 g (3000 rpm) for 15 minutes until the plasma 
and the cells are well separated. Label 2 blue cap transfer vials lengthwise with the appropriate 
barcode labels indicating “plasma (blue)”. Clearly print the study number “Study XXX”, 
patient ID number, date and time of the blood draw. Transfer ~1.5 mL of plasma into each of 
the 2 blue top transfer vials labeled “plasma (blue).” 


92 
Abbreviated Title: ONC201 in advanced cancers 
Version Date: 06/17/2020 
 
 
15.6.3 Serum Processing  
After filling the tubes, let the tubes stand at room temperature until a clot has formed in the red 
top tube (approximately 30 minutes). Centrifuge the tube at 1500 g (3000 rpm) for 15 minutes 
until the serum and the cells are well separated. Label 2 yellow cap transfer vials lengthwise 
with the appropriate barcode labels indicating “serum (red)”. Clearly print the study number 
“Study XXX”, the patient ID number, date and time of the blood draw. Transfer ~1.5 mL of 
serum into each of the 2 yellow top transfer vials labeled “serum (red)”. 
 
Obtaining Archived Tumor Tissue Sections  
Archived tumor blocks obtained prior to treatment with ONC201 are to be obtained as a baseline 
sample.  If multiple blocks are available, preference will be given to the most recently obtained 
tissue. A total of 5 slides should be prepared from this archival tissue. The archival tissue should be 
returned to its original storage location.  
Using black permanent marking pen, clearly print the study number “Study XXX”, patient ID 
number and the date of collection (i.e., biopsy) on each slide. 
 
Storage Instructions  
The clinical site laboratory is responsible for proper storage of the samples.  Do NOT store 
plasma/serum specimens in a frost-free refrigerator-top freezer--results may be affected by 
temperature variation during the freezer cycle.  Store in a freezer with minimum -20ºC or 
preferably -70ºC. Take all precautions to ensure the specimens remain frozen at the study site.  
Duplicate aliquots of plasma and serum specimens will be prepared.  One set of aliquots is to be 
kept stored frozen at the clinical site laboratory, and the second set is to be shipped according to 
this procedures manual. 
 
Shipping Instructions  
All shipments must be authorized by the Sponsor.  Before preparing the shipment, the clinical site 
personnel preparing the shipment must contact the Sponsor and e-mail a copy of the completed 
Specimen Shipping Form to the Sponsor Project Office: rohinton.tarapore@oncoceutics.com.  
 
Preparation of the Dry Ice Shipments  
The frozen plasma/serum aliquots must be shipped on dry ice to the designated analytical 
laboratory.  Ensure that specimens remain frozen during preparation of the shipment.   
 
Specimens must be shipped by overnight courier service on dry ice on a Monday, Tuesday or 
Wednesday only. Shipments are not to be initiated between Thursday and Sunday as it is not 
possible to ensure specimens will remain frozen if shipment is delayed, or upon receipt over 
weekends or on a holiday.   


93 
Abbreviated Title: ONC201 in advanced cancers 
Version Date: 06/17/2020 
 
 
 
All packaging must conform to IATA Packaging Instruction 650 for shipment of non-infectious 
human specimens.  Samples from participants known to be infectious (Hepatitis B virus, HIV-I 
and HIV-II non-cultured) are not to be shipped. 
 
Ensure sufficient dry ice is used to keep the specimens solidly frozen until they arrive at the 
designated analytical laboratory.  Place half of the dry ice in the bottom of the shipping box.  
Place the resealable bag containing the specimens in transfer vials, filter paper and absorbent on 
top of the dry ice. Do not put dry ice inside the plastic resealable bags.  Cover and surround the 
specimens with the remaining dry ice.  Place the lid on the Styrofoam portion of the shipper.  
 
DO NOT TAPE BOX SHUT. Ensure the Hazardous Goods label for Dry Ice is affixed to the 
box (diamond with upper half stripped and ‘9’ at bottom). Record the amount of dry ice (in Kg 
or pounds) added to the box on the small label with a permanent black marking pen.  Prepare 
shipment documentation for over-night shipping of the package (FedEx is preferred). 
 
Affix the clear, resealable plastic courier envelope to the side of the dry ice box. Please ask 
your local courier for a supply of these plastic courier envelopes. Prepare a Specimen Shipping 
Form and include it in the plastic courier envelope.   
 
Ask your courier for a version of the airway bill that allows you to indicate the shipment is 
packed with dry ice.  Meticulous attention to labeling will ensure prompt delivery of dry ice 
shipments.  The “Nature and Quantity of Goods” box of the air waybill must show “UN 3373”, 
the text “BIOLOGICAL SUBSTANCE, CATEGORY B” and the number of packages.   In 
addition, since the package contains dry ice, you also need to write “Dry Ice - UN1845” and the 
number of packages and the net quantity of dry ice per package.  Finally, these markings must 
be accompanied by the Class 9 label for Miscellaneous Dangerous Goods. 
 
Preparing Tumor Sections for Shipping 
The tumor section slides should be shipped at room temperature (RT) to the Tumor Specimen 
Repository.  Samples on glass or plastic slides must be adequately cushioned.  Place the slides 
in a primary receptacle such as a slide box.  Place this primary receptacle into a secondary leak-
proof sturdy outer container or flexible-envelope packaging.  The shipment must be packaged 
in compliance with IATA Packaging Instruction 650 for shipment of non-infectious human 
specimens.  Use of the FedEx Clinical Pak is an option.  Indicate the # of boxes shipped, and 
their total weight.  Select ‘Overnight Service’, or other appropriate service assuring delivery 
within 24 hours.   
 
One aliquot of plasma should be shipped to XenoBiotic Laboratories while the duplicate aliquot 
is shipped to Scisafe. Both the serum aliquots and tumor slides should be shipped to Scisafe.  


94 
Abbreviated Title: ONC201 in advanced cancers 
Version Date: 06/17/2020 
 
 
15.6.4 Arranging for Shipments   
 
• In the Ship From section:  Enter name and address of person responsible for the 
shipment from the clinical site. 
 
• In the Ship To section: Enter name and address of designated laboratory as below: 
 
Ship PLASMA Samples to: 
Sample Receiving Officer 
XenoBiotic Laboratories, Inc. 
107 Morgan Lane 
Plainsboro, NJ 08536 
Tel. 609-799-2295 X252 
Email: sro@xbl.com 
 
Ship SERUM Samples to: 
John Coolidge, Biorepository Manager - Boston 
SciSafe, Inc. 
35 Dunham Road 
Billerica, MA 01821 
Tel. 404-242-1578 
Email:  jfc@scisafe.com 
 
Ship TUMOR Slides to: 
John Coolidge 
Biorepository Manager - Boston 
SciSafe, Inc. 
35 Dunham Road 
Billerica, MA 01821 
Tel.  404-242-1578 
Email: jfc@scisafe.com  
 
Sign and date the waybill. Tear off “Senders Copy” for retention.  It is recommended that all 
shipments be tracked to ensure timely delivery. 
Notification of Shipment   
At the time of shipment, the laboratory must e-mail the completed Specimen Shipping Form to 
the following: 
 
a)  Sponsor Project Office at rohinton.tarapore@oncoceutics.com  
 


95 
Abbreviated Title: ONC201 in advanced cancers 
Version Date: 06/17/2020 
 
 
b)  Plasma Pharmacokinetics Laboratory at sro@xbl.com 
OR 
Serum Pharmacodynamic Laboratory at jfc@scisafe.com  
OR 
Tumor Tissue Repository at jfc@scisafe.com  
 
c)  Local study nurse or coordinator 
 
 
 


96 
Abbreviated Title: ONC201 in advanced cancers 
Version Date: 06/17/2020 
 
 
Specimen Collection Log – Patient Specific 
 
 
 
 
 
 
  
PATIENT ID#__________________________ 
 
 
 
 
 
Type of Specimen and 
Protocol-Specified Time 
Point 
Date / Time of Collection 
(mm/dd/yyyy) ; (mm:hh) 
Notes 
 
□Tumor Tissue  
Archival sample at time of 
enrollment. 
  
 
 
□Plasma:   
Cycle 1 = Baseline 
  
 
 
□Plasma:   
Cycle 1 =  6 hrs (±15 
minutes) post-
administration of ONC201 
  
 
 
□Serum:   
Cycle 1 = Baseline; pre-
dose 
  
 
 
□Serum:   
Cycle 1 =  6 hours after 1st 
dose  
  
 
 
□Serum:   
Cycle 2 =  Day 1 
 
 
 
 
 
 


97 
Abbreviated Title: ONC201 in advanced cancers 
Version Date: 06/17/2020 
 
 
 
Specimen Collection Log  
Patient Specific, Continuation Page for Additional Treatment Cycles 
 
 
 
 
 
 
  
PATIENT ID#__________________________ 
 
 
 
 
 
Cycle 
Type of Specimen and 
Protocol-Specified Time 
Point 
Date / Time of Collection 
(mm/dd/yyyy) ; (mm:hh) 
Notes 
2 
□ Serum 
Pre-Dose 
 
 
 
3 
□ Serum 
Pre-Dose 
 
 
 
4 
□ Serum 
Pre-Dose 
 
 
 
5 
□ Serum 
Pre-Dose 
 
 
 
6 
□ Serum 
Pre-Dose 
 
 
 
7 
□ Serum 
Pre-Dose 
 
 
 
8 
□ Serum 
 
 


98 
Abbreviated Title: ONC201 in advanced cancers 
Version Date: 06/17/2020 
 
 
Pre-Dose 
 
9 
□ Serum 
Pre-Dose 
 
 
 
10 
□ Serum 
Pre-Dose 
 
 
 


99 
Abbreviated Title: ONC201 in advanced cancers 
Version Date: 06/17/2020 
 
 
15.6.5  Oncoceutics Specimen Shipping Form 
(Check a single applicable sample type; use additional forms as needed) 
 □ Plasma 
 
□ Serum 
 
□ Tissue  
 
Date:  ______________________________________ 
Total Number of Specimens in Shipment: ______ 
Courier and Tracking Number: _________________________________ 
 
Contact Information for Person Preparing Shipment:  
Name: _______________________________________________________ 
Institution: ___________________________________________________ 
Phone Number: ___________________________ 
E-mail: ___________________________________ 
 
 
Patient ID# 
Date / Time of Collection 
(mm/dd/yyyy) ; (mm:hh) 
Packed By: 
Initials/Date 
Received By: 
Initials/Date 
1 
 
  
  
 
2 
 
  
  
 
3 
 
  
  
 
4 
 
  
  
 
5 
 
  
  
 
6 
 
  
  
 
7 
 
  
  
 
8 
 
  
  
 
9 
 
  
  
 
10 
 
  
  
 
11 
 
  
  
 


100 
Abbreviated Title: ONC201 in advanced cancers 
Version Date: 06/17/2020 
 
 
12 
 
  
  
 
13 
 
  
  
 
14 
 
  
  
 
15 
 
  
  
 
16 
 
  
  
 
17 
 
  
  
 
18 
 
  
  
 
19 
 
  
  
 
20 
 
  
  
 
 
 

ICF_001.pdf: 
MEDICAL RECORD
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY
•
Adult Patient or 
• Parent, for Minor Patient
INSTITUTE:
National Cancer Institute
STUDY NUMBER:
18-C-0034
PRINCIPAL INVESTIGATOR:
Alexandra Zimmer, MD
STUDY TITLE: 
A Phase 2 Study of ONC201 in recurrent/refractory metastatic breast cancer and 
advanced endometrial carcinoma  
Continuing Review Approved by the IRB on 11/19/18  
Amendment Approved by the IRB on 09/20/18 (C) 
Date posted to web: 12/01/18
Standard
PATIENT IDENTIFICATION
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY
•
Adult Patient or
•
Parent, for Minor Patient
NIH-2514-1 (07-09)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent (1) 
INTRODUCTION 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
First, we want you to know that: 
Taking part in NIH research is entirely voluntary. 
You may choose not to take part, or you may withdraw from the study at any time.  In 
either case, you will not lose any benefits to which you are otherwise entitled.  However, 
to receive care at the NIH, you must be taking part in a study or be under evaluation for 
study participation. 
You may receive no benefit from taking part.  The research may give us knowledge that 
may help people in the future. 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions).  If you 
have such beliefs, please discuss them with your NIH doctors or research team before you agree 
to the study. 
Now we will describe this research study.  Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with anyone at NIH, or with family, 
friends or your personal physician or other health professional.   
Why is this study being done?  
You are taking part in the Phase II study of an investigational drug called ONC201. The main 
purpose of this study is to see if ONC201 will help to shrink tumors in people with certain types 
of breast or endometrial cancers. This study also looks at how long the tumors respond to the 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:       18-C-0034 
CONTINUATION: page 2 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
treatment. ONC201 is manufactured by Oncoceutics, Inc and is not approved by the United 
States (U.S.) Food and Drug Administration (FDA) to treat any type of breast, or endometrial 
cancer, or any other type of disease. The exact mechanism of ONC201 is unknown at this time, 
but we suspect that it works through interrupting activity of the mitochondria (the “powerhouse” 
of the cell). Mitochondria are important for metabolism of all cells but cancer cells rely more 
heavily on mitochondria for their function than normal cells. The researchers in this study hope 
that by blocking the mitochondrial activity it will cause tumor cells to die, thereby shrinking 
tumors.  
Why are you being asked to take part in this study? 
You are being asked to take part in this study because you have: 
• Metastatic estrogen receptor positive breast cancer OR 
• Metastatic triple negative breast cancer OR 
• Advanced or metastatic endometrial cancer 
How many people will take part in this study?  
Up to 90 people will take part in this study. 
Description of Research Study 
What will happen if you take part in this research study?   
Before you begin the study 
Certain standards (criteria) have been established to ensure that you are a medically appropriate 
candidate for this trial. These criteria also make sure that the results of this study can be used to 
help make decisions about treating other patients.  
Before you begin this study, you will need to have the following exams and tests to make sure 
you are eligible for this study. The exams and tests are part of regular cancer care.  
• A review of any past or current medical conditions, medicines you are taking and cancer 
history. 
• Physical examination, including height, weight, vital signs 
• Electrocardiogram (EKG – a record of your heartbeat)  
• Review of your symptoms and your ability to perform your normal activities. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:       18-C-0034 
CONTINUATION: page 3 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
• Imaging Assessments – a computed tomographic scan (CT) that produces a picture of 
your body using a small amount of radiation and magnetic resonance imaging (MRI) that 
uses a magnetic field to produce an image of your body. These will be used to examine 
your chest, abdomen, pelvis, bones and brain.  
• You will have blood drawn for: 
o routine blood tests to find out if you are anemic, have low blood counts, and if your 
liver, kidneys, and other organs are working well. 
o Tests for HIV, Hepatitis B and Hepatitis C. 
• If you have not been tested for BRAC ½ mutations (for breast cancer) or for Lynch 
Syndrome (for endometrial cancer), a small amount of blood will be collected for genetic 
analysis. If you have been previously tested for these mutations, you will not need to 
have blood drawn for this as long as you can show the researchers the test results.  
• Pregnancy serum or urine test if you are a woman who can have children. 
• You will be asked to provide a pathologist’s report from an accredited laboratory or 
sample of your tumor from a previous surgery so that we may confirm your diagnosis. 
If you are eligible to participate in this trial and wish to do so, an image-guided biopsy of your 
tumor will be required for research purposes before you start treatment. To help researchers 
determine the way ONC201 works on tumor cells, an additional image-guided biopsy will be 
required after you have had 5 weekly doses of ONC201. If/when your tumor no longer responds 
to the treatment and it starts to grow, you can decide if you would like to undergo an additional 
image-guided biopsy so that researchers can study what made the tumors stop responding to 
ONC201.  
Blood donation 
Patients should not donate blood while participating in this study, nor for 90 days following the 
last dose of ONC201. 
During the study 
During the study, the study doctor and staff will monitor you for any side effects and monitor 
your cancer. You may receive supportive care to manage side effects during this study. Ask the 
study doctor or staff if you have questions about supportive care. Each cycle is 28 days long. 
You will take ONC201 weekly for a total of 4 doses of ONC201 during 1 cycle. During Cycle 1, 
you will receive weekly phone calls to ask about whether there have been any changes to your 
health and about any other medications that you may be taking.  
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:       18-C-0034 
CONTINUATION: page 4 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Day 1  
On Day 1, the study staff will perform a complete physical exam. They will ask if there have 
been any changes to your physical health and about any medications you have taken since your 
screening visit. They will check your vital signs and may do some routine laboratory tests. 
Laboratory tests that were completed within the last 4 days before Cycle 1 Day 1, will not be 
repeated. Blood will also be drawn for research tests to assess certain cancer markers (about 2 
tablespoons). A CT scan of the chest, abdomen, and pelvis will not be repeated if you had one 
done within 17 days prior to the start of Cycle 1 Day 1. After signing this consent form, a CT-
assisted biopsy of your tumor will be performed for research purposes before you start treatment 
with ONC201. 
ONC201 Therapy  
You will receive the study drug ONC201 by mouth every 7 days of each 28-day cycle.  
You will take this study drug by mouth every 7 days while you are on trial.   
Day 28  
On Day 28, the first treatment cycle will end. You will be asked about whether there have been 
any changes to your health and about any other medications you have taken. You will have a 
complete physical exam and have about 3 tablespoons of blood drawn for routine laboratory 
tests.  
Cycle 2 and beyond  
Some tests will be performed every cycle, some will be performed every other cycle, some will 
be performed every three cycles, and some will be completed in the first cycle only. You will 
undergo blood draws at the start of each cycle and you will have imaging studies to evaluate the 
effect ONC201 has on your cancer every 2 cycles (every 8 weeks). To help researchers 
determine the way ONC201 works on tumor cells, an additional image-guided biopsy will be 
performed on Cycle 2 Day 2. If/when your tumor no longer responds to the treatment and it starts 
to grow, you can decide if you would like to undergo an additional image-guided biopsy so that 
researchers can study what made the tumors stop responding to ONC201.  
When you are finished taking the drugs (treatment) 
You will be invited for a follow up safety visit approximately one month after the last day you 
take the study drug. At this visit, you will have the following tests:  
• Physical exam and vitals 
• Review of your symptoms and your ability to perform your normal activities. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:       18-C-0034 
CONTINUATION: page 5 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
• Routine blood tests to find out if you are anemic, have low blood counts, your blood is 
clotting normally and if your liver, kidneys, and other organs are working well. 
• You will also be given the option for another biopsy of your tumor as well as for research 
labs. These tests may help researchers determine why your tumor didn’t response or 
stopped responding to treatment.  
Birth Control 
If you are a woman who is breast feeding or pregnant, you may not take part in the study because 
we don’t know how this medicine would affect your baby or your unborn child. If you are a 
woman who can become pregnant, or are the partner of a woman who can become pregnant, you 
will need to practice two effective forms of birth control before starting study treatment, during 
study treatment, and for at least one month after you finish study treatment.  If you think that you 
or your partner is pregnant, you should tell your study doctor or nurse at once.   
Effective forms of birth control include:  
• abstinence  
• intrauterine device (IUD) 
• hormonal [birth control pills, injections, or implants] 
• tubal ligation 
• vasectomy 
What tests will be done on my samples?  
Your tissue (tumor and normal tissue) and blood that are collected will be used to look for 
specific changes in the cell signaling, DNA repair, mitochondrial, or other pathways in tumors.  
This analysis could be used to develop new ways of diagnosing and treating cancer. In order to 
examine the tumor and normal tissue, we may use several different techniques depending on the 
type of tissue we collect. Also, we will look for changes of DNA damage repair markers, 
circulating tumor cells, and immune cells in the blood. We will study whether these changes link 
to your health outcomes.  
When we are conducting these tests, it is possible that we could identify possible changes in 
other parts of your DNA that are not related to this research. These are known as “incidental 
medical findings.” However, the analyses that we perform in our laboratory are for research 
purposes only; they are not nearly as sensitive as the tests that are performed in a laboratory that 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:       18-C-0034 
CONTINUATION: page 6 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
is certified to perform genetic testing. Changes that we observe unrelated to our research may or 
may not be valid.  
Therefore, we do not plan to inform you of the results of testing on your tissue and blood that is 
performed in our research lab. However, in the unlikely event that we discover a finding that is 
believed to be clinically important based on medical standards at the time that we first analyze 
your results, we will contact you. This could be many years in the future. We will ask you to 
have an additional tube of blood drawn to verify the findings we have seen in our lab. If the 
results are verified, you will be re-contacted and offered a referral to a genetic healthcare 
provider to discuss the results 
Release of genetic information  
Your privacy is very important to us and we will use many safety measures to protect your 
privacy. However, in spite of all of the safety measures that we will use, we cannot guarantee 
that your identity will never become known. Although your genetic information is unique to you, 
you do share some genetic information with your children, parents, brothers, sisters, and other 
blood relatives. Consequently, it may be possible that genetic information from them could be 
used to help identify you. Similarly, it may be possible that genetic information from you could 
be used to help identify them.  
While the databases developed for this project are not open to everyone and also will not contain 
information that is traditionally used to identify you, such as your name, address, telephone 
number, or social security number, people may develop ways in the future that would allow 
someone to link your genetic or medical information in our databases back to you. For example, 
someone could compare information in our databases with information from you (or a blood 
relative) in another database and be able to identify you (or your blood relative). It also is 
possible that there could be violations to the security of the computer systems used to store the 
codes linking your genetic and medical information to you.  
Your individual genomic data and health information may be put in a controlled access database. 
This means that only researchers who apply for and get permission to use the information for a 
specific research project will be able to access the information. Your genomic data and health 
information will not be labeled with your name or other information that could be used to 
identify you. Researchers approved to access information in the database have agreed not to 
attempt to identify you.  
Although your genetic information is unique to you, you do share some genetic information with 
your children, parents, brothers, sisters, and other blood relatives. 
Consequently, it may be possible that genetic information from them could be used to help 
identify you. Similarly, it may be possible that genetic information from you could be used to 
help identify them. Patterns of genetic variation also can be used by law enforcement agencies to 
identify a person or his/her blood relatives.  


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:       18-C-0034 
CONTINUATION: page 7 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
It is possible also that someone could get unauthorized access or break into the system that stores 
information about you. Every precaution will be taken to minimize this risk. There also may be 
other privacy risks that we have not foreseen. There also may be other privacy risks that we have 
not foreseen.  
Since some genetic variations can help to predict future health problems for you and your 
relatives, this information might be of interest to health care providers, life insurance companies, 
and others. However, Federal and State laws provide some protections against discrimination 
based on genetic information. For example, the Genetic Information Nondiscrimination Act 
(GINA) makes it illegal for health insurance companies, group health plans, and most employers 
to discriminate against you based on your genetic information. However, GINA does not prevent 
companies that sell life insurance, disability insurance, or long-term care insurance from using 
genetic information as a reason to deny coverage or set premiums. GINA also does not apply to 
members of the United States military, individuals covered by the Indian Health Service, or 
veterans obtaining health care through the Veteran’s Administration. Lastly, GINA does not 
forbid insurance medical underwriting based on your current health status though the Affordable 
Care Act limits consideration of pre-existing conditions by insurers.  
Who else besides the investigators on this study will know the results of my sample testing?  
Once we obtain any of the samples listed above, the investigators take all your personal 
information off those samples and label them with a study code number. Only the investigators 
on this study know who the sample came from. The key linking your personal information with 
the code number is kept in a secure computer data base, with access only to the 2-3 research staff 
who will be discussing this study with you. Once the sample has been labeled with a code, it is 
sent to a variety of NIH laboratories for storage and testing. No one testing your samples will be 
able to link the results to you personally. Specimens obtained during your participation in this 
study may be sent for testing to investigators outside of NCI or the NIH. All samples will be 
coded to protect your privacy and no personal information will be included. Other investigators 
on this study will have access to limited clinical and biologic data such as age, gender and 
disease status.  
How long will your samples be stored?  
The samples collected during this study will be stored for as long as the study is open. When this 
study is closed, we would like to keep the samples for future research. We will request your 
permission to do so, later in this consent.  
Risks or Discomforts of Participation 
As with all treatments, there are several side effects or risks from the treatment provided in this 
study. However, doctors don’t know all the side effects that may happen with this drug, so it is 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:       18-C-0034 
CONTINUATION: page 8 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
important to report any changes that you notice, even if your study team does not ask specifically 
about them. Side effects may be mild or severe. Your study team will give you medicines to help 
lessen side effects. Many side effects go away with those medicines and others may go away 
soon after you stop treatment. In some cases, side effects can be serious, long-lasting, or may 
never go away. In very rare instances, they could cause death.  
What side effects or risks can I expect from being in this study?  
Potential Side effects from ONC201 
To date, over 70 patients have taken at least one dose of ONC201 and it has been generally well 
tolerated.  Very few side effects have been attributed to ONC201.   
 
Likely 
Less Likely 
Rare but Serious 
• Fever  
• Fatigue (tiredness) 
• Elevated Amylase  
• Nausea/Vomiting 
• Rash 
• Neutropenia  
• Twitching 
• Abnormal breathing  
• Abnormal walking or 
standing 
• Stroke, also known as 
cerebrovascular 
accident (CVA). This 
is the sudden death of 
brain cells due to lack 
of oxygen, caused by 
blockage of blood 
flow or rupture of an 
artery to the brain. 
Sudden loss of speech, 
weakness, or paralysis 
of one side of the body 
can occur.  It may 
have a long-term 
effect on brain 
function, and it could 
be fatal. At this time it 
is unclear if it’s linked 
to the use of ONC201. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:       18-C-0034 
CONTINUATION: page 9 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Tumor Biopsy  
If your doctor determines it is safe we will obtain a piece of your tumor (biopsy) using a needle 
with minimal risk to you. You will be given local anesthesia (numbing medicine) and a sedative 
prior to the biopsy. The biopsy will be taken through a needle put through the skin into your 
tumor. Depending upon the location of your tumor, a CT scan or other imaging modality such as 
an ultrasound may be used to assist the biopsy. After the procedure, the nurses will watch your 
blood pressure and other vital signs. This biopsy is not optional and you cannot participate in this 
study if you do not agree to the biopsy. If the first biopsy is too difficult, you will be able to 
continue on the protocol without undergoing the second (required) and third (optional) biopsies. 
However, an attempt at the first biopsy is needed to enter this study. There are other studies at 
NIH which may also be options for you and which do not involve biopsies.  
Risk of Radiation  
This research study involves exposure to radiation from up to 3 CT scans that may be used 
during your tumor biopsies. This radiation exposure is not required for your medical care and is 
for research purposes only. The amount of radiation you will receive in this study is 2.4 rem, 
which is below the guideline of 5 rem per year allowed for research subjects by the NIH 
Radiation Safety Committee. The average person in the United States receives a radiation 
exposure of 0.3 rem per year from natural sources, such as the sun, outer space, and the earth's 
air and soil. If you would like more information about radiation, please ask the investigator for a 
copy of the pamphlet, An Introduction to Radiation for NIH Research Subjects. While there is no 
direct evidence that the amount of exposure received from participating in this study is harmful, 
there is indirect evidence it may not be completely safe. There may be a very slight increase in 
the risk of cancer.  
Please tell your doctor if you have had any radiation exposure in the past year, either from other 
research studies or from medical tests or care, so we can make sure that you will not receive too 
much radiation. Radiation exposure includes x-rays taken in radiology departments, cardiac 
catheterization, and fluoroscopy as well as nuclear medicine scans in which radioactive materials 
were injected into your body.  
If you are pregnant you will not be permitted to participate in this research study. It is best to 
avoid radiation exposure to unborn infants since they are more sensitive to radiation than adults.  
Blood Sampling  
Risks of blood sampling include bruising or bleeding at the needle site; rarely infection. This is 
treated with bandages, pressure and, if infection, antibiotic medicines. For more information 
about risks and side effects, ask your study team.  


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:       18-C-0034 
CONTINUATION: page 10 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Potential Benefits of Participation 
Are there benefits to taking part in this study?  
The aim of this study is to see if treatment with ONC201 will cause your tumors to shrink.   We 
do not know if you will receive personal, medical benefit from taking part in this study.  These 
potential benefits could include shrinking of your tumor or lessening of your symptoms, such as 
pain, that are caused by the cancer.  Because there is not much information about the drug’s 
effect on your cancer, we do not know if you will benefit from taking part in this study, although 
the knowledge gained from this study may help others in the future who have cancer.   
Alternative Approaches or Treatments 
What other choices do I have if I do not take part in this study?  
Instead of being in this study, you have these options: 
 
• Getting treatment or care for your cancer without being in a study, with standard 
chemotherapy or CDK4/6 inhibitors. 
• Taking part in another study 
• Getting comfort care, also called palliative care.  This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer.  It does not treat 
the cancer directly.  Instead, it tries to improve how you feel.  Comfort care tries to keep 
you as active and comfortable as possible. 
Please talk to your doctor about these and other options. 
Stopping Therapy 
Your doctor may decide to stop your therapy for the following reasons: 
• if he/she believes that it is in your best interest 
• if your disease comes back during treatment 
• if you become pregnant  
• if you have side effects from the treatment that your doctor thinks are too severe 
• if new information shows that another treatment would be better for you 
• if the study is closed for any reason 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:       18-C-0034 
CONTINUATION: page 11 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
In this case, you will be informed of the reason therapy is being stopped. 
You can stop taking part in the study at any time. However, if you decide to stop taking part in 
the study, we would like you to talk to the study doctor and your regular doctor first. 
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to Oncoceutics, Inc. or their 
designated representatives. If you withdraw your consent and leave the trial, any samples of 
yours that have been obtained for the study and stored at the NCI can be destroyed upon request. 
However, any samples and data generated from the samples that have already been distributed to 
other researchers or placed in the research databases cannot be recalled and destroyed. 
Research Subject’s Rights 
What are the costs of taking part in this study?  
If you choose to take part in the study, the following will apply, in keeping with the NIH policy: 
• 
You will receive study treatment at no charge to you. This may include 
surgery, medicines, laboratory testing, x-rays or scans done at the 
Clinical Center, National Institutes of Health (NIH), or arranged for you 
by the research team to be done outside the Clinical Center, NIH if the 
study related treatment is not available at the NIH.  
• 
There are limited funds available to cover the cost of some tests and 
procedures performed outside the Clinical Center, NIH.  You may have 
to pay for these costs if they are not covered by your insurance company. 
• 
Medicines that are not part of the study treatment will not be provided or 
paid for by the Clinical Center, NIH. 
• 
Once you have completed taking part in the study, medical care will no 
longer be provided by the Clinical Center, NIH. 
 
Will your medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Organizations that may look at 
and/or copy your medical records for research, quality assurance, and data analysis include: 
• The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), which are involved in keeping research safe for people. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:       18-C-0034 
CONTINUATION: page 12 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
• National Institutes of Health Intramural Institutional Review Board 
• Qualified representatives from Oncoceutics, Inc., the pharmaceutical company who 
produces ONC201. 
 
A description of this clinical trial will be available on http://www.Clinicaltrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most the 
Web site will include a summary of the results.  You can search this Web site at any time. 
We may put your research data in a large database for broad sharing with the research 
community. These databases are commonly called data repositories. These data repositories 
might or might not be located at the NIH. The information in this database could include but is 
not limited to genetic information, ethnicity and sex.  If your individual research data is placed 
in one of these repositories, it will not be labeled with your name or other information that 
could be used to easily identify you, and only qualified researchers will be able to look at your 
data. These researchers must receive prior approval from individuals or committees to access 
the data. 
Your summary genomic data is being placed in an unrestricted database, so researchers will be 
able to access summary information about all the participants included in the study (including 
you), or summary information combined from multiple studies, without applying for permission. 
The risk of anyone identifying you with this information is very low. 
Certificate of Confidentiality  
To help us protect your privacy, we have obtained a Certificate of Confidentiality. The 
researchers can use this Certificate to legally refuse to disclose information that may identify you 
in any federal, state, or local civil, criminal, administrative, legislative, or other proceedings, for 
example, if there is a court subpoena. The researchers will use the Certificate to resist any 
demands for information that would identify you, except as explained below. 
You should also know that there are several circumstances in which the Certificate does not 
provide coverage. These include when information:  
• will be used for auditing or program evaluation internally by the NIH; or  
• must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA).  
• is necessary for your medical treatment and you have consented to this disclosure;  
• is for other research.  
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:       18-C-0034 
CONTINUATION: page 13 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
In addition, identifiable, sensitive information protected by this Certificate cannot be admissible 
as evidence or used for any purpose in any action, suit, or proceeding without your consent.  
You should understand that a Certificate of Confidentiality does not prevent you or a member of 
your family from voluntarily releasing information about yourself or your involvement in this 
research. If an insurer, employer, or other person obtains your written consent to receive research 
information, then the researchers will not use the Certificate to withhold that information. 
The Certificate of Confidentiality will not protect against the required reporting by hospital staff 
of information on suspected child abuse, reportable communicable diseases, and/or possible 
threat of harm to self or others. 
Conflict of Interest 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a Protocol Review Guide.  You may ask your research 
team for a copy of the Protocol Review Guide or for more information.  Members of the research 
team who do not work for NIH are expected to follow these guidelines but they do not need to 
report their personal finances to the NIH. 
 
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest.  
 
Oncoceutics, Inc. is providing the investigational agent, ONC201, for this study to NIH without 
charge.  No NIH investigator involved in this study receives payments or other benefits from any 
company whose drug, product or device is being tested.  However, there are some non-NIH 
collaborators on this study who may receive payments or benefits, limited by the rules of their 
workplace. 
 
Use of Specimens and Data for Future Research 
To advance science, it is helpful for researchers to share information they get from studying 
human samples.  They do this by putting it into one or more scientific databases, where it is 
stored along with information from other studies. A researcher who wants to study the 
information must apply to the database and be approved.  Researchers use specimens and data 
stored in scientific databases to advance science and learn about health and disease.   
We plan to keep some of your specimens and data that we collect and use them for future 
research and share them with other researchers. We will not contact you to ask about each of 
these future uses.  These specimens and data will be stripped of identifiers such as name, address 
or account number, so that they may be used for future research on any topic and shared broadly 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:       18-C-0034 
CONTINUATION: page 14 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
for research purposes. Your specimens and data will be used for research purposes only and will 
not benefit you.  It is also possible that the stored specimens and data may never be used.  
Results of research done on your specimens and data will not be available to you or your doctor.  
It might help people who have cancer and other diseases in the future.   
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data.  Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers. 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER:  18-C-0034 
CONTINUATION: page 15 of 16 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
OTHER PERTINENT INFORMATION 
1. 
Confidentiality.  When results of an NIH research study are reported in medical journals 
or at scientific meetings, the people who take part are not named and identified.  In most cases, 
the NIH will not release any information about your research involvement without your written 
permission.  However, if you sign a release of information form, for example, for an insurance 
company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance 
company to sell you insurance. 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you 
should know that the Act allows release of some information from your medical record without 
your permission, for example, if it is required by the Food and Drug Administration (FDA), 
members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations. 
2. 
Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-
term medical care for any injury resulting from your participation in research here.  In general, 
no long-term medical care or financial compensation for research-related injuries will be 
provided by the National Institutes of Health, the Clinical Center, or the Federal Government.  
However, you have the right to pursue legal remedy if you believe that your injury justifies such 
action. 
3. 
Payments.  The amount of payment to research volunteers is guided by the National 
Institutes of Health policies.  In general, patients are not paid for taking part in research studies at 
the National Institutes of Health.  Reimbursement of travel and subsistence will be offered 
consistent with NIH guidelines. 
4. 
Problems or Questions.  If you have any problems or questions about this study, or 
about your rights as a research participant, or about any research-related injury, contact the 
Principal Investigator, Alexandra Zimmer, M.D., Building 10, Room 2B50A, Telephone:  240-
760-6132. You may also call the Clinical Center Patient Representative at 301-496-2626. If you 
have any questions about the use of your specimens or data for future research studies, you may 
also contact the Office of the Clinical Director, Telephone:  240-760-6070. 
5. 
Consent Document.  Please keep a copy of this document in case you want to read it 
again. 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER:  18-C-0034 
CONTINUATION: page 16 of 16 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby consent to 
take part in this study. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby give 
permission for my child to take part in this 
study.   
(Attach NIH 2514-2, Minor’s Assent, if 
applicable.) 
 
  
  
 
 
 
Signature of Adult Patient/ 
Legal Representative 
Date 
Signature of Parent(s)/ Guardian Date 
 
 
Print Name 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to 
participate in the study. 
 
  
  
 
Signature of Parent(s)/Guardian 
Date 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM NOVEMBER 19, 2018 THROUGH DECEMBER 3, 2019.  
 
 
 
 
 
 
 
 
Signature of Investigator 
Date 
Signature of Witness 
Date 
 
 
Print Name 
 
 
Print Name