Clinical trial NCT03733119
Conditions: Triple Negative Breast Cancer
Sponsor: University of Wisconsin, Madison
Start date: 2018-11-13; Completion date: 2021-02-13
Enrollment: 4 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase II trial studies how well Akt/ERK inhibitor ONC201 (ONC201) with a methionine-restricted (MR) diet works in treating participants with triple negative breast cancer that has spread to other places in the body or cannot be removed by surgery. ONC201 activates a process that leads to the death of a cell. ONC201 is able to target tumor cells to get rid of them, but does not affect normal cells. MR diet is a methionine-free amino acid modified medical food. The addition of an intermittent MR diet may enhance the activity of ONC201. Giving ONC201 and an MR diet may work better in treating participants with breast cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine objective response rate (ORR) to ONC201 with a methionine-restricted diet in patients with metastatic triple negative breast cancer (TNBC).

SECONDARY OBJECTIVES:

I. To determine progression-free survival (PFS) to ONC201 with a methionine-restricted diet in patients with metastatic TNBC.

II. To determine clinical benefit rate (complete or partial response plus stable disease) (CBR) at 4 months to ONC201 with a methionine-restricted diet in patients with metastatic TNBC.

III. To determine overall survival (OS) to ONC201 with a methionine-restricted diet in patients with metastatic TNBC.

IV. To assess metabolic indices in patients with metastatic TNBC treated with ONC201 and a methionine-restricted diet.

V. To assess the expression of TRAIL receptor in circulating tumor cells (CTCs) prior, during and upon progression in patients with metastatic TNBC treated with ONC201 with a methionine-restricted diet.

EXPLORATORY OBJECTIVES:

I. To determine time to development of brain metastases or worsening of brain metastases in patients with metastatic TNBC treated with ONC201 with a methionine-restricted diet.

STUDY DESIGN Patients with metastatic TNBC will be enrolled in a single-arm study evaluating ONC201 with a methionine-restricted diet.

After completion of study treatment, participants are followed up every 3 months for 2 years.

Arms: arm 1: Participants receive Akt/ERK inhibitor ONC201 PO on days 3, 10, and 17. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. arm 2: Participants receive Akt/ERK inhibitor ONC201 PO on days 3, 10, and 17. Participants also receive methionine-restricted diet PO on days 1-5, 8-12, and 15-19. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Akt/ERK Inhibitor ONC201 intervention 2: Methionine-Restricted Diet
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
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UWCCC Protocol #:  UW17107 
 
 
ClinicalTrials.gov Identifier:  NCT03733119 
 
IND#: 138830 
 
TITLE: Phase 2 study of ONC201 with a methionine-restricted diet in patients with 
metastatic triple negative breast cancer 
 
 
Coordinating Center: 
University of Wisconsin Carbone Cancer Center  
 
 
Principal Investigator: 
Kari Wisinski, MD 
 
Department of Medicine 
 
Division of Hematology and Medical Oncology 
 
University of Wisconsin Carbone Cancer Center 
1111 Highland Avenue, WIMR 6033 
Madison, WI 53705-2275 
Phone: 608-262-2876 
Fax: 608-265-6905 
32Tkbwisinski@medicine.wisc.edu 
U32T 
 
32TCo-Investigators: 
32TVincent L. Cryns, MD 
 
Department of Medicine  
 
University of Wisconsin Carbone Cancer Center 
1111 Highland Avenue, WIMR 3003 
Madison, WI 53705-2275 
Phone: 608-262-4786 
Fax: 608-263-9983 
32Tvlcryns@medicine.wisc.edu32T 
 
 
Amye Tevaarwerk, MD 
 
Department of Medicine 
 
Division of Hematology and Medical Oncology 
 
University of Wisconsin Carbone Cancer Center 
1111 Highland Avenue, WIMR 6037 
Madison, WI 53705-2275 
Phone: 608-262-2837 
32Tat4@medicine.wisc.edu 
 
 
 
 
 
 


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Mark E. Burkard, MD/PhD 
 
Department of Medicine 
 
Division of Hematology and Medical Oncology 
 
University of Wisconsin Carbone Cancer Center 
1111 Highland Avenue, WIMR 6059 
Madison, WI 53705-2275 
Phone: 608-262-2803 
32Tmeburkard@medicine.wisc.edu32T 
 
 
Andreas Friedl, MD 
 
Department of Pathology and Laboratory Medicine  
 
University of Wisconsin Carbone Cancer Center 
600 Highland Avenue,  
Madison, WI 53705-2275 
32Tafriedl@wisc.edu32T 
 
Joshua Coon, PhD 
Professor of Biomolecular Chemistry 
and Chemistry 
University of Wisconsin-Madison 
Room 4426 
425 Henry Mall 
Madison, WI 53706 
Phone: (608) 263-1718 
32Tjcoon@chem.wisc.edu32T 
 
 
Statistician: 
 
Program Manager: 
Emmanuel Sampene, PhD 
Tammy Koehn 
Department of Biostatistics and 
University of Wisconsin Carbone Cancer Center 
Medical Informatics 
600 Highland Ave, K5/6 
600 Highland Ave, Box 4675 
Madison, WI 53792 
Madison, WI 53792-4675 
 32Ttmkoehn@medicine.wisc.edu32T 
(608)265-8725 
 
32Tsampene@biostat.wisc.edu32T 
 
 
 
WON Contact: 
Affiliate Coordinator 
600 Highland Ave, K5/6 
Madison, WI 53792 
(608) 265-2867 
(608)256-5676 (Fax) 
     
32TAffiliatecoordinators@uwcarbone.wisc.edu32T 
 
Funding Sponsor:  Wisconsin Partnership Program, V Foundation 
 
 


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INVESTIGATOR SIGNATURE PAGE 
 
Protocol Number: 
 
UW17107 
Protocol Title: 
Phase 2 study of ONC201 with a methionine-restricted diet in patients 
with metastatic triple negative breast cancer 
 
 
47TI have read this protocol and agree to conduct this trial in accordance with this document, good 
clinical practice, the Declaration of Helsinki, and all applicable laws and regulations. I understand 
that it must be reviewed and approved for conduct by the Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC).   
 
 
47T______________________________________________          _________________________  
Principal Investigator Name (Printed) 
 
      Title 
 
 
47T______________________________________________          _________________________  
47TPrincipal Investigator Signature 
 
 
      Date 
 
 
Site Name and Address:       
 
 
47T____________________________________________________ 
 
47T____________________________________________________ 
 
47T____________________________________________________ 
 
47T____________________________________________________ 
 
 
 


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SYNOPSIS 
 
TITLE 
Phase 2 study of ONC201 with a methionine-restricted diet in patients 
with metastatic triple negative breast cancer 
SHORT TITLE 
ONC201 and methionine-restricted diet in TNBC 
PHASE  
II 
STUDY OBJECTIVES  
Primary Objective:  
• To determine objective response rate (ORR) to ONC201 with a 
methionine-restricted diet in patients with metastatic triple 
negative breast cancer (TNBC). 
 
Secondary Objectives:  
• To determine progression-free survival (PFS) to ONC201 with 
a methionine-restricted diet in patients with metastatic TNBC. 
• To determine clinical benefit rate (complete or partial 
response plus stable disease) (CBR) at 4 months to ONC201 
with a methionine-restricted diet in patients with metastatic 
TNBC. 
• To determine overall survival (OS) to ONC201 with a 
methionine-restricted diet in patients with metastatic TNBC. 
• To assess metabolic indices in patients with metastatic TNBC 
treated with ONC201 and a methionine-restricted diet.  
• To assess the expression of TRAIL receptor in circulating 
tumor cells (CTCs) prior, during and upon progression in 
patients with metastatic TNBC treated with ONC201 with a 
methionine-restricted diet.  
Exploratory Objective: 
• To determine time to development of brain metastases or 
worsening of brain metastases in patients with metastatic 
TNBC treated with ONC201 with a methionine-restricted diet.
 
 
 
STUDY DESIGN 
Patients with metastatic TNBC will be enrolled in a single-arm study 
evaluating ONC201 with a methionine-restricted diet. 
BRIEF ELIGIBILITY 
CRITERIA  
1. Metastatic or unresectable TNBC (ER<10%, PR<10% and HER2 
negative either by IHC or in situ hybridization method by ASCO-
CAP guidelines). 
2. Measurable disease by RECIST 1.1. 
3. Any number of prior lines of systemic therapy for metastatic 
disease is allowed.  
4. ECOG PS of 0 or 1. 
5. No active CNS metastatic disease; subjects with prior definitive 
treatment of their CNS disease by surgical resection, SBRT or 


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WBRT >28 days ago will be eligible if asymptomatic and off 
systemic steroids. 
6. Life expectancy of greater than 12 weeks. 
7. Normal organ and marrow function as defined per protocol 
definitions.  
8. Excludes patients who follow a vegan or vegetarian diet 
STATISTICAL 
CONSIDERATIONS 
 
The primary objective is to evaluate efficacy of ONC201 with a 
methionine-restricted diet in metastatic TNBC. The study is designed 
as a single-arm phase II trial. The primary endpoint is ORR. Secondary 
endpoints include CBR, PFS, OS, safety, metabolic indices and CTC 
TRAIL-receptor expression. The null hypothesis is that the probability 
of ORR is no more than 0.1, i.e., HR0R: p≤0.1, and the alternative 
hypothesis is HR1R: p≥0.25. In this single arm study, a Simon's two stage 
design will be utilized.  The null hypothesis that the true ORR is 0.1 
will be tested against a one-sided alternative.  The study will be 
powered to detect an ORR of 25% with the combination of ONC201 
with a methionine-restricted diet, using a power of 80% and a type I 
error rate of 10%. The first stage sample size will be 13. After testing 
the combination on 13 subjects in the first stage, the trial will be 
terminated if 1 or fewer subjects respond. If the trial goes on to the 
second stage, a total of 34 subjects will be studied (i.e. additional 21 
subjects will be recruited). If the total number responding or having 
ORR is less than or equal to 5, the combination of ONC201 with a 
methionine-restricted diet will be rejected. 
 Time to event outcomes such as PFS and OS will be analyzed using 
Kaplan-Meier method and Cox proportional hazards regression.  
 
TOTAL  
NUMBER OF 
SUBJECTS 
Number of subjects in the phase II study: 34 
 
ESTIMATED 
ENROLLMENT 
PERIOD 
Estimated 30 months 
ESTIMATED STUDY 
DURATION  
Estimated 36 months 
 
 


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TABLE OF CONTENTS 
 
INVESTIGATOR SIGNATURE PAGE .............................................................................................................................. 3 
SYNOPSIS ................................................................................................................................................................................... 4 
STUDY SCHEMA ..................................................................................................................................................................... 9 
1. 
Background and rationale ........................................................................................................................................ 12 
1.1 
Disease background ........................................................................................................................................... 12 
1.2 
Targeting pro-apoptotic TRAIL receptors in cancer ........................................................................... 12 
1.3 
Selective metabolic vulnerability of tumors and cancer stem cells to methionine 
restriction (MR) ................................................................................................................................................................ 12 
1.4 
Methionine deprivation primes TNBC to pro-apoptotic therapy .................................................. 13 
1.5 
ONC201 ................................................................................................................................................................... 15 
1.6 
Circulating Tumor Cells (CTCs) to assess TRAIL receptor expression ........................................ 24 
1.7 
Study rationale ..................................................................................................................................................... 24 
2. 
Study Objectives and endpoints ............................................................................................................................ 24 
2.1 
Primary Objective: .............................................................................................................................................. 24 
2.2 
Secondary Objectives: ....................................................................................................................................... 24 
2.3 
Exploratory Objective: ...................................................................................................................................... 25 
3. 
Eligibility Criteria ......................................................................................................................................................... 25 
3.1 
Inclusion criteria ................................................................................................................................................. 25 
3.2 
Exclusion criteria ................................................................................................................................................ 26 
4. 
Registration procedures ........................................................................................................................................... 27 
4.1 
Patient Registration ........................................................................................................................................... 27 
4.2 
General Guidelines ............................................................................................................................................. 28 
5. 
Treatment plan ............................................................................................................................................................. 28 
5.1 
Overview of treatment plan ........................................................................................................................... 28 
5.2 
ONC201 administration ................................................................................................................................... 28 
5.3 
Methionine-restricted diet .............................................................................................................................. 28 
5.4 
Study drug compliance and accountability ............................................................................................. 30 
5.5 
Concomitant medications ................................................................................................................................ 30 
5.6 
Supportive care Guidelines ............................................................................................................................. 31 
6. 
Toxicities and Dose Delays/Dose Modifications ............................................................................................ 31 
6.1 
Adjustments to Methionine-Restricted Diet ........................................................................................... 31 
6.2 
ONC201 Dose Adjustments ............................................................................................................................ 32 


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6.3 
Protocol therapy discontinuation ................................................................................................................ 33 
6.4 
Evaluable subject ................................................................................................................................................ 34 
6.5 
Protocol discontinuation ................................................................................................................................. 34 
6.6 
Criteria for Early Trial Termination ........................................................................................................... 34 
7. 
Study calendars and evaluations .......................................................................................................................... 36 
8. 
Biospecimen studies and procedures ................................................................................................................. 38 
8.1 
Tumor tissue ......................................................................................................................................................... 38 
8.2 
Circulating tumor cells (CTCs) ...................................................................................................................... 39 
8.3 
Plasma methionine and methionine metabolites ................................................................................. 39 
8.4 
Confidentiality of biospecimens ................................................................................................................... 39 
9. 
Criteria for disease evaluation ............................................................................................................................... 40 
9.1 
Measurable Disease ........................................................................................................................................... 40 
9.2 
Non-measurable Lesions ................................................................................................................................. 40 
9.3 
Target Lesions ...................................................................................................................................................... 40 
9.4 
Non-target Lesions ............................................................................................................................................. 41 
9.5 
Evaluation of Target Lesions ......................................................................................................................... 41 
9.6 
Evaluation of Non-target Lesions ................................................................................................................ 41 
9.7 
Evaluation of Best Overall Response .......................................................................................................... 42 
9.8 
Definitions for Response Evaluation – RECIST 1.1 ............................................................................... 44 
10. 
Drug information ..................................................................................................................................................... 44 
10.1 
ONC201 ............................................................................................................................................................... 44 
10.2 
Hominex-2 shakes .......................................................................................................................................... 47 
11. 
Adverse events ......................................................................................................................................................... 47 
11.1 
Definitions ......................................................................................................................................................... 47 
11.2 
Procedures for Recording and Reporting Adverse Events ........................................................... 49 
12. 
Data and safety monitoring plan ...................................................................................................................... 50 
12.1 
Oversight and Monitoring Plan ................................................................................................................ 50 
12.2 
Monitoring and Reporting Guidelines ................................................................................................... 51 
12.3 
Review and Oversight Requirements .................................................................................................... 51 
12.4 
Expedited Reporting of Serious Adverse Events .............................................................................. 53 
12.5 
Other Reporting Requirements ................................................................................................................ 58 
13. 
Statistical methods ................................................................................................................................................. 58 
13.1 
Study design...................................................................................................................................................... 58 
13.2 
Sample size and accrual ............................................................................................................................... 58 


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13.3 
Analysis datasets ............................................................................................................................................ 59 
13.4 
Assessment of safety ..................................................................................................................................... 59 
13.5 
Demographic and baseline characteristics ......................................................................................... 59 
13.6 
Assessment of efficacy .................................................................................................................................. 59 
13.7 
Data analysis plan .......................................................................................................................................... 59 
13.8 
Interim analysis .................................................................................. Error! Bookmark not defined. 
14. 
Trial management ................................................................................................................................................... 60 
14.1 
Data Quality Oversight Activities ............................................................................................................. 60 
14.2 
Compliance with Trial Registration and Results Posting Requirements ............................... 61 
15. 
Data handling and record keeping ................................................................................................................... 61 
15.1 
Data Management .......................................................................................................................................... 61 
15.2 
Case Report Forms and Submission ....................................................................................................... 61 
15.3 
Record Retention ............................................................................................................................................ 61 
15.4 
Confidentiality ................................................................................................................................................. 62 
15.5 
WON Site Oversight ....................................................................................................................................... 62 
16. 
Ethics ............................................................................................................................................................................ 62 
16.1 
Institutional Review Board (IRB) Approval ........................................................................................ 62 
16.2 
Ethical Conduct of the Study ...................................................................................................................... 63 
16.3 
Informed Consent Process .......................................................................................................................... 63 
17. 
References .................................................................................................................................................................. 64 
 
 
 


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STUDY SCHEMA 
 
 
WEEKLY SCHEDULE:
 
 
ONC201 is taken weekly on days 3 and 4 at 625mg by mouth. 
*Optional tumor biopsy is obtained at baseline. 
#Blood for circulating tumor cells (black triangle) will be taken at baseline, on day 5 
of cycle 2, and at end of treatment.  
MR (methionine-restricted diet) will be followed days 1 through 5 weekly.  
 
 
 
Metastatic 
TNBC 
  
  
Biopsy 
ONC201 (625 mg on days 3 & 4 every 7 days)  
with 
Dietary MR 
Blood 
Blood 
Blood 
(after MR completed) 


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47LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation  
Definition 
_____________________________________________________________________________ 
AE 
 
 
adverse event 
ANC 
 
 
absolute neutrophil count 
ALT 
 
 
alanine aminotransferase 
AQUA  
 
automated quantitative analysis 
ASCO  
 
American Society of Clinical Oncology 
AST 
 
 
aspartate aminotransferase 
BCSC  
 
breast cancer stem cell 
BSA  
 
 
body surface area 
CBC 
 
 
complete blood count 
CBR 
 
 
clinical benefit rate 
cm 
 
 
centimeter 
CMP 
 
 
comprehensive metabolic panel 
CNS 
 
 
central nervous system 
CR 
 
 
complete response 
CTC 
 
 
circulating tumor cell 
CTCAE 
 
(NCI) Common Terminology Criteria for Adverse Events 
CTEP  
 
Cancer Therapy Evaluation Program 
CYP 
 
 
cytochrome P450 
dL 
 
 
deciliter 
DOR 
 
 
duration of response 
DSMC  
 
Data and Safety Monitoring Committee 
DSMP  
 
Data and Safety Monitoring Plan 
ECG 
 
 
electrocardiogram 
ECOG  
 
Eastern Cooperative Oncology Group 
ER 
 
 
endoplasmic reticulum 
ER 
 
 
estrogen receptor 
ERK 
 
 
extracellular regulated signal kinase 
FDA 
 
 
Food and Drug Administration 
h 
 
 
hour 
Hcy 
 
 
homocysteine 
HDPE  
 
high-density polyethylene 
HER2  
 
human epidermal growth factor receptor 2 
HFSR  
 
hand-foot skin reaction 
HIPAA  
 
Health Insurance Portability and Accountability Act 
HPMC  
 
hydroxypropyl methylcellulose 
IHC 
 
 
immunohistochemistry 
IND 
 
 
Investigational New Drug 


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IRB 
 
 
institutional review board 
ISR 
 
 
integrated stress response 
kg 
 
 
kilogram 
lbs 
 
 
pounds 
LC-MS  
 
liquid chromatography–mass spectrometry 
LLN 
 
 
lower limit of normal 
mg 
 
 
milligram 
min 
 
 
minute 
mL 
 
 
milliliter 
mm3  
 
cubic millimeters 
MR 
 
 
methionine restriction 
MTA  
 
5’-methythioadenosine 
NCI 
 
 
National Cancer Institute 
MTD  
 
maximum tolerated dose 
ORR 
 
 
overall response rate 
OS 
 
 
overall survival 
PD 
 
 
progressive disease 
PFS 
 
 
progression-free survival 
PI3K  
 
phosphoinositide 3-kinase 
PK 
 
 
pharmacokinetics 
PPE 
 
 
polypropylene 
PR 
 
 
partial response 
PR 
 
 
progesterone receptor 
PS 
 
 
performance status 
PSR 
 
 
Protocol Summary Report 
RECIST 
 
Response Evaluation Criteria in Solid Tumors 
RP2D  
 
recommended phase II dose 
SAE 
 
 
serious adverse event 
SAH 
 
 
S-adenosylhomocysteine 
SAM 
 
 
S-adenosylmethionine 
SD 
 
 
stable disease 
SOP 
 
 
standard operating procedure 
TNBC  
 
triple negative breast cancer 
ULN 
 
 
upper limit of normal 
US  
 
 
United States 
wt 
 
 
weight 
WON  
 
Wisconsin Oncology Network 
 
 


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1. BACKGROUND AND RATIONALE 
 
1.1 
Disease background 
Breast cancer remains an important global health issue. One of eight U.S. women is 
diagnosed with breast cancer during her lifetime[1]. The American Cancer Society 
estimates that 234,190 new cases of invasive breast cancer will be diagnosed in the 
United States in 2015 with 40,730 deaths[2] Triple-negative breast cancer (TNBC) 
constitutes approximately 15% of breast cancers and lacks expression of estrogen 
receptor (ER), progesterone receptor (PR), and human epidermal growth factor 
receptor-2 (HER2). TNBC is associated with African-American and Hispanic race, 
younger age at diagnosis, advanced stage, high mitotic index, and BRCA1 
mutations[3-7]. Due to the absence of any targeted therapies, cytotoxic 
chemotherapy remains the mainstay of medical treatment for TNBC, but outcomes 
are poor compared with other subtypes[8, 9]. Median survival for women with 
advanced TNBC remains a dismal 13 months[9]. Improved understanding of this 
disease to advance our treatment approaches are urgently required.  
 
1.2 
Targeting pro-apoptotic TRAIL receptors in cancer 
TRAIL and agonistic humanized monoclonal antibodies (mAbs) targeting its death 
receptors (TRAIL-R1/DR4 and TRAIL-R2/DR5) have garnered great interest as 
cancer therapeutics because they preferentially activate apoptosis in transformed 
cells independent of p53 status and exhibit broad antitumor activity in preclinical 
models[10]. We demonstrated that a humanized agonistic TRAIL-R2 mAb suppressed 
lung metastases in a murine TNBC model[11]. Although TRAIL and agonistic TRAIL-
R2 mAbs have been demonstrated to be safe in clinical trials, they have failed to 
demonstrate a therapeutic benefit in advanced solid malignancies[12-14]. 
 
1.3 
Selective metabolic vulnerability of tumors and cancer stem cells to 
methionine restriction (MR) 
Diverse tumors are selectively vulnerable to specific amino acid deficiencies, 
including methionine[15]. Methionine depletion inhibits cell cycle progression and 
induces apoptosis in many transformed cells, but not normal cells[16, 17]. Dietary MR 
inhibits tumor growth in diverse murine models[18]. Intriguingly, we have observed 
that breast cancer stem cells (BCSCs), rare stem-like cells within breast tumors that 
likely contribute to chemotherapy-resistance and metastasis[19], are dependent on 
methionine for cell survival as determined by mammosphere assays and BCSC 
markers (CD44hi/CD24low) (Fig. 1). Eradication of chemotherapy-resistant BCSCs is 
likely to be critical to prevent relapses/recurrence[19]. Hence, the tumor-selectivity 
of MR, coupled with its activity against BCSCs, make it an attractive cancer therapy 
and distinguish it from cytotoxic agents. Methionine restriction also reduces 
adiposity, improves metabolic indices and extends lifespan in rodents[20-22]. 
Although methionine plays a critical role in protein synthesis and methylation of 
nucleic acids and proteins, the mechanisms underlying the “methionine dependence” 
of cancer is poorly understood[18]. 
 


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Fig. 1. MR inhibits breast cancer stem cells. A) MDA-MB-
231 (231), GILM2 and BT20 TNBC cells were grown as 
mammospheres in 0% methionine (Met) or control media. 
***P < 0.001. B) The CD44 and CD24 populations of cells 
grown in 0% Met or control media was determined by flow 
cytometry (percentage of cells in each quadrant is 
indicated).  
 
 
1.4 
Methionine deprivation primes TNBC to pro-apoptotic therapy 
We recently demonstrated that methionine deprivation exposes a targetable 
vulnerability TNBC cells by enhancing TRAIL receptor-2 (TRAIL-R2) mRNA levels 
and cell surface 
expression (Fig. 2).  
 
Fig. 2. MR induces TRAIL 
receptor expression.  A) 
Normalized mRNA levels of 
TRAIL-R2 and TRAIL-R1 in 
MDA-MB-231 (231), GILM2 
and MDA-MB-468 (468) TNBC 
cells grown in 0% Met or 
control media for 72 h. B) Cell 
surface expression of TRAIL-
R2 or TRAIL-R1 determined by 
flow cytometry in TNBC cells 
grown in 0% Met (red line) or 
control media (black line) for 
72 h. Gray bar is IgG negative 
control. 
Taken 
from 
our 
published work[23].  
 
 
The resulting 
increased TRAIL-R2 
expression renders TNBC cells susceptible to TRAIL-R2 agonists such as the 
humanized TRAIL-R2 mAb lexatumumab (Fig. 3). Strikingly, this metabolic priming 


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of MR is specific for TNBC cells and does not occur in non-transformed cells or in 
other breast cancer subtypes[23].  
 
 
Fig. 3. MR sensitizes TNBC cells to the TRAIL-R2 agonist lexatumumab.  A) Crystal violet assay 
and B) Annexin V labeling of TNBC cells grown in 0% Met or control media and treated with vehicle, 
doxorubicin (Dox) or lexatumumab (Lexa) for 48 h (A) or 6 h (B, percentage of cells in each quadrant 
is indicated). Taken from our published work[23]. 
 
 
We also demonstrated that a brief exposure to dietary MR is well tolerated by mice 
and enhances the antitumor activity of lexatumumab  against mammary tumors and 
lung metastases in an orthotopic TNBC model (Fig. 4). Our current findings point to 
methionine deprivation as a novel nutritional intervention to metabolically prime 
TNBC to respond to a pro-apoptotic TRAIL-R2 mAb, thereby enhancing their 
therapeutic efficacy. Moreover, phase I and phase II trials of a methionine-free diet 
alone or in combination with chemotherapy in patients with metastatic or recurrent 
solid tumors have confirmed the safety and tolerability of methionine deprivation 
(up to 39 weeks)[24, 25]. 
 
 


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1.5 
ONC201 
ONC201 (TIC10) is a first-in-class small molecule that activates apoptosis in tumor 
but not normal cells in a p53-independent manner. In solid tumors studies, ONC201 
indirectly inactivates the Ras effector target kinases, Akt and ERK[26]. Akt and ERK 
are well-established targets for novel oncology drug development due to their 
cooperative pro-apoptotic effects. The downside of drugs with high selectivity for 
single targets that have been developed as a result of the pursuit of these pathways 
include a lack of high selectivity between malignant and normal cells and as a result, 
a high toxicity from the attempt to simultaneously inhibit both kinases. In addition, 
there is a frequent and often rapid development of resistance. The dual inactivation 
of Akt and ERK by ONC201 results in broad-spectrum cytotoxic activity that includes 
activation of apoptosis and other downstream antitumor effects to produce a potent 
antitumor response.  
 
Hematological malignancies are highly sensitive to endoplasmic reticulum (ER) 
stress, which results from an overload of misfolded proteins in the ER. ER stress can 
be triggered by multiple mechanisms and has been targeted by several 
Fig. 4. Dietary MR enhances the antitumor effects of the TRAIL-R2 agonist lexatumumab 
in a mouse TNBC model. A) Female NSG mice with MDA-MB-468 mammary tumors (10 mice 
per group) were treated with vehicle and control diet, lexatumumab (Lexa) and control diet, 
MR (Diet) or MR and lexatumumab (Diet/Lexa) for 3 weeks (indicated by arrows). % original 
mammary tumor volume is shown. B) Real-time PCR analysis of TRAIL-R2 mRNA in mammary 
tumors. C) Fluorescent whole lung images. Metastatic tumor burden was measured by % 
surface of lung occupied by metastases and number of macrometastases. *P < 0.05, **P < 0.01, 
and ***P < 0.001. Taken from our published work [23]. 


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pharmacological agents indicated for cancer. This includes HSP90 and proteasome 
inhibitors such as bortezomib, which is approved by the FDA to treat multiple 
myeloma and mantle cell lymphoma. Robust activation of the pro-apoptotic arm of 
ER stress in tumor cells has been observed in response to ONC201 treatment in both 
solid and liquid tumors. Inactivation of Akt and ERK signaling has been linked to ER 
stress induction in several cancer cell lines.  
 
The safety margin (ratio of therapeutic dose to lowest dose with a mild adverse event) 
of ONC201 is at least 10-fold in rats and dogs in GLP toxicology studies. The efficacy 
of ONC201 has been consistently demonstrated in >80 in vitro models and 16 in vivo 
experiments (subcutaneous, orthotopic, and transgenic) and confirmed by multiple 
leading cancer research institutions. The profile of ONC201 is well suited for an 
oncology product: efficacious with infrequent administration, broad-spectrum 
activity independent of mutations, orally active, compelling safety profile, combines 
synergistically and safely with many approved therapies, highly active by employing 
a combination of established anti-tumor/pro-apoptotic pathways, highly stable, 
water soluble, and penetrates the blood-brain barrier.  
 
1.5.1 Preclinical Efficacy 
ONC201 induces broad-spectrum cell death in tumor cells harboring diverse 
mutations in genes such as p53, KRAS, Raf, EGFR and others that render resistance to 
chemotherapies and targeted agents. ONC201 induces caspase-mediated apoptosis in 
cancer cell lines and exhibits broad-spectrum cytotoxicity in vitro. ONC201 displays 
single agent anti-tumor effects (Fig. 5) in subcutaneous and orthotopic colon cancer, 
subcutaneous triple negative breast cancer, subcutaneous non-small cell lung cancer, 
subcutaneous and orthotopic intracranial glioblastoma, and immunocompetent 
lymphoma transgenic mouse models. ONC201 also cooperates extensively with 
paclitaxel, docetaxel, sorafenib, and bevacizumab. Importantly, MR robustly 
sensitizes TNBC cells to ONC201 (Fig. 6). 
 


U W 1 7 1 0 7
V 5 0 2 / 1 6 / 2 0 2 1
P a g e | 1 7
Fi g u r e 5 O N C 2 0 1 a ntit u m o r a cti vit y  i n s u b c ut a n e o u s x e n o g r aft s. S u bc ut a n e o us x e n o gr afts i n at h y mic n u d e 
mic e r ec ei vi n g a si n gl e d os e of O N C 2 0 1 ( 1 0 0 m g / k g, I P).  D at a s h o w n is a p pr o xi m at el y 1 w e e k f oll o wi n g si n gl e 
d os e a d mi nistr ati o n a n d is r el ati v e t o t h e t u m or si z e o n t h e d a y of a d mi nistr ati o n. 
Fi g. 6. M R s e n siti z e s T N B C c ell s t o O N C 2 0 1. T h e i n dic at e d T N B C c ells w er e gr o w n i n c o ntr ol or 0 % m et hi o ni n e 
m e di a a n d tr e at e d wit h v e hicl e or 5 
M O N C 2 0 1 f or 7 2 h. Vi a bl e c ells w er e st ai n e d wit h cr yst al vi ol et, a n d t h e % 
c o nfl u e nc e of vi a bl e c ells w as d et er mi n e d. ** P  < 0. 0 1 or ***P < 0. 0 0 1 vs. v e hicl e or t h e i n dic at e d c o m p aris o n. 


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1.5.2 Mechanism of Action 
ONC201 is a selective antagonist of the G protein-coupled receptor DRD2 that was 
identified through a phenotypic screen as a p53-independent small molecule 
inducer of TRAIL gene transcription in tumor cells. A series of gene expression 
profiling and cell signaling investigations have unraveled signaling pathways that 
are engaged in tumor cells following ONC201 treatment.  
 
Downstream 
of 
target 
engagement, 
ONC201 activates the integrated stress 
response (ISR), which is the same 
signaling pathway activated by ER stress-
inducing compounds such as proteasome 
inhibitors (e.g. bortezomib). When the ISR 
is 
activated 
by 
ER 
stress-inducing 
compounds, the pathway is often referred 
to as the ER stress response. ONC201 
causes an early-stage increase in the 
phosphorylation of eIF2-alpha at serine 
51, which results in attenuation of protein 
translation and upregulation of the 
transcription factor ATF4 (Fig. 7). ATF4 
upregulates CHOP, which is also a 
transcription factor that regulates several 
apoptosis-related genes such as the 
TRAIL-receptor DR5. ATF4 and CHOP 
upregulate expression of TRB3, which interacts directly with Akt to decrease its 
kinase activity. TRB3 also serves as a scaffold protein in the MAPK signaling pathway 
that can negatively regulate this pathway. Decreased levels of phospho-MEK, -ERK, 
and -Akt have been documented in response to ONC201. The decreased ERK and Akt 
kinase activity results in less phosphorylated Foxo3a, which is a transcription factor 
that regulates both the TRAIL and DR5 genes. Dephosphorylated Foxo3a undergoes 
nuclear translocation and activation in response to ONC201.  
 
In summary, ONC201 inhibits DRD2 to cause downstream activation of ATF4, which 
causes induction of genes that lead to apoptosis. DRD2 antagonism also 
downregulates Akt and ERK activity to cooperatively induce complementary 
downstream apoptotic effects. ONC201 may not activate eIF2-alpha through PERK. 
This distinct mechanism may explain the lack of cross-resistance between ONC201 
and other ER stress-inducing agents such as bortezomib. In addition, ONC201 has 
enhanced antitumor efficacy in combination with bortezomib that may be explained 
by engaging parallel stimuli that lead to an enhanced activation of the ISR in tumor 
cells. 
 
ONC201 has been reported to decrease the phosphorylated active forms of the 
oncogenic kinases Akt, MEK, and ERK. The decreased phosphorylation of Akt and 
ERK causes decreased kinase activity, leading to dephosphorylation of its 
Figure 7 Proposed model of ONC201 in tumor cells.  


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substrates that include the mutual substrate Foxo3a[27]. ONC201-induced effects 
on these signaling pathways have been demonstrated in several tumor types in 
vitro with diverse genetic mutations in p53, KRAS, PTEN, and others. Targeting the 
Ras signaling pathway, which includes two arms ending at the effector kinases Akt 
and ERK, has been an unattainable therapeutic goal for decades[28]. Ras and its 
upstream activating receptors such as EGFR are very commonly activated in human 
cancer through mutations, amplification, or other mechanisms. This critical signaling 
pathway transduces stimulus signals from the extracellular environment into the 
nucleus to regulate genes that drive survival and proliferation. While the field widely 
accepts the enormous impact that inhibiting Ras would have in oncology, directly 
targeting Ras in tumors has not been performed successfully in the clinic. The 
challenge underlying this absence lies in the fact that Ras is a GTPase rather than a 
routinely drugged class of proteins such as a kinase. Nevertheless, targeting effector 
kinases downstream of Ras have been vigorously pursued in recent years as a 
chemically viable strategy by combining small molecule PI3K/Akt inhibitors with 
MEK/ERK inhibitors. While the dual inhibition of these pathways is widely reported 
to be synergistic it is plagued by toxicity and other limitations[29-31]. This 
combinatorial approach has several efficacy-limiting shortcomings that include 
toxicity [32] as these kinases are important for several physiological processes, 
compounding toxicity, drug-drug interactions, and the need for synchronous delivery 
to tumors.  
 
In contrast to Akt and MEK inhibitors, ONC201 inactivates Akt and ERK indirectly in 
tumor cells while these kinases are uninhibited in normal cells. The lack of dual 
inhibition in normal cells means that ONC201 does not induce death of normal cell , 
allowing ONC201 to be safe at efficacious doses in cancer models in vitro and in 
vivo[26]. The inhibition of Akt and ERK in cancer cells is sustained following drug 
removal, maintained in the face of upstream mutations (e.g. KRAS), and is 
independent of upstream ligand stimulation (e.g. EGF). Furthermore, the ability of 
ONC201 to inhibit these two kinases as a single molecule results in concomitant dual 
inactivation that yields synergistic efficacy and also eliminates complications with 
combination therapy such as compounding toxicity and drug-drug interactions.  
 
Recent gene expression profiling studies in solid and liquid tumor cell lines revealed 
transcriptome changes consistent with induction of the ER stress response. 
Subsequent experiments validated that ONC201 activated the pro-apoptotic arm of 
ER stress in cancer cells, which is also activated by proteasome inhibitors. CHOP is a 
pro-apoptotic transcription that is induced as a critical effector of the maladaptive 
apoptotic ER stress response. Robust induction of CHOP expression in response to 
ONC201 treatment has been observed in multiple models in a response- and time-
dependent manner. ER stress may be linked to prior observations related to Akt and 
ERK signaling in solid tumor cells with ONC201 treatment, as previously reported 
with ER stress-inducing compounds. Based on these findings, CHOP, pERK, pAkt, 
TRAIL, and DR5 should be evaluated for clinical utility as biomarkers in patients 
receiving ONC201 treatment. 
 


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Figure 8: Mean ONC201 plasma concentrations versus time 
following the first dose of ONC201. Concentrations are shown as (A) 
A mean for each dose cohort, or (B) for individuals treated at 625 mg.  
1.5.3 Pharmacokinetic studies in humans 
In a Phase I dose escalation clinical trial of ONC201 in advanced solid tumors, the 
pharmacokinetics of single agent ONC201 was determined by LC-MS-MS analysis of 
plasma collected in the first cycle of therapy within 21 days of drug administration 
(Fig. 8; Table 1). Trends of increasing exposure with dose were consistent with dose 
proportionality. Patients receiving 625mg ONC201 exhibited a mean half-life of 11.3  
hours and achieved a Cmax of 3.6 ug/mL (~9.3 uM), which occurred at 1.8 hours 
following administration (Tmax). The mean volume of distribution was 369 L, 
consistent with a large distributive volume.  
 
Mean AUC was 37.7 h.μg/mL and mean CL/F was 25.2 L/h. Generally, CL/F was 
observed to be variable but consistent across all dose groups. There were no 
apparent relationships between drug CL/F and patient sex and age. Noticeable, 
shallow trends were observed with patient weight and body surface area (BSA). An 
overall increase in CL/F was observed as weight and BSA increased. Although a 
slight upward trend was observed, there was no strong correlation between CL/F 
and CLCR.  
 
Stronger correlations were observed with the distributive volume estimate and 
patient weight and BSA.  An increase in volume of distribution was observed with 
increasing patient weight or BSA, as expected. Trends of decreasing exposure with 
increasing weight were observed in plots of Cmax/Dose and AUC/Dose versus 
patient weight. Weight normalized CL/F was plotted versus Dose, showing a similar 
trend to un-normalized CL/F.  
 
 
 
 
 
 
 
 
 
 


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Table 1 ONC201 pharmacokinetic parameters determined in patients receiving 
625 mg ONC201 (n=24). 
 
 
 
In a Phase I/II clinical trial of ONC201 in adults with acute leukemias or high-risk 
myelodysplastic syndromes (NCT02392572), the pharmacokinetics of single agent 
ONC201 administered once every one or three weeks was determined by LC-MS-MS 
analysis of plasma collected in the first cycle of therapy within 21 days of drug 
administration. Oral doses of ONC201 were given at 125, 250, 375, 500 and 625mg, 
twice each week on two consecutive days (e.g. Monday and Tuesday of each week). 
This dosing schedule maintained systemic concentrations that exceeded 1,000ng/mL 
therapeutic thresholds of ONC201 for >72 hours in patients who received 375mg or 
625mg. In contrast, exposure with weekly dosing generally maintained >1,000 ng/mL 
concentrations for <24 hours (Figure below). In vitro studies indicate that maximum 
antiproliferative and pro-apoptotic effects of ONC201 can require continuous 
incubation for at least 48 hours in some cancer cell lines. 
 
 
Figure 9. Plasma concentrations of ONC201 administered (A) once per week or (B) 
twice per week on two consecutive days to adults with relapsed/refractory acute 
leukemias or high-risk myelodysplastic syndromes. Hour 0 is the baseline sampled 
before the first dose on ONC201. Error bars reflect SEM of samples from patients 
enrolled to receive the same dose.   Based on this, the proposed dosing schedule 
of ONC 201 is 675mg twice weekly on two consecutive days. 
 
1.5.4 Clinical Studies 
The clinical safety of ONC201 has been evaluated in a phase I clinical trial. The design 
was an open-label, dose-escalation phase I trial of mono-agent ONC201 in patients 
with advanced, refractory tumors who had exhausted or refused standard treatment 
options for their respective indications. The primary objective of this study was to 
determine the recommended phase II dose (RP2D) of ONC201 administered orally in 


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patients with advanced cancers, as well as to evaluate the safety and tolerability of 
the drug. Secondary objectives included pharmacokinetics and pharmacodynamics 
evaluation of ONC201 and preliminary assessment of anti-tumor efficacy.  
 
An accelerated dose escalation design was employed to reduce the number of patients 
treated at potentially sub-therapeutic dose and to accelerate the determination of the 
recommended phase II dose. Ten evaluable patients (aged 47-80 years) received oral 
ONC201 once every 3 weeks at five dose levels ranging from 125 to 625 mg. The study 
design included only one patient per cohort until any patient experiences a grade 2 
adverse event during the first cycle of treatment, defined as 21 days. Five dose levels 
(125 mg, 250 mg, 375 mg, 500 mg, 625 mg) were selected for the study. Enrollment 
at each subsequent dose level required that all patients enrolled at the prior dose 
level completed Cycle 1 dosing and were evaluated 21 days later to assess safety.  
 
On average, patients received 3.1 doses of ONC201. Nine out of ten patients 
completed at least 2 cycles, 4 patients completed at least four cycles, and one patient 
received six cycles and remains on therapy. 625 mg was the highest dose 
administered and was determined to be the RP2D that surpassed the absorption 
saturation threshold by two dose levels.  The only adverse event during the dose 
escalation phase that was possibly attributed to ONC201 was a low grade fever. No 
drug-related toxicities Grade >1 were observed in any patients in this study. 
Explorative laboratory studies and physical exams did not reveal any drug-related 
abnormalities. Similarly, cardiovascular assessments revealed no drug-related 
effects. Three Medwatch reports were filed with the FDA that reported events that 
were not attributed to the study drug. 
 
Clinical and laboratory results indicated that the drug possessed biological activity in 
the treated patients. Patient #3, a 72 year old with advanced clear cell endometrial 
(uterine) cancer had a mixed objective response with >50% decrease in 
lymphadenopathy (10/11 afflicted lymph nodes responded) after 2 doses. Patient #4, 
a 62-year-old male with renal cancer and bone metastasis with debilitating pain in 
the clavicle experienced relief from his clavicular pain. Patient #6, a 69-year-old 
patient with prostate adenocarcinoma, has received 7 doses of ONC201 and has stable 
disease. Patient #8, a 71-year old colon cancer patient had stable disease for at least 
12 weeks with 4 doses of ONC201.  
 
A 47-year-old male with appendiceal cancer (patient #2) had CA27.29 tumor 
biomarker of 30 units that was in the abnormal range, which decreased to 20 units 
(normal range) after 4 doses of ONC201. Given the heterogeneity of the tumor types 
in the enrolled patients, no widely used biomarker was available to uniformly assay 
all patient samples. Since most solid tumors express cytokeratin-18, the serum M30 
assay was selected to detect a caspase-cleaved form of cytokeratin-18 that occurs 
during apoptosis. Clinical studies have demonstrated the M30 assay to be predictive 
of clinical response [33] in solid tumors. Induction of the M30 assay for apoptosis was 
noted in 67% of patients treated at the RP2D with a range of 1.25- to 4-fold increase.  
 


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An expansion phase of this Phase I trial with ONC201 enrolled 18 additional patients 
with advanced solid tumors to confirm the tolerability of the 625mg ONC201 RP2D. 
The only adverse events among the 18 patients enrolled in the expansion phase that 
were attributed as possibly-related to ONC201 were: nausea (1 patient), emesis (2 
patients), and increased level of serum amylase (2 patients). All of these adverse 
events were Grade 1 and reversed rapidly. Laboratory studies and physical exams 
did not reveal any drug-related abnormalities. Similarly, cardiovascular assessments 
revealed no drug-related effects. 
 
Another arm of this study has been opened to evaluate weekly dosing. Three 
patients have been treated with 375mg ONC201 on a weekly basis and six patients 
have been treated with 625mg on a weekly basis. There have been no reports to the 
sponsor of any drug-related adverse events in any of these patients. All three 375mg 
and ten of the 625mg patients have successfully completed the DLT window (21 
days).  
 
A clinical trial is currently being conducted at the MD Anderson Cancer Center 
investigating the safety of ONC201 in patients with acute leukemias and 
myelodysplastic syndrome (study #2014-0731; NCT02392572).  Thus far, 9 
patients have been enrolled in this study using 2 administration schedules – once 
every 3 weeks and once every week. 6 patients were dosed at once every 3 weeks 
schedule at various dose escalation cohorts (125mg, 250mg, 365mg, 500mg, 
625mg) and 3 patients were dosed on weekly cohorts (125mg, 250mg, 375mg). 
There were reported instances of febrile neutropenia, lung infection (pneumonia), 
gastrointestinal disorders and abdominal pain. None of these adverse events were 
attributed as drug-related by the investigator.  
 
Study #2014-0632 (NCT02420795) being conducted at the MD Anderson Cancer 
center, is a 3+3 design dose-escalation design to determine the safety of ONC201 in 
patients with relapsed/refractory Non-Hodgkin’s Lymphoma (NHL). Thus far, 3 
patients have been enrolled at 125 mg and 1 patient at 250 mg dosed once every 3 
weeks. In addition, 1 patient has also been enrolled at the weekly schedule and has 
received twelve 125mg doses. No drug-related adverse events have been reported. 
 
Study #PH-077 (NCT02609230) is a Phase I dose-escalation study of ONC201 in 
patients with solid tumors and multiple myeloma, being conducted at Fox Chase 
Cancer Center.  Thus far, 6 patients have received ONC201 125mg once every 3 
weeks. Patient 1 experienced an SAE that was initially assessed as possibly drug 
related (progressed from Grade 2 fatigue at baseline to Grade 3 fatigue). The patient 
had brain metastases at baseline and rapid progression of underlying disease and 
associated symptoms within 2 weeks of initiating ONC201 treatment. The SAE 
attribution that triggered the initial report is under reassessment based on the 
evidence of progressive underlying disease.    
 
Study #15-318 (NCT02525692) is a Phase II study of ONC201 in patients with 
recurrent glioblastoma, being conducted at Massachusetts General Hospital and Dana 


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Farber Cancer Institute. 17 patients have been treated to date at 625mg ONC201 once 
every three weeks. One patient had a possibly drug-related incident of abnormal 
neutrophil count that was quickly resolved and classified as not-serious and the same 
patient had a mild allergic reaction after 6 doses. In this study, another patient had a 
PR with a 82% decrease in tumor volume after 8 doses of drug and is still on therapy, 
while another patient remains disease-free for more than 32 weeks.  
 
1.6 
Circulating Tumor Cells (CTCs) to assess TRAIL receptor expression 
CTCs will be isolated by a novel microfluidics CTC platform (VERSA Chip) that 
integrates CTC capture (>90% efficiency) with quantitative immunofluorescence and 
nucleic acid extraction/analysis[34-39]. CTCs will be captured using multiple 
antibodies (EpCAM, cell surface vimentin, MUC1, and CD133) determined by analysis 
of CTCs isolated in preclinical studies. Captured CTCs will be analyzed by quantitative 
immunofluorescence (TRAIL, TRAIL-R1 and TRAIL-R2) followed by RT-PCR analysis 
of mRNA levels of these targets using the VERSA Chip[37, 38].  
 
CTCs will be drawn and analyzed if funding is secured.  
 
1.7 
Study rationale 
We hypothesize that ONC201 with an intermittent MR-diet will be effective in 
patients with metastatic TNBC.  Expression of TRAIL receptor will be assessed in 
CTCs.   
 
2. STUDY OBJECTIVES AND ENDPOINTS 
 
2.1 
Primary Objective:  
2.1.1 To determine objective response rate (ORR) to ONC201 with a methionine-
restricted diet in patients with metastatic TNBC.  
 
2.2 
Secondary Objectives:  
2.2.1 To determine progression-free survival (PFS) to ONC201 with a methionine-
restricted diet in patients with metastatic TNBC.  
 
2.2.2 To determine clinical benefit rate (complete and partial response plus stable 
disease) (CBR) at 4 months to ONC201 with a methionine-restricted diet in 
patients with metastatic TNBC. 
 
 
2.2.3 To determine overall survival (OS) to ONC201 with a methionine-restricted 
diet in patients with metastatic TNBC. 
 
 
2.2.4 To determine the safety of adding a methionine-restricted diet to ONC201 in 
patients with metastatic TNBC 
 
 
2.2.4 To assess metabolic indices in patients with metastatic TNBC treated with 
ONC201 and a methionine-restricted diet.  
 


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______ 
______ 
______ 
______ 
______ 
______ 
______ 
______ 
______ 
2.2.5 To assess the expression of TRAIL receptor in CTCs prior, during and upon 
progression in patients with metastatic TNBC treated with ONC201 with a 
methionine-restricted diet.  
 
2.3 
Exploratory Objective: 
2.3.1 To determine time to development of brain metastases or worsening of brain 
metastases in patients with metastatic TNBC treated with ONC201 with a 
methionine-restricted diet.  
 
3. ELIGIBILITY CRITERIA 
 
3.1 
Inclusion criteria 
 
3.1.1 Metastatic or unresectable TNBC (ER<10%, PR< 10% and HER2 negative 
either by IHC or in situ hybridization method by ASCO-CAP guidelines). For 
patients with a previous tumor sample with positive ER, PR and/or HER2 
results, if the most recent biopsy meets study criteria, they will be eligible 
 
3.1.2 Measurable disease by RECIST 1.1. within 28 days prior to registration. 
 
3.1.3 Written informed consent and HIPAA authorization for release of personal 
health information. NOTE: HIPAA authorization may be included in the 
informed consent or obtained separately 
 
3.1.4 Females 18-74 years of age at the time of consent.  Men are not eligible to 
participate. 
 
3.1.5 Any number of prior lines of systemic therapy for metastatic disease.   
 
3.1.6 ECOG PS of 0 or 1 
 
3.1.7 Prior cancer treatment, including radiotherapy, must be completed at least 
14 days prior to registration and the subject must have recovered from all 
reversible acute toxic effects of the regimen to ≤ grade 1 or to baseline prior 
to initiation of that therapy. Grade 2 or higher exceptions include alopecia, up 
to grade 2 neuropathy or lymphopenia,and other grade 2 AEs or lab values 
not constituting a safety risk in the opinion of the treating physician. This 
criterion does not apply to lab tests outlined in criteria 3.1.10.  
 
3.1.8 No active CNS metastatic disease; subjects with prior definitive treatment of 
their CNS disease by surgical resection, SBRT or WBRT >28 days ago will be 
eligible if asymptomatic and off systemic steroids. 
 
3.1.9 Life expectancy of greater than 12 weeks. 
 
 


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______ 
______ 
______ 
______ 
______ 
______ 
______ 
______ 
______ 
 
3.1.10 Normal organ and marrow function as defined per protocol definitions. 
a.  ANC > 1.5 x 103/μL 
b.  Platelet count > 100 x 103/μL 
c.  Hemoglobin > 9 g/dL 
d.  Total bilirubin < 1.5 x ULN 
e.  Transaminases AST/SGOT and ALT/SGPT ≤ 2.5 x ULN. If patient has 
liver metastases, ≤ 5x ULN.   
f.  Creatinine <  ULN (institutional normal) 
 
3.1.11 Females of childbearing potential must have a negative serum pregnancy test 
within 7 days prior to registration. NOTE: Females are considered of child 
bearing potential unless they are surgically sterile (have undergone a 
hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are 
naturally postmenopausal for at least 12 consecutive months. 
 
3.1.12 Females of childbearing potential must be willing to abstain from 
heterosexual activity or must agree to use adequate contraception (hormonal 
or barrier method) for the duration of study participation and for 90 days 
after discontinuation of study treatment. 
 
3.1.13 Ability of the subject to understand and comply with study procedures for 
the entire length of the study. 
 
3.1.14 Able to swallow ONC201 
 
3.1.15 Be willing to discontinue vitamin and mineral supplements for the duration 
of the study if randomized to receive the methionine restricted diet.  
 
3.2 
Exclusion criteria 
 
3.2.1 No prior therapy with TRAIL receptor agonists 
 
3.2.2 Active infection requiring systemic therapy.  Patients with a known history of 
HIV must have a CD4 count ≥ the institutional lower limit of normal within 
28 days prior to registration. Patients with HIV must also be on a stable anti-
retroviral regimen for ≥ 28 days before registration.  
 
3.2.3 Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future 
use while the mother is being treated on study). 
 
 


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______ 
______ 
______ 
______ 
______ 
______ 
______ 
 
3.2.4 Known additional malignancy that is active and/or progressive requiring 
treatment; exceptions include basal cell or squamous cell skin cancer, in situ 
cervical or bladder cancer, or other cancer for which the subject has been 
disease-free for at least three years. 
 
3.2.5 Treatment with any investigational drug agent < 14 days prior to registration 
or within 5 half-lives of that investigational product, whichever is longer. 
 
3.2.6 Subject who has had major surgery < 14 days prior to registration or has not 
recovered from major side effects of the surgery (tumor biopsy is not 
considered as major surgery). 
 
3.2.7 Known hypersensitivity to any of the excipients of ONC201. 
 
3.2.8 Any impairment of gastrointestinal (GI) function or GI disease that may 
significantly alter the absorption of the study drugs (e.g., ulcerative diseases, 
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small 
bowel resection). 
 
3.2.9 Any concurrent severe and/or uncontrolled medical condition that would, in 
the investigator’s judgment, cause unacceptable safety risks, contraindicate 
subject participation in the clinical study or compromise compliance with the 
protocol (e.g. chronic pancreatitis, chronic active hepatitis, active untreated 
or uncontrolled fungal, bacterial or viral infections, etc.). 
 
3.2.10 Patients who follow a vegan or vegetarian diet  
 
 
_____________________________________________             _____________ 
Investigator Signature 
 
 
 
Date 
 
 
_____________________________________________             _____________ 
Coordinator Signature 
 
 
 
Date 
 
 
4. REGISTRATION PROCEDURES 
 
4.1 
Patient Registration 
Each subject enrolled in the study is to be registered into the UWCCC OnCore 
Database prior to starting protocol treatment.  Research personnel at WON sites 
who enter data into OnCore must have completed human subjects training and 
Health Insurance Portability and Accountability Act (HIPAA) training.  WON site 
research personnel receive training from UWCCC staff on how to enter subject data 
into OnCore.   


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At the time of registration, the following will be required and verified by UWCCC:   
• Copy of required laboratory tests 
• Signed subject consent form 
• HIPAA authorization form 
• Eligibility Screening Worksheet 
To complete the registration process, UWCCC staff will:   
• assign a subject study number 
• register the subject on the study 
• fax or e-mail the subject study number to the participating site 
 
4.2 
General Guidelines 
Following registration, subject must have cycle 1 day 1 within 7 days. Issues that 
would cause treatment delays should be discussed with the Principal Investigator.  
If a subject does not receive protocol therapy or MR diet following registration, the 
subject may be replaced.   
 
5. TREATMENT PLAN 
 
5.1 
Overview of treatment plan 
This is a phase 2 trial in which subjects will receive ONC201 with a MR diet.   
 
5.2 
ONC201 administration  
The study drug, ONC201, will be supplied in capsule form for oral dosing. ONC201 
625 mg (5 tablets of 125 mg each) will be given by mouth on Days 3 and 4 of each 
week for each cycle (administered on days 3,4, 10,11 and 17,18). Treatment will be 
administered primarily on an outpatient basis, but can be administered as an 
inpatient.  A cycle is equal to 21 days. 
 
Subjects should take the dose of ONC201 specified by their physician 2 hours prior or 
2 hours following food or a meal.  If the subject vomits after taking ONC201, they 
should not retake the dose. Missed doses will not be made up, if more than 1 day pass 
from the intended day of administration.  
 
ONC201 should be taken with a glass of water and consumed over as short a time as 
possible. Subjects should swallow the capsules as a whole and not chew them.  Do not 
crush or empty the capsule. If vomiting occurs during the course of treatment, no re-
dosing of the subject is allowed before the next scheduled dose. The occurrence and 
frequency of any vomiting during a treatment cycle must be noted as an adverse 
event. 
 
5.3 
Methionine-restricted diet 
Under the supervision of a registered dietitian (either at the site or from the 
coordinating site) and the site investigator, subjects will receive an individualized 
dietary prescription that incorporates a methionine-free amino acid-modified 


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medical food (Hominex-2, Abbott Nutrition) supplemented with low-methionine 
foods (Table 2). Hominex-2 contains a mixture of L-amino acids but lacks 
methionine. Subjects will be instructed by the dietician in the preparation of 
Hominex-2 shakes to deliver 100% of daily protein requirements (0.8 g/kg/day) 
and 75% of the caloric requirements. The remaining calories will be met with low-
methionine foods, including fruits, vegetables, grains (e.g., specified cereal and 
bread), margarine and cooking oils. Subjects will be provided with a list of foods 
that are low in methionine. Calories will not be restricted. Subjects will be 
encouraged to follow their usual level of physical activity and instructed to maintain 
a daily diet and exercise diary that will be reviewed by the dietitian.  Subjects will 
take the MR diet days 1 through 5 of each week (defined as a 7-day period) while 
taking the ONC201 Subjects may resume a general diet on days 6 and 7 each week.  
Phase I and phase II trials of a methionine-free diet alone or in combination with 
chemotherapy in subjects with metastatic or recurrent solid tumors have confirmed 
the safety and tolerability of methionine deprivation (up to 39 weeks)[24, 25]. 
 
A 24-hour dietary recall exercise [40] will be completed by a dietician prior to 
starting the methionine restricted diet during cycle 1.  The recall and food diaries 
will be analyzed using Food ProcessorP® 
PNutrition and Fitness Software, ESHA 
Research, Salem, OR, USA.  Food intake will be entered in and a report detailing the 
nutritional components of the food taken will be generated and provided back to the 
dietician.  Gender, age, height and weight will be entered for use with the analysis of 
the diet taken.  This dietary analysis will not be provided to the subjects. 
 
Table 2: Methionine-restricted diet shakes 
 
Regimen Description 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Methionine-free 
amino acid-
modified medical 
food 
None 
 
shakes 
Oral 
Per dietician 
recommendation 
Days 1 
through 
5* of 
every 7-
day 
period. 
Cycle = 
21 days 
 
 
 
*Subjects should follow the methionine restricted diet for days 1-5 of every 7-day 
period. However, 1 day of methionine restriction may be skipped in this 5-day 
restriction period if needed to allow flexibility around holidays, vacations, etc. The 
4-5 days of the diet during each 7-day period must be consecutive. The diet must be 


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followed for a minimum of 24 hours prior to the collection of CTCs and for a 
minimum of 24 hours prior to dosing with ONC201.  
 
The subject will be requested to maintain a medication diary of each dose of 
medication. The medication diary (one for ONC201 and for the shakes) and the 
diet/exercise diary will be returned to clinic staff at the end of each cycle of therapy.  
It will not be a deviation if the subject isn’t able to complete the diet/exercise diary.   
Subjects will meet with the dietician on day 1 of cycles 1 and 2 to review the 
diet/exercise diary. Additionally, the dietician will contact the subject during the 
initial week of cycle 1 to assess tolerance of the diet and to address questions the 
subjects may have. Subjects will be able to contact the dietician during normal 
business hours to discuss dietary questions or concerns related to the study.     
 
Recipes for the methionine restricted shakes will be developed to fit the needs of 
individual subjects (taste preferences, energy needs, etc.).  
 
5.4 
Study drug compliance and accountability 
Compliance will be assessed by the investigator and/or study personnel at each 
subject visit at each participating site. Drug diaries will be used by subjects to record 
study medication taken and number of shakes taken.   A drug accountability log at 
each respective site will be used to track the receipt and dispensing of ONC201.   
 
5.5 
Concomitant medications 
 
5.5.1 Allowed concomitant medications 
Medications required to treat AEs, manage cancer symptoms, concurrent diseases 
and supportive care agents, such as pain medications, anti-emetics and anti-
diarrheal medications are allowed. In general, the use of any concomitant 
medication deemed necessary for the care of the subject is permitted in this study, 
except as specifically prohibited below. 
 
The subject must be told to notify their respective participating investigational site 
staff about any new medications she takes after the start of the study treatment. All 
medications (other than study drugs) and significant non-drug therapies (including 
vitamins, herbal medications, physical therapy and blood transfusions) 
administered within 30 days of study entry and during the study must be listed on 
the Concomitant medications/Significant non-drug therapies section of the subject 
record.  
 
Bisphosphonates and Denosumab: 
Bisphosphonates and denosumab are permitted for the treatment of osteoporosis 
and prevention of skeletal related events for subjects with bone metastases.  
 
Hematopoietic growth factors: 
Hematopoietic growth factors may be used according to ASCO guidelines.  
 


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5.5.2 Prohibited concomitant medications 
To date, no prohibited concomitant medications have been identified.  
 
5.6 
Supportive care Guidelines 
Supportive measures including analgesics, blood transfusions, anti-microbials and 
hematopoietic colony stimulating factors for treatment of cytopenias are permitted.  
 
Nausea/vomiting: 
Subjects with treatment-related nausea should be treated initially with a 
phenothiazine (prochlorperazine – 10 mg every 8 hours orally as needed). If this is 
inadequate, a benzodiazepine or ondansetron 4-8 mg orally should be added until 
acute nausea is controlled or toxicity is limiting. 
 
After acute nausea has resolved, consideration should be given to initiation of 
prophylactic antiemetic therapy. If nausea recurs despite reasonable medical 
intervention (as outlined above), dose reduction will be needed as described. 
 
Diarrhea: 
Diarrhea should be managed with loperamide: 4 mg at first onset, then 2 mg every 
2-4 hours until diarrhea is controlled (maximum = 16 mg loperamide per day). 
 
Neutropenia and Neutropenic fever and other cytopenias: 
Subjects with neutropenic fever or infection should be evaluated promptly and 
treated with IV antibiotic therapy or therapeutic colony-stimulating factors as 
appropriate following the ASCO guidelines. Packed red blood cell and platelet 
transfusion should be administered as clinically indicated. 
 
6. TOXICITIES AND DOSE DELAYS/DOSE MODIFICATIONS  
The NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 
(v5.0) will be used to grade adverse events. 
 
Subjects enrolled in this study will be evaluated clinically and with standard 
laboratory tests before and at regular intervals during their participation in this 
study as specified in Study Calendar. 
 
Subjects will be evaluated for adverse events (all grades), serious adverse events, 
and adverse events requiring study drug interruption or discontinuation as 
specified in Study Calendar. 
 
6.1 
Adjustments to Methionine-Restricted Diet 
The dietician may modify the volume and concentration of shakes to increase 
tolerability. 
 
Best supportive care should be used for side effects attributable to the methionine 
restricted diet/medical food.  
 


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Subjects who discontinue the methionine restricted diet may continue ONC201. 
 
Table 3: Dose adjustment rules for Adverse Events (in addition to Table 5 
below)  
 
CTCAE Grade 
Management for the methionine-restricted diet  
 
Weight loss 
Grade 2 or higher  
 Methionine restricted diet must be discontinued. 
Homocysteine levels 
(to be captured as:  Metabolism and Nutrition disorders – other, specify) 
Grade 2 or higher 
Methionine restricted diet must be discontinued 
 
 
Normal homocysteine levels are 5-15 micro mol/L. 
For purposes of this study homocysteine levels will graded per the table below: 
 
Table 4: 
 
Grade 1 
Grade 2 
Grade 3 
Homocysteine 
Level 
>15 - <30 micro 
mol/L 
> 30 - < 100 micro 
mol/L 
> 100 micro mol/L 
 
 
6.2 
ONC201 Dose Adjustments  
The descriptions and grading scales found in the revised NCI CTCAE v5.0 will be 
utilized for dose delays and dose modifications  
 
Criteria for disrupting treatment, dose modification, or discontinuation are listed in 
Table 5.  
 
For subjects who do not tolerate the dosing schedule, dose adjustments are 
permitted in order to allow the subject to continue the study treatment. 
 
Below are dose modifications (Table 5) for adverse events that are at least possibly, 
probably or definitely attributable to study drug, including: nausea, vomiting, 
diarrhea, neutropenia, and thrombocytopenia. If a patient experiences other adverse 


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events, or several adverse events and there are conflicting recommendations based 
on grade, the investigator will use the recommended dose adjustment that reduces 
the dose. Dose modifications will be made based on an adverse event that occurs any 
time during a cycle.  
 
Table 5:  Dose adjustment rules for Adverse Events (AEs), including nausea, 
diarrhea, neutropenia, thrombocytopenia, and other AEs. Alopecia does not require 
dose adjustments. Lymphopenia does not require dose adjustment unless clinically 
significant per treating physician.   
 
CTCAE Grade 
Management/Next Dose for ONC201 
≤ Grade 2 
No change in dose 
Grade 3 or 4* 
Hold until < Grade 2.  If resolved to < Grade 2 within 7 days, 
resume dosing at 500mg if previously dosed at 625mg or 
resume dosing at 375mg if previously dosed at 500mg.** 
(See monitoring guidelines below) 
*Patients requiring a delay of ONC201 for >3 weeks must go off protocol therapy. 
Patients with grade 3 neutropenia associated with fever must also discontinue ONC201. 
**Patients requiring > two dose reductions must discontinue ONC201. 
 
 
Participants who experience an adverse event that requires a treatment delay or 
dose reduction should be monitored with appropriate laboratory testing or other 
clinical evaluation at least weekly until resolution; if the adverse event does not 
resolve within 3 weeks, the interval for testing may be reduced after consultation 
and written approval by the study PI.  
 
6.3 
Protocol therapy discontinuation 
In addition to discontinuation from therapy related to toxicities as outlined in 
section 6.1, a subject will also be discontinued from protocol therapy and followed 
up per protocol under the following circumstances: 
• 
Documented disease progression 
• 
Discontinue methionine restricted diet for weight loss grade 2 or higher  
• 
The treating physician thinks a change of therapy would be in the best 
interest of the subject 
• 
The subject requests to discontinue protocol therapy, whether due to 
unacceptable toxicity or for other reasons 
o If a subject decides to prematurely discontinue protocol therapy (“refuses 
treatment”), the subject should be asked if he or she may still be 


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contacted for further scheduled study assessments. The outcome of that 
discussion should be documented in the medical records.  
• 
A female subject becomes pregnant 
• 
If protocol therapy is interrupted for >21 days. 
 
Subjects will be removed from protocol therapy, and the site investigator notified, 
when any of the criteria listed above apply. The reason for discontinuation of 
protocol therapy will be documented on the eCRF in OnCore. 
 
Subjects who discontinue protocol therapy will be followed every 3 months for 2 
years after the end of treatment visit.  Survival status and anti-cancer therapy (to 
include only first cancer directed therapy after study) will be collected from review 
of medical records or via telephone follow up.  
 
If subjects discontinue study treatment prior to disease progression, scans during 
follow-up will be completed per standard of care, but RECIST measurements must 
be completed until disease progression or start of new anti-cancer therapy.  
 
6.4 
Evaluable subject 
Evaluable for response: Any subject who receives at least 80% of ONC201 doses 
during the first two cycles of treatment (i.e., at least 9 doses of ONC201) and have at 
least one disease re-evaluation will be evaluable for response. Dose reductions will 
not be included in this 80%, just number total doses taken will be included.   
 
Evaluable for toxicity: Any subject who receives at least one dose of treatment on 
this protocol should be evaluable for toxicity. Safety will be assessed by NCI CTCAE 
v5.0.  
 
6.5 
Protocol discontinuation 
If a subject decides to withdraw from the study (and not just from protocol therapy) 
all efforts should be made to complete and report study assessments as thoroughly 
as possible until the date of withdrawal. The treating investigator should contact the 
subject or a responsible relative by telephone to establish as completely as possible 
the reason for the study withdrawal. A complete final evaluation at the time of the 
subject’s study withdrawal should be made with an explanation of why the subject 
is withdrawing from the study. If the reason for removal of a subject from the study 
is an adverse event, it will be recorded on the eCRF. 
 
6.6 
Criteria for Early Trial Termination 
Early trial termination will occur if any of the following are met: 
  
a. Incidence or severity of adverse drug reactions in this or other studies 
using this drug that indicates a potential health hazard to subjects. 
b. Plans to modify or discontinue the study drug (ONC201), such that the 
original study drug is no longer provided by the sponsor. 


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c. Financial support of the study is withdrawn such that protocol activities 
can no longer be conducted. 
d. If enrollment or subject withdrawal will impact the ability of the study to 
meet the stated objectives. 
e. UWCCC Data Safety Monitoring Committee recommendation based on 
review of required study documents (outlined in section 12). 
 
 


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7. STUDY CALENDARS AND EVALUATIONS 
 
 
 
 
 
Cycle = 21 days 
Screening 
Cycle 
1 
Cycle 
2 
Odd # 
cycles 
Begin 
at 
Cycle 3 
Even # 
cycles 
Begin 
at 
Cycle 4 
End of 
Treatment 
Long-
term 
Follow-
up 
-28 days 
Day 1 
+/- 2 
days 
Day 1 
+/- 2 
days 
Day 1 
+/- 2 
days 
Day 1 
+/- 2 
days 
35 days from 
last dose of 
study 
treatment 
+/- 5 days 
 
Every 3 
months 
(+/- 7 
days) for 
2 years 
from 
EOT 
Informed 
consent 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Diagnosis and 
staging 
X 
 
 
 
 
 
 
Physical Exam 
X 
X13 
X 
X 
X 
X 
 
Vital signs, wt, 
waist 
circumferenceP8
P, 
ECOG 
performance 
status 
X 
X13 
X 
X 
X 
X 
 
AEs & 
concomitant 
medications, 
drug diary 
reviewP7 
X 
X 
X 
X 
X 
X 
 
 
LABORATORY ASSESSMENTS 
CBC with 
differential 
(minimum to 
include: Hgb, 
WBC, Plt, ANC) 
X 
X13 
X 
X 
X 
X 
 
CMP9 
X 
X13 
X 
X 
X 
X 
 
Blood for 
metabolic 
indicesP1  
 
 
X 
X 
 
X 
X 
 
Homocysteine/
cysteine11 
 
X 
 
X 
X 
 


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Cycle = 21 days 
Screening 
Cycle 
1 
Cycle 
2 
Odd # 
cycles 
Begin 
at 
Cycle 3 
Even # 
cycles 
Begin 
at 
Cycle 4 
End of 
Treatment 
Long-
term 
Follow-
up 
-28 days 
Day 1 
+/- 2 
days 
Day 1 
+/- 2 
days 
Day 1 
+/- 2 
days 
Day 1 
+/- 2 
days 
35 days from 
last dose of 
study 
treatment 
+/- 5 days 
 
Every 3 
months 
(+/- 7 
days) for 
2 years 
from 
EOT 
Pregnancy test 
(serum)P6 
- 7 days 
XP6 
 
 
 
 
 
Diet/Exercise 
Diary  
 
X 
X 
X 
X 
 
 
24 Hour 
Dietary Recall 
Form  
 
X 
 
 
 
 
 
 
DISEASE ASSESSMENTS 
CT chest, CT or 
MRI of  
abdomen and 
pelvisP10 
X 
 
 
 
XP10 
 
X 
MRI brain 
XP3 
 
 
 
 
 
 
Bone scan 
XP3 
 
 
 
XP3 
 
 
 
TREATMENT EXPOSURE 
ONC201 
 
Days 3 
and 4, 
weekly 
Days 3 
and 4, 
weekly  
Days 3 
and 4, 
weekly  
Days 3 
and 4, 
weekly  
 
 
MR diet  
 
Days 1 
-5 
weekly 
Days 1 
- 5 
weekly 
Days 1 -
5 
weekly 
Days 1 -
5 
weekly 
 
 
 
CORRELATIVE STUDIES (SPECIMEN COLLECTION) 
Archival 
Tissue12 
X 
 
 
 
 
 
 
Circulating 
tumor cells 
 
XP5 
XP5 
 
 
XP5 
 
Plasma 
methionine & 
methionine 
metabolites  
 
XP2 
XP2 
 
XP2 
XP2 
 
 
FOLLOW-UP 
Survival 
 
 
 
 
 
 
X 
 


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(1) Blood will be taken to assess metabolic indices at baseline, cycle 2 day 5, then 
day 5 of every other cycle, and at end of treatment. Indices are fasting: glucose, 
insulin, IGF-1, and leptin levels. If necessary, these labs may be drawn as early as 
day 2, but prefer to be as close to day 5 as possible without going over. 
(2) Blood will be taken to assess plasma methionine levels at baseline, cycle 2 day 5, 
then day 5 of every other cycle, and at end of treatment. Subjects must be fasting. 
If necessary, these labs may be drawn as early as day 2, but prefer to be as close 
to day 5 as possible without going over.  
(3) If clinically indicated. 
(4) Optional biopsy prior to study entry.  
(5) Blood for circulating tumor cells will be taken at baseline, day 5 of cycle 2, and at 
end of treatment. If necessary, these labs may be drawn as early as day 2, but 
prefer to be as close to day 5 as possible without going over. 
(6) For women of childbearing potential. To be completed within 7 days of 
randomization. Must be repeated at cycle 1 day 1 if not completed in previous 7 
days.  
(7) Subjects whose treatment is interrupted or permanently discontinued due to an 
adverse event (including lab values) should be followed per section 11.1.1. 
(8) Waist circumference, optional if not possible due to site limitations.  Not 
required at screening.  
(9) CMP to include sodium, potassium, chloride, carbon dioxide, glucose, BUN, 
creatinine, calcium, albumin, total protein, alkaline phosphatase, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin.  
(10) CT chest with or without contrast and CT with contrast or MRI of 
Abdomen/Pelvis to be completed during screening and ≤ 7 days prior to every 
third cycle starting at cycle four (approximately every 9 weeks; e.g. cycles 4, 7, 
10, etc.). If subjects discontinue study treatment prior to disease progression, 
scans during follow-up will be completed per standard of care, but RECIST 
measurements must be completed until disease progression or start of new 
anti-cancer therapy.  
(11) Homocysteine/cysteine level at:  baseline and every 3 cycles while on study 
(C1, C4, C7, etc.) and at end of treatment. 
(12) One block or 10 unstained slides. 
(13) labs/physical exam/ECOG PS does not need to be repeated if done within 7   
         days prior to C1D1 
 
8. BIOSPECIMEN STUDIES AND PROCEDURES 
 
8.1 
Tumor tissue 
Subjects will be consented for use of archived tissue for analysis.  To determine the 
effects of dietary MR on tumor expression of TRAIL receptors, mRNA levels of TRAIL-
R1 and TRAIL-R2 will be determined by real-time PCR.P 
PIn addition, quantitative 
immunofluorescence of cell surface TRAIL-R1 and TRAIL-R2 expression in breast 
tumor cells identified by cytokeratin expression will be determined by automated 
quantitative analysis (AQUA) of digitally captured images.  These studies will be 
performed in the UW Carbone Cancer Center Translational Research Initiatives in 


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Pathology (TRIP) Lab under the supervision of our co-investigator Dr. Andreas Friedl. 
We will also determine the effects of treatment on the expression of the cancer stem 
cell markers CD44 and CD24 by immunohistochemistry. 
 
8.2 
Circulating tumor cells (CTCs) 
If funding is secured, CTCs will be enumerated and evaluated for TRAIL expression.   
We hypothesize that treatment with MR diet will increase the expression of TRAIL 
receptors on CTCs and reduce the number of CTCs. 
 
Time points: CTCs will be collected at baseline, on day 5 of cycle 2, and at end of 
treatment. If the CTC sample is not collected at baseline, the remaining samples 
should not be collected.  Missed CTC samples will not be considered a protocol 
deviation. 
 
Please note that CTC samples must be shipped Monday –Thursdays only.  Samples 
must be shipped to arrive at the Lang lab by Fridays by 12:00 p.m. CTC samples will 
be drawn only at those sites identified by the coordinating site as having adequate 
resources (shipping and funding) to provide the samples. 
 
Sample Requirements: 
Please refer to the Study Procedures Manual for sample collection, processing, 
labeling, and shipping instructions. 
 
8.3 
Plasma methionine and methionine metabolites 
Blood will be collected after an overnight fast before dietary methionine restriction 
at baseline, cycle 2 day 5, then day 5 of every other cycle, and at end of treatment. 
Plasma will be stored at -80º C for analyses of methionine and its metabolites. Plasma 
concentrations of methionine and methionine metabolites [5’-methythioadenosine 
(MTA), 
homocysteine 
(Hcy), 
S-adenosylhomocysteine 
(SAH), 
and 
S-
adenosylmethionine (SAM)] will be determined by high-throughput targeted LC-MS 
assay to measure methionine and these metabolites.  Using these methods, we 
demonstrated that TNBC cells grown in 0% methionine have robust reductions in 
methionine levels and modest reductions in some methionine metabolites. Plasma 
methionine levels are predicted to serve as an index of dietary compliance. 
 
Blood samples (one 6 mL heparinized green top tube per timepoint) will be drawn 
and processed at the CRU, stored in Professor Vincent Cryns’ lab at -80º C, and sent in 
batches to the Laboratory of Professor Josh Coon in the UW Department of Chemistry.  
All samples provided will be identified by UWCCC study number, unique subject 
number and date and time sample was collected.  Outside sites should refer to the 
Study Procedures Manual for collection, processing, labeling, and shipping 
instructions. 
 
8.4 
Confidentiality of biospecimens 
Samples that are collected will be identified by the study number, the subject’s study 
number assigned at the time of registration to the trial and the date and time of 


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sample collection. Any material issued to collaborating researchers will be 
anonymized and only identified by the subject’s unique sequence number, study 
number, date of collection.  
 
9. CRITERIA FOR DISEASE EVALUATION 
The following sections describe the recommended method to track disease response 
for solid tumor trials as per the Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1.[41] 
 
9.1 
Measurable Disease 
Measurable disease is defined as the presence of at least one measurable lesion. 
Measurable lesions are defined as those that can be accurately measured in at least 
one dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 
mm with CT scan, or >10 mm with calipers by clinical exam. All tumor 
measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
 
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. 
 
9.2 
Non-measurable Lesions 
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 subject, these are preferred for selection as target lesions. 
 
9.3 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and 
recorded and measured at baseline. Target lesions should be selected on the basis of 
their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible 
repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest 
lesion which can be measured reproducibly should be selected. A sum of the 


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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. 
 
9.4 
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. 
 
9.5 
Evaluation of Target Lesions 
NOTE: In addition to the information below, also see section 4.3.2 in the 
international criteria proposed by the Response Evaluation Criteria in Solid Tumors 
(RECIST) Committee, version 1.1 (Eur J Cancer 45;2009:228-247) for special notes 
on the assessment of target lesions. 
 
Complete 
Response (CR) 
Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction 
in short axis to <10 mm. 
Partial 
Response (PR) 
At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum 
diameters 
Progressive 
Disease (PD) 
At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on 
study (this includes the baseline sum if that is the smallest 
on study). In addition to the relative increase of 20%, the 
sum must also demonstrate an absolute increase of at least 
5 mm. (Note: the appearance of one or more new lesions is 
also considered progressions). 
Stable Disease 
(SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
sum diameters while on study 
 
9.6 
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 


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subject 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 investigator at the respective participating site should prevail in such 
circumstances, and the progression status should be confirmed at a later time by the 
UW investigator. 
 
9.7 
Evaluation of Best Overall Response 
 
Target Lesions 
Non-Target Lesions 
New 
Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/ Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD/ or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all 
evaluated 
Non-PD 
No 
Non-evaluable 
PD 
Any 
Yes or No 
PD 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Subjects with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
classified as having “symptomatic deterioration”. Every effort should be made to 
document the objective progression even after discontinuation of treatment. 
 


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In some circumstances it may be difficult to distinguish residual disease from 
normal tissue. When the evaluation of complete response depends on this 
determination, it is recommended that the residual lesion be investigated (fine 
needle aspirate/biopsy) to confirm the complete response status. 
 
Confirmatory Measurement/Duration of Response 
 
To be assigned a status of PR or CR, changes in tumor measurements must be 
confirmed by repeat assessments that should be performed 4-6 weeks after the 
criteria for response are first met. In the case of SD, follow-up measurements must 
have met the SD criteria at least once after study entry at a minimum interval of 6 
weeks (see below). 
 
Overall Response 
First time point 
Overall Response 
Subsequent time 
point 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD/PD/PR* 
CR 
SD 
SD provided minimum criteria for 
SD duration met, otherwise, PD 
CR 
PD 
SD provided minimum criteria for 
SD duration met, otherwise, PD 
CR 
NE 
SD provided minimum criteria for 
SD duration met, otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for 
SD duration met, otherwise, PD 
PR 
NE 
SD provided minimum criteria for 
SD duration met, otherwise, NE 
NE 
NE 
NE 
* If a CR is truly met at first time point, then any disease seen at a subsequent time point, 
even disease meeting PR criteria relative to baseline, makes the disease PD at that point 
(since disease must have reappeared after CR). Best response would depend on whether 
minimum duration for SD was met. However, sometimes ‘CR’ may be claimed when 
subsequent scans suggest small lesions were likely still present and in fact the subject had 
PR, not CR at the first time point. Under these circumstances, the original CR should be 
changed to PR and the best response is PR. 
 


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9.8 
Definitions for Response Evaluation – RECIST 1.1 
 
9.8.1 First Documentation of Response 
The time between initiation of therapy and first documentation of PR or CR. 
 
9.8.2 Confirmation of Response 
To be assigned a status of complete or partial response, changes in tumor 
measurements must be confirmed by repeat assessments performed no less than 
four weeks after the criteria for response are first met. 
 
9.8.3 Duration of Response 
Duration of overall response—the period measured from the time that 
measurement criteria are met for complete or partial response (whichever status is 
recorded first) until the date that recurrent or progressive disease is objectively 
documented (taking as reference for progressive disease the smallest 
measurements recorded since treatment started). 
 
9.8.4 Duration of Overall Complete Response 
The period measured from the time that measurement criteria are met for complete 
response until the first date that recurrent disease is objectively documented. 
 
9.8.5 Objective Response Rate  
The objective response rate is the proportion of all subjects with confirmed PR or 
CR according to RECIST 1.1, from the start of treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the start of treatment). 
 
9.8.6 Progression-Free Survival 
A measurement from the date of treatment initiation until the criteria for disease 
progression is met as defined by RECIST 1.1 or death occurs. Subjects who have not 
progressed will be right-censored at the date of the last disease evaluation. 
 
9.8.7 Overall Survival 
Overall survival is defined by the date of treatment initiation to date of death from 
any cause. 
 
10. DRUG INFORMATION 
 
10.1 
ONC201 
 
10.1.1 Drug Product Supply and Inventory 
Handling: Qualified personnel, familiar with procedures that minimize undue 
exposure to themselves and the environment, should undertake the preparation, 
handling, and safe disposal of the chemotherapeutic agent in a self-contained and 
protective environment. 
 


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Availability: ONC201 is provided by Oncoceutics Inc. 
 
Accountability: The investigator, or a responsible party designated by the 
investigator, should maintain a careful record of the inventory and disposition of the 
agent using the NCI Drug Accountability Record Form (DARF) or another comparable 
drug accountability form.  (See the NCI Investigator’s Handbook for Procedures for 
Drug Accountability and Storage). 
 
Destruction and Return: Unused supplies of the agent should be returned to the 
Sponsor within 60 days of the completion of the study. Unused supplies of the agent 
may also be destroyed on-site upon completion of the study, after accountability has 
been audited by the Sponsor or designated representative. 
 
Dispensing:  
ONC201 must be dispensed only from official study sites and to eligible subjects 
under the supervision of the site investigator. ONC201 should be stored in a secure 
area according to local regulations. It is the responsibility of the site investigator to 
ensure that study drug is only dispensed to subjects.  
 
10.1.2 Pharmaceutical information 
The study drug ONC201 is provided as 125 mg free base (approximately 150 mg of 
dihydrochloride), 
with 
or 
without 
microcrystalline 
cellulose, 
filled 
into 
hydroxypropyl methylcellulose (HPMC) capsule shells.  Alternative strengths may be 
manufactured.  
 
The ONC201 drug product capsules are intended for oral administration. The product 
is stored in a multi-dose container. The capsules are packaged in high-density 
polyethylene (HDPE) white opaque bottles, closed with an induction seal and capped 
with a white ribbed SecuRx® polypropylene (PPE) cap.  
 
The capsules are to be stored in the original closed container at room temperature 
(15 to 30°C). 
 
The study drug bottle label bears the following information. If alternative strengths 
are manufactured, the dosage on the label will be inserted in place of ‘125 mg’.  
 


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Drug Substance Description 
 
 
Form: ONC201 will be provided as hydroxypropyl methylcellulose (HPMC) capsules 
filled with the active ingredient (ONC201 dihydrochloride), intended for oral 
administration. The ONC201•2HCl drug substance is a white to off-white solid. The 
drug product will be packaged as 25 capsules per bottle. The capsules are filled into 
30cc high-density polyethylene (HDPE) white opaque bottles with induction seal and 
28mm white ribbed SecuRx polypropylene (PPE) cap.  
 
Storage and Stability: Based on the current stability data at 40°C/75%RH room 
temperature (25°C/60%RH) will be used for the drug product storage. Drug product 
stability studies found no change after 1 month at 40°C/75%RH when stored with or 
without desiccant. Similarly no changes have been observed when stored a room 
temperature for 1 year. Clinical trial batches will be produced without desiccant. No 
shelf-life has been established for this product at this point. However, representative 


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clinical trial batches have been placed on stability. Any batches that are out of 
specifications will be removed from the trial.  
 
For the ONC201 drug substance, stability results show little to no change in assay, 
impurities or appearance. The only changes observed under the accelerated 
conditions (40°C/75%RH) where a slight increase in moisture content was observed, 
from 1.2% at time 0, to 6.5% at 2 months, and to 6.2% at 3 months. The moisture 
content plateaued at approximately the monohydrate. The increase in moisture 
content did not result in increased impurity levels or decreased potency. These 
results suggest robust stability of the drug substance when stored at room 
temperature and accelerated conditions. 
 
10.2 
Hominex-2 shakes 
Subjects will receive an individualized dietary prescription that incorporates a 
methionine-free amino acid-modified medical food (Hominex-2, Abbott Nutrition) 
supplemented with low-methionine foods. Hominex-2 is an amino acid modified 
medical food that contains a mixture of L-amino acids but lacks methionine. It is 
used to provide nutritional support for individuals with vitamin B6-nonresponsive 
homocystinuria or hypermethioninemia. Additional information is available at: 
32Thttp://abbottnutrition.com/brands/products/hominex-232T 
 
11. ADVERSE EVENTS 
 
11.1 
Definitions 
 
11.1.1 Adverse Event (AE) 
An AE is any untoward medical occurrence whether or not considered related to the 
study drug that appears to change in intensity during the course of the study. AEs 
will be graded using the NCI CTCAE v5. The following are examples of AEs:  
• Unintended or unfavorable sign or symptom 
• A disease temporally associated with participation in the protocol 
• An intercurrent illness or injury that impairs the well-being of the subject 
 
Hospitalization for elective surgery or routine clinical procedures that are not the 
result of an AE (e.g., surgical insertion of central line) should not be recorded as an 
AE. 
 
All subjects who discontinue study treatment, including those who refuse to return 
for a final visit, should be contacted for safety evaluations (i.e., assessment of AEs 
and/or SAEs, concomitant medications) within 30 days after the last dose of study 
drugs. Subjects whose treatment is interrupted or permanently discontinued due to 
an adverse event should be followed at least weekly for four weeks via telephone or 
in-person visit per physician discretion. Subsequently they should be followed at a 
minimum of 4-week intervals until resolution or stabilization of the event. If subject 
discontinues study treatment due to an abnormal lab value, appropriate laboratory 


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testing should be repeated per physician discretion (minimum ≤ once per week) 
until resolution to ≤ grade 1 or the treating physician determines the value is not 
expected to improve.   
 
11.1.2 Serious Adverse Event (SAE) 
An SAE is an adverse event that: 
• Results in death. NOTE: Death due to disease progression should not be 
reported as a SAE, unless it is attributable by the site investigator to the 
study drug(s) 
• Is life-threatening (defined as an event in which the subject was at risk of 
death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe) 
• Requires inpatient hospitalization for >24 hours or prolongation of existing 
hospitalization. NOTE: Hospitalization for anticipated or protocol specified 
procedures such as administration of chemotherapy, central line insertion, 
metastasis interventional therapy, resection of primary tumor, or elective 
surgery, will not be considered serious adverse events. Hospitalization for 
routine treatment or monitoring of the studied indication, not associated 
with any deterioration in condition (i.e. to perform study related 
assessments), elective or pre-planned treatment for a pre-existing condition 
that is unrelated to the indication under study and has not worsened since 
signing the informed consent, social reasons and respite care in the absence 
of any deterioration in the subject’s general condition or treatment on an 
emergency outpatient basis that does not result in hospital admission and 
involves an event not fulfilling any of the definitions of a SAE given above is 
not a serious adverse event. 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly or birth defect 
• Is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based 
upon appropriate medical and scientific judgment, may jeopardize the 
subject or may require intervention (e.g., medical, surgical) to prevent one of 
the other serious outcomes listed in the definition above). Examples of such 
events include, but are not limited to, intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
not resulting in hospitalization; or the development of drug dependency or 
drug abuse. 
 
11.1.3 Unexpected Adverse Event 
For this study, an AE is considered unexpected when it varies in nature, intensity or 
frequency from information provided in the current IB, package insert, or when it is 
not included in the informed consent document as a potential risk. Unexpected also 
refers to AEs that are mentioned in the IB as occurring with a class of drugs or are 
anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation. 


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11.1.4 Relatedness 
AEs will be categorized according to the likelihood that they are related to the study 
drug(s). Specifically, they will be categorized using the following terms:  
Unrelated 
The Adverse Event is not related to the drug(s)  
Unlikely 
The Adverse Event is doubtfully related to the 
drug(s)  
Possible 
The Adverse Event may be related to the drug(s)  
Probable 
The Adverse Event is likely related to the drug(s)  
Definite 
The Adverse Event is clearly related to the drug(s)  
11.2 
Procedures for Recording and Reporting Adverse Events 
 
11.2.1 Adverse Events 
• AEs will be recorded from time of informed consent until 30 days after 
discontinuation of study drug(s). 
• AEs will be recorded regardless of whether or not they are considered 
related to the study drug(s). 
• All AEs will be recorded in the subject’s medical record, AE log in the subject 
research chart, and on the appropriate study specific eCRF form within 
OnCore. 
• All AEs considered related to study drug(s) will be followed until resolution 
to ≤ Grade 1 or baseline, deemed clinically insignificant, and/or until a new 
anti-cancer treatment starts, whichever occurs first. 
• All WON sites should follow the AE reporting procedures outlined in the 
WON Operations Manual in addition to following the non-UW specific 
procedures outlined above 
 
11.2.2 Reporting of Pregnancy: 
• Pregnancy will be reported from time of first study drug until 30 days after 
discontinuation of either study drug(s). 
• Pregnancy will be reported to UW as an SAE within 1 business day of 
discovery of the event. 
• Pregnancy follow-up will be reported to UW as follow-up to the initial SAE.  
 
The pregnancy will be followed to determine outcome, including spontaneous or 
voluntary termination, details of the birth, and the presence or absence of any birth 
defects, congenital abnormalities, or maternal and/or newborn complications. 
 
Each local site investigator is responsible for informing the IRB and/or other local 
regulatory bodies of the event as per local requirements. 
 


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11.2.3 Serious Adverse Events (SAEs) 
 
11.2.3.1 
Site Requirements for Reporting SAEs  
• SAEs will be reported from time of on-study until 30 days after 
discontinuation of either study drug(s). 
• Any SAEs experienced after this 30-day period will only be reported if the 
investigator suspects the event is at least possibly related to the study 
treatment. 
• SAEs will be reported to Oncoceutics within 24 hours of discovery of the 
event. Reporting to the UWCCC will occur per the timelines listed in table 5. 
• SAEs include events related and unrelated to the study drug(s). 
• All SAEs will be recorded in the subject’s medical record and on the 
appropriate study specific eCRF form within OnCore. 
• All SAEs, regardless of relation to study drug, will be followed until 
resolution to ≤ Grade 1 or baseline and/or deemed clinically insignificant 
and/or until a new anti-cancer treatment starts, whichever occurs first. 
• Recurrent episodes, complications, or progression of the initial SAE will be 
reported as follow-up to the original episode within 24 hours of the 
investigator receiving the follow-up information. 
 
Please see section 12.4 for SAE reporting requirements. 
 
12. DATA AND SAFETY MONITORING PLAN 
 
12.1 
Oversight and Monitoring Plan 
The UWCCC Data and Safety Monitoring Committee (DSMC) is responsible for the 
regular review and monitoring of all ongoing clinical research in the UWCCC. A 
summary of DSMC activities are as follows: 
• Reviews all clinical trials conducted at the UWCCC for subject safety, protocol 
compliance, and data integrity. 
• Reviews all Serious Adverse Events (SAE) requiring expedited reporting, as 
defined in the protocol, for all clinical trials conducted at the UWCCC, and studies 
conducted at external sites for which the UWCCC acts as an oversight body. 
• Reviews reports generated through the UWCCC DSMS elements (Internal Audits, 
Quality Assurance Reviews, Response Reviews, Compliance Reviews, and 
Protocol Summary Reports). 
• Notifies the protocol Principal Investigator of DSMC decisions and, if applicable, 
any requirements for corrective action related to data or safety issues. 
• Works in conjunction with the UW Health Sciences IRB in the review of relevant 
safety information as well as protocol deviations, non-compliance, and 
unanticipated problems reported by the UWCCC research staff. 


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• Ensures that notification of SAEs requiring expedited reporting is provided to 
external sites participating in multi-institutional clinical trials coordinated by 
the UWCCC. 
12.2 
Monitoring and Reporting Guidelines 
UWCCC quality assurance and monitoring activities are determined by study 
sponsorship and risk level of the protocol as determined by the PRMC. All protocols 
(including Intervention Trials, Non-Intervention Trials, Behavioral and Nutritional 
Studies, and trials conducted under a Training Grant) are evaluated by the PRMC at 
the time of committee review. UWCC monitoring requirements for this trial are as 
follows: 
 
12.2.1 Intermediate Monitoring 
Protocols subject to intermediate monitoring generally include UW Institutional 
Phase I/II and Phase II Trials. These protocols undergo review of subject safety at 
regularly scheduled DOT meetings where the results of each subject’s treatment are 
discussed and the discussion is documented in the DOT meeting minutes. These 
discussions may include the number of subjects enrolled, significant toxicities, dose 
adjustments, and responses observed. Protocol Summary Reports are submitted on 
a semi-annual basis by the study team for review by the DSMC. 
 
12.3 
Review and Oversight Requirements 
 
12.3.1 Serious Adverse Event – Reported within 24 Hours 
Serious Adverse Events requiring reporting within 24 hours (as described in the 
protocol) must also be reported to the Data and Safety Monitoring Committee 
(DSMC) Chair via an email to saenotify@uwcarbone.wisc.edu within one business 
day. The OnCore SAE Details Report must be submitted along with other report 
materials as appropriate (NCI AdEERS form or FDA Medwatch Form #3500 and/or 
any other documentation available at that time of initial reporting). The DSMC Chair 
will review the information and determine if immediate action is required. Within 5 
calendar days, all available subsequent SAE documentation must be submitted 
electronically along with a 24-hour follow-up SAE Details Report and a completed 
UWCCC SAE Routing Form to saenotify@uwcarbone.wisc.edu. All information is 
entered and tracked in the UWCCC database. 
 
The Principal Investigator notifies all investigators involved with the study at the 
UWCCC, the IRB, the sponsor, and the funding agency and provides documentation 
of these notifications to the DSMC. If the SAE occurs on a clinical trial in which the 
UW PI serves as the sponsor-investigator, the PI reviews the event to determine 
whether the SAE requires reporting to the FDA and other participating 
investigators. For a multiple-institutional clinical trial the PI is responsible for 
ensuring SAEs are reported to the FDA as well as to all participating investigators. 
 


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12.3.2 Serious Adverse Event – Reported within 10 Days 
Serious Adverse Events requiring reporting within 10 days (as described in the 
protocol) must also be reported to the DSMC Chair via an email to 
saenotify@uwcarbone.wisc.edu. The OnCore SAE Details Report must be submitted 
along with other report materials as appropriate (NCI AdEERS form or FDA 
Medwatch Form #3500 and/or any other documentation available at the time of 
initial reporting). The DSMC Chair will review the information and determine if 
further action is required. All information is entered and tracked in the UWCCC 
database.  
 
The Principal Investigator notifies all investigators involved with the study at the 
UWCCC, the IRB, the sponsor, and the funding agency and provides documentation 
of these notifications to the DSMC.  
 
If the SAE occurs on a clinical trial in which the UW PI serves as the sponsor 
investigator, the PI reviews the event to determine whether the SAE requires 
reporting to the FDA and other participating investigators.  
 
For a multiple-institutional clinical trial the PI is responsible for ensuring SAEs are 
reported to the FDA as well as to all participating investigators.  
 
12.3.3 Sponsor-Investigator Responsibilities for SAE Review 
In the event the UWCCC Principal Investigator is acting as the Sponsor-Investigator 
(i.e., the PI holds the IND), the PI assumes responsibilities of the study sponsor in 
accordance with FDA 21 CFR 312.32. In this capacity, the UWCCC PI reviews all 
reports of serious adverse events occurring on the study at the UWCCC and 
participating external sites and makes a determination of 1) suspectedness (i.e., 
whether there is a reasonable possibility that the drug caused the AE); and 2) 
unexpectedness (the event is not listed in the Investigator’s Brochure or is not 
listed at the specificity or severity that has been observed) in the context of this 
study. SAE with suspected causality to study drug and deemed unexpected are 
reported as IND Safety Reports by the UWCCC PI to the FDA, all participating 
investigators on the study, and the external global sponsor (if applicable) within 15 
calendar days. All fatal or life-threatening SAE that are unexpected and have 
suspected causality to the study drug will be reported by the UWCCC PI to the FDA, 
all participating investigators on the study, and the external global sponsor (if 
applicable) within 7 calendar days. 
 
Refer to Section 12.5 for UWCCC PI instructions for reporting to the FDA. 
 
12.3.4 Study Progress Review 
Protocol Summary Reports (PSR) are required to be submitted to the DSMC in the 
timeframe determined by the risk level of the study (quarterly; semi-annually; or 
annually). The PSR provides a cumulative report of SAEs, as well as instances of 
noncompliance, protocol deviations, and unanticipated problems, toxicities and 


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responses that have occurred on the protocol in the timeframe specified. PSRs for 
those protocols scheduled for review are reviewed at each DSMC meeting. 
 
Protocol Summary Reports enable DSMC committee members to assess whether 
significant benefits or risks are occurring that would warrant study suspension or 
closure. This information is evaluated by the DSMC in conjunction with other 
reports of quality assurance activities (e.g., reports from Internal Audits, Quality 
Assurance Reviews) occurring since the prior review of the protocol by the DSMC. 
Additionally, the DSMC requires the study team to submit external DSMB or DSMC 
reports, external monitoring findings for industry-sponsored studies, and any other 
pertinent study-related information 
 
In the event that there is significant risk warranting study suspension or closure, the 
DSMC will notify the PI of the DSMC findings and ensure the appropriate action is 
taken for the protocol (e.g., suspension or closure). The DSMC ensures that the PI 
reports any temporary or permanent suspension of a clinical trial to the sponsor 
(e.g., NCI Program Director, Industry Sponsor Medical Monitor, Cooperative Group 
Study Chair) and other appropriate agencies. DSMC findings and requirements for 
follow-up action are submitted to the CRC. 
 
12.4 
Expedited Reporting of Serious Adverse Events 
Depending on the nature, severity, and attribution of the serious adverse event an 
SAE report will be phoned in, submitted in writing, or both according to Table 5 
below. All serious adverse events must also be reported to the UWCCC Data and 
Safety Monitoring Committee (DSMC) Chair. Serious adverse events must also be 
reported to the UW IRB per their guidance (https://kb.wisc.edu/hsirbs/18324#UP), 
and any sponsor/funding agency not already included in the list. 
 
Determine the reporting time line for the SAE in question by using the following 
table. Then refer to sections A and B below if the SAE occurred at the UWCCC or 
sections C and D if the SAE occurred at a WON Site. 
 
Table 5. Phase 1 and Early Phase 2 Studies: Expedited Reporting 
Requirements for Adverse Events that Occur on Studies under an IND/IDE 
within 30 Days of the Last Administration of the Investigational 
Agent/Intervention P1,2 
 
FDA Reporting Requirements for Serious Adverse Events (21 CRF Part 312) 
NOTE: Investigators MUST immediately report to the University of Wisconsin 
Carbone Cancer Center and any other parties outlined in the protocol ANY Serious 
Adverse Events, whether or not they are considered related to the investigational 
agent(s)/intervention (21 CFR 312.64). 
An adverse event is considered serious if it results in ANY of the following outcomes: 
1) Death. 


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2) A life-threatening adverse event (the patient was at risk of death at the time of 
the event; it does not refer to an event that hypothetically might have caused 
death if it were more severe). 
3) An adverse event that results in inpatient hospitalization or prolongation of 
existing hospitalization for ≥ 24 hours. 
4) A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
5) A congenital anomaly/birth defect. 
6) Important Medical Events (IME) that may not result in death, be life 
threatening, or require hospitalization may be considered serious when, 
based upon 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 (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately 
reported to the UWCCC within the timeframes detailed in the table below: 
Hospitalization 
Grade 1 and Grade 2 
Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
hospitalization  
≥ 24 hrs 
10 Calendar Days 
24 Hour; 5 Calendar Days 
Not resulting in 
Hospitalization 
≥ 24 hrs 
Not required 
Expedited AE reporting timelines are defined as: 
• 
24-Hour; 5 Calendar Days – The AE must initially be reported within 24 
hours of learning of the AE, followed by a complete expedited report within 5 
calendar days of the initial 24-hour report. 
• 
10 Calendar Days – A complete expedited report on the AE must be 
submitted within 10 calendar days of learning of the AE 
P1 
PSerious adverse events that occur more than 30 days after the last administration of 
investigational agent/intervention and have an attribution of possible, probable, or 
definite require reporting as follows: 
Expedited 24-hour notification followed by complete report within 5 calendar 
days for: 
• 
All Grade 3, 4, and 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
P2
P For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 
radioactive half-lives, rounded UP to the nearest whole day, after the 
agent/intervention was last administered.  Footnote “1” above applies after this 
reporting period. 
 


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12.4.1 SAE Requiring 24 hour Reporting Occurs at UWCCC: 
 
12.4.1.1 
Report to the UWCCC: 
Reference the SAE SOP (Standard Operating Procedure) and the SAE Reporting 
Workflow for DOTs on the UWCCC website 
(https://kb.wisc.edu/uwccc/internal/page.php?id=54655) for specific instructions 
on how and what to report to the UWCCC for [24] hour initial and follow-up reports. 
A follow-up report is required to be submitted within 5 calendar days of the 
initial [24] hour report. 
 
For this protocol, the following UWCCC entities are required to be notified: 
a. UWCCC DSMC: saenotify@uwcarbone.wisc.edu32T 
b. UWCCC PI: Kari Wisinski, MD 
c. UWCCC Breast Clinical Team Manager: Tamara Koehn 
d. Any other appropriate parties listed on the SAE Routing Form 
12.4.1.2 
Report to the Sponsor: 
Serious adverse events (whether or not related to study drugs) will also be reported 
to Oncoceutics or designee within 24 hours from the time the Investigator first 
becomes aware of the SAE.  After the initial SAE notification to Oncoceutics or 
designee, follow-up SAE information will be submitted each time that important 
follow-up information (e.g., diagnosis, outcome, causality assessment, results of 
specific investigations) becomes available. 
 
Any serious adverse event, or follow up to a serious adverse event, including death 
due to any cause other than progression of the cancer under study that occurs to 
any subject from the time of initiation of therapy through 30 days following 
cessation of treatment, or the initiation of new anti-cancer therapy, whichever is 
earlier, must be reported to Oncoceutics. This applies whether or not the event is 
related to ONC201.  
 
If serious medical occurrences, including death, occur outside of the safety follow-up 
window established by the protocol and are reported to or observed by the 
Investigator to be related to the administration of the investigational product, it is 
the Investigator’s responsibility to report this occurrence to Oncoceutics or 
designee within 24 hours from the time site personnel become aware of the 
occurrence. 
 
In addition to SAEs, the following reportable events must also be submitted to 
Oncoceutics within 24 hours from the time the Investigator first becomes aware of 
them: 
• Exposure during Pregnancy or Breastfeeding (even if not associated with an 
adverse event) 


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• Occupational exposure (even if not associated with an adverse event) 
Reports should be made to Oncoceutics using FDA form 3500A (MedWatch) 
or the UWCCC SAE form may be used.  
Contact information for submission of reportable events to 
Oncoceutics: 
 
Fax: 1-844-245-7650 
Specifying: 
• PROTOCOL Number 
• SUBJECT Number 
• SITE Number/PI Name 
• SAE/ONSET DATE 
 
12.4.1.3 
Report to the IRB: 
Consult the UW Health Sciences website (32Thttps://kb.wisc.edu/hsirbs/18324#UP32T) 
for reporting guidelines. 
 
12.4.2 SAE Requiring 10 Day Reporting Occurs at UWCCC: 
 
12.4.2.1 
Report to the UWCCC: 
Reference the SAE SOP and the SAE Reporting Workflow for DOTs on the UWCCC 
website (32Thttps://kb.wisc.edu/uwccc/internal/page.php?id=32T54655) for specific 
instructions on how and what to report to the UWCCC for [10] day reports.  
For this protocol, the following entities are required to be notified: 
a. UWCCC DSMC: 32Tsaenotify@uwcarbone.wisc.edu32T 
b. Any appropriate parties listed on SAE Routing form 
12.4.2.2 
Report to the Sponsor: 
See section 12.4.1.2 - SAEs must be reported to Oncoceutics or designee within 24 
hours.  
 
12.4.2.3 
Report to the IRB: 
Consult the UW Health Sciences IRB website 
(32Thttps://kb.wisc.edu/hsirbs/18324#UP32T) for reporting guidelines. 
 
12.4.3 SAE Requiring 24 Hour Reporting Occurs at a WON Site: 
 
12.4.3.1 
Report to the UWCCC: 
Reference the SAE SOP and the SAE Reporting Workflow for 1SP, JC, and other 
Affiliates on the UWCCC website 
(https://kb.wisc.edu/uwccc/internal/page.php?id=54655) for specific instructions 
on how and what to report to the UWCCC for [24]  hour initial and follow-up 


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reports.  A follow-up report is required to be submitted within 5 calendar days of 
the initial [24] hour report.    
  
Send the OnCore SAE details report and any supporting, applicable documentation 
to: saenotify@uwcarbone.wisc.edu   
  
NOTE:  After a WON site has submitted the [24] hour SAE follow-up report, the 
report is triaged initially to the UW Principal Investigator or Study Chair, the DOT 
Program Manager, the Affiliate Coordinator, and the DSMC Chair for review.  The 
Principal Investigator is then responsible for ensuring the SAE is reported to 
the FDA, the global sponsor (if applicable), the UW IRB, and any other entity 
requiring notification, in accordance each entities’ reporting requirements. 
 
12.4.3.2 
Report to the Sponsor: 
The UW Principal Investigator is responsible for ensuring the SAE is reported to the 
sponsor, Oncoceutics.  
12.4.3.3 
Report to the IRB: 
WON sites should follow their own local IRB reporting guidelines for SAE 
submission. The UW PI is responsible for the submission of the SAE to the UW 
Health Sciences IRBs for any site for which the UW serves as the IRB of record. 
Additionally, the UW PI is responsible for the submission of the SAE to the UW 
Health Sciences IRB for any site if it meets the definition of unanticipated problem.  
 
12.4.4 SAE Requiring 10 Day Reporting Occurs at a WON site: 
 
12.4.4.1 
Report to the UWCCC: 
Reference the SAE SOP and the SAE Reporting Workflow for 1SP, JC, and other 
Affiliates on the UWCCC website 
(https://kb.wisc.edu/uwccc/internal/page.php?id=54655) for specific instructions 
on how and what to report to the UWCCC for [10] day reports.  
  
Send the OnCore SAE details report and any supporting, applicable documentation 
to: saenotify@uwcarbone.wisc.edu   
  
NOTE:  After a WON site has submitted the [10] day SAE follow-up report, the report 
is triaged initially to the UW Principal Investigator or Study Chair, the DOT Program 
Manager, the Affiliate Coordinator, and the DSMC Chair for review.  The Principal 
Investigator is then responsible for ensuring the SAE is reported to the FDA, 
the global sponsor (if applicable), the UW IRB, and any other entity requiring 
notification, in accordance each entities’ reporting requirements. 
 
12.4.4.2 
Report to the Sponsor: 
The UW Principal Investigator is responsible for ensuring the SAE is reported to the 
sponsor, Oncoceutics.  
 


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12.4.4.3 
Report to the IRB:  
WON sites should follow their local IRB reporting guidelines for SAE submission. 
The UW PI is responsible for the submission of the SAE to the UW Health Sciences 
IRBs for any site for which the UW serves as the IRB of record.  Additionally, the UW 
PI is responsible for the submission of the SAE to the UW Health Sciences IRB for 
any site if it meets the definition of an unanticipated problem.  
 
12.5 
Other Reporting Requirements 
 
Reporting to the FDA 
Serious Adverse Events occurring on studies on which a UW PI is acting as sponsor-
investigator must be reported to the FDA as determined by the completion of the 
UW Sponsor-Investigator Determination Form for FDA Reporting of Safety Events.  
Mandatory and voluntary reporting guidelines and instructions are outlined on the 
FDA website: 32Thttp://www.fda.gov/Safety/MedWatch/HowToReport/default.htm32T 
13. STATISTICAL METHODS 
 
13.1 
Study design 
We propose a phase II clinical trial, non-randomized, single arm, open label study of 
the combination of ONC201 with of ONC201 with intermittent MR diet in patients 
with metastatic TNBC. 
Accrual is competitive such that each site can contribute any number of subjects 
until the study maximum of 34is reached.   
 
The primary objective is to evaluate the rate of patients with  objective response to 
ONC201 with a MR diet. 
 
13.2 
Sample size and accrual 
The primary objective is to evaluate efficacy of ONC-201 with dietary MR in 
metastatic TNBC. The study is designed as a single-arm phase II trial.  The primary 
endpoint is ORR.  Secondary endpoints include CBR at 4 months, PFS, OS, safety, 
metabolic indices and CTC TRAIL-receptor expression. The null hypothesis is that 
the probability of overall response is no more than 0.1, i.e., HR0R: p≤0.1, and the 
alternative hypothesis is HR1R: p≥0.25.  
 
In this single arm study, a Simon's two stage design will be utilized.  The null 
hypothesis that the true ORR is 0.1 will be tested against a one-sided alternative.  
The study will be powered to detect an ORR of 25% with the combination of 
ONC201 with a methionine-restricted diet, using a power of 80% and a type I error 
rate of 10%. The first stage sample size will be 13. After testing the combination on 
13 subjects in the first stage, the trial will be terminated if 1 or fewer subjects 
respond. If the trial goes on to the second stage, a total of 34 subjects will be studied 
(i.e. additional 21 subjects will be recruited). If the total number responding or 
having ORR is less than or equal to 5, the combination of ONC201 with a 
methionine-restricted diet will be rejected. 


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 The estimated total sample size for the study is 34 subjects. 
 
One subject was enrolled to the ONC201 +MR diet prior to changing the dosing 
schedule.  This subject will be replaced for efficacy analysis, but will be considered 
part of the safety analysis. 
 
13.3 
Analysis datasets 
 
Population 
Definition 
Evaluable for Safety 
This will comprise all subjects who receive at least 
one dose of trial drug and either undergo at least 
one post-baseline assessment or die before any 
evaluation. 
Evaluable for Efficacy 
 
This will comprise all subjects who receive at 
least 80% of ONC201 + MR diet doses during the 
first two cycles of treatment (i.e., at least 9 doses 
of ONC201) and have at least one disease re-
evaluation. Subjects who are not evaluable for 
response, however, will be replaced. 
 
13.4 
Assessment of safety 
Any subject who receives at least one dose of treatment on this protocol should be 
evaluable for toxicity. Safety will be assessed by NCI CTCAE v5.0.  
 
13.5 
Demographic and baseline characteristics 
Descriptive statistics will be provided to summarize demographics and baseline 
characteristics parameters. Categorical data will be summarized as frequency and 
its corresponding percentage. For continuous data, frequency (n), mean, standard 
deviation, median (as appropriate), minimum, and maximum will be provided for 
each of the parameters. 
 
13.6 
Assessment of efficacy 
All subjects who have received at least 80% of ONC201 + MR diet during the first 
two cycles of treatment and have their disease re-evaluated will be evaluable for 
assessment of objective response.   
 
13.7 
Data analysis plan 
 
13.7.1 Analysis plans for primary objective 
ORR will be estimated according to RECIST 1.1, by dividing the total number of 
responders (complete plus partial responses plus CR or PR) or (CR or PR), 
respectively, by number of subjects with measurable disease and the exact 95% 
confidence interval will be provided. In evaluating ORR, subjects with missing data 
will be considered non-responders. 


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13.7.2 Analysis plans for secondary objectives 
 
PFS and OS will be summarized using Kaplan-Meier estimates of the median 
survival times.  Point estimates as well as 95 % confidence intervals will be 
provided.  PFS based on degree of AR expression by IHC (AR >0% vs. AR ≥10%) will 
be compared using the log-rank test. Additional exploratory analyses using 
proportional hazards model to control for other factors may be performed. 
 
CBR at 4 months will be estimated according to RECIST 1.1, by dividing the total 
number of responders (complete plus partial responses plus CR or PR or stable 
disease (SD)), by number of subjects with measurable disease and the exact 95% 
confidence interval will be provided. In evaluating CBR, subjects with missing data 
will be considered non-responders. Also, duration of response (DOR) will be 
measured using Kaplan-Meier methodology. A 95% confidence interval will be 
provided for the median duration of response. Subjects who do not relapse will be 
censored at the day of the last objective tumor assessment. In evaluating response 
duration, non-responders will be excluded from analysis.  
 
In addition, correlation analyses will be performed to assess the expression of 
TRAIL receptor in CTCs prior, during and upon progression of disease. Formal 
statistical tests will be performed based on the outcome types and the biomarker 
quantification. 
 
Safety and Tolerability by NCI CTCAE v5.0 will be assessed by frequency tables. Also, 
metabolic indices in patients with metastatic TNBC treated with ONC-201 and a 
methionine-restricted diet will be assessed by frequency tables and descriptive 
statistics. 
 
13.7.3 Analysis plans for exploratory objectives 
Kaplan-Meier methodology will be used to summarize time-to-event data, such as 
time to development of brain metastases or worsening of brain metastases in 
patients with metastatic TNBC treated with ONC-201 with a methionine-restricted 
diet. Graphical techniques (e.g., waterfall plots, KM curves, line plots) may be used 
when such methods are appropriate and informative. 
 
 
14. TRIAL MANAGEMENT 
 
14.1 
Data Quality Oversight Activities 
Remote validation of OnCore data will be completed on a continual basis throughout 
the life cycle of the study. A summary report (QC Report) of these checks together 
with any queries resulting from manual review of the eCRFs will be generated for 
each site and transmitted to the site and the site monitor. Corrections will be made 
by the study site personnel. 
 


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There will be at least one routine visit per site per year for sites that have accrued. 
Additional for cause visits may occur as necessary. Source documents will be 
reviewed for verification of agreement with data entered into OnCore. It is 
important for the site investigator and their relevant personnel to be available for a 
sufficient amount of time during the monitoring visits or audit, if applicable.  
 
The trial site may also be subject to quality assurance audit by Oncoceutics or its 
designee as well as inspection by appropriate regulatory agencies. 
 
14.2 
Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) 
and the Food and Drug Administration Amendments Act (FDAAA), the sponsor-
investigator of the trial is solely responsible for determining whether the trial and 
its results are subject to the requirements for submission to the Clinical Trials Data 
Bank, http://www.clinicaltrials.gov. The sponsor-will register the trial and post the 
results on clinicaltrials.gov. Information posted will allow subjects to identify 
potentially appropriate trials for their disease conditions and pursue participation 
by calling a central contact number for further information on appropriate trial 
locations and study site contact information. 
 
15. DATA HANDLING AND RECORD KEEPING 
 
15.1 
Data Management 
UWCCC will serve as the Clinical Research Office for this trial. Data will be collected 
through the web-based clinical research platform, OnCore, a system compliant with 
Good Clinical Practices and Federal Rules and Regulations. UWCCC personnel will 
coordinate and manage data for quality control assurance and integrity. All data will 
be collected and entered into OnCoreP 
Pby study site personnel from participating 
institutions.  The Study Procedures Manual will outline EDC entry guidelines. 
 
15.2 
Case Report Forms and Submission 
Generally, clinical data will be electronically captured in OnCoreP 
Pand correlative 
results will be captured in OnCoreP 
Por other secure database(s). If procedures on the 
study calendar are performed for standard of care, at minimum, that data will be 
captured in the source document. Select standard of care data will also be captured 
in OnCore, according to study-specific objectives. Please see the Data and Safety 
Oversight Process (DSOP) guidelines for further details.  
 
The completed dataset is housed at UWCCC and is the sole property of the 
University of Wisconsin. It should not be made available in any form to third parties, 
except for authorized representatives of appropriate Health/Regulatory Authorities, 
without written permission from the sponsor-investigator.  
 
15.3 
Record Retention 
To enable evaluations and/or audits from Health Authorities, the site investigator 
agrees to keep records, including the identity of all subjects (sufficient information 


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to link records; e.g., hospital records), all original signed informed consent forms, 
copies of all source documents, and detailed records of drug disposition. All source 
documents are to remain in the subject’s file and retained by the site investigator in 
compliance with local and federal regulations. No records will be destroyed until 
UWCCC confirms destruction is permitted. 
 
15.4 
Confidentiality 
There is a slight risk of loss of confidentiality of subject information. All records 
identifying the subjects will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available. Information 
collected will be maintained on secure, password protected electronic systems. 
Paper files that contain personal information will be kept in locked and secure 
locations only accessible to the study site personnel.  
 
Subjects will be informed in writing that some organizations, including the sponsor-
investigator and his/her research associates, Oncoceutics, Inc., IRB, or government 
agencies, like the FDA, may inspect their medical records to verify the information 
collected, and that all personal information made available for inspection will be 
handled in strictest confidence and in accordance with local data protection laws. 
 
If the results of the study are published, the subjects’ identity will remain 
confidential. 
 
15.5 
WON Site Oversight 
The UWCCC Affiliate Office serves as the coordinating center for WON. Coordinating 
center responsibilities are shared between the Affiliate Coordinator and UWCCC 
Breast/Melanoma DOT. A detailed description of coordinating center 
responsibilities, as well as other WON processes and procedures, is provided in the 
WON Manual available on the UWCCC website 
(32Thttps://kb.wisc.edu/uwccc/internal/page.php?id=4287832T). 
 
Regular communication between the UWCCC Affiliate Office and WON sites ensures 
that all participating parties are notified of protocol changes, informed consent 
document revisions, action letters, study status changes, reportable events/Serious 
Adverse Events (as necessary), and any other applicable information. This 
communication is accomplished through regular email updates and conference calls. 
 
16. ETHICS 
 
16.1 
Institutional Review Board (IRB) Approval 
The final study protocol and the final version of the informed consent form must be 
approved in writing by the UW IRB. The approved final study protocol and informed 
consent form will then be provided by the Affiliate Coordinator each participating 
site to be submitted to each site’s local IRB of record. 
 


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The UW PI and participating site investigators are responsible for informing their 
respective IRBs of any amendment to the protocol in accordance with local 
requirements. In addition, each respective IRB must approve all advertising used to 
recruit subjects for the study as local regulations require. The protocol must be re-
approved by each respective IRB, as local regulations require.  
 
Progress reports and notifications of adverse events will be provided to each 
respective IRB according to local regulations and guidelines. 
 
16.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles originating from 
the Declaration of Helsinki. Conduct of the study will be in compliance with ICH 
Good Clinical Practice, and with all applicable federal (including 21 CFR parts 56 & 
50), state, or local laws. 
 
16.3 
Informed Consent Process 
The site investigator will ensure the subject is given full and adequate oral and 
written information about the nature, purpose, possible risks and benefits of the 
study. Subjects must also be notified they are free to discontinue from the study at 
any time. The subject should be given the opportunity to ask questions and allowed 
time to consider the information provided. 
 
The subject’s signed and dated informed consent must be obtained before 
conducting any procedure specifically for the study. The site investigator must store 
the original, signed informed consent form. A copy of the signed informed consent 
form must be given to the subject. 
 
 
 


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