Clinical trial NCT04159896
Conditions: Castration Levels of Testosterone Castration-Resistant Prostate Carcinoma Metastatic Prostate Carcinoma Prostate Carcinoma Metastatic in the Bone Stage IVB Prostate Cancer AJCC v8
Sponsor: Barbara Ann Karmanos Cancer Institute
Start date: 2019-11-13; Completion date: 2022-03-01
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies the side effects of ESK981 and nivolumab and to see how well they work for the treatment of castration resistant prostate cancer that has spread to other places in the body (metastatic). ESK981 is an investigational drug that targets several important pathways that are believed to play a role in the spread of cancer. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. This study is being done to see if giving ESK981 and nivolumab together works better in treating metastatic castration resistant prostate cancer compared to usual treatments.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the prostate specific antigen (PSA) \>= 50% response rate (PSA50) from baseline using the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria to pan-VEGFR/TIE2 tyrosine kinase inhibitor CEP-11981 (ESK981) plus nivolumab in men with metastatic castration resistant prostate cancer (mCRPC) who have progressed on enzalutamide (an oral androgen-receptor inhibitor) and/or abiraterone acetate (an androgen synthesis inhibitor) and chemotherapy (docetaxel and/or cabazitaxel).

II. To assess the safety and tolerability of ESK981 plus nivolumab.

SECONDARY OBJECTIVES:

I. To determine the time to PSA response (TTPR) in patients with mCRPC. II. To determine the duration of PSA response (PRD) in patients with mCRPC. III. To determine PSA progression rates as defined by the PCWG3 criteria. IV. To determine PSA progression free survival (PPFS) as defined by the PCWG3 criteria.

CORRELATIVE/EXPLORATORY/TERTIARY OBJECTIVE:

I. To assess exploratory biomarkers from blood and tumor biopsies.

OUTLINE:

Patients receive ESK981 orally (PO) once daily (QD) for 5 consecutive days per week, followed by a 2-day break. Patients also receive nivolumab intravenously (IV) on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 5 years.

Arms: arm 1: Patients receive ESK981 PO QD for 5 consecutive days per week, followed by a 2-day break. Patients also receive nivolumab IV on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Pan-VEGFR/TIE2 Tyrosine Kinase Inhibitor CEP-11981 intervention 2: Nivolumab
Intervention descriptions: intervention 1: Given PO intervention 2: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
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Phase II Multi-center Trial of ESK981 in Combination with Nivolumab in Patients with Metastatic 
Castrate Resistant Prostate Cancer 
 
Prostate Cancer Clinical Trials Consortium, LLC (PCCTC) 
 
PCCTC #: c19-240 
IND #: 144476 
 
Karmanos Cancer Institute/Esanik Therapeutics/Bristol-Myers Squibb 
 
 
Principal Investigator: 
Elisabeth I. Heath, MD FACP 
Karmanos Cancer Institute 
4100 John R 
Detroit, MI 48201 
Phone: 313-576-8717 
Fax: 313-576-8767 
Email: heathe@karmanos.org 
 
Co-Investigator: 
 
Frank Cackowski, MD, PhD 
Karmanos Cancer Institute 
4100 John R 
Detroit, MI 48201 
Phone: 313-576-8321 
Fax: 313-576-8767 
Email: cackowskif@karmanos.org 
 
  
 
Biostatistician: 
Lance K. Heilbrun, PhD 
Karmanos Cancer Institute 
87 East Canfield 
Detroit, MI 48201 
Phone: 313-576-8652 
Fax: 313-576-8656 
Email: Heilbrun@karmanos.org  
 
 
 
 
 
Coordinating Center: 
Karmanos Cancer Institute 
 
Participating Sites:  
University of Michigan 
 
Site Principal 
Investigator: 
Ajjai Alva, MD  
Hematology/Oncology University of Michigan 7316 Cancer Center  
1500 E. Medical Center Drive Ann Arbor, MI 48109  
Phone: (734) 936-0091  
Fax: (734) 615-2719  
Email: ajjai@umich.edu 
 
 
Study Drugs: 
ESK981 (other names: CEP-11981) – Investigational  
Nivolumab (Opdivo) - Standard of care 
 


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Protocol Date: 
 April 18, 2019, April 29, 2019, June 17, 2019, January 22, 2020, June 24, 
2020
CONFIDENTIALITY STATEMENT 
The information in this document is provided to you as an investigator, potential investigator, 
consultant, or contractor, for review by you, your staff, and the appropriate Institutional Review 
Board or Ethics Committee. By accepting this document, you agree that the information 
contained herein will not be disclosed to others without written authorization from the lead 
site/sponsor, except to the extent necessary to initiate the study or conduct study-related 
activities. 


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Table of Contents 
Glossary of Abbreviations and Acronyms………………………………………………………... 5 
Study Schema………………………………………………………………………………………….. 
7 
Study Synopsis………………………………………………………………………………………… 8 
1.  Background and Rationale…………………………………………………………………...... 
12 
 
1.1 Disease Background………………………………………………………………………… 12 
 
1.2 Treatment Background……………………………………………………………………… 13 
 
1.3 Rationale………………………………………………………………………………………. 21 
 
1.4 Rationale for Correlative Studies…………………………………………………………. 22 
2.  Objectives………………………………………………………………………………............... 
23 
 
2.1 Primary Objective…………………………………………………………….……………... 
23 
 
2.2 Secondary Objectives………………………………….……………………..................... 
23 
 
2.3 Correlative/Exploratory/Tertiary Objectives……………………...………………….… 
23 
3.  Patient Selection………………………………………………………………………………… 
23 
 
3.1 Inclusion Criteria……………………………………………………………………….…… 
23 
 
3.2 Exclusion Criteria……………………………………………………………………….….. 
25 
 
3.3 Screen Failures………………………………………………………………………….….. 
26 
4. 
Enrollment Plan andSubject Registration……………..…………………………….……... 
26 
5. 
Treatment/Intervention Plan…………………………………………..………………………. 
27 
 
5.1 Removing Subjects from the Protocol………………………………....….................... 
27 
 
5.2 Definition of Compliance with Self-Adjusted Oral Agent ESK981…....................... 
28 
6. 
Therapeutic Agent……………………………………………………………….………..…..... 
28 
 
6.1 ESK981 Drug Supply and Return………………………….………….………………….. 
28 
 6.2 Drug Accountability………………………………………….…………..……………….… 
29 
 
6.3 Pharmacokinetics…………………………………………….……….…….………………. 
29 
 
6.4 Supply, Preparation, Storage and Administration……….………….………………… 
34 
 
6.5 Dose Modifications for Adverse Events…………………….…………………….……… 34 
 
6.6 Management of Expected Toxicities……………………………….……………………. 
36 
 
6.7 Concomitant Medications and Supportive Care…………………..…………………... 
38 
7. 
Safety Evaluation……….…………………………………………………………….…………. 
39 
 
7.1 Definitions…………………………………………………………….……………………… 
39 
 
7.2 Recording and Grading of Adverse Events…………………….……………………… 
41 
 
7.3 Adverse Events Reporting………………………………………….…………………….. 
42 
 
7.4 Serious Adverse Event Reporting……………………………...……….……..…….….. 
44 
 
7.5 Procedure in Case of Pregnancy………………………………..……....................…… 
45 
8. 
Criteria for Outcome Assessment/Therapeutic Response………………..……….…….. 
45 
 
8.1 Outcome Assessment................................................................................................. 
45 
 
8.2 Therapeutic Response………………………………………………………………..……. 
46 
 
8.3 Response Criteria………………………………………………………………..…....……. 
48 
 
8.4 Confirmatory Measures/Duration of Response……………………..…………………. 
51 
9. 
Correlatives……………………………………………………………..…………………..……. 
53 
10. Data Reporting and Regulatory Requirements……….……………………………....…… 
54 
 
10.1 Data Collection and Management…………………………………..………………..… 
54 
 
10.2 Data Safety and Monitoring Board……...………………………..……………..……... 
55 
11. Statistical Considerations…….…………………………………………..………..………..... 
55 
 
11.1 Objectives………………………..………………………………………….……………… 
55 
 
11.2 Endpoints……………………..…………………………………………………………….. 
56 
 
11.3 Design………………..……………………………………………………………………… 
56 
 
11.4 Analysis………………………………………………………………………….………….. 
58 
 
11.5 Statistical Monitoring Plan for Toxicity………………………………………………… 58 
 
11.6 Expected Accrual Rate, Accrual Duration, and Total Study Duration….………... 
59 
12. Regulation and Protection of Human Subjects…………….………………………….…… 
59 


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12.1 Roles and Responsibilities………………………………………………..…................. 
59 
 
12.2 Ethical Considerations……………………………….…………………………………… 
59 
 
12.3 Written Informed Consent……………………………………………………………….. 
59 
 
12.4 Protection of Privacy………………………………………………………...…………… 
60 
 
12.5 Terminating or Modifying the Study…………………………………………………… 
60 
13. Quality Assurance and Audits………………………………………………………….….…. 
60 
14. References…………………………………………………………………………….…....……. 
61 
Appendix A: Performance Status Criteria……………………………………………..…..…….. 
63 
Appendix B: Medications with the potential for Drug-Drug Interaction………..…………... 
64 
Appendix C: Study Calendar…………………………………………………………..…………… 
65 
Appendix D: Pill Diary……………………………………………………………………………….. 
66 
Appendix E: DSM Report form…………………………………………………………………….. 
67 
 


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Glossary of Abbreviations and Acronyms 
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ALC 
Absolute Lymphocyte Count 
AR 
Androgen Receptor 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulation 
CMP 
Comprehensive Metabolic Panel 
CR 
Complete Response 
CRF 
Case Report Form 
CRPC 
Castration Resistant Prostate Cancer 
CSPC 
Castrate Sensitive Prostate Cancer 
CT 
Computed Tomography 
CTC 
Circulating Tumor Cell 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTSU 
Clinical Trials Support Unit 
DSMC 
Data and Safety Monitoring Committee 
ECOG 
Eastern Cooperative Oncology Group 
ESK981 
Study Drug 
FDA 
Food and Drug Administration 
FGFR1 
Fibroblast Growth Factor 1 
H&P 
History & Physical Exam 
HIPAA 
Health Insurance Portability and Accountability Act 
HRPP 
Human Research Protections Program 
IC50 
50% Inhibition of Activity 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat Population 
IV (or iv) 
Intravenously 
LD 
Longest Diameter 
mCRPC 
Metastatic Castration Resistant Prostate Cancer 
MTD 
Maximum Tolerated Dose 
MTKI 
Multi-Tyrosine Kinase Inhibitor 
NCI 
National Cancer Institute 
NLCB 
No Longer Clinically Benefitting 
NOD 
Non-Obese Diabetic 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PBMCs 
Peripheral Blood Mononuclear Cells 
PCCTC 
Prostate Cancer Clinical Trials Consortium 


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PCWG3 
Prostate Cancer Working Group 3 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PI 
Principal Investigator 
PO 
By mouth/orally 
PR 
Partial Response 
PRC 
Protocol Review Committee 
PSA 
Prostate Specific Antigen 
PSA50 
PSA ≥ 50% Response Rate 
RCC 
Renal Cell Carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SCID 
Severe Combined Immunodeficiency 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SPGT 
Serum Glutamic Pyruvic Transaminase 
TIE1, TIE2 Tyrosine Kinase with Immunoglobulin-like and EGF-like 
TMZ 
Temozolomide 
UaP 
Unanticipated Problem 
ULN 
Upper Limit of Normal 
VEGF 
Vascular Endothelial Growth Factor 
WBC 
White Blood Cells 
 
 
 


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Study Schema 
Combination Therapy: 
 
ESK981 160 mg PO D1-5 
off 2d / q week for 28 d cycles plus 
Nivolumab 480 mg IV q 4 wks 
Imaging q 2 cycles x 3, then q 3 
cycles 
Until Progression / Intolerance 
Eligible Metastatic Prostate Cancer 
Run-in Cohort:  
 
ESK981 160 mg PO D1-5 
off 2d / q week for 28 d cycles plus 
Nivolumab 480 mg IV q 4 wks 


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Study Synopsis 
Title 
Phase 2 Multi-center Trial Of ESK981 in combination with Nivolumab In 
Patients With Metastatic Castration Resistant Prostate Cancer 
Phase 
II 
Methodology 
Single arm with run-in phase 
Study Duration 
30-37 months (26-33 months for accrual, and 4 months of additional follow-up 
and biomarker determinations.) 
Study Center(s) 
Multi-Center: 2 sites total including Karmanos Cancer Institute/Wayne State 
University and University of Michigan 
Objectives 
Primary Objectives: 
To determine the PSA ≥ 50% response rate (PSA50) from baseline using the 
PCWG3 criteria to ESK981 plus nivolumab  in men with mCRPC who have 
progressed on enzalutamide (an oral androgen-receptor inhibitor) and/or 
abiraterone acetate (an androgen synthesis inhibitor) and progression on 
chemotherapy (docetaxel and/or cabazitaxel). 
 
To assess the safety and tolerability of ESK981 plus nivolumab.   
Secondary Objectives 
To determine the time to PSA response (TTPR)  in patients with mCRPC 
To determine the duration of PSA response (PRD)  in patients with 
mCRPC 
To determine PSA progression rates as defined by the PCWG3 criteria.  
To determine PSA progression free survival (PPFS) as defined by the 
PCWG3 criteria. 
Exploratory Objectives 
To assess exploratory biomarkers from blood and tumor biopsies. Examples 
of these may include, but are not limited to: whole exome sequencing, 
capture whole transcriptome analysis, AR and ARv7 analysis, ki-67,
apoptosis, etc. 
Number of Subjects Up to 49 patients 


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Inclusion Criteria 
Males 18 years of age and above at time of informed consent 
Eastern Cooperative Group (ECOG) performance status ≤1 
Recovery to baseline or ≤ Grade 1 CTCAE v.5 from toxicities related to any prior 
treatments, unless AE(s) are clinically non-significant and/or stable on supportive 
therapy 
Adequate organ and marrow function as outlined in Table 3 on page 24  
Patient must have progressive disease while receiving androgen deprivation therapy 
(ADT) defined by any one of the following as per the PCWG3 criteria for PSA, 
measureable or non-measurable (bone) disease and must have a castrate serum 
testosterone level (i.e. ≤ 50 ng/dL) at screening:  
• 
PSA: At least two consecutive rises in serum PSA, obtained at a minimum of 1-
week intervals, with the final value ≥ 2.0 ng/mL. 
• 
Measurable disease (by RECIST 1.1): ≥20% increase (with an absolute 
increase of at least 5mm) in the sum of diameters of all measurable lesions or 
the development of one or more new lesions. The short axis of a target lymph 
node must be more than 15mm to be assessed for change in size. 
• 
Non-measurable (bone) disease: The appearance of two or more new areas of 
uptake on bone scan consistent with metastatic disease compared to previous 
imaging during castration therapy. The increased uptake of pre-existing lesions 
on bone scan will not be taken to constitute progression, and ambiguous results 
must be confirmed by other imaging modalities (e.g. X-ray, CT or MRI). 
Histologic 
diagnosis 
of 
adenocarcinoma 
of 
the 
prostate 
with 
metastatic(M1)disease as documented by appropriate medical imaging (i.e. CT-Scan, 
PET scan or bone scan) 
 
Progression on a hormonal agent (abiraterone/enzalutamide) and on a chemotherapy 
agent (docetaxel and/or cabazitaxel) in the metastatic castration resistant setting as 
per PCWG3 criteria. Progression of disease within 6 months of completing docetaxel 
in the metastatic castrate-sensitive setting is acceptable. 
 
Have signed an informed consent document indicating that the subject understands 
the purpose of and procedures required for the study and are willing to participate in 
the study 
Be willing and able to adhere to the prohibitions and restrictions specified in this 
protocol 
Willingness to use contraception by a method that is deemed effective by the 
Investigator throughout the treatment period and for at least 5 months following the 
last dose of therapy 
Willingness and ability to comply with study procedures and follow-up examination 
Willingness and ability to undergo mandatory whole blood sample collections at 
baseline, weeks 2-4 in the first cycle, and then monthly 
Able to swallow and retain oral medication 
Willingness and ability to undergo mandatory tumor biopsy at baseline and at the cycle 
3 visit


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Exclusion Criteria 
Systemic therapy (other than a GnRH agonist/antagonist) for CRPC within the past 
two weeks from cycle 1/day 1 including: 
aCYP-17 inhibitors (e.g. ketoconazole, abiraterone); Antiandrogens (e.g.
bicalutamide, nilutamide)  
Second 
generation 
antiandrogens 
(e.g. 
enzalutamide, 
ARN-509,
Galeterone); 
Immunotherapy 
(e.g. 
sipuleucel-T, 
ipilimumab);
Chemotherapy (e.g. docetaxel, cabazitaxel) 
 
Prior radiopharmaceutical therapy (e.g. radium-223, strontium-89, samarium-153,
etc.) within the past year. 
Have any condition that, in the opinion of the investigator, would compromise the
well-being of the subject or the study or prevent the subject from meeting or
performing study requirements. 
The patient is currently on warfarin or heparin therapy. 
The patient has any pre-existing coagulopathy, recent hemoptysis, gross hematuria
or gastrointestinal bleeding. 
The patient has a history of a clinically significant cardiovascular or cerebrovascular
event within 3 months prior to study entry. 
The patient has uncontrolled hypertension defined as a blood pressure
measurement greater than 150 mm Hg systolic or 90 mm Hg diastolic. 
The patient has previously been enrolled in the study or received ESK981. 
The patient has known hypersensitivity to gelatin or lactose monohydrate. 
The patient has taken a medication known to be a potent inducer of CYP1A2,
CYP2C8, or CYP3A4 within 4 weeks prior to the first dose of study drug. 
Prior treatment with anti-PD/PD-L1/CTLA4/IDO antibody. 
Untreated brain metastases or spinal cord compression. 
Major surgical procedure or significant traumatic injury within 6 weeks prior to study
registration. (>6 weeks prior to registration is permitted as long as they have fully
recovered from any such procedure). 
History of another primary malignancy except for: malignancy treated with curative
intent and no known active disease for ≥5 years, adequately treated non-melanoma
skin cancer without evidence of disease, adequately treated carcinoma in situ
without evidence of disease. 
Angina, myocardial infarction symptomatic congestive heart failure, cerebrovascular
accident, transient ischemic attack, arterial embolism, pulmonary embolism,
percutaneous angioplasty or Coronary arterial bypass surgery within the past 3
months. 
The patient has received any investigational drug within 28 days prior to registration
or 5 half-lives of the investigational drug, whichever is sooner. 


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Study Product(s), 
Dose, Route, 
Regimen 
ESK981 160 mg PO Q Days 1-5, 2 days off Nivolumab 480 mg IV q 4 
weeks (as is consistent with the FDA approved dosage and administration) 
Duration of 
Administration 
Until disease progression or specific criteria applies (see section 5.1) 
Statistical 
Methodology 
We will utilize a single group two-stage Phase II design for the study, with a 
run-in phase for safety determination. For the run-in phase, a starting 
combination dose (Level 0) and two retreat combination doses (Level -1 
and Level -2).  
In the run-in phase, patients will receive Level 0 starting doses of 160mg (4 
capsules) of ESK981 dosed once daily for five consecutive days followed 
by a two consecutive day treatment break, and a flat dose of 480 mg of 
nivolumab for a cycle of 28 days. 


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1. Background and Rationale 
 
1.1 Disease Background 
Prostate cancer is the second leading cause of cancer deaths in men. According to American Cancer 
Society estimates, in 2018 as many as 164,690 American men will be diagnosed with prostate cancer, 
and nearly 29,430 will die of the disease.1 Yet, localized prostate carcinoma is often curable, and 
even metastatic disease frequently responds to treatment. 
 
The course of prostate cancer from diagnosis to death is best categorized as a series of clinical states 
defined by the status of the primary tumor, the presence or absence of distant disease (metastatic 
versus non-metastatic), testosterone levels, and the lines of therapy a patient has received.2 These 
clinical states involve the complex interplay of a network of signaling molecules that collectively 
promote net cell proliferation relative to cell death. The clinical states model aligns with the indications 
and uses of currently approved drugs and provides a framework for a decision tree that closely follows 
contemporary clinical practice (Figure 1). 
 
Figure 1. Clinical states of prostate cancer 
 
 
Although advanced prostate cancer usually responds to therapies that suppress androgen-axis 
signaling, resistance inevitably develops, leading to the emergence of castration-resistant prostate 
cancer (CRPC). Importantly, the clinical efficacy of novel therapies targeting androgen receptor (AR) 
signaling, such as abiraterone and enzalutamide, have confirmed that in most CRPC, AR signaling 
remains intact.3-5 Since resistance to these therapies inevitably develops, approaches to improve the 
duration of response and address the key pathways of resistance are very much needed. 
  
Despite promising early phase clinical trial results,6 a recently presented Phase III trial evaluating the 
multi-tyrosine kinase inhibitor (MTKI) cabozantinib in CRPC did not meet its primary survival 
endpoint.7 Although the AR signaling status was unknown in trial participants, the majority of men 
with CRPC retain active AR signaling.8,9 Our preclinical study provided a mechanistic basis and 
rationale of combining cabozantinib with enzalutamide to co-target the MET kinase and AR 
respectively and, furthermore, provided a potential explanation for the failure of cabozantinib 
monotherapy in the pivotal Phase III study.10  
 
In a search for alternate MTKIs that could be re-positioned for the treatment of metastatic CRPC 
(mCRPC), we synthesized and evaluated ESK981 amongst a panel of other MTKIs. Interestingly, as 
our preliminary data will highlight, ESK981 exhibited nanomolar activity in the inhibition of prostate 
cancer cell line growth relative to other MTKIs tested including cabozantinib and crizotinib (both of 
which have been evaluated clinically in mCRPC). These early results further piqued our interest in 
deciphering the molecular basis for the log-fold increased sensitivity to ESK981 relative to other 
MTKIs in prostate cancer cells. 
 
Additionally, immunotherapy has recently been introduced for the treatment of many solid cancers 
such as bladder cancer, renal cell carcinoma, melanoma, and non-small-cell carcinoma. Antibodies 
against programmed cell death protein 1 (PD-1) and its ligand, PD-L1 and CTLA-4 block the 
interaction between T-cells to stimulate T cell-mediated immune response. Two anti-PD-1 agents, 


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nivolumab and ipilimumab were studied in CRPC, but failed to meet primary endpoints. However, 
several case studies have shown that nivolumab cause a reduction in measurable lesions.11-13 
 
Nivolumab is a humanized anti-PD-1 antibody that is FDA approved for the treatment of advanced 
renal cell carcinoma. It is generally well tolerated; however, immune-mediated pneumonitis has 
developed in some cases. Clinical testing indicated a geometric mean elimination half-life of 25 days, 
decreasing to 24.8 days given in conjunction with ipilimumab. Steady state concentrations were 
achieved by approximately 12 weeks. In a meta-analysis, overall response rate was increased in 
melanoma, non-small-cell lung cancer, head and neck carcinoma, and renal carcinoma.14  
 
ESK981 is an orally active multiplex kinase inhibitor with favorable safety, pharmaceutical, ADME 
(absorption, distribution, metabolism, and excretion), and pharmacokinetic profiles. Clinical testing 
demonstrated linear dose-related oral exposure in humans with 8-15 h half-life and a high level of 
patients achieving stable disease at doses at or right below the expected Phase II dose. Given our 
observation of a direct activity of ESK981 on prostate cancer cell autophagy coupled with its anti-
angiogenesis activities and the combined use of a checkpoint inhibitor, nivolumab, provides a 
compelling rationale to investigate this combination in the treatment of mCRPC patients. 
 
1.2 Treatment Background 
ESK981, formally known as CEP-11981, is a novel 
oral multi-TKI originally developed by Cephalon.15 
The compound was initially identified as an oral 
angiogenesis inhibitor targeting several important 
pathways involved in the angiogenic response, but 
without the off-target activities of other TKIs, like 
sunitinib and sorafenib, resulting in adverse events. 
ESK981 has potent activity in kinases implicated in 
angiogenesis including vascular endothelial growth 
factor receptor 1 (VEGFR-1), VEGFR-2, and Tie-2, 
(IC50 of 3, 4, 22nM, respectively). ESK981 
treatment potently inhibited HUVEC capillary tube 
formation and aortic ring explant angiogenesis in 
vitro and inflammation-induced angiogenesis in 
Tucker 
mice 
and 
several 
VEGF-induced 
angiogenesis models in vivo. ESK981 was tested in 
a dose-escalating Phase I clinical trial to determine 
its pharmacokinetics and pharmacodynamics in 
patients with advanced, relapsed, or refractory solid 
tumors.16 ESK981 was acceptably tolerated up to a 
dose of 97.4 mg/m2 (maximum tolerated dose) that 
was determined to be the recommended Phase II 
dose. Most adverse events were grade 1 or grade 2 
and included fatigue, nausea, diarrhea, decreased appetite, abdominal pain, back pain, vomiting, 
constipation, headache, dizziness, and dyspnea. Grade 3/4 neutropenia was observed in the highest-
dose cohorts. More importantly, up to 85% of patients achieved stable disease when measured at ≥6 
weeks in cohorts receiving ≥73.0 mg/m2. 
 
Figure 2. Kinases overexpressed in mCRPC (in red) 
and their in vitro inhibition with 25 nM ESK981 
(blue). 
Log-fold change of kinases in mCRPC relative to benign 
prostate assessed from a compendia of RNA-seq data. Rank 
ordered inhibition profile of 25 nM ESK981 determined in in 
vitro kinase assays. Intensity of color is associated with log-
fold change or inhibitory activity. 


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After Cephalon was acquired by TEVA, further 
development of the compound was halted due 
to TEVA’s decision to discontinue internal 
oncology drug development and focus on other 
therapeutic areas. Due to the exciting data seen 
in 
pre-clinical 
prostate 
cancer 
models 
highlighted 
in 
this 
proposal, 
Esanik 
Therapeutics (in which Dr. Chinnaiyan serves 
on the Scientific Advisory Board), acquired the 
rights to develop ESK981 in prostate cancer 
and other indications. To better understand the 
mechanism of action in prostate cancer, the 
kinase screen was repeated with modern 
kinase assays and lower drug concentrations, 
identifying novel mutant oncogenic kinases 
inhibited by ESK981 at single digit nanomolar 
potency. The new screen also confirmed the 
potency of ESK981 against TKs involved in 
angiogenesis as well as a number of other 
kinases involved in cancer processes including 
PDGFRA, PDGFRB, RET, FGFR1, FGFR2, 
AURKA, and AURKB among others (IC50 of 
43, 12, 9, 92, 80, 12, and 17nM, respectively). 
We carried out a preliminary analysis of the top 
kinases overexpressed   (by RNA-seq) in 
mCRPC and kinases most inhibited by ESK981 
to provide leads to identify the kinase target in 
mCRPC (Figure 2). Importantly, as our 
preliminary data will cover, ESK981, at 
nanomolar levels, induces robust vacuolization associated with activation of the autophagy pathway, 
suggesting that a kinase involved in this pathway was being inhibited. Other MTKIs, such as 
cabozantinib and crizotinib, did not have this autophagic vacuolization effect even at high micromolar 
concentrations. In vitro data also suggested combined effects with enzalutamide and continued 
sensitivity in enzalutamide-resistant cell lines. Interestingly, in addition to AR+ prostate cancer cell 
lines, AR- prostate cancer cell lines were similarly sensitive to ESK981 intimating its potential use in 
small cell/neuroendocrine variants of prostate cancer. In vivo, ESK981 monotherapy inhibited 
castrated VCaP xenograft growth in a dose-dependent fashion. Tumors from mice treated with 
ESK981 displayed vacuolization associated with autophagy as well as marked decreases in 
proliferation (by Ki67 staining). 
 
Autophagy is an evolutionarily conserved and orderly process of degradation and destruction of 
cellular components (Figure 3). As part of this process, double membraned vesicles known as 
autophagosomes are formed by engulfing cytoplasmic constituents, which then fuse with lysosomes 
to initiate degradation and recycling.17 Exaggerated activation of the autophagic process can be 
observed as gross vacuolization of cells. Monoallelic loss of beclin-1, a gene critical for the autophagy 
pathway, has been found in 40 - 75% of human breast, prostate, and ovarian cancers.17,18 Thus, 
autophagy has been considered an important tumor suppressive pathway, and sustained activation 
of autophagy in tumor cells leads to apoptosis. A number of approaches to regulate the autophagy 
pathway are being explored clinically in the treatment of cancer.17 
 
 
 
 
Figure 3. Overview of the autophagy pathway 
Adapted from Yang et al.[17] The ULK kinase pathway is the 
key proximal kinase complex that controls autophagy. It can 
be regulated by a number of up-stream kinases including 
receptor tyrosine kinase (RTKs), PI3K, AKT, and TOR. The 
beclin1 complex is a mediator of autophagy. LC3 processing is 
a key step in autophagosome maturation. Chloroquine and 
Bafilomycin A1 block late stage autophagy by blocking 
lysosomal fusion. ESK981 presumably activates autophagy in 
CRPC by inhibiting an upstream TK. 


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1.2.1. Nonclinical activity 
ESK981 is an orally active inhibitor of a number of receptor tyrosine kinases, specifically human TIE- 
2, VEGFR-1 and VEGFR-2, and FGFR-1, with concentrations resulting in 50% inhibition of activity 
(IC50) of 22±6 nM, 4±1 nM, 3±1 nM, and 13±2 nM, respectively, in enzyme-based assays. These 
kinase targets have been shown to have essential and non-redundant roles in tumor angiogenesis 
and vascular maintenance, and ESK981 is designed to inhibit tumor growth by blocking these 
processes. ESK981 shows comparable activity against a number of other kinases including 
tropomyosin receptor kinase (Trk) A (3 nM), TrkB (5 nM), receptor tyrosine kinase (RET) (5 nM), B 
lymphocyte kinase (Blk) (8 nM), hemopoietic cell kinase (Hck) (13 nM), lymphocyte-specific protein 
tyrosine kinase (Lck) (12 nM), TGF-ß activated kinase 1 (TAK1) (14 nM), and mammalian STE20-like 
kinase 2 (MST2) (21 nM). Some of these kinases are also known to be involved in tumor growth and 
survival. ESK981 demonstrates a significant concentration-related activity in a range of experimental 
systems, including VEGF-A, -C, -D-induced, Angiopoietin-1-induced, and fibroblast growth factor-2 
(FGF2)-induced human and murine endothelial cell proliferation, chemotaxis, migration, and survival 
in vitro, and microvessel outgrowth and branching in primary rat aortic ring explant cultures ex vivo. 
 
1.2.2. Preclinical studies 
Significant oral anti-angiogenic efficacy has been observed in VEGF-A-induced, tumor-induced and 
inflammation-induced neo-vascularization models in rodents. Sustained dose-related anti-tumor 
activity has been demonstrated with ESK981 in vitro across a panel of human and murine tumor cell 
lines. Significant dose-related and exposure driven in vivo anti-tumor efficacy is observed with 
ESK981 in multiple subcutaneous (melanoma, glioblastoma, breast carcinoma, prostate carcinoma) 
and orthotopic human and rodent solid (colon carcinoma, renal carcinoma, and glioblastoma) and 
hematologic (acute leukemia) tumor xenograft models in normal and immunocompromised hosts. 
Depending upon tumor models with differing dosing regimens, ESK981 exhibits dose-related tumor 
growth, inhibitory and anti-angiogenic effects, as well as sustained partial and complete tumor 
regressions when administered as monotherapy. Specific intermittent oral dosing schedules (drug 
dosing/drug holidays) of ESK981 using once daily and twice daily dosing regimens demonstrate 
significant anti-tumor efficacy (tumor growth inhibition and partial and complete regressions). In both 
solid and hematologic tumor models, however, daily and twice daily continuous administration is 
optimal. ESK981 is generally well tolerated when administered chronically with cytotoxic agents (e.g., 
temozolomide [TMZ]), and the combination of ESK981 with TMZ conferred a significant benefit on 
median survival of orthotopic human glioblastoma-bearing animals relative to that achieved with TMZ 
alone. In a series of pharmacologic anti-tumor and anti-angiogenic studies conducted in various 
murine strains, the maximum tolerated dose of ESK981 is 60 mg/kg/day or higher in syngeneic, nude, 
and severe immunocompromised mice (SCID) mice, and 30 mg/kg/day or higher in non-obese 
diabetic, severely immunocompromised (NOD-SCID) tumor-bearing mice. 
 
ESK981 has been intensively evaluated pre-clinically in human prostate cancer at the University of 
Michigan. In our preliminary assessment we evaluated the growth inhibitory effect of ESK981 against 
a library of tyrosine kinase inhibitors consisting of 167 compounds in DU145 cells. We found that 
ESK981 exhibited potent growth inhibition at 300nM concentration compared to Src inhibitors (KX2- 
391, Dasatinib) and HER2 inhibitor (Mubritinib) that were reported to be efficacious in DU145 cells, 
whereas crizotinib and cabozantinib exhibited no such growth inhibitory effect at comparable 
concentrations (Fig. 4a). Among the 168 compounds, only ESK981 triggered a cytoplasmic 
vacuolization morphology that prompted us to further investigate its functional significance (Fig. 4b). 
Using 7 prostate cancer cell lines, we examined their sensitivity to ESK981 in long-term survival 
assays. After 2 weeks of growth, cells were stained with crystal violet and subsequently quantified. 
ESK981 exhibited IC50 values ranging from 35nM to 192nM. In contrast, cabozantinib and crizotinib 
exhibited only micromolar IC50 values in the cell lines tested (Fig. 4c). 
 
 
 
 


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The morphological alterations triggered by ESK981 led us to explore whether the autophagy pathway 
is involved. Initially, we investigated ESK981-associated cellular vacuole in combination with various 
autophagic pathway inhibitors. The anti-malarial drug, chloroquine, has been used as an inhibitor of 
autophagy and lysosomal fusion. Strikingly, chloroquine completely negated the cellular vacuolization 
effects of ESK981 in DU145 cells after a 6-hour incubation. The phenotype was recapitulated by 
another lysosome inhibitor bafilomycin (BF) as well as early autophagasome inhibitor 3- 
Methyladenine (3-MA). This strongly suggested that ESK981-induced vacuolization involves the 
autophagy process (Fig. 5a). We next employed CYTO-ID autophagy detection kit (Enzo) to visualize 
cytoplasmic vacuoles in DU145 cells (Fig. 5b); quantified fluorescent intensity showed dose- 
dependent induction of autophagy signal in LNCaP and VCaP cells as well (Fig. 5c). Five prostate 
cell lines (VCaP, LNCaP, MDA-PCa-2b, LNCaP-AR and PC3) that have been tested thus far exhibited 
LC3 cleavage in an ESK981 dose-dependent manner suggesting autophagy activation (Fig.5d).
Figure 4. Prostate cancer cell lines are 
more sensitive to ESK981 than FDA-
approved 
MTKIs 
Cabozantinib 
or 
Crizotinib. 
A. Percentage viability of DU145 for 
300nM ESK981 and other 167 tyrosine 
kinase inhibitors compared to vehicle 
control. 
Top 
5 
most 
inhibitory 
compounds are listed in the table, as 
well as cabozantinib and crizotinib 
(highlighted in orange). ESK981 is 
highlighted in red. 
B.  Morphological differences of 300nM 
ESK981, crizotinib or cabozantinib 
treated 
nuclear 
restricted 
RFP 
expressing DU145. 
C.  A long-term survival assay was used to 
calculate 
half-maximum 
inhibitory 
concentration (IC50) after 2 weeks of 
incubation with serial dilutions of 
indicated 
drugs. 
Top, 
Long-term 
survival assays of VCaP prostate 
cancer cells 
exposed 
to 
MTKIs. 
Bottom, (IC50) of ESK981, crizotinib 
and cabozantinib in a panel of prostate 
cancer cell lines. 
 


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We observed that ESK981 increased cytokine CXCL10 secretion in cell culture medium in an 
autophagy-dependent manner, thus, we hypothesized that ESK981 may play a role in immune cell 
recruitment. These preliminary data led us to expand our investigation to immune response using 
syngeneic mouse prostate cancer Myc-CaP cells. We confirmed that ESK981 is effective in Myc-CaP 
cells and has lower IC50 than cabozantinib or crizotinib (Fig. 6a) autophagy and CXCL10 were 
increased upon ESK981 treatment in Myc-CaP cells (Fig. 6b-c). Finally, we wanted to test whether 
ESK981 is able to potentiate immune checkpoint blockade. In immune competent mice, ESK981 and 
immune checkpoint inhibitor, anti-PD1 in combination exerted maximum tumor inhibition (Fig. 7a-b). 
With tumor inhibition, autophagy was observed in individual tumors upon ESK981 treatment (Fig. 7c). 
Overall, our data demonstrate that ESK981, alone or in combination with anti-PD1 therapy, is a 
promising candidate for clinical development; it targets a novel pathway and shows greater efficacy 
than tyrosine kinase inhibitors commonly in use. 
 
Figure 5. ESK981 induced cellular vacuolization is part of autophagy activation. 
A. Autophagy inhibitors negated ESK981 induced cellular vacuolization. Morphology of DU145-RFP cells treated 
with ESK981, and various autophagy inhibitors 3-Methyladenine (3-MA), chloroquine (CQ), bafilomycin (BF) 
alone and in combination of for 6 hours. Red indicates nuclei. 
B. Autophagic vacuoles were visualized by green fluorescence in DU145 treated with either control or ESK981 
for 24 hours, and nuclei were indicated by blue. 
C. VCaP and LNCaP cells were treated with increasing concentration of ESK981 for 24 hours, and autophagic 
activity were measured by CYTO-ID kit, and quantification of autophagy activity is shown on right. Rapamycin 
served as a positive control for autophagy induction. 
D. Protein levels of LC3 in indicated prostate cancer cell lines. 
 


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1.2.3. Clinical Activity 
 
Phase I open-label, dose-escalating study pharmacokinetics 
ESK981 was tested in an open-label dose-escalating Phase 1 clinical trial to determine its 
pharmacokinetics (PK) and pharmacodynamics (PD) in patients with advanced, relapsed, or refractory 
solid tumors (Study C11981/1047/ON/US, NCT00875264).16 After daily oral administration of ESK981 to 
cancer patients, the median tmax values for ESK981 were typically in the range of 2 to 4 hours (Table1 
and Table 2). However, for most of the dose groups there appeared to be considerable inter-patient 
variability in this pharmacokinetic parameter. The reason(s) for the large inter-patient variability in tmax is 
(are) not presently known, but may be related to the fed/fasted state of the patients or other unknown 
factors which could potentially influence drug absorption (e.g., disease state, concomitant medications). 
 
 
 
 
Figure 6. Mouse prostate cancer cell Myc-CaP is sensitive to ESK981. 
A. IC50 of ESK981, cabozantinib, crizotinib were determined in Myc-CaP cells. 
B. LC3 protein levels were determined by western blot in Myc-CaP treated with various concentration of ESK981 
for 24 hours. 
C. Mouse CXCL10 mRNA levels were measured by qPCR in Myc-CaP cells treated with various concentration 
of ESK981 for 24 hours. 
Figure 7. ESK981 enhances immune checkpoint blockade in mouse prostate cancer model. 
A. Schematic illustration of study design 
B. Tumor volume of Myc-CaP after indicated treatments. 
C. Protein levels of LC3 and Myc were detected in individual tumors. 


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Table 1. Mean (SD) Pharmacokinetic Parameters for SK981 in Cancer Patients on Day 1 of Daily 
Oral Administration of ESK981 
 
 
 
Table 2. Mean (SD) Pharmacokinetic Parameters for ESK981 in Cancer Patients on Day 15 of 
Daily Oral Administration of ESK981 
 
 
 
After reaching peak plasma levels, ESK981 declined in a bi-phasic manner that was characterized by an 
initial phase of drug distribution and a slower terminal elimination phase. For some profiles, however, 
only the later phase was evident due to what appeared to be a more prolonged period of drug absorption. 
The mean t1/2 of the terminal elimination phase was generally in the range of approximately 8 to 10 hr; 
however, the values tended to be slightly larger after multiple doses at the higher dose levels (i.e., doses 
≥55 mg/m2) (Table 1 and Table 2). 
 
The systemic exposures (i.e., Cmax and AUC) of patients to ESK981 generally increased with increasing 
dose across the dose range evaluated on both days 1 and 15 (Table 1 and Table 2). There were some 
dose groups for which the mean values of Cmax and AUC did not show an increase relative to the values 
from the preceding 1 or 2 dose levels. However, this result was not surprising given the large inter-patient 
variability and the fact that most dose increments were less than 40%. Nonetheless, the overall results 


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obtained are not suggestive of the presence of any obvious non-linearity in absorption and/or elimination 
of ESK981 in this dose range. 
 
 
After once-daily administration of ESK981 at doses ranging from 3.0 to 126.6 mg/m2, there was a small 
to moderate amount of accumulation of the compound in plasma at each dose level. The overall mean 
observed accumulation ratio (Robs) for ESK981 was 1.5 (range = 1.1 to 1.9), which was slightly larger 
than the value predicted from the single-dose data (overall mean Rpred = 1.2; range = 1.0 to 1.3) (Table 
1 and Table 2). Although the mean Robs was slightly larger than the Rpred, this is not believed to be a 
strong indication of the presence of any time-dependent pharmacokinetic processes. 
 
1.2.4. Clinical Safety and Efficacy  
Adverse events 
 
All 43 patients experienced ≥1 adverse event, and 38 patients (88.3%) were deemed to have had adverse 
events possibly, probably, or definitely related to study drug. The most frequently reported adverse event 
of any grade was fatigue (n= 22, or 51%). Other frequently reported adverse events (≥20% of patients) 
were nausea (47%), diarrhea (33%), decreased appetite (33%), abdominal pain (30%), back pain (28%), 
vomiting (28%), constipation (28%), headache (28%), dizziness (28%), and dyspnea (23%). These 
adverse events were reported at a similar frequency between dosage cohorts, and no relationship with 
dose was evident. Most adverse events were grade 1 or grade 2. 
 
Grade 3 or 4 adverse events occurred in 16 (37%) patients across dosing cohorts (14 [32.6%] Grade 3 
and 2 [4.7%] Grade 4). Treatment-related grade 3 or 4 adverse events were most frequent in the 97.4 
mg/m2 cohort. Grade 3 or 4 laboratory hematologic toxicities were reported in 8 (18.6%) patients across 
dosage cohorts. The most common grade 3 or 4 laboratory hematologic toxicity was lymphopenia, which 
occurred in 8 patients and across dosage cohorts (5.9, 29.6, 55.0, 97.4, and 126.6 mg/m2). Grade 4 
leukopenia occurred in 1 patient in the 126.6 mg/m2 cohort. Grade 3 or Grade 4 neutropenia also occurred 
in 2 patients in the 97.4 mg/m2 cohort (Grade 3) and in 1 patient in the 126.6 mg/m2 cohort (Grade 4). 
Serious adverse events occurred in 12 patients; most were deemed unlikely or not related to ESK981. 
Three patients (1 patient in the 97.4 mg/m2 cohort and 2 patients in the 126.6 mg/m2 cohort) experienced 
serious adverse events that were categorized as possibly or definitely related to ESK981: pyrexia, 
hemolytic anemia, hyperbilirubinemia, dyspnea, neutropenia, ECG change, and chest discomfort. No 
deaths occurred during the study. 
 
Tumor response 
 
Of 43 patients who received ≥1 dose of study drug, 37 patients were evaluated for tumor response. 
Although no enrolled patients had complete or partial response according to RECIST criteria, 19 of 37 
(51%) patients evaluated for tumor response had stable disease at ≥6 weeks; 18 had disease 
progression. The frequency of stable disease (defined as <30 % decrease and <20 % increase in the 
sum of the longest diameter of the target lesions) was higher in cohorts receiving doses ≥73.0 mg/m2 (8 
of 14 [57.1%] patients) compared with cohorts receiving ≤55.0 mg/m2 (11 of 29 [37.9%] patients) (Figure 
8). 
 
 
 
 
 
 
 
 
 
 
 


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Figure 8. Best overall tumor response per cohort at >/= 6 weeks 
Depicts tumor response, with bars above the x-axis indicating patients (n = 19) who achieved stable 
disease and bars below the x-axis indicating patients (n = 18) with disease progression. aNo patient 
achieved complete or partial response. bSix patients were not evaluable at dosages of 19.7, 29.6, 
55.0, and 126.6 mg/m2 (n = 1, each); 97.4 mg/m2 (n = 2) 
 
 
1.3 Rationale 
ESK981 has cleared a dose-escalating Phase I clinical trial and demonstrated favorable 
pharmacokinetics and pharmacodynamics in patients with advanced, relapsed, or refractory solid tumors 
with up to 85% of patients achieving stable disease at doses ≥73.0 mg/m2. 
 
ESK981 is an orally active multi-targeted receptor tyrosine kinase inhibitor that inhibits the human 
receptor for Angiopoietin-1 and Angiopoietin-2 (TIE-2), VEGFR-1, VEGFR-2, and FGFR-1 receptor 
tyrosine kinases. In addition to its effects on the angiogenesis promoting receptors VEGF and TIE-2, 
ESK981 treatment also induced robust cellular vacuolization indicative of cell death by autophagy, a 
mechanism not observed with other multiple tyrosine kinase inhibitors like crizotinib and cabozantinib. 
 
A Phase I study has shown the compound to be safe and tolerable.16 The most frequently reported 
adverse event of any grade was fatigue (n = 22, or 51%). Other frequently reported adverse events (≥20 
% of patients) were nausea (47%), diarrhea (33%), decreased appetite (33%), abdominal pain (30%), 
back pain (28%), vomiting (28%), constipation (28%), headache (28 %), dizziness (28 %), and dyspnea 
(23%). These adverse events were reported at a similar frequency between dosage cohorts, and no 
relationship with dose was evident. Most adverse events were grade 1 or 2. Although no enrolled patients 
had complete or partial response according to RECIST criteria, 19 of 37 (51%) patients evaluated for 
tumor response had stable disease at ≥ 6 weeks. Of note, the majority of patients on this trial had tumor 
types that have been historically refractory to TKIs. The 0% response rate is similar to response rates 
seen when other VEGF-TKIs have been tried in non-kidney cancers such as colorectal cancer.19 
 
 
 
 


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A Phase II clinical trial of single agent ESK981 is underway with pharmacodynamic endpoint 
assessments. Patients in this trial with metastatic, castrate resistant prostate cancer have progressed on 
abiraterone, enzalutamide, or both but not have been treated with chemotherapy. 
 
Nivolumab 
 
Nivolumab (Opdivo), a PD-1 antibody, is FDA approved for the treatment of advanced renal cell 
carcinoma after disease progression on prior anti-angiogenic therapy. In the CHECKMATE-025 trial, 
nivolumab demonstrated improved overall survival compared with everolimus in the randomized clinical 
trial setting (25 months vs 19.6 months, HR 0.73, p-value 0.0018).20 
 
ESK 981 in combination with anti-PD1 immunotherapy 
 
VEGF inhibition in combination with immunotherapy in the form of anti-PD1 or anti-PD-L1 therapy has 
already been demonstrated in other drug combinations. Bevacizumab, an anti-VEGF therapy, in 
combination with atezolizumab (anti-PD-L1), was studied in ten patients with previously untreated 
metastatic RCC, and was well-tolerated. In this small cohort, there were 4 partial responses and 4 
patients with stable disease.21 A randomized multi-arm Phase III clinical trial is currently ongoing 
evaluating the combination of lenvatinib, a multikinase inhibitor, with either everolimus or pembrolizumab 
compared with sunitinib in patients with advanced renal cell carcinoma (NCT02811861). 
 
Given the superior activity of ESK981 compared to other small molecule VEGFR inhibitors, especially 
potent inhibition of Tie-2, and additional autophagy inducing activity of ESK981, and the emerging clinical 
data on synergy between VEGFR inhibition and anti-PD1/L1 antibody immunotherapy, we propose a 
single group, single stage Phase II study with a run-in phase for safety determination. For the run-in 
phase, a starting combination dose (level 0) and two retreat combination doses (Level -1 and -2) are 
defined in the protocol for men with metastatic Castrate-resistant prostate cancer. 
 
1.4 Rationale for Correlative Studies 
1.4.1.1 Autophagy induction 
ESK981 demonstrated a unique autophagy induction property in our pre-clinical in vitro and in vivo 
models through provoking robust cellular vacuolization. Thus, autophagy can serve as biomarker for 
patient response to ESK981 treatment.  
 
1.4.1.2 Angiogenesis inhibition 
Considering ESK981’s anti-VEGFR-A property and our in vivo preliminary data that ESK981 strongly 
attenuated angiogenesis, we believe that angiogenesis can be a biomarker for patient response to 
ESK981 treatment. 
 
1.4.1.3 Phosphorylation reduction 
According to the kinase inhibition profile data from ESANIK, ESK981 inhibits a group of kinases that have 
been validated in our preliminary in vitro models. Using immunohistochemistry (IHC) to determine 
phosphorylation levels of these targets can help to assess ESK981 pharmacodynamics in patients. 
 
1.4.1.4 Tumor cellular proliferation rate 
Preliminary data have shown that ESK981 significantly inhibited tumor cell proliferation in vitro and in 
vivo xenografts. Therefore, we believe that determining proliferation rate by Ki67 IHC will also be a 
potential biomarker for patient response to ESK981 treatment. 
 
 
 


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1.4.1.5 Exploratory evaluation  
Immunohistochemistry to quantify PD-1 and PD-L1 expression and presence of CD8+ tumor infiltrating 
lymphocytes in response to nivolumab 
 
1.4.1.6 Other potential markers 
Overall patient survival, assessment by radiography, radiographic progression free survival, and PSA 
progression free survival can be monitored clinically as surrogates for treatment outcomes. Mutation 
analysis by whole genome sequencing can be useful in exploratory evaluation. In addition, select genetic 
and epigenetic characteristics of the patients’ tumors will be assessed as surrogate biomarkers for clinical 
benefit. These evaluations are expected to identify genomic correlates of response (biochemical 
recurrence, onset of pain), complications (osteoblastic lesions in bone, cachexia), and survival. The 
specific biomarker candidates were identified based on their inclusion in either of the following 
actionable/informative categories: (i) immediate link with the ESK981 mechanism of action, (ii) high 
prevalence in mCRPC and/or routine clinical testing, (iii) potential less-invasive detection in biofluids. 
Respectively, the proposed correlative endpoints include expression levels of ESK981 target kinases, 
ETS-status, and AR amplification/levels in circulating tumor cells. The rationale for each biomarker choice 
and correlative assessment is listed in section 1.4, while methodological and statistical considerations for 
the genomic screening are reviewed in section 11.4.  
 
2.  Objectives 
 
2.1 Primary Objectives 
2.1.1. To determine the PSA ≥ 50% response rate (PSA50) from baseline using the PCWG3 criteria to 
ESK981 plus nivolumab  in men with mCRPC who have progressed on enzalutamide (an oral androgen-
receptor inhibitor) and/or abiraterone acetate (an androgen synthesis inhibitor) and chemotherapy 
(docetaxel and/or cabazitaxel). 
2.1.2. To assess the safety and tolerability of ESK981 plus nivolumab. 
2.2. Secondary Objectives 
To determine the time to PSA response (TTPR) in patients with mCRPC 
2.2.1. To determine the duration of PSA response (PRD) in patients with mCRPC 
2.2.2. To determine PSA progression rates as defined by the PCWG3 criteria.  
2.2.3. To determine PSA progression free survival (PPFS) as defined by the PCWG3 criteria. 
2.3. Correlative/Exploratory/Tertiary Objectives 
2.3.1. To assess exploratory biomarkers from blood and tumor biopsies. Examples of these may include, 
but are not limited to: whole exome sequencing, capture whole transcriptome analysis, AR and ARv7 
analysis, ki-67, apoptosis, etc. 
3. Patient Selection 
A total of 42-54 patients with metastatic CRPC will be included in this study. Each subject will be 
counseled by a study investigator about the planned study procedures, risk and benefits of participating 
in the study, and alternative therapeutic options. Each subject must sign an Institutional Review Board 
(IRB)/ Independent Ethics Committee (IEC)-approved consent form and written authorization to use 
protected health information as outlined in the Health Insurance Portability and Accountability Act 
(HIPAA) of 1996, prior to the initiation of any study related procedures. 
 
 
3.1 Inclusion Criteria 
Patients should meet all of the following criteria at the time of registration: 
 
3.1.1 Males 18 years of age and above at time of informed consent 
 
3.1.2 Eastern Cooperative Group (ECOG) performance status ≤1 


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3.1.3 Recovery to baseline or ≤ Grade 1 CTCAE v.5 from toxicities related to any prior treatments, 
unless AE(s) are clinically non-significant and/or stable on supportive therapy 
 
3.1.4 Adequate organ and marrow function as outlined in Table 3 below:  
 
 
Table 3. Laboratory Values for Organ and Marrow Function (Inclusion criteria) 
System 
Laboratory Value 
Hematological 
Absolute Neutrophil Count (ANC) 
≥ 1.5 K/mm3 
Hemoglobin (Hgb) 
≥ 9 g/dL 
Platelets (Plt) 
≥ 100,000/mm3 
Renal 
Calculated creatinine clearance 
Serum creatinine ≤ 1.5 times the upper limit of 
normal  
OR creatinine clearance 
>30mL/min by Cockcroft-Gault formula 
Hepatic 
Total Bilirubin 
≤ 1.5 × upper limit of normal (ULN) 
Aspartate aminotransferase (AST) 
≤ 2.5 × ULN (≤ 5 × ULN with known hepatic 
metastases) 
Alanine aminotransferase (ALT) 
≤ 2.5 × ULN (≤ 5 × ULN with known hepatic 
metastases) 
Prothrombin time (PT) and activated 
partial thromboplastin time (aPTT) 
levels 
≤ 1.5x ULN (If patient is receiving anticoagulation 
that is expected to alter these levels, should be in 
targeted therapeutic range for that agent) 
 
 
3.1.5 Patient must have progressive disease while receiving androgen deprivation therapy (ADT) 
defined by any one of the following as per the PCWG3 criteria for PSA, measureable or non-
measurable (bone) disease and must have a castrate serum testosterone level (i.e. ≤ 50 ng/dL) 
at screening:  
3.1.5.1 PSA: At least two consecutive rises in serum PSA, obtained at a minimum of 1-week 
intervals, with the final value ≥ 2.0 ng/mL. 
3.1.5.2 Measurable disease (by RECIST 1.1): ≥20% increase (with an absolute increase of at 
least 5mm) in the sum of diameters of all measurable lesions or the development of one 
or more new lesions. The short axis of a target lymph node must be more than 15mm to 
be assessed for change in size. 
3.1.5.3 Non-measurable (bone) disease: The appearance of two or more new areas of uptake on 
bone scan consistent with metastatic disease compared to previous imaging during 
castration therapy. The increased uptake of pre-existing lesions on bone scan will not be 
taken to constitute progression, and ambiguous results must be confirmed by other 
imaging modalities (e.g. X-ray, CT or MRI). 
3.1.6 Histologic diagnosis of adenocarcinoma of the prostate with metastatic disease (M1) as 
documented by appropriate medical imaging (i.e. CT-Scan, PET scan or bone scan) 
 


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3.1.7 Progression on a hormonal agent (abiraterone/enzalutamide) and on a chemotherapy agent 
(docetaxel and/or cabazitaxel) in the metastatic castration resistant setting as per PCWG3 criteria. 
Progression of disease within 6 months of completing docetaxel in the metastatic castrate-
sensitive setting is acceptable. 
 
3.1.8 Have signed an informed consent document indicating that the subject understands the purpose 
of and procedures required for the study and are willing to participate in the study 
 
3.1.9 Be willing and able to adhere to the prohibitions and restrictions specified in this protocol 
 
3.1.10 Willingness to use contraception by a method that is deemed effective by the Investigator 
throughout the treatment period and for at least 5 months following the last dose of therapy 
 
3.1.11 Willingness and ability to comply with study procedures and follow-up examination 
 
3.1.12 Able to swallow and retain oral medication 
 
3.1.13 Willingness and ability to undergo mandatory tumor biopsy at baseline and at the cycle 3 visit 
 
3.1.14 Willingness and ability to undergo mandatory whole blood sample collections at baseline, weeks 
2-4 in the first cycle, and then monthly 
 
3.2 Exclusion Criteria 
 
3.2.1 Systemic therapy (other than a GnRH agonist/antagonist) for CRPC within the past two weeks 
from cycle 1/day 1 including: 
a. CYP-17 inhibitors (e.g. ketoconazole, abiraterone);  
b. Antiandrogens (e.g. bicalutamide, nilutamide)  
c. Second generation antiandrogens (e.g. enzalutamide, ARN-509, Galeterone);  
d. Immunotherapy (e.g. sipuleucel-T, ipilimumab) 
e. Chemotherapy (e.g. docetaxel, cabazitaxel) 
3.2.2 Prior radiopharmaceutical therapy (e.g. radium-223, strontium-89, samarium-153, etc.) within the 
past year. 
3.2.3 Have any condition that, in the opinion of the investigator, would compromise the well-being of 
the subject or the study or prevent the subject from meeting or performing study requirements. 
3.2.4 The patient is currently on warfarin or heparin therapy. 
3.2.5 The patient has any pre-existing coagulopathy, recent hemoptysis, gross hematuria or 
gastrointestinal bleeding. 
3.2.6 The patient has a history of a clinically significant cardiovascular or cerebrovascular event within 
3 months prior to study entry. 
3.2.7 The patient has uncontrolled hypertension defined as a blood pressure measurement greater than 
150 mm Hg systolic or 90 mm Hg diastolic. 
 
3.2.8 The patient has previously been enrolled in the study or received ESK981. 
 
3.2.9 The patient has known hypersensitivity to gelatin or lactose monohydrate. 
 


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3.2.10 The patient has taken a medication known to be a potent inducer of CYP1A2, CYP2C8, or 
CYP3A4 within 4 weeks prior to the first dose of study drug. 
 
3.2.11 Prior treatment with anti-PD/PD-L1/CTLA4/IDO antibody. 
 
3.2.12 Untreated brain metastases or spinal cord compression. 
 
3.2.13 Major surgical procedure or significant traumatic injury within 6 weeks prior to study registration. 
(>6 weeks prior to registration is permitted as long as they have fully recovered from any such 
procedure). 
 
3.2.14 History of another primary malignancy except for: malignancy treated with curative intent and no 
known active disease for ≥5 years, adequately treated non-melanoma skin cancer without 
evidence of disease, adequately treated carcinoma in situ without evidence of disease. 
 
3.2.15 Angina, myocardial infarction symptomatic congestive heart failure, cerebrovascular accident, 
transient ischemic attack, arterial embolism, pulmonary embolism, percutaneous angioplasty or 
Coronary arterial bypass surgery within the past 3 months. 
 
3.2.16 The patient has received any investigational drug within 28 days prior to registration or 5 half-lives 
of the investigational drug, whichever is sooner. 
 
3.3 
Screen Failures 
Minimal data for subjects who fail screening will be collected such as demographic information and the 
reason for screen failure. Such subjects may be re-screened at the discretion of the Principal investigator. 
The reason for the need to re-screen a subject will be documented in the subject’s source documents. 
 
4.0 Enrollment Plan and Subject Registration 
 
Patient registration for this trial will be centrally managed by the KCI Cancer Center Clinical Trials Office 
at (313) 576-9837. At the time of registration, a pre-study form and all information required to verify 
eligibility shall be necessary on each patient prior to treatment.  
 
A potential study subject who has been screened for the trial and who has signed the Informed Consent 
document will be initially documented by the participating site on a Screening and Enrollment Log. 
 
It is the responsibility of the local site investigator to determine patient eligibility prior to submitting patient 
registration request to the KCI Coordinating Center. After patient eligibility has been determined, a copy 
of the completed Eligibility Worksheet together with all the pertinent de-identified source documents will 
be submitted by the requesting site to KCI the Coordinating Center, by email to Kimberlee Dobson at 
dobsonk@karmanos.org. 
 
The Multi-Site Coordinator (MSC) of the Coordinating Center will review the submitted documents and 
process the registration. Sites should inform the Multi-Site Coordinator of a potential registration and 
allow 24-48 hours for document review and registration. Same day registrations cannot be guaranteed. 
 
An email will be sent by the MSC to the requesting site registrar to confirm patient registration and to 
provide the study identification number that has been assigned to the patient. In addition, a copy of the 
completed Eligibility Worksheet signed and dated by the MSC, will be sent back to the requesting site 
registrar. 
 
Patients found to be ineligible for participation after being consented will be considered screen failures 
and documented as such in a Screening and Enrollment Log. These patients will not have study 


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identification number assigned to them, and will not receive study treatment. 
 
5.0 Treatment/Intervention Plan 
Protocol treatment must start within 14 calendar days of enrollment to the study. 
 
This will be a single group, two-stage Phase 2 design for the study, with a run-in phase for safety 
determination of the combination of ESK981 and nivolumab in patients with mCRPC who have had prior 
enzalutamide and/or abiraterone and chemotherapy (docetaxel and/or cabazitaxel).  
For the run-in cohort, a starting combination dose (Level 0) and two retreat combination doses (Level -1 
and Level -2) are defined in Table 4 below. Patients will receive one dose of nivolumab 480 mg and 4 
weeks of ESK981 dosed once daily for five consecutive days followed by a two consecutive day treatment 
break for a cycle of 28 days, and then be evaluated for their rate of PSA decline of ≥ 50% from baseline 
(PSA50), using the PCWG3 criteria.  
In the subsequent combination therapy, patients will receive a flat dose of 480 mg of nivolumab and level 
deemed safe starting doses (160mg, 120 mg, or 80 mg) of ESK981 dosed once daily for five consecutive 
days followed by a two consecutive day treatment break for a cycle of 28 days.  
 
Table 4. Dose Reduction Table 
 
 
 
 
 
Assessments and procedures that will occur during the study are detailed in Appendix C.  
5.1 
Removing Subjects from the Protocol 
In the absence of treatment delays because of adverse events, treatment will continue for 8 weeks. If at 
the conclusion of the 8-week period, no disease progression has occurred, the participant can stay on 
trial until one of the following criteria applies: 
5.1.1 Subject decides to withdraw from the study. 
5.1.2 Disease progression 
• 
symptomatic disease progression at any time 
• 
objective clinical disease progression 
5.1.3 Subject is no longer clinically benefitting (NLCB) from treatment. 
5.1.4 Intercurrent illness that prevents further administration of treatment. 
5.1.5 Unacceptable adverse event(s) that may or may not be directly related to treatment but that, in 
the judgment of the treating physician, makes it dangerous for the subject to be retreated. 
5.1.6 General or specific changes in the patient’s condition that render the patient unacceptable for 
further treatment, in the judgment of the investigator. 
Because an excessive rate of withdrawals can render the study uninterpretable, unnecessary withdrawal 
of subjects should be avoided. When a subject discontinues treatment early, the investigator should make 
every effort to contact the subject and to perform a final evaluation. The date and the specific reason(s) 
for withdrawal should be recorded. 
 
5.2 Definition of compliance with the self-administered oral agent ESK981 
Based on pill counts made by the Research Coordinator from the bottles of ESK981 returned by the 
Dose Level 
    Dose of ESK981 
        Dose of nivolumab  (once/4 wks) 
     Level 0 
      160 mg 
          480 mg flat dose 
     Level -1 
      120 mg 
          480 mg flat dose 
     Level -2 
        80 mg 
          480 mg flat dose 


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patient, the % of intended ESK981 pills presumably consumed will be calculated. If that % is ≥ 75% over 
Cycle 1 (the first 28 days of ESK981 treatment), then the patient will be deemed “compliant” with the 
intended oral ESK981 treatment regimen. 
6. Therapeutic Agents 
6.1 ESK981 Drug Supply and Return 
 
Shipment and Receipt 
Esanik Therapeutics, Inc has contracted with Sharp Clinical Services Inc. as the vendor for the storage 
and shipping of ESK981 (CEP11981); therefore, all drug shipments will be received from Sharp and not 
directly from Esanik. All drug shipments will be sent to the attention of the appropriate pharmacy contact, 
which will be identified in advance by the Investigator as responsible for the management of 
investigational product. This includes study drug receipt, accountability, storage/handling, and proper 
dispensation. 
Note:  The initial shipment will be at least 12 bottles of ESK981, and subsequent shipments will be at the 
request of the Investigator based on site enrollment. Sites should have enough ESK981 (CEP11981) in 
stock for initial 8 week treatment course prior to enrolling a patient into the study. If pharmacy space is 
limited, please contact your Esanik representative for in-treatment resupply plan.  
ESK981 will be shipped via an express courier under refrigeration directly to each participating 
center from Sharp upon authorization from Esanik. Esanik will be notified of the shipping date when 
confirmed by Sharp. If the shipment does not arrive as scheduled, please notify your Esanik 
representative immediately. 
Upon receipt of the shipment, the package should be inspected for excessive damage or evidence of 
opening prior to arrival. If the package appears compromised, sequester the shipment and contact Esanik 
for further instructions. This supply must not be placed in the active inventory or used in the clinical trial 
without Esanik’s approval.  
The Pharmacy should open the package as soon as possible and compare the Drug Shipment Form to 
the contents of the shipment upon receipt. If there is a discrepancy between the Drug Shipment Form 
and the shipment contents, if bottles arrive damaged, or a temperature deviation is noted from the 
monitoring device (see below), the Pharmacy should note the problems on the packing invoice and 
contact Esanik immediately for further instruction. 
All shipments will arrive in insulated shippers at approximately 2-8°C, and will include a temperature 
monitoring device to verify temperature during transit. Upon receipt of the shipment, please follow the 
steps below as expeditiously as possible: 
1. Open the package, locate temperature log device. 
2. Follow the instructions provided to review the temperature tracking. 
3. If a temperature deviation is noted, please contact Esanik. 
4. If no temperature deviations are noted, the study drug may be accepted into the active inventory.  
 
Storage 
Upon acceptance, ESK981 must be immediately removed from the shipping cooler and stored 
refrigerated at 2-8°C. The storage temperature should be monitored and recorded daily to ensure 
temperatures are maintained at 2-8°C. Sites unable to record daily temperatures must provide verification 
that there are no temperature deviations.  
ESK981 must be kept in a secure place with limited access under the appropriate storage conditions at 
all times. All personnel involved in the dispensing of investigational product should be aware of its 
location. Any deviations in accountability and/or storage should be reported to Esanik. 
 
Resupply of Investigational Product 
All investigational product resupply requests should be made by faxing or e-mailing the Site 


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Investigational Drug Shipping Request Form (Attachment 2) your CRA or designee. A minimum of two 
weeks (10 business days) is required for routine resupply; therefore, pharmacies are encouraged to 
proactively manage drug inventory to avoid supply problems.  
Nivolumab will be provided by Bristol Myers Squibb and shipped to KCI and University of Michigan 
pharmacy as per institutional Standard Operating Procedures. 
 
Drug Return 
At the conclusion of the study, the pharmacy will receive specific instructions on how to handle any 
undispensed investigational product. Pharmacists are not to return or destroy any unused investigational 
product until these instructions are received.   
 
6.2 Drug Accountability 
General Statement 
Investigators are required to establish a record of receipt, use, and disposition of all investigational 
product for a period of two years following the date that the investigational product is approved by the 
regulatory authority. These drug accountability records must be readily available upon request, and will 
be reviewed during the study. To avoid error, the investigator should contact Esanik Therapeutics, Inc. 
before the destruction of any records pertaining to the study to ensure they no longer need to be retained.  
Study related forms located in the Attachment Section of this manual should be completed using 
permanent black ink only. Any error should be crossed through with a single pen stroke, initialed and 
dated. Do not attempt to cover up an error by scratching it out or concealing it with correction fluid. The 
correct information should be recorded next to the error in an appropriate space. 
 
GC4419 Drug Accountability Record 
Pharmacies may use institutional forms and systems for managing inventory and accountability provided 
they meet regulatory requirements for investigational agents. A log entry is made each time ESK981 is 
received and dispensed by the site.     
The investigator, or a responsible party designated by the investigator, must maintain a careful record of 
the inventory and disposition of the drug Nivolumab. The drug accountability records will capture drug 
receipt, drug dispensing, drug return and final disposition. 
 
6.3 Pharmacokinetics 
 
 6.3.1 ESK981 (aka CEP-11981) 
The pharmacokinetic, ADME, and toxicokinetic characteristics of ESK981 have been extensively studied 
in Sprague Dawley rats and cynomolgus monkeys after intravenous and oral doses and preliminarily in 
Balb/c nude mice after oral doses. In order to facilitate comparisons between studies and species, all 
doses are presented in this summary as milligrams of ESK981 free base per kilogram of body weight, 
regardless of the form administered, unless specifically noted otherwise. 
The intravenous dose in rats was administered in 3% dimethylsulfoxide, 30% Solutol®, and 67% 
phosphate-buffered saline at a volume of 1 mL/kg. In monkeys, the intravenous vehicle was 47.4% 
polyethylene glycol (PEG) 400, 31.1% water, 20.7% hydroxy-β-cyclodextrin (HPBCD), and 0.8% 
Pluronic® F-68 at a volume of 0.5 mL/kg. Pharmacokinetic parameters obtained after single intravenous 
(bolus) administration of ESK981 are summarized in Table 5. 


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Table 5. Pharmacokinetics after Single Intravenous Administration of ESK981. 
 
In rats, the systemic clearance is low relative to the estimated total hepatic plasma flow; the volume of 
distribution is approximately that of total body water. There are apparent sex-related differences in the 
pharmacokinetics of ESK981 in rats, with lower clearance and longer half-life in female rats than in male 
rats. The volume of distribution is numerically less in female rats, but the significance of this difference is 
doubtful. 
In monkeys, the half-life is similar to that in rats, but the systemic clearance is substantially larger than 
that in rats, as is the volume of distribution. The difference in clearance is consistent with the higher rate 
of metabolism of ESK981 in incubations with monkey liver microsomes than with rat liver microsomes. 
The origin of the larger volume of distribution in monkeys is not known. 
Pharmacokinetic parameters obtained after single, low-dose oral administration of ESK981 are 
summarized in Table 6. 
Table 6. Pharmacokinetics after Single Oral Administration of ESK981. 
 
Dose administration in mice was as a suspension of the free base in 0.6% methylcellulose:Tween 80 
(99.5:0.5) at a volume of 25 mL/kg. In rats and monkeys, the dose was administered as a suspension of 
the tosylate salt in Ora-Plus oral suspending vehicle at volumes of 2 and 5 mL/kg, respectively. 
Significant oral bioavailability was obtained in both rats and monkeys. The lack of an intravenous 
comparator dose in mice precluded calculation of the absolute bioavailability in that species, but the 
similarity in systemic exposure in mice relative to rats would suggest that oral bioavailability is 
comparable. 
The effect of fed versus fasted state on the pharmacokinetics of ESK981 was assessed in a preliminary 
study in rats. Cmax and AUC 0-∞ were minimally affected by the fed/fasted state of the animals, but the 


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tmax was shifted from 2.7 to 5.3 hours postdose when the animals had been fed before dosing. 
At higher oral doses of ESK981, there was evidence of dose-dependent pharmacokinetics in all three 
species. In mice, single-dose systemic exposure increased in a slightly more than dose-proportional 
manner between 1 and 10 mg/kg, but did not show consistent further increase at 20 or 30 mg/kg. After 
23 daily doses, the dose response and concentrations were similar to those after single doses at 1, 3, or 
10 mg/kg, but were approximately two times higher in the 20- and 30-mg/kg groups on day 23 versus 
day 1 of dosing. Systemic exposure after multiple daily doses of 20 and 30 mg/kg was dose-related, 
although not dose-proportional, relative to that at 10 mg/kg. 
In male rats, Cmax was approximately dose proportional between 5 and 15 mg/kg, but was less than dose 
proportional between 15 and 40 mg/kg. The increase in AUC0-∞ was greater than dose-proportional 
between 5 and 15 mg/kg, but was approximately dose proportional between 15 and 40 mg/kg. 
In monkeys, increases in both Cmax and AUC0-∞ were greater than dose proportional between 3 and 13.5 
mg/kg. Similar (i.e., greater-than-dose-proportional) increases in systemic exposure were also noted in 
a preliminary study that tested single oral doses as high as 100 mg/kg in monkeys. 
Due to changes in the form of ESK981 that was obtained from successive synthetic campaigns, a series 
of single-dose oral studies were conducted in rats and monkeys to which different forms of the compound 
and/or different dosage regimens were administered. The outcome of those studies indicated that milled 
ESK981 tosylate, administered as a suspension in aqueous methylcellulose and provides systemic 
exposures that are in the targeted ranges in both species. It is that form with which the bulk of the 
nonclinical toxicity testing was done and which will be the form of the compound used in early clinical 
testing. 
The tissue distribution of [14C]- ESK981 was studied in male albino (Sprague Dawley) and pigmented 
(Lister hooded) rats after single doses orally at 10 mg/kg and intravenously at 1 mg/kg, respectively, as 
the tosylate salt. Radioactivity was broadly distributed, with highest concentrations (exclusive of the 
gastrointestinal tract) in the liver, kidney, and adrenal gland. 
Minimal radioactivity was detected in barriered tissues, i.e., brain and testis, but there was apparent 
association with melanin-containing structures such as uveal tract and pigmented skin in the pigmented 
animals. The bulk of the radioactivity was removed from the tissues during the 168- and 24-hour test 
periods in the albino and pigmented animals, respectively. 
 ESK981 is extensively metabolized in vitro by liver microsomes from male Swiss CD1 mice, male 
Sprague Dawley rats, male New Zealand rabbits, male beagle dogs, male cynomolgus monkeys, and 
humans. The relative order of loss of parent compound during 20 minutes of incubation was: monkeys > 
humans > mice ≈ dogs > rats ≈ rabbits. 
Incubations with individual recombinant human CYP enzymes suggested that three enzymes, ie, 
CYP1A2, CYP2C8, and CYP3A4, may play significant roles in the metabolic elimination of ESK981. 
Other CYP enzymes that were also capable of metabolizing the compound in vitro are either minimally 
expressed in adult human liver (i.e., CYP1A1 and CYP3A7) or are polymorphic, being expressed in a 
minority of individuals (i.e., CYP3A5). The results of experiments assessing the effect of CYP-specific 
inhibitors on loss of ESK981 during incubation with human liver microsomes also identified CYP3A 
enzymes as playing a key role in metabolic elimination of the compound. 
After oral administration of [14C] - ESK981, radioactivity was predominantly recovered in the feces in 
both rats and monkeys, with less than 1% of the radiochemical dose recovered in urine of either species. 
Hence, metabolic profiling was conducted in rat bile, in which parent [14C] - ESK981 was the most 
prominent radioactive component, especially in the female rat. 
The most prominent metabolite in both sexes, but especially male, was a monohydroxylated derivative. 
Overall, the reactions previously observed in vitro, i.e., ring hydroxylation, N-demethylation, and reduction 
(didehydrogenation) accounted for all of the ESK981-derived compounds detected in vivo. 
The potential for ESK981 to affect the metabolic elimination of co-administered drugs was tested in vitro 


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through examination of its capacity for induction of CYP enzymes activities in primary human hepatocyte 
cultures and for inhibition of CYP activities in human hepatic microsomal preparations. 
The levels of mRNA for CYP1A1, CYP1A2, CYP2C9, and CYP3A4 were measured after incubation of 
ESK981 with hepatocytes for 30 hours at concentrations of 1 to 30 μM. No indication of induction was 
obtained, but suppression of CYP2C9 and CYP3A4 message was observed at the highest concentration. 
However, due to apparent cellular toxicity at that concentration, this result was likely an artifact. 
ESK981 did not inhibit the activities of CYP2B6, CYP2C9, CYP2C19, CYP2D6, or CYP4A9/11. Marginal 
inhibition of CYP1A2 was observed, but with an estimated Ki that is higher than exposures expected 
clinically. CYP3A4/5 activity was inhibited with a Ki of 2.6 and 2.2 μM for the two reactions examined, 
i.e., testosterone 6β-hydroxylation and midazolam 1′-hydroxylation, respectively. Much of the inhibition 
was reversible and competitive in nature, with a metabolism-dependent component, but at least some of 
the inhibition was irreversible for both reactions tested. 
In addition to the pharmacokinetic and ADME studies, bioanalytical and pharmacokinetic support has 
been provided to the toxicokinetics portions of nonclinical safety studies in rats and monkeys. 
The longest nonclinical safety study conducted to date in rats was a 4-week oral toxicity study at daily 
doses of 0 (vehicle only), 5, 10, 20 (lowered to 15 on day 8), and 40 mg/kg. ESK981 was administered 
as suspensions of its tosylate salt in Ora-Plus oral suspending vehicle. Key toxicokinetic parameters from 
the study are tabulated in Table 7. 
Table 7. Toxicokinetics Results for the 4-Week Oral Toxicity Study in Rats. 
 
As noted in the pharmacokinetic studies, the systemic exposures were higher in female rats than in male 
rats and, in groups having both single-dose and multiple-dose datasets, were higher on day 28 than on 
day 1. Values of Cmax and AUC were dose-related over the dose range tested, but increases in AUC 
were more than dose-proportional over portions of the dose range, suggesting that 1 or more of the 
pharmacokinetic characteristics of ESK981 are dose-dependent. 
Two 4-week oral toxicity studies of ESK981 have been conducted in monkeys. In the first study (study 
DS-2006-020), daily doses of 0 (vehicle only), 5, 10, and 25 mg/kg were administered as suspensions of 
the free base in Ora-Plus oral suspending vehicle. Due to a subsequent change in the form of the 
compound to its tosylate salt, a second 4-week study (study DS-2006-042) was conducted testing daily 
doses of 0 (vehicle only) and 3 mg/kg. Key toxicokinetic parameters from the study are tabulated in Table 


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8. 
Table 8. Toxicokinetics Results for the 4-Week Oral Toxicity Studies in Monkeys. 
 
The monkeys did not show the sex-related differences in systemic exposure that were evident in the rats, 
but there was a suggestion, as in the pharmacokinetic studies, that some aspect(s) of the 
pharmacokinetics of the compound might be dose-dependent, especially at higher doses. 
Overall, the pharmacokinetic and ADME properties of ESK981 have been studied in vitro using blood 
and tissue fractions from mice, rats, rabbits, dogs, monkeys, and humans and in vivo in mice, rats, and 
monkeys. The estimated half-life in rats and monkeys after an intravenous dose is approximately 2 to 3 
hours. Despite its low aqueous solubility, ESK981 is generally well absorbed in mice, rats, and monkeys 
at dose levels associated with pharmacologic responses in preclinical disease models. At higher doses, 
evidence of dose-dependent pharmacokinetics has been obtained in all three species. After an oral or 
intravenous dose, [14C]- ESK981-derived radioactivity is broadly distributed into tissues, generally at 
concentrations higher than those in blood. Only in barriered tissues, e.g., brain and testis, are 
concentrations lower than those in blood. The compound is extensively metabolized, but is also excreted 
in rats via the bile as the parent drug. Excretion is predominantly in the feces in both rats and monkeys. 
 
6.3.2 Nivolumab (OPDIVO) 
Nivolumab pharmacokinetics (PK) was assessed using a population PK approach for both single-agent 
nivolumab and nivolumab with ipilimumab. The PK of single-agent nivolumab was studied in patients 
over a dose range of 0.1 to 20 mg/kg administered as a single dose or as multiple doses of nivolumab 
every 2 or 3 weeks. Nivolumab clearance decreases over time, with a mean maximal reduction (% 
coefficient of variation [CV%]) from baseline values of approximately 24.5% (47.6%) resulting in a 
geometric mean steady state clearance (CLss) (CV%) of 8.2 mL/h (53.9%); the decrease in CLss is not 
considered clinically relevant. The geometric mean volume of distribution at steady state (Vss) (CV%) is 
6.8 L (27.3%), and geometric mean elimination half-life (t1/2) is 25 days (77.5%). Steady-state 
concentrations of nivolumab were reached by approximately 12 weeks when administered at 3 mg/kg 
every 2 weeks, and systemic accumulation was approximately 3.7-fold. The exposure to nivolumab 
increased dose proportionally over the dose range of 0.1 to 10 mg/kg administered every 2 weeks. 


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The PK of nivolumab with ipilimumab resulted in a geometric mean (CV%), CL, Vss, and terminal half-
life of nivolumab were 10.0 mL/h (50.3%), 7.92 L (30.1%), and 24.8 days (94.3%), respectively. When 
administered in combination, the CL of nivolumab was increased by 24%, whereas there was no effect 
on the clearance of ipilimumab. 
 
6.4  Supply, Preparation, Storage and Administration 
6.4.1 Supply and packaging 
 
ESK981 monotosylate is a fully synthetic drug substance containing a core indolocarbazolone ring 
system. ESK981 monotosylate drug substance is a yellow to orange powder that has a molecular weight 
of 649.77 g/mol. The drug substance contains 73.5% theoretical weight percent of the active moiety 
ESK981 (free base). 
 
ESK981 drug product is an off-white to orange opaque, hard gelatin capsule containing 40 mg (free base 
equivalents) of ESK981 monotosylate. The drug product is packaged in a high-density polyethylene 
(HDPE) bottle with a child resistant closure and an induction-sealed inner seal. The formulation also 
contains lactose monohydrate. 
Nivolumab is a human IgG4 anti-PD-1 monoclonal antibody provided as sterile, non-pyrogenic, single-
use, isotonic aqueous solutions for intravenous (IV) infusion in 40 mg/Vial (10 mg/mL), 100 mg/Vial (10 
mg/mL), and 240 mg/Vial (10 mg/mL). Nivolumab has a molecular weight of 143.6 kg/mol. clear to 
opalescent, colorless to pale-yellow solution which may contain light (few) particles. Dilute nivolumab 
with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP, to prepare an infusion 
with a final concentration ranging from 1 mg/mL to 10 mg/mL.  
 
 
 
6.4.2 Storage and handling 
 ESK981 capsules should be stored refrigerated at 2°C to 8°C (36°F to 46°F). The stability of the drug 
substance and drug product continues to be monitored. 
Vials of nivolumab injection must be stored at 2°C to 8°C (36°F to 46°F) and protected from light and 
freezing. The unopened vials can be stored at room temperature (up to 25°C, 77°F) and room light for 
up to 48 hours. The administration of nivolumab infusion must be completed within 24 hours of 
preparation. Discard partially used or empty vials of nivolumab. 
 
6.4.3 Administration 
ESK981 capsules will be distributed to patient, who will then take them orally as directed.  
Nivolumab injection is to be administered as an IV infusion through a 0.2-micron to 1.2-micron pore size, 
low-protein binding (polyethersulfone membrane) in-line filter at the protocol-specified doses and infusion 
times. Coadministration of other drugs through the same intravenous line is prohibited. During drug 
product preparation and handling, vigorous mixing or shaking is to be avoided and flushing the IV line at 
the end of infusion is required. 
 
6.5 Dose Modifications for Adverse Events 
6.5.1 ESK981 
Patients with NCI-CTCAE v.5 Grade 3 adverse events judged to be (at least possibly) related to ESK981 
will have their ESK981 held until the adverse event resolves to Grade 2 or lower. Standard management 
of adverse events should be utilized. Patients may then be restarted on ESK981 at dose level -1.   
Following a dose reduction, patients who have a second NCI-CTCAE v.5 Grade 3 or first Grade 4 adverse 
event judged to be at least possibly related to ESK981 will have their ESK981 held until the adverse 
event resolves to Grade 2 or lower. Patients may then be restarted on ESK981 at dose level -2. Following 
a dose reduction, patients who have a third NCI-CTCAE v.5 Grade 3 or second Grade 4 adverse event 
judged to be at least possibly related to ESK981 will be discontinued from the study. Permanently 
discontinue for some Grade 3 non-hematologic toxicities (e.g. uncomplicated myocardial infarction), 


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Grade 4 non-hematologic toxicity after consult with the PI. If drug cannot be restarted within 3 weeks of 
being held, ESK981 should be discontinued.  
 
6.5.2 Nivolumab 
Withhold nivolumab for any of the following: Grade 2 pneumonitis, Grade 2 or 3 colitis, Aspartate 
aminotransferase (AST) or alanine aminotransferase (ALT) greater than 3 and up to 5 times upper limit 
of normal (ULN) or total bilirubin greater than 1.5 and up to 3 times ULN, Creatinine greater than 1.5 and 
up to 6 times ULN or greater than 1.5 times baseline, or any other severe or Grade 3 treatment-related 
adverse reactions. Resume nivolumab in patients whose adverse reactions recover to Grade < 2. There 
will be no dose reductions of nivolumab. 
Permanently discontinue nivolumab for any of the following: any life-threatening or Grade 4 adverse 
reaction, Grade 3 or 4 pneumonitis, AST or ALT greater than 5 times ULN or total bilirubin greater than 
3 times ULN, creatinine greater than 6 times ULN, any severe or Grade 3 treatment-related adverse 
reaction that recurs, inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent 
per day within 12 weeks, persistent Grade 2 or 3 treatment-related adverse reactions that do not recover 
to Grade 0-1 within 12 weeks after last dose of nivolumab. 
Hematological Toxicity Dose Reductions for ESK981 
ANC1 
Platelets 
Action 
≥ 1,500/µL or 
>100,000/µL 
None. 
1000-1499/µL or 
75,000-99,000/µL 
-1st Occurrence: Hold current dose until ANC ≥ 
1,500/µL and platelets ≥ 100,000/µL. Do not 
replace missed doses. Restart next treatment at 
1 dose lower. 
-2nd Occurrence: Hold current dose until ANC ≥ 
1,500/µL and platelets ≥ 100,000/µL. Do not 
replace missed doses. Restart next treatment at 
1 dose lower if available or discontinue if not 
available 
-3rd Occurrence: Discontinue protocol therapy. 
500-999/µL or 
50,000-74,000/µL 
-1st Occurrence: Hold current dose until ANC ≥ 
1,500/µL and platelets ≥ 100,000/µL. Do not 
replace missed doses. Restart next treatment at 
1 dose lower if available or discontinue if not 
available. 
-2nd Occurrence: Hold current dose until ANC ≥ 
1,500/µL and platelets ≥ 100,000/µL. Do not 
replace missed doses. Restart next treatment at 
1 dose lower if available or discontinue if not 
available. 
-3rd Occurrence: Discontinue protocol therapy. 
<500/µL or 
<50,000/µL 
-1st Occurrence: Hold current dose until ANC ≥ 
1,500/µL and platelets ≥ 100,000/µL. Restart 
next treatment at 1 dose lower if available or 
discontinue if not available. 
-2nd Occurrence: Discontinue protocol therapy. 
1Note: G-CSF (Filgrastim) may be added for low ANC on day of treatment BEFORE a dose 
reduction is instituted at treating physician’s discretions. Neulasta® is NOT allowed. 


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Non-hematological Toxicities 
NCI CTCAE v.5 Grade ESK981 
Nivolumab 
0-2 
No change from original starting 
dose 
No change from original starting 
dose 
3 
Hold until resolved to ≤ Grade 2, 
then reduce to1 dose lower if 
available or discontinue if not 
available 
Hold until resolved to ≤ Grade 2, 
For some serious non-
hemotologic grade 3 
toxicities (e.g. 
uncomplicated 
myocardial infarction) 
Remove subject from trial 
Remove subject from trial 
Second episode of grade 
3  
Hold until resolved to ≤ Grade 2, 
then reduce to 1 dose lower if 
available or discontinue if not 
available 
Hold until resolved to ≤ Grade 2,  
Third episode of grade 3 
or 2nd episode grade 4 
toxicity 
Remove subject from trial 
Remove subject from trial 
 
6.6 
Management of Expected Toxicities 
Event Name 
Nausea 
Grade of Event 
Management/Next Dose 
Grade 1 
No change in dose 
Grade 2 
No change in dose 
Grade 3-4 
Hold until ≤ Grade 2. Resume at one dose level lower, if 
indicated per Section 6.5. 
Recommended management:  antiemetics. 
 
Event Name 
Vomiting 
Grade of Event 
Management/Next Dose 
Grade 1 
No change in dose 
Grade 2 
No change in dose 
Grade 3-4 
Hold until ≤ Grade 2. Resume at one dose level lower, if 
indicated per Section 6.5. 
Recommended management:  antiemetics. 
 
Event Name 
Diarrhea 
Grade of Event 
Management/Next Dose 
Grade 1 
No change in dose 
Grade 2 
No change in dose 
Grade 3-4 
Hold until ≤ Grade 2. Resume at one dose level lower, if 
indicated per Section 6.5. 
Recommended management:  Loperamide anti-diarrheal therapy 
Dosage schedule:  4 mg at first onset, followed by 2 mg with each loose motion 


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until diarrhea-free for 12 hours (maximum dosage:  16 mg/24 hours) 
Adjunct anti-diarrheal therapy is permitted and should be recorded when used. 
 
Event Name 
Neutropenia 
Grade of Event 
Management/Next Dose 
Grade 1 
No change in dose 
Grade 2 
No change in dose 
Grade 3-4 
Hold until ≤ Grade 2. Resume at one dose level lower, if 
indicated per Section 6.5. 
Recommended management:  Use of growth factors is not recommended. 
Management of neutropenia should be by dose reduction. For grade 4 febrile 
neutropenia, discontinue treatment. 
 
Event Name 
Anemia 
Grade of Event 
Management/Next Dose 
Grade 1 
No change in dose 
Grade 2 
No change in dose 
Grade 3-4 
Hold until ≤ Grade 2. Resume at one dose level lower, if 
indicated per Section 6.5. 
Recommended management:  Treat by using local standards. 
 
Event Name 
Thrombocytopenia 
Grade of Event 
Management/Next Dose 
Grade 1 
No change in dose 
Grade 2 
No change in dose 
Grade 3-4 
Hold until ≤ Grade 2. Resume at one dose level lower, if 
indicated per Section 6.5. 
Recommended management:  Treat by using local standards. 
 
Event Name 
Hypertension 
Grade of Event 
Management/Next Dose 
Grade 1 
No change in dose 
Grade 2 
No change in dose 
Grade 3-4 
Hold until ≤ Grade 2. Resume at one dose level lower, if 
indicated per Section 6.5. 
Recommended management:  Treat by optimizing or adding antihypertensive 
medications to achieve well-controlled blood pressure of < 150/90 mmHg. 
 
 
Event Name 
Left Ventricular Dysfunction 
Grade of Event 
Management/Next Dose 
Grade 1 
No change in dose 
Grade 2 
No change in dose 
Grade 3-4 
Hold until ≤ Grade 2. Resume at one dose level lower, if 
indicated per Section 6.5. 
Recommended management: Treat by optimizing or adding cardiovascular 
medications for management of congestive heart failure. 
 
Event Name 
Cardiac Arrhythmias 
Grade of Event 
Management/Next Dose 
Grade 1 
No change in dose 
Grade 2 
No change in dose 


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Grade 3-4 
Hold until ≤ Grade 2. Resume at one dose level lower, if 
indicated per Section 6.5. 
Recommended management: Identify appropriate arrhythmias such as atrial 
fibrillation, atrial flutter, atrioventricular blocks, and other conduction disorders. 
Treat appropriate medications or procedures as established by standard of care. 
 
Event Name 
Fatigue 
Grade of Event 
Management/Next Dose 
Grade 1 
No change in dose 
Grade 2 
No change in dose 
Grade 3-4 
Hold until ≤ Grade 2. Resume at one dose level lower, if 
indicated per Section 6.5. 
Recommended management: Optimize supportive care. 
 
If nivolumab is discontinued, ESK981 may continue and vice versa. 
 
6.7 
Concomitant Medications and Supportive Care 
Because of the potential for drug-drug interaction, the concurrent use of all other drugs, over-the-counter 
medications, and alternative therapies must be documented on the CRF. The principal investigator 
should be alerted if the patient is taking any agent found in Appendix B (a listing of medications with the 
potential for drug-drug interaction). 
Systemic corticosteroids greater than the equivalent of 10 mg of prednisone or equivalent alternative 
steroid (except physiologic dose for adrenal replacement therapy) or other immunosuppressive agents 
(such as cyclosporine or methotrexate) and any other medications that could potentially impact the 
efficacy or safety of the study as judged by the treating investigator are NOT permitted from time of 
registration to subjects completing protocol therapy unless clinically indicated to manage adverse events 
or life threatening or serious conditions as determined by the treating investigator. 
 
Subjects are prohibited from receiving the following therapies during the Screening and Treatment Phase 
of this trial: 
Immunotherapy not specified in this protocol 
Chemotherapy not specified in this protocol 
Investigational agents other than ESK981 or checkpoint inhibitor immunotherapy 
Neulasta® 
Live vaccines within 30 days prior to the initial study treatment administration through the last 
dose of study treatment. Examples of live vaccines include, but are not limited to, the following: 
measles, mumps, rubella, varicella/zoster, yellow fever, intranasal influenza, rabies, BCG 
(tuberculosis vaccine), and typhoid vaccine. If precluded by local regulations, live vaccines should 
not be given for 120 days after the last dose of checkpoint inhibitor immunotherapy is 
administered. 
Systemic glucocorticoids or other immunosuppressive drugs for any purpose other than to 
modulate symptoms from a drug-related AE of immunologic etiology. The use of physiologic 
doses of corticosteroids may be approved after consultation with the Study PI. Use of prophylactic 
corticosteroids to avoid allergic and other adverse reactions (e.g., to IV contrast dye or 
transfusions) is permitted. 
 
Use of intermittent inhaled steroids or local injection of corticosteroids is permitted upon 
consultation with the Principal Investigator. Physiologic doses of prednisone ≤10 mg (or 
equivalent) per day. 
 
Other Modalities or Procedures 
No other modalities or procedures will be used in this protocol. 


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6.7.1 Supportive Care Medications 
Patients should receive appropriate supportive care for CRPC and appropriate treatment for 
comorbidities, subject to the restrictions to due potential drug-drug interactions detailed in Section 6.5.3.  
 
6.7.2  Prohibited before enrollment and during administration of study treatment 
Concomitant systemic treatments for CRPC (other than a GnRH agonist/antagonist) or within two weeks 
of cycle 1/day 1 are prohibited including: CYP-17 inhibitors (e.g. ketoconazole, abiraterone), 
antiandrogens (e.g. bicalutamide, nilutamide), second generation antiandrogens (e.g. enzalutamide, 
ARN-509, Galeterone), immunotherapy (e.g. sipuleucel-T, ipilimumab), and chemotherapy (e.g. 
docetaxel, cabazitaxel). 
 
6.7.3  Potential for drug-drug interactions 
ESK981 is metabolized via CYP1A2, CYP2C8, and CYP3A4. Inhibitors of CYP1A2, CYP2C8, and 
CYP3A4 have the potential to increase plasma concentration of ESK981. Inducers of CYP1A2, CYP2C8, 
and CYP3A4 have the potential to decrease plasma concentrations of ESK981. Concomitant use of a 
medication known to be a potent inhibitor of CYP1A2, CYP2C8, or CYP3A4 (see Appendix B), or a potent 
inducer of CYP1A2, CYP2C8, or CYP3A4 (see Appendix B) should be avoided unless deemed to be 
medically necessary by the investigator. Patients on specific medications deemed medically necessary 
by the investigator (e.g. anti-arrhythmic drugs and anticoagulants) that are expected to have an 
interaction and could be potentially high risk should be excluded from this study. In addition, nonclinical 
studies have identified the potential for ESK981 to inhibit CYP3A4/5 (Ki 2.2μM). ESK981 has the potential 
to increase plasma concentration of concomitant mediations that are CYP3A4/5 substrates. Caution 
should be used, or alternative treatments considered, if concomitant treatment with CYP3A4/5 substrates 
that have a narrow therapeutic range is needed (see Appendix B). 
 
7. Safety Evaluation 
 
7.1 Definitions 
7.1.1 Adverse Event (AE)  
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship with 
this treatment (ICH E2A). An adverse event for the purposes of this protocol is the appearance of 
(or worsening of any pre-existing) undesirable sign(s), symptom(s), or medical condition(s) 
occurring after signing the informed consent even if the event is not considered to be related to 
the study drug(s). An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not related to the medicinal product. 
 
An abnormality identified during a medical test (e.g. laboratory parameter, vital sign, ECG data, 
physical exam) should be defined as an AE only if the abnormality meets one of the following 
criteria: 
• 
Requires active intervention 
• 
Requires interruption or discontinuation of study medication 
The abnormality or investigational value is clinically significant in the opinion of the investigator. 
An adverse event will be recorded and followed from treatment administration to 30 days post-
treatment or resolution. 
 
7.1.2 Expected Adverse Events 
Expected adverse events are those that have been previously identified as resulting from 
administration of the agent. An adverse event can be considered expected when it appears in the 
current adverse event list, the Investigator’s Brochure, the package insert or is included in the 


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informed consent document as a potential risk. 
 
7.1.3 Unexpected Adverse Events 
Adverse reactions are those that the nature or severity of which is not consistent with the 
applicable product information (e.g., Investigator's Brochure for an unapproved investigational 
medicinal product) (ICH E2A). 
 
Contact the Principal Investigator or sponsor to confirm unexpected adverse events when 
necessary.  
 
7.1.4 Adverse Drug Reaction (ADR) 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered adverse drug reactions (ICH E2A). 
  
The phrase "response to a medicinal product" means that a causal relationship between a 
medicinal product and an adverse event is at least a reasonable possibility, i.e., the relationship 
cannot be ruled out. ‘‘Reasonable possibility’’ means there is evidence to suggest a causal 
relationship between the drug and the adverse event.  
 
7.1.5 Serious Adverse Event (SAE) 
An SAE/ADR as defined in the Code of Federal Regulations (21 CFR § 312.32) is any event that: 
• 
results in death 
• 
is life-threatening 
• 
results in inpatient hospitalization or prolongation of existing hospitalization 
• 
results in persistent or significant disability or incapacity 
• 
results in congenital anomaly or birth defect 
• 
is medically significant in the opinion of the investigator 
 
Events that are not considered serious adverse events include: 
• 
routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, or for elective procedures 
• 
elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and did not worsen since signing the informed consent 
• 
emergency outpatient treatment for an event not fulfilling the serious criteria outlined 
above and not resulting in inpatient admission 
• 
respite care 
 
7.1.6 Progression of malignancy 
Progression of a patient’s malignancy should not be considered an AE, unless in the investigator’s 
opinion, study treatment resulted in an exacerbation of the patient’s condition. If disease 
progression results in death or hospitalization while on study or within 30 days of the last dose, 
progressive disease will be considered an SAE. 
 
7.1.7 Life-threatening  
An adverse event or suspected adverse reaction is considered “life-threatening “if, in the view of 
either investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred 
in a more severe form, might have caused death (FDA 21 CFR § 312.32). 
 
7.1.8 Hospitalization (or prolongation of hospitalization) 
Hospitalization encompasses any inpatient admission (even for less than 24 hours) resulting from 
a precipitating, treatment-emergent adverse event. For chronic or long-term patients, inpatient 
admission also includes transfer within the hospital to an acute or intensive care inpatient unit. 


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Hospitalizations for administrative reasons or a non-worsening preexisting condition should not 
be considered AEs (e.g., admission for workup of a persistent pretreatment laboratory 
abnormality, yearly physical exam, protocol-specified admission, elective surgery). Preplanned 
treatments or surgical procedures should be noted in the baseline documentation. Hospitalization 
because of an unplanned event will be deemed an SAE. 
 
Prolongation of hospitalization is any extension of an inpatient hospitalization beyond the stay 
anticipated or required for the original reason for admission. 
 
7.1.9 Persistent or Significant disability/incapacity 
Any AE that results in persistent or significant incapacity or substantial disruption of the patient’s 
ability to conduct normal life functions. 
 
7.1.10 Congenital anomaly 
If the female partner of a male patient becomes pregnant during the course of the study, the 
treating physician must be notified immediately. All confirmed pregnancies must be immediately 
reported to the sponsor-investigator. All pregnancies will be followed until resolution (i.e., 
voluntary or spontaneous termination or birth) and assessed for congenital anomalies and birth 
defects. 
 
7.2 Recording and Grading of Adverse Events 
7.2.1 Recording 
All observed or volunteered adverse events, regardless of treatment group, severity, suspected 
causal relationship, expectedness, or seriousness will be recorded on the Medical History/Current 
Medical Conditions Electronic Case Report Form. 
The occurrence of adverse events should be sought by non-directive questioning of the patient at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the patient during or between visits or through physical examination, laboratory test, or other 
assessments. As far as possible, each adverse event should be evaluated to determine: 
a. 
The severity grade (CTCAE v.5 grade 1-4) 
b. 
Its relationship to each study drug (suspected/not suspected) 
c. 
Its duration (start and end dates or if continuing at final exam) 
d. 
Action taken (no action taken; study drug dosage adjusted/temporarily interrupted; study drug 
permanently discontinued due to this adverse event; concomitant medication taken; non-
drug therapy given; hospitalization/prolonged hospitalization) 
Adverse events (but not serious adverse events) occurring before starting study treatment, but 
after signing the informed consent form are recorded on the Medical History/Current Medical 
Conditions Electronic Case Report Form. Abnormal laboratory values or test results constitute 
adverse events only if they induce clinical signs or symptoms, are considered clinically significant 
or require therapy (e.g., any hematologic abnormality that requires transfusion or cytokine 
treatment), and should be recorded on the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them. In addition, isolated abnormal laboratory values that are 
considered clinically significant (e.g., cause study discontinuation or constitutes in and of itself a 
Serious Adverse Event) should be recorded on the Adverse Events CRF. SAEs occurring after 
the start of treatment are recorded on the Adverse Event CRF. 
A clinically significant change in a physical examination finding or an abnormal test result should 
be recorded as an AE, if it: 
• 
is associated with accompanying symptoms, 
• 
requires additional diagnostic testing or medical or surgical intervention, 


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• 
leads to a change in study dosing or discontinuation from the study, 
• 
requires additional concomitant drug treatment or other therapy, or 
• 
is considered clinically significant by the investigator.  
An abnormal test result that is subsequently determined to be in error does not require recording 
as an adverse event, even if it originally met one or more of the above criteria. 
 
7.2.2 Grading severity 
Adverse events will be assessed according to the Common Toxicity Criteria for Adverse Events 
[CTCAE] version 5. If CTCAE v.5 grading does not exist for an adverse event, the severity of mild, 
moderate, severe, and life-threatening, or Grades 1 - 4, will be used. CTCAE v.5 Grade 5 (death) 
will not be used in this study; rather, this information will be collected in the End of Treatment or 
Survival Information CRF page. Adverse event monitoring should be continued for at least 4 
weeks following the last dose of study treatment. 
 
7.2.3 Attributing causality 
After assigning a grade to an adverse event, the investigator must evaluate all AEs for possible 
causal relationship to the investigational agent. Causality attribution will be decided using the 
criteria outlined in Table 9. 
Table 9. Relationship of Adverse Event to Study 
Drug 
Relationship 
Description 
Unrelated 
AE is clearly not related  
Unlikely 
AE is doubtfully related  
Possible 
AE may be related  
Probable 
AE is likely related  
Definite 
AE is clearly related  
 
7.3 Adverse Events Reporting 
7.3.1 Regulatory and reporting requirements 
These will be followed per IND requirements (if applicable) as well as sponsor requirements and 
WSU IRB requirements. 
 
7.3.2 WSU IRB Adverse Event Reporting Guidelines 
Unexpected Problem – Risk to participant or others. A problem that is a) unforeseen, b) indicates 
that participants or others are at increased risk of harm, and c) is related or possibly related to the 
research. The following are examples of unexpected problems:  
1. 
Adverse Event: Any harm experienced by a participant regardless of whether the event was 
internal (on-site) or external (off-site) and regardless of whether the event meets the FDA 
definition of “serious adverse event”, which in the opinion of the principal investigator are both 
unexpected, related (definitely, probably, or more likely than not), and suggests that 
participants are at greater risk than was previously known or recognized.  
a. An adverse event is “unexpected” when its specificity and severity are not accurately reflected 
in the informed consent document, the protocol or the investigator’s brochure.  
b. An adverse event is “related to the research procedures” if in the opinion of the principal 
investigator it was more likely than not to be caused by the research procedures, or if it is 
more likely than not that the event affects the rights and welfare of current participants.  


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2. 
Any harm experienced by a participant or others as a result of involvement in research 
activities (internal or external excluding adverse events).  
3. 
Information that indicates a change to the risks or potential benefits of the research. For 
example:  
a. An interim analysis or safety monitoring report indicates that frequency or magnitude of harm 
or benefit may be different than initially presented to the IRB.  
b. A paper is published from another study that shows the risks or potential benefits to your 
research may be different than initially presented to the IRB.  
c. Study put on hold by the PI, FDA, or the Sponsor for reasons that may include safety, toxicity 
and/or efficacy.  
4. 
A change in FDA labeling or withdrawal from marketing of a drug, device, or biologic used in a 
research protocol.  
5. 
Change to the protocol taken without prior IRB review to eliminate an apparent immediate 
hazard to a research participant.  
6. 
Research conducted without prior WSU IRB approval.  
7. 
Event that requires prompt reporting to the sponsor.  
8. 
Unanticipated adverse device effect: Any serious adverse effect on health or safety, or any life-
threatening problem or death caused by, or associated with, a device if that effect, problem, or 
death was not previously identified in natured, severity, or degree of incidence in the 
investigational plan or application (including a supplementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or welfare 
of subjects.  
9. 
Sponsor-imposed suspension for risk.  
10. Complaint of a participant when the complaint indicates unexpected risks or cannot be resolved 
by the research team.  
11. A breach of confidentiality.  
12. Protocol violation/deviation (meaning an accidental or unintentional change to the IRB-
approved protocol) that harmed participants or others, that indicates participants or others may 
have been placed at increased risk of harm, or rights of research participants were violated. For 
example:  
a. Failure to draw safety labs  
b. Request for continuation submitted late to the IRB three years in a row  
c. Wrong informed consent signed or failure to obtain informed consent  
13. Incarceration of a participant in a protocol not approved to enroll prisoners. 
14. All deaths that have happened at WSU or one of its affiliates within 30 days of the last 
study intervention, and not related to progressive disease. 
15. Any death, if the PI feels that it is significant no matter when it occurs.  
 
IRB Policy  
Principal investigators must report any of the above to the IRB as soon as possible, but in all 
cases within 5 working days.  
 
7.4   Serious Adverse Event Reporting  


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After the start of treatment and up to 30 days after the last dose, the investigator will complete and 
submit a Medwatch 3500a form, containing all required information (reference CFR § 312.32) within 
24 hours of awareness of a serious adverse event, whether or not related to the study drug. The 
investigator will submit a copy of this Medwatch 3500a form to the sponsor-investigator, Esanik and 
Bristol-Myers Squibb by either e-mail or fax, within the same timeframe. 
The SAE documentation, including the Medwatch 3500A form and available source records should 
be emailed or faxed to:  
 
Email: drugsafety@esanik.com 
 
Worldwide.Safety@BMS.com 
Fax: 610-408-0321 (Esanik) 
 
609-818-3804 (BMS) 
The following minimum information is required:  
• 
study number 
• 
subject number, sex and age  
• 
the date of report  
• 
a description of the SAE (event, seriousness of the event)  
• 
causal relationship to the study drug. Follow-up information for the event should be 
sent within 7 days as necessary. Copy of above should also be sent to coordinating 
site (PI- Dr. Elisabeth Heath).  
Sponsor-Investigator:  
Elisabeth I. Heath, MD FACP 
 
 
Tel: 313-576-8717 
4100 John R 
 
 
 
 
Fax: 313-576-8767 
Detroit, MI 48201  
 
 
 
Email: heathe@karmanos.org 
 
7.4.1  Safety Reporting Requirements for IND Holders  
In accordance with 21 CFR § 312.32, sponsor-investigators of studies conducted under an IND 
must comply with following safety reporting requirements:  
Expedited IND Safety Reports: 
 
7.4.2  Calendar-Day Telephone or Fax Report:   
The Sponsor-Investigator is required to notify the FDA of any fatal or life-threatening adverse 
event that is unexpected and assessed by the investigator to be possibly related to the use of 
ESK981 and Nivolumab. An unexpected adverse event is one that is not already described in the 
Investigator Brochure. Such reports are to be telephoned or faxed to the FDA within 7 calendar 
days of first learning of the event. Each telephone call or fax transmission (see fax number below) 
should be directed to the FDA new drug review division in the Center for Drug Evaluation and 
Research or in the product review division for the Center for Biologics Evaluation and Research, 
whichever is responsible for the review of the IND. 
15 Calendar-Day Written Report:   
The Sponsor-Investigator is also required to notify the FDA and all participating investigators, in 
a written IND Safety Report, of any serious, unexpected AE that is considered possibly related to 
the use of ESK981 and Nivolumab. An unexpected adverse event is one that is not already 
described in the Investigator Brochure. 
Written IND Safety Reports should include an Analysis of Similar Events in accordance with 
regulation 21 CFR § 312.32. All safety reports previously filed with the IND concerning similar 


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events should be analyzed. The new report should contain comments on the significance of the 
new event in light of the previous, similar reports.  
Written IND safety reports with Analysis of Similar Events are to be submitted to the FDA, Esanik 
Drug Safety, and all participating investigators within 15 calendar days of first learning of the 
event. The FDA prefers these reports on a MedWatch 3500a Form but alternative formats are 
acceptable (e.g. summary letter). 
FDA fax number for IND Safety Reports: 
1 (800) FDA-0178 
IND Annual Reports  
In accordance with the regulation 21 CFR § 312.32, the Sponsor-Investigator shall within 60 days 
of the anniversary date that the IND went into effect submit a brief report of the progress of the 
investigation. Please refer to Code of Federal Regulations, 21 CFR § 312.32 for a list of the 
elements required for the annual report. All IND annual reports submitted to the FDA by the 
Sponsor-Investigator should be copied to Esanik.  
 
7.5   Procedure in Case of Pregnancy  
The effect of study drugs in pregnant and lactating women is not known, but the exposure of a 
fetus or nursing infant is considered a potential risk, as study drugs may cause fetal harm based 
on its mechanism of action. Subjects receiving study drugs must be willing to use contraception by 
a method that is deemed effective by the Investigator throughout the treatment period and for at 
least 5 months following the last dose of therapy. 
If, during the conduct of the clinical trial, a male subject impregnates his partner, the subject should 
report the pregnancy to the investigator. The investigator should report the pregnancy to the 
sponsor as an SAE within 24 hours of awareness of the event. The expected date of delivery or 
expected date of the end of the pregnancy, last menstruation, estimated fertility date, pregnancy 
result and neonatal data etc., should be included in this information.  
The investigator should report the outcome of the pregnancy (independent of outcome, e.g., full 
term delivery, pre-term delivery, spontaneous abortion, induced abortion, stillbirth, death of 
newborn, congenital anomaly [including anomaly in a miscarried fetus, etc.]) in accordance with 
the same reporting procedure as for SAEs. The date of outcome of the pregnancy, gestational 
age, date of birth and neonatal data etc., should be included in this information. 
 
8. Criteria for Outcome Assessment/Therapeutic Response 
8.1 Outcome Assessment 
All baseline evaluations will be performed as closely as possible to the beginning of treatment (<4 
weeks). For subsequent evaluations, the method of assessment and techniques will be the same 
as those used at baseline. 
8.1.1 Measurement of clinical lesions 
Only superficial clinical lesions (e.g., skin nodules and palpable lymph nodes) are considered 
measurable. In the case of skin lesions, documentation by color photography, including a ruler to 
estimate the size of the lesion, is recommended. 
8.1.2 Chest x-ray 
Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and 
surrounded by aerated lung; however, CT is preferable to x-ray. 
8.1.3 Conventional CT, MRI, positron emission tomography (PET), bone scan 
To assess the antitumor effect of a treatment, imaging-based evaluation is preferable to 
evaluation by clinical examination. CT and MRI should be performed using contiguous slices of 
10 mm or less. Spiral CT should be performed using a 5-mm contiguous reconstruction 


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algorithm (interval). If a 5-mm contiguous reconstruction algorithm (interval) is not used, as a 
general rule, the lesion diameter should be no less than double the reconstruction algorithm 
(interval) and must be at least 20 mm for a nonspiral CT or at least 10 mm for spiral CT. (If 
available, spiral CT is preferred in all instances.) A technetium-99m bone scan will be performed 
at screening and at each tumor assessment during the study to evaluate bone metastasis. For 
adequate assessment of bone lesions, it is expected that the radiologist will adjust window 
leveling accordingly. This applies to tumors of the chest, abdomen, and pelvis. Head and neck 
tumors and those of the extremities typically require specific protocols.  
 
8.1.4 Ultrasound 
When the primary endpoint of the study is objective response, ultrasound should not be used to 
measure tumor lesions. Ultrasound may be appropriate, however, as a possible alternative to 
clinical measurements of superficial, palpable lymph nodes, subcutaneous lesions, or thyroid 
nodules, or to confirm the complete disappearance of superficial lesions (usually assessed by 
clinical examination). 
 
8.1.5 Endoscopy/laparoscopy 
Using endoscopy of laparoscopy for objective tumor evaluation has not yet been fully validated 
and should be restricted. These techniques may be useful, however, to confirm complete 
pathological response when biopsies are obtained.  
 
8.1.6 Tumor markers 
Tumor markers alone cannot be used to assess response. If markers are initially above the ULN, 
they must normalize for a patient to be considered in complete clinical response.  
 
8.1.7 Cytology/histology 
In certain situations, cytology and histology can be used to differentiate response (e.g., residual 
lesions in tumor types, such as germ cell tumors, where known residual benign tumors can 
remain). When the measurable tumor has met criteria for response or stable disease, cytological 
confirmation of the neoplastic origin of any effusion that appears or worsens during treatment is 
mandatory to differentiate between response, stable disease, and progressive disease. 
 
8.2 Therapeutic Response 
Response and progression will be evaluated in this study using a combination of the revised Response 
Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria22 and the guidelines for prostate cancer 
endpoints developed by the Prostate Cancer Clinical Trials Working Group (PCWG3).2 
 
Trial objectives are defined based on controlling, relieving, or eliminating disease manifestations that are 
present when treatment is initiated, or preventing or delaying the development of disease manifestations 
that are expected to occur (or in some cases both). Identify whether control/relieve/eliminated or 
prevent/delay endpoints. Traditional measures of response reflect when a treatment is working and 
measures of progression indicate when a drug should be stopped. Because assessing response in bone 
(the most common site of prostate cancer spread) is uncertain and the clinical significance of PSA 
changes in response to therapy is not a reliable predictor of response, measures of response have been 
expanded in consortium trials to include measures of progression. 
Patients will need to be reevaluated for response every cycle (or more frequently if indicated), 
according to the guidelines below. 
 
 
8.2.1 PSA 
In this study, PSA testing is being performed on days 8, 15, and 22 of Cycle 1, Day 1 of Cycle 2 and each 
subsequent cycle (every 4 weeks) with the threshold PSA level at 2.0 ng/mL. To report PSA-based 
outcomes, PCWG3 recommends that the percent of change in PSA from baseline to 8 weeks (or earlier 


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for those who discontinue therapy) and the maximum decline in PSA that occurs at any point after 
treatment be reported for each patient using a waterfall plot.2 Because the rate of rise has shown 
prognostic significance, estimate a pretreatment PSA doubling time (PSA-DT) if at least 3 values are 
available, but do not delay either treatment or enrollment onto a trial simply to estimate PSA-DT. Because 
declines in serum PSA, if they occur, may not do so for several weeks, PSA measurements obtained 
during the first 8 weeks should not be used as the sole criterion for clinical decision making. 
 
Change in PSA from pretreatment baseline to Week 8 (i.e., after completion of Cycle 2 of treatment) will 
be determined. A decrease of ≥ 50% (i.e., a change of -50% or greater decrease) will be considered a 
PSA 50% response. The primary endpoint will be denoted “PSA50”, (yes/no). 
 
8.2.2 Measurable Disease 
Measurable lesions are defined as those that can be accurately measured in at least one dimension as 
≥ 20 mm by chest x-ray, as ≥ 10 mm with CT or MRI scan, or ≥ 10 mm with calipers by clinical exam. All 
tumor measurements must be recorded in millimeters. NOTE: tumor lesions that are situated in a 
previously irradiated area may or may not be considered measurable. If the investigator thinks it 
appropriate to include, then the conditions under which such lesions should be considered must be 
defined in the protocol. 
 
Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph node must be ≥ 15 mm in short axis 
when assessed by CT or MRI scan (CT scan slice thickness recommended to be no greater than 5 mm). 
At baseline and in follow-up, only the short axis will be measured and followed. 
 
Non-measurable Disease 
All other lesions (or sites of disease), including small lesions (longest diameter < 10 mm or pathological 
lymph nodes with ≥ 10 to < 15 mm short axis) are considered non-measurable disease. Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pneumonitis, 
inflammatory breast disease and abdominal masses (not followed by CT or MRI) are considered as non-
measurable. Non-measurable also includes lesions that are < 20mm buy chest x-ray. Cystic lesions that 
meet the criteria for radiographically defined simple cysts should not be considered as malignant lesions 
(neither measurable nor non-measurable) since they are, by definition, simple cysts. ‘Cystic lesions’ 
thought to represent cystic metastases can be considered as measurable lesions, if they meet the 
definition of measurability described above. However, if non-cystic lesions are present in the same 
patient, these are preferred for selection as target lesions. 
 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative 
of all involved organs, should be identified as target lesions and recorded and measured at baseline. 
Target lesions should be selected on the basis of their size (lesions with the longest diameter, shortest 
diameter for lymph nodes), be representative of all involved organs, but in addition should be those 
that lend themselves to reproducible repeated measurements. It may be the case that, on occasion, 
the largest lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion which can be measured reproducibly should be selected. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions 
will be calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the 
sum, then only the short axis is added into the sum. The baseline sum of the diameters will be used as 
reference to further characterize any objective tumor regression in the measurable dimension of the 
disease. 
Non-target Lesions 
All other lesions (or sites of disease) including any measurable lesions over and above the 5 target 
lesions should be identified as non-target lesions and should also be recorded at baseline. 


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Measurements of these lesions are not required, but the presence or absence of unequivocal 
progression of each should be noted throughout follow- up. 
 
8.2.3 Methods for Evaluation of Disease 
Conventional CT and MRI 
This guideline has defined measurability of lesions on CT scan based on the assumption that CT slice 
thickness is 5 mm or less. If CT scans have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness. MRI is also acceptable in certain situations (e.g. 
for body scans). 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; 
however, there are many image acquisition variables involved in MRI which greatly impact image 
quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable 
globally. As with CT, if an MRI is performed, the technical specifications of the scanning sequences 
used should be optimized for the evaluation of the type and site of disease. Furthermore, as with 
CT, the modality used at follow-up must be the same as was used at baseline and the lesions 
should be measured/assessed on the same pulse sequence. It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body parts, and 
diseases. 
Ideally, the same type of scanner should be used and the image acquisition protocol should be followed 
as closely as possible to prior scans. Body scans should be performed with breath-hold scanning 
techniques, if possible. 
 
8.2.4    Methods for Evaluation of Bone Disease 
 
Evaluation of Radionuclide Bone Scans: Bone disease will be evaluated using radionuclide bone scan. 
NOTE: Will follow PCWG3 
Interpretation of serial changes in a radionuclide bone scan is well recognized to be highly subjective. 
Thus, the primary outcome will be whether the bone scan is stable or improved, vs. worse or 
progression. Changes in intensity will not be used as an outcome measure. The 2+2 rule will be applied 
for interpretation of bone scans: 
Stable or Improved: Include the appearance of at least 2 new skeletal lesions on the first post-
treatment scan performed 6 or more weeks later or changes in intensity of a preexisting lesion will be 
considered stable disease unless associated with other signs of progression. 
Progression (Non-Response): Must be documented as the appearance of at least two additional new 
lesions on the next scan after the first 2 new lesions were noted. If at least two additional new lesions 
are seen on the next (confirmatory) scan the date of progression is the date of the first post treatment 
san when the first two new lesions were documented. An increase in the size or intensity of known 
skeletal lesions will not be considered progression. 
8.3 Response Criteria  
8.3.1. Evaluation of Target Lesions 
 
Complete Response (CR) 
Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must 
have reduction in short axis to < 10 mm. 
 
Partial Response (PR) 
At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline 
sum diameters. 
 
Progressive Disease (PD) 


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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 progression (see “Evaluation of New 
Lesions” below). 
 
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. (Note: a change of 20% or more that does not increase the 
sum of the diameters by 5 mm or more is coded as stable disease) 
 
To be assigned a status of stable disease, measurements must have met the stable disease criteria 
at least once after study entry at a minimum interval of 8 weeks. 
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 (e.g., fine needle aspirate or biopsy) before confirming the complete response 
status. 
Changes in nodal and visceral sites should be recorded and reported separately, and lymph nodes in the 
pelvis must measure at least 2 cm in greatest diameter to be considered target lesions. Complete 
elimination of disease at a particular site should be recorded separately. Any favorable change should 
be confirmed using a second follow-up scan. 
 
8.3.2   Evaluation of Non-Target Lesions 
 
Complete Response (CR) 
Disappearance of all non-target lesions. All lymph nodes must be non-pathological in size (< 10 mm 
short axis). 
 
Non-CR/Non-PD 
Persistence of one or more non-target lesion(s) and/or the maintenance of tumor marker levels above 
the normal limits.  
 
Progressive Disease (PD) 
Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions 
(see “Evaluation of New Lesions” below). Unequivocal progression should not normally trump target 
lesion status. It must be representative of overall disease status change, not a single lesion increase. 
 
When the patient also has measurable disease, there must be an overall level of substantial worsening 
in non-target disease such that, even in the presence of SD or PR in target disease, the overall tumor 
burden has increased sufficiently to merit discontinuation of therapy. A modest “increase” in the size of 
one or more non-target lesions is usually not sufficient to qualify for unequivocal progression status. 
The designation of overall progression solely on the basis of change in non-target disease in the face 
of SD or PR of target disease will therefore be extremely rare. 
When the patient only has non-measurable disease, the increase in overall disease burden should be 
comparable in magnitude to the increase that would be required to declare PD for measurable 
disease: i.e., an increase in tumor burden from “trace” to “large”, an increase in nodal disease from 
“localized” to “widespread”, or an increase sufficient to require a change in therapy. 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed at a 
later time by the review panel (or Principal Investigator). 
 
8.3.3  Evaluation of New Lesions 


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The appearance of new lesions constitutes Progressive Disease (PD). 
A growing lymph node that did not meet the criteria for reporting as a measurable or non-measurable 
lymph node at baseline should only be reported as a new lesion (and therefore progressive disease) if 
it: 
• 
increases in size to ≥ 15 mm in the short axis, or 
• 
there is new pathological confirmation that it is disease (regardless of size). 
• 
new effusion or ascites that appears during treatment should only be reported as a new lesion 
(and therefore progressive disease) if it has cytological confirmation of malignancy. 
 
8.3.4 PSA Response 
As long as patient safety is the primary concern, in the absence of other indicators of disease progression, 
therapy should not be discontinued solely on the basis of a rise in PSA after week 8. 
 
PSA progression is defined as the date that a 25% or greater increase and an absolute increase of 
2.0 ng/mL or more from the nadir is documented and confirmed by a second value obtained 3 or more 
weeks later. Where no decline from baseline is documented, PSA progression is defined as a 25% 
increase from the baseline value along with an increase in absolute value of 2.0 ng/mL or more after 8 
weeks. 
 
8.3.5 Evaluating best overall response 
The best overall response is the best response recorded from the start of treatment until either disease 
progression or recurrence. The investigator’s determination of best overall response will be based both 
on response criteria and on confirmation criteria (Table 10). To be assigned a status of partial response 
or complete response, changes in tumor measurements must be confirmed by repeat assessment 
performed 4-6 weeks after the criteria for response are first met. To confirm stable disease, follow-up 
measurements must meet SD criteria at a minimum interval of 6-8 weeks after SD was first documented.  
 Note: If unconfirmed progression noted at the first time point is not confirmed at a second time point, the 
next assessment time point after the first that meets the criteria for progression will be treated as time 
point 1. 
Subjects 
with global 
deterioration of health status who require treatment to be discontinued without objective evidence of 
disease progression should be classified as having symptomatic deterioration. Every effort should be 
made to document their objective progression, even after discontinuing treatment. 
Subjects who do not have tumor response assessment due to rapid progression or toxicity will be 
considered nonresponders, will be included in the denominator for the response rate, and will be 
classified into one of the categories listed below: 
• 
death attributed to disease progression 
Table 10. Assessing Overall Response. 
Target 
Lesions 
Nontarget Lesions 
New 
Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Incomplete 
response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abreviations: CR, complete response; PD, progressive disease; PR, partial 
response; SD, stable disease. 


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• 
early discontinuation attributed to disease progression 
• 
death attributed to drug toxicity 
• 
early discontinuation attributed to drug toxicity 
Note: If a subject receives subsequent therapy before tumor progression is documented, the 
reason for changing therapy must be reported. Reasons include clinical progression, drug toxicity, 
or secondary therapy for maintaining tumor response. 
 
8.4 
Confirmatory Measures/Duration of Response (see Table 11 for specific PCWG3 
measures) 
 
8.4.1 Confirming time-to-event outcomes 
Any post-treatment change in disease status, be it favorable or unfavorable, should be confirmed 
using a second assessment at a later time 6-8 weeks. 
 
8.4.2 Duration of overall response 
Duration of overall response is measured from the time when partial response or complete 
response is first noted until the date when recurrent or progressive disease is objectively 
documented. Duration of overall complete response is measured from the time the criteria for 
complete response are first met until the first date that recurrent disease is objectively 
documented. Duration of stable disease is measured from the start of treatment until the criteria 
for progression are met.  
 
8.4.3 Progression-free survival 
Progression-free survival (PFS) is a composite endpoint defined as the time from study entry or 
random assignment to disease progression in bone or soft-tissue, symptoms, or death. Use an 
interval-censored approach in which all assessments of the composite PFS endpoint (i.e., PSA, 
bone, CT scans, and symptom assessments) are performed at the same time points. All 
assessments of disease should be collected at the same time interval (e.g., bone scan, CT scan, 
and PSA at 12-week intervals). In addition to PSA, confirm post-treatment changes in measurable 
target lesions, radionuclide bone scans, and symptoms. 
 
 


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Table 11. Prostate Cancer Clinical Trials Working Group 3 (PCWG3) Outcome Measures. 
Variable 
Control/Relieve/Eliminate Endpoints 
Prevent/Delay Endpoints 
PSA 
Record the percent change from 
baseline (rise or fall) at 8 weeks and, 
separately, the maximal change (rise or 
fall) at any time using a waterfall plot 
Decline from baseline: record time from 
start of therapy to first PSA increase that is 
~25% and ~2.0 ng/mL above the nadir, 
and which is confirmed by a second value 
3 or more weeks later (i.e., a confirmed 
rising trend) † 
Recording the duration of PSA decline of 
little value 
No decline from baseline: PSA 
progression ~25% and ~2.0 ng/mL after 8 
weeks 
Soft-tissue lesions 
Use RECIST with caveats: 
Only report changes in lymph nodes that 
were ~2 cm in diameter at baseline 
Record changes in nodal and visceral 
soft tissue sites separately 
Record complete elimination of disease 
at any site separately 
Confirm favorable change with second 
scan 
Record changes using waterfall plot 
Use RECIST criteria for progression, with 
additional requirement that progression at 
first assessment be confirmed by a second 
scan 6 or more weeks later 
Note that for some treatments, a lesion 
may increase in size before it decreases 
Bone 
Record outcome as either new lesions or  
no new lesions 
First scheduled reassessment: 
No new lesions: continue therapy 
New lesions: perform a confirmatory 
scan 6 or more weeks later 
Confirmatory scan: 
No new lesions: continue therapy 
Additional new lesions: progression 
Subsequent scheduled reassessments: 
No new lesions: continue 
New lesions: progression 
The appearance of ~2 new lesions, and, 
for the first reassessment only, a 
confirmatory scan performed 6 or more 
weeks later that shows at least 2 or more 
additional new lesions 
The date of progression is the date of the 
first scan that shows the change 
Symptoms 
Consider independently of other outcome measures 
Document pain and analgesia at entry with a run-in period and measure repeatedly at 
3- to 4-week intervals 
Perform serial assessments of global changes in HRQOL, urinary or bowel 
compromise, pain management, additional anticancer therapy 
Ignore early changes (~12 weeks) in pain or HRQOL in absence of compelling 
evidence of disease progression 
Confirm response or progression of pain or HRQOL endpoints ~3 weeks later 
Abbreviations: PSA, prostate-specific antigen; HRQOL, health-related quality of life.  
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9. Correlatives 
The correlative assessments in this section are proposed as tertiary or exploratory objectives of the 
study. If exceptional responders/non-responders are observed, the comprehensive sequencing based 
profiling of tumors is expected to delineate putative molecular biomarkers, and refine the understanding 
of ESK981’s mechanism of action. 
9.1  The Association of Somatic and Germline Mutations with Exceptional Response/Resistance 
to ESK981  
In addition to the prevalent TP53 mutations, AR amplifications, and ETS-fusions, mutations in the PTEN-
PI3K-AKT pathway as well as germline and somatic events in the DNA repair pathway are frequently 
observed in mCRPC tumors. We propose integrative genomic sequencing to comprehensively profile 
the spectrum of genetic aberrations. The specific endpoints will be: activation through a hotspot mutation 
or amplification (gain-of-function), and inactivation through two-hit missense/nonsense mutation or 
deletion (loss-of-function) for genes from select pathways recurrently altered in mCRPC. Somatic and 
germline mutations will be identified through DNA sequencing of tumor and matched patient normal 
tissue utilizing the Oncoseq1700 platform. NGS-based analyses of copy-number alterations (CNA) and 
loss-of-heterozygosity (LOH) will be employed to probe for focal amplifications (e.g. AR, CCND1, 
PIK3CB) and deletions (e.g. PTEN, RB1). 
9.2  The Association of ETS / Kinase Gene Fusions with Exceptional Response/Resistance to 
ESK981 
Capture RNA sequencing will be used to detect further genetic events, such as activating and inactivating 
genes fusions. It is expected that this will identify activating ETS fusions (ERG, ETV1, ET4, ETV5), driver 
kinase fusions (BRAF, RAF1, FGFR2, FGFR3), as well as additional inactivating events in tumor 
suppressors (e.g. PTEN, TP53, RB1, BRCA1/2, ATM). To increase statistical power, mutations will be 
evaluated for association with clinical outcomes, both independently and grouped by molecular 
pathways: PTEN-PI3K-AKT, homologous recombination (e.g. BRCA1, BRCA2, PALB2), cell-cycle 
checkpoints (e.g. RB1, CCND1). 
9.3  The association of AR signaling with Exceptional Response to ESK981 
Furthermore, since modulation of androgen receptor (AR) signaling through tyrosine kinases is observed 
as a mechanism of resistance to androgen deprivation therapy and androgen-independence, we 
hypothesize that the loss of dependence on AR signaling will be an additional independent predictor of 
response and outcomes. The trial is designed to enrich for AR-independent patients in the Enza/Abi-
refractory cohort who will allow us to evaluate our hypotheses. Aggregate scores of AR-dependence and 
AR-independence will be derived from the expression levels of canonical AR targets and trans-
differentiation markers. 
9.4  Metastatic Kinome Activity Profiles as Predictive Biomarkers for Response to ESK981 
Since the mechanism of ESK981 is based on the multiplex inhibition of a set of protein kinases we 
hypothesize that a tumor’s dependence on kinase signaling pathways (kinome activity profile) will 
correlate with sensitivity to multiplex kinase inhibition by ESK981. Similarly, kinome activity profiles will 
be quantified through the expression levels of individual tyrosine and serine/threonine kinases targeted 
by ESK981 and, by proxy of gene expression signatures, the activity of their downstream signaling 
pathways. The activity of each targeted kinase will be correlated with the clinical endpoints 
independently, and in conjunction with the tumor’s AR status and other genetic alterations. 
9.5  Evaluation of Circulating and Disseminated Tumor Cells as Pharmacodynamic Biomarkers 
of ESK981 response.  
The burden of circulating (CTC) and disseminated tumor cells (DTC) has been associated with survival 
in a number of solid tumors. Further, a decrease in the number of CTC is a reliable indicator of response 
for a number of oncological therapies. Therefore, we hypothesize that ESK981 treatment will reduce the 
burden of CTCs in the blood and DTCs obtained from the bone marrow. Blood samples will be collected 
at intervals of 4 weeks for the total duration of treatment (from 8 weeks to 6 months or disease 
progression). Circulating Tumor Cells (CTC) will be enriched from 7.5ml of whole blood using the 
AdnaTest ProstateCancerSelect assay. The expression of marker genes associated with androgen 


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signaling, cell proliferation, kinome activity, autophagy, will be assessed pre-amplified cDNA (AdnaTest 
ProstateCancerDetect) using qPCR. In addition, blood samples will be processed using RareCtye 
platform for further characterizing CTCs in single cell level. Similarly, to detect DTCs bone marrow 
aspirates will be collected. DTCs will be enriched by negative (lymphocyte markers) and positive 
(epithelial markers) selection using flow cytometry. The enriched DTCs will be profiled for single-cell gene 
expression using the 10X genomics sequencing platform (The Chromium System). Specifically, we will 
evaluate whether clinical response is associated with: (i) the pre-treatment CTCs/DTC burden, (ii) a 
reduction in CTCs/DTCs during response, (iii) changes CTC/DTC expression profiles. Forty (40) ml of 
whole blood will be collected at each respective time-point, please see lab manual for collection and 
processing guidelines. 
9.6  Pathological assessment of phenotypic tumor and host responses to ESK981 treatment. 
ESK981 treatment results in a striking and conserved phenotype (autophagy) in preclinical in vitro and in 
vivo models. However, the drug can in principle target other kinases expressed in normal cells from the 
tumor microenvironment for example. To differentiate between the direct and indirect effects of ESK981, 
we will collect tumor biopsies from baseline and 8 weeks of treatment for histopathological evaluation. 
We will perform immunohistochemistry (IHC) for the following protein markers: Ki67 (cell proliferation); 
AR (androgen receptor); CD31, NG2 and desmin (angiogenesis); PDGFR1/2, VEGFR1/2, Tie2, c-Kit, 
FGFR (tyrosine kinase receptor); LC3 (autophagy). We will evaluate whether treatment response is 
associated with a phenotypic change in the tumor histology (vacuolization), microenvironment 
(vascularization, immune infiltration), and the tumor's’ molecular characteristics (AR status, kinome 
profile). 
10. Data Reporting and Regulatory Requirements 
10.1 
Data Collection and Management 
Data collected during this study will be entered into a secure database. 
10.1.1 Electronic Case Report Forms (eCRFs) 
Data will be collected and maintained on study specific electronic case report forms in the Oncore 
Research Enterprise system at Karmanos Cancer Institute. Training and support will be provided for all 
staff entering data upon local regulatory approval. Data entry must occur within 2 weeks of visits along 
with submission of applicable source documentation. KCI is responsible for ensuring eCRF’s are 
completed accurately and submitted in a timely manner. 
10.1.2 Source Documents 
Source documentation refers to original records of observations, clinical findings and evaluations that are 
subsequently recorded as data. Source documentation will be made available to support the subject’s 
research record.  
10.1.3 Record Retention 
The investigator will maintain adequate and accurate records to enable the conduct of the study to be 
fully documented and the study data to be subsequently verified. After study closure, the investigator will 
maintain all source documents and study-related documents. Records are to be retained and securely 
stored until the later of: (a) two (2) years following the date a New Drug Application is approved for the 
Study Drug that is the subject of the Clinical Trial; or (b) two (2) years after the Investigational New Drug 
Application for such Study Drug is terminated or withdrawn, or such longer period of time as may be 
required by Participant policies, applicable laws, rules or regulations. 
10.1.4  Data Submission Timelines 
All data should be transmitted within 14 days of visit except for SAE submission (see section 7.4).  
10.1.5 Data Review and Queries 
Karmanos will review data and source documentation as it is submitted. Data will be monitored against 
source documentation as necessary and discrepancies will be sent as queries. In addition, the Karmanos 
monitor will review data for logic, consistency, and obvious anomalies. Queries will be sent by the 
Karmanos monitor.  


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10.1.6 Protocol Amendments or Changes in Study Conduct 
Any change or addition (excluding administrative) to this protocol requires a written protocol amendment 
that must be reviewed and approved. Amendments significantly affecting the safety of subjects, the scope 
of the investigation or the scientific quality of the study require additional approval by the IRB. A copy of 
the written approval of the IRB must be provided. Examples of amendments requiring such approval are:  
1. increases in drug dose or duration of exposure of subjects,  
2. significant changes in the study design (e.g. addition or deletion of a control group),  
3. increases in the number of invasive procedures,  
4. addition or deletions of a test procedure required for monitoring of safety.  
These requirements for approval should in no way prevent any immediate action from being taken by the 
investigator or by in the interests of preserving the safety of all patients included in the trial. If an 
immediate change to the protocol is felt to be necessary by the investigator and is implemented for safety 
reasons PI must be notified and the IRB at the center must be informed immediately. Amendments 
affecting only administrative aspects of the study do not require formal protocol amendments or IRB 
approval but the IRB must be kept informed of such administrative changes. Examples of administrative 
changes not requiring formal protocol amendments and IRB approval include:  
1. changes in the staff used to monitor trials  
2. minor changes in the packaging or labeling of study drug 
10.2 Data Safety and Monitoring Board 
10.2.1 Scheduled meetings will be held monthly or more frequently depending on the activity of the 
protocol. These meetings will include the protocol investigators and data managers involved with the 
conduct of the protocol.  
 
10.2.2 During these meetings the investigators will discuss matters related to: 
• Safety of protocol participants (Adverse Event reporting)  
• Validity and integrity of the data  
• Enrollment rate relative to expectation of target accrual, characteristics of participants  
• Retention of participants, adherence to the protocol (potential or real protocol violations)  
• Data completeness on case report forms and complete source documentation 
10.2.3 Completed Data and Safety Monitoring Reports of these regular investigator meetings will be 
kept on file in the office of the Clinical Trials Core (see form in Appendix F). The data manager assigned 
to the clinical trial will be responsible for completing the report form. The completed reports will be 
reviewed and signed off by the Principal Investigator (PI) or by one of the Co-PI’s in the absence of the 
PI. The signed off forms will then be forwarded to the Director, Clinical Trials Core for review of 
completeness and processing with the Data and Safety Monitoring Committee.  
10.2.4 The Barbara Ann Karmanos Cancer Institute, Data and Safety Monitoring Committee will meet 
on a monthly basis to review the prior months Serious Adverse Event forms and Data and Safety 
Monitoring study specific reports that have been filed.  
11. Statistical Considerations 
11.1 Objectives 
The primary objectives of this study are: 
1) To determine the PSA ≥ 50% response rate (PSA50) from baseline using the PCWG3 criteria to 
ESK981 plus nivolumab  in men with mCRPC who have progressed on enzalutamide (an oral androgen-
receptor inhibitor) and/or abiraterone acetate (an androgen synthesis inhibitor) and chemotherapy 
(docetaxel and/or cabazitaxel). 


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2) To assess the safety and tolerability of ESK981 plus nivolumab.   
The secondary objectives of this study are: 
1) To determine the time to PSA response (TTPR) in patients with mCRPC 
2) To determine the duration of PSA response (PRD) in patients with mCRPC 
3) To determine PSA progression rates as defined by the PCWG3 criteria.  
4) To determine PSA progression free survival (PPFS) as defined by the PCWG3 criteria. 
The correlative/exploratory/tertiary objectives of this study are: to assess exploratory biomarkers from 
blood and tumor biopsies. Examples of these may include, but are not limited to: whole exome 
sequencing, capture whole transcriptome analysis, AR and ARv7 analysis, ki-67, apoptosis, etc. 
11.2 Endpoints 
11.2.1 The first primary endpoint (PSA50) is a PSA decline of ≥ 50% from baseline (PSA50), using the 
PCWG3 criteria. Refer to Section 8.2.1. 
The second primary endpoint(s) (toxicities) is (are) defined in Section 7. Adverse events of all grades will 
be captured by the National Cancer Institute - Common Terminology Criteria for Adverse Events, version 
5 (NCI-CTCAE v5) and GCP standards.  
11.2.2 The secondary endpoints are defined as follows: 
Time to PSA response (TTPR) is defined as the time from treatment start until the first documented 
occurrence of PSA50. PSA50 is defined in Section 11.2.1.  
Duration of PSA response (PRD) is defined as the time from start of PSA50 until PSA progression 
(defined in Section 8.3.4).  
PSA progression free survival (PPFS) is defined in Section 8.3.4 except that it will be based on PSA 
assessments only. PSA progression rates will be estimated from the PSA-only PFS distribution. 
11.2.3 The correlative/exploratory/tertiary endpoints (and the methods of their determination) are 
described in Section 9.    
11.3 Design 
We will utilize a single group two-stage Phase 2 design for the study, with a run-in phase for safety 
determination of the combination of ESK981 and nivolumab. For the run-in phase, a starting combination 
dose (Level 0) and two retreat combination doses (Level -1 and Level -2) are defined in the table on page 
27. 
11.3.1  In the run-in phase, patients will receive flat dose of 480 mg IV of nivolumab once and level 0 
starting doses of 160mg (4 capsules) of ESK981 dosed once daily for five consecutive days followed by 
a two consecutive day treatment break for a cycle of 28 days. 
The algorithm to determine a safe combination dose of ESK981 plus nivolumab is in Table 4 in Section 
5.0 page 27 
At Level 0, If there is ≤ 1 Grade 3 or higher AE at least possibly related to treatment in the first 3 patients, 
then 3 additional patients are enrolled at Level 0. If there are < 2 such AEs in all 6 patients in 28 days, 
then the Level 0 combination dose is deemed safe for the combination trial. 
 
At Level 0, if there are ≥ 2 such AEs in the first 3 patients, then dose de-escalation occurs, and 3 patients 
are enrolled at Level -1. The same algorithm just described for Level 0 is then applied to 3-6 Level -1 
patients to determine whether the Level -1 combination dose is deemed safe for the combination trial. 
 
At Level -1, If there are ≥ 2 AEs in the first 3 patients, then dose de-escalation will occur again, and 3-6 
patients will be treated at Level -2 of the combination dose to determine whether Level -2 is deemed safe 
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If Level -2 is not found safe for the combination trial, enrollment will stop and consultation with the 
sponsors will occur to determine how to proceed. This run-in phase for safety determination will require 
anywhere from 6 to 18 patients. 
 
11.3.2  In the combination portion of the study, after 8 weeks (2 cycles), patients will be evaluated for 
their rate of PSA decline of ≥ 50% from baseline (PSA50), using the PCWG3 criteria.   All 13 patients 
from the 2017-065 trial of single agent ESK981  had  PSA values available at baseline and at the 8 week 
time point. Their PSA50 response rate  was  0/13 = 0%, with a 2-sided Wilson type 80% confidence 
interval (CI) of (0% - 11%). The 80% confidence level was chosen given the small denominator of 13 
patients. Recognizing the width of that CI, in the Simon 2-stage design described below, a design 
parameter of p0 = 0.05 (i.e., 5%) has been chosen. 
 
Preliminary data from an ongoing Phase 2 study of a similar population of similar mCRPC patients has 
been recently reported.25 The regimen under study is Nivolumab + Ipilumumab. We believe that the 
Nivolumab is the primary driver of PSA response in that drug combination. Hence this study should 
provide reasonable PSA response reference data. It reported a PSA50 response rate = 6/34 = 17.6%,   
with a 2-sided Wilson type 95% confidence interval (CI) of (8% - 34%). Recognizing both the point 
estimate and the CI, a design parameter of p1 = 0.25 (i.e., 25%) has been chosen as clinically meaningful 
for the Simon 2-stage design described below. 
 
A 2-stage near optimal Simon design will be used based on the following parameter assumptions: 
p0 = 5%;   p1 = 25%;   1-sided alpha = 0.05;   and power = 0.90. The resulting sample size milestones 
are:   N1 = 15;   R1 = 1;   N = 29;   and R = 3. Hence, if at least 2 PSA50 responses are observed in 
Stage 1, then the study will proceed to Stage 2, otherwise it will terminate for lack of efficacy. If at least 
4 PSA50 responses are observed among all 29 patients, then the regimen will be considered promising.   
Otherwise, the regimen will be considered to have insufficient efficacy to pursue in a subsequent larger 
trial. 
 
The primary operating characteristics of this design are a probability of early termination (PET) = 0.829, 
under H0 (that the true PSA50 rate is at most 5%), and an average sample number (ASN) = 17.39. Taken 
together, this indicates a very efficient statistical study design for the proposed Phase 2 trial. 
  
11.3.3  The required sample sizes and operating characteristics stated above were determined from the 
“Two-Stage Phase II Clinical Trials” program within the PASS  16 (2018) software.23   
11.3.4   Sample size adjustment for non-compliance will be made as follows. A major goal of this study 
is to evaluate the efficacy (in addition to the effectiveness) of ESK981 plus nivolumab upon the PSA50 
rate, safety, and tolerability. For each individual patient, we will allow for a treatment non-compliance of 
up to 25% (i.e., up to 25% of intended ESK981 pills were not taken).   
Our initial analytic focus will be on the patients who are eligible (per Section 3), and evaluable (i.e., were 
on treatment for at least Cycle 1 [28 days]), and compliant (took at least 75% of the intended ESK981 
pills during Cycle 1).   
The patients meeting all 3 such requirements will be considered the eligible, evaluable, and compliant 
(“EEC”) subset. We anticipate that up to 15% of the enrolled patients will not become EEC for one reason 
or another.   
To obtain the requisite maximum of 18 run-in phase patients plus a maximum of 23 more combination 
phase patients, all of whom are fully compliant (i.e., completely EEC), while allowing for an overall attrition 
rate (“a”) of up to 15% of patients, we will need to enroll up to  N’ = [N / (1 – a)] = [(18 + 23)  / (1 – 0.15)] 
= 41 / 0.85  =  49 patients.  
The consequence of non-compliance (i.e, not being completely EEC) is that such patients would still be 
utilized in analyses of the effectiveness of ESK981 plus nivolumab. For example, that would focus on the 


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patients who were “EE” but not compliant.  Another effectiveness analysis would focus on the patients 
who were eligible, but neither evaluable nor compliant. All of these analyses of non-EEC patients would 
be viewed as sensitivity analyses of the efficacy analysis of only the EEC patients.  These supplemental 
analyses would provide a more complete assessment of the feasibility and efficacy combined of the oral 
ESK981 plus nivolumab treatment in this study population. 
11.4 Analysis      
11.4.1  For the Primary Objectives, all analyses point and (1-sided Wilson type 90% lower) CI estimates 
of the primary endpoint (PSA50) will be calculated. 
Adverse events will be tabulated by incidence and severity graded according to the National Cancer 
Institute – Common Terminology Criteria for Adverse Events (CTCAE) version 5. Other statistics will 
include point and (2-sided) CI estimates of overall toxicity and of specific types of toxicity. 
11.4.2 For Secondary Objective 1, descriptive statistics of TTPR will be used to summarize the time to 
PSA response. These descriptives will include N, median, mean, standard deviation (SD), interquartile 
range (IQR), minimum, and maximum. 
11.4.3 For Secondary Objectives 2 and 3, the censored distributions of duration of response (RD) and 
PSA progression free survival (PFS) will be summarized with the Kaplan-Meier (K-M) survivorship 
estimate. A graph of the K-M curve for PRD and for PPFS will be generated along with the Hall-Wellner 
90% confidence band, and a display of the number of patients at risk at several time points, below the X-
axis. Summary statistics (6-month rate, 12-month rate, median, etc.) will be calculated from the K-M life 
table, each one with its respective 80% confidence interval (CI).  
11.4.4 For the Correlative (Exploratory) Objectives, frequency distributions of all categorical variables 
(grade of specific types of toxicity, and categorical biomarkers or other correlatives) will be generated. 
Serial PSA levels will be displayed using spaghetti plots, and changes in PSA using waterfall plots. 
Descriptive statistics will be used to summarize all continuous correlatives (e.g., PSA, continuous 
biomarkers and other correlatives), and changes in them pre/post ESK981 treatment. Gene expression 
levels will be log2 transformed prior to descriptive analysis. Multiple boxplots and scatterplots will be used 
to display summary statistics of biomarkers/correlatives and interrelationships between continuous 
correlatives, respectively. 
Details of the planned determination of bioinformatics correlatives are given in Section 9. Response 
(whether PSA50 or overall), a categorical clinical outcome, will be statistically modeled as a function of 
each correlative using exact logistic regression. TTPR, a continuous uncensored clinical outcome (limited 
to only the PSA50 responders), will be statistically modeled as a function of each correlative using linear 
regression. 
Time to event clinical outcomes (PRD and PPFS) will be statistically modeled as a function of each 
correlative using Cox proportional hazards regression. Examples of categorical correlatives include:  
gene mutation status (Sec. 9.1 and 9.2); AR dependence (Sec. 9.3); and vacuolization status or 
vascularization status (Sec. 9.6). Examples of continuous correlatives include:  kinase expression levels 
(Sec. 9.4); CTC and DTC counts (Sec. 9.5); and levels of Ki67, AR, and LC3 (Sec. 9.6).  
11.5 
Statistical Monitoring Plan for Toxicity 
 
11.5.1  The following statistical monitoring plan for any Grade ≥ 3 toxicity that is at least possibly related 
to treatment (i.e., with Attribution level ≥ 3) shall be used. Using upper 1-sided 80% confidence limits, we 
have determined when the sample toxicity rate estimate from the accumulating toxicity-evaluable 
(t-e) patients indicates that the true (unknown) rate of Grade ≥ 3 toxicity with Attribution level ≥ 3 could 
be  ≥  15%. That would be a signal to halt patient accrual, and to reconsider the treatment regimen before 
proceeding. 
 
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re-evaluation of the study for safety reasons according to the statistical monitoring plan for Grade ≥ 3 
toxicity with Attribution level ≥ 3 as given in the following table. 
 
Statistical Monitoring Plan for Grade ≥ 3 Toxicity with Attribution level ≥ 3 
We would recommend re-evaluation of the study for safety reasons if there were X many occurrences of 
Grade ≥ 3 toxicity of any type (with Attribution level ≥ 3) among the first N (or fewer) patients treated: 
 
X  
 
 
 N 
 
 
    p 
 
 
 UCL 
1 
 
 
14 
 
 
0.0714  
 
0.1522 
2 
 
 
22 
 
 
0.0909  
 
0.1560 
 
 In the above table, X = the cumulative number of t-e patients with a Grade ≥ 3 toxicity (with Attribution 
level ≥ 3) observed thus far; N = the number of  t-e patients treated thus far; p = the observed (i.e., 
sample) toxicity rate; and UCL = the Wilson type 1-sided upper 80% binomial confidence limit for p. After 
treating 22 patients, the potential toxicity of this regimen would be very well defined, and thereafter the 
possible need for termination of the study based on Grade ≥ 3 toxicity with Attribution level ≥ 3 would be 
negligible. 
11.6 Expected Accrual Rate, Accrual Duration, and Total Study Duration  
11.6.1 This will be a clinical trial at Karmanos Cancer Institute (KCI) and the University of Michigan (UM). 
We expect to accrue 12-15 patients/year from KCI and 6-8 patients/year from UM. That provides a 
combined 2-institution expected accrual rate of 18-23 patients/year.   
11.6.2 The run-in phase for safety determination will require 6-18 patients (as described in Sec. 11.3.1). 
The last 6 patients treated at the combination dose deemed safe for the combination phase will be 
considered as the first 6 patients of the Phase 2 trial. 
 After compensatory adjustment for non-compliance (see Section 11.3.4), the overall study will require 
up to N = 49 patients. At the combined 2-institution expected accrual rate of 18 - 23 patients/year, we 
can accrue 49 patients in –26 - 33 months. 
11.6.3 Allowing an additional 4 months to finish determining the PSA50 result and all biomarkers and 
correlatives in all patients yields an estimated total study duration of –30 - 37 months.  
12. Regulation and Protection of Human Subjects 
12.1 Roles and Responsibilities 
12.1.1 Sponsor Investigator 
The Sponsor Investigator is responsible for performing the following tasks: 
• 
Responsibility for the overall conduct of the study and for monitoring the progress of the study 
• 
Reviewing and ensuring reporting of Serious Adverse Events (SAEs) 
• 
Reviewing data  
12.2 Ethical Considerations 
This study will be conducted in compliance with the protocol, GCP guidelines established by the 
International Conference on Harmonisation, and the ethical standards set forth in the Declaration of 
Helsinki 2004 (available at: www.laakariliitto.fi/e/ethics/helsinki.html). 
12.3 Written Informed Consent 
Before obtaining consent, members of the study team will review the rationale for the treatment program 
with the patient. The discussion will review the alternatives available (including hormonal therapy, 
chemotherapy, or supportive care as appropriate), the potential benefits of this program, the risks and 


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the probability of their occurrence, and the procedures to minimize these risks. Should an adverse event 
occur, the provisions available to ensure medical intervention will also be reviewed. Why the risks are 
reasonable in relation to the anticipated benefits, incentives, or costs that will or may be incurred as a 
result of participating in the study, as well as the efforts to maintain confidentiality, will also be discussed 
with the patient. 
Patients will be required to sign and date an informed consent form that meets the requirements of the 
Code of Federal Regulations (Federal Register Vol. 46, No. 17, January 27, 1981, part 50) and the IRB. 
The medical record will include a statement that written informed consent was obtained (and document 
the date that it was obtained) before the patient is enrolled in the study. The original signed document 
will become part of the patient’s medical record, a copy will be forwarded to the lead site/sponsor pursuant 
to sponsor registration and to the PCCTC and a copy will be sent home with each patient. 
The consent form will include the following: 
• 
the nature and objectives, potential toxicities, and benefits of the intended study 
• 
the length of therapy and likely follow-up required 
• 
alternatives to the proposed therapy (including available standard and investigational therapies) 
• 
the name of the investigator(s) responsible for the protocol 
• 
the right of the patient to accept or refuse treatment and to withdraw from participation in this 
study 
• 
Text regarding the consortium and the coordinating center should be added to all institutional 
informed consent documents and sections in the research authorization/HIPAA forms (e.g., 
“Prostate Cancer Clinical Trial Consortium”) 
12.4 Protection of Privacy 
Patients will be informed of the extent to which their confidential health information generated from this 
study may be used for research purposes. After this discussion, they will be asked to sign a Notice of 
Privacy Practice research authorization/HIPAA form. The original signed documents will become part of 
the patient’s medical records, and each patient will receive a copy of the signed documents. The use and 
disclosure of protected health information will be limited to the individuals described in the research 
authorization form. The research authorization form must be completed by the principal investigator and 
approved by the IRB. 
12.5 Terminating or Modifying the Study 
Adverse event and laboratory data from this trial will be assessed by the lead site or the sponsor’s medical 
monitor on an ongoing basis. SAEs will be reviewed as they are reported to the lead site/sponsor, and 
the medical monitor will make an assessment regarding the safety of continuing or modifying the study. 
This assessment will be shared with the investigators either in writing or as part of a teleconference. 
Should the assessment of either the lead site/sponsor or the principal investigator be that the study should 
be terminated; the study will be closed to further accrual. Patients who are receiving an investigational 
agent will be assessed individually by the investigator to see if it is in the patients’ best interest to continue, 
which might be the case for a patient that is responding to the intervention. Follow-up safety assessments 
will be performed for all patients who are terminated from the study prematurely. 
13. Quality Assurance and Audits 
The DSMC can request a ‘for cause’ quality assurance audit of the trial if the committee identifies a 
need for a more rigorous evaluation of study-related issues. 
 
A regulatory authority (e.g. FDA) may also wish to conduct an inspection of the study, during its 
conduct or even after its completion. If an inspection has been requested by a regulatory authority, the 
site investigator must immediately inform the Coordinating Center that such a request has been made. 
 


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14. 
References 
 
1. 
American Cancer Society. Cancer Facts & Figures 2016. Atlanta, GA; 2016. 
2. 
Scher HI, Morris MJ, Stadler WM, et al. Trial Design and Objectives for Castration-Resistant 
Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working 
Group 3. J Clin Oncol 2016. 
3. 
Ferraldeschi R, Pezaro C, Karavasilis V, de Bono J. Abiraterone and novel antiandrogens: 
overcoming castration resistance in prostate cancer. Annu Rev Med 2013; 64: 1-13. 
4. 
Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous 
chemotherapy. N Engl J Med 2013; 368(2): 138-48. 
5. 
Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after 
chemotherapy. N Engl J Med 2012; 367(13): 1187-97. 
6. 
Smith DC, Smith MR, Sweeney C, et al. Cabozantinib in patients with advanced prostate cancer: 
results of a Phase II randomized discontinuation trial. J Clin Oncol 2013; 31(4): 412-9. 
7. 
Smith M, De Bono J, Sternberg C, et al. Phase III Study of Cabozantinib in Previously Treated 
Metastatic Castration-Resistant Prostate Cancer: COMET-1. J Clin Oncol 2016. 
8. 
Nelson PS. Targeting the androgen receptor in prostate cancer--a resilient foe. N Engl J Med 
2014; 371(11): 1067-9. 
9. 
Grasso CS, Wu YM, Robinson DR, et al. The mutational landscape of lethal castration-resistant 
prostate cancer. Nature 2012; 487(7406): 239-43. 
10. 
Qiao Y, Feng FY, Wang Y, et al. Mechanistic Support for Combined MET and AR Blockade in 
Castration-Resistant Prostate Cancer. Neoplasia 2016; 18(1): 1-9. 
11. 
Eze C, Manapov F, Gratzke C et al. Concurrent radiotherapy and nivolumab in metachronous 
metastatic primary adenosquamous-cell carcinoma of the prostate. Eur J Cancer 2018;95: 109-
111. 
12.  
Bracarda S, Altavilla A, Hamzaj A et al. Immunologic checkpoints blockade in renal cell, prostate, 
and urothelial malignancies. Semin Oncol 2015; 42: 495-505. 
13. 
Basnet A, Khullar G, Mehta R, and Chittoria N. A case of locally advanced castration-resistant 
prostate cancer with remarkable response to nivolumab. Clin Genitourinary Can 2017; 15(5): 
e881-884. 
14. 
Carretero-Gonzalez A, Lora D, Ghanem I et al. Analysis of response rate with anti PD1/PD-L1 
monocolonal antibodies in advanced solid tumors: a meta-analysis of randomized clinical 
trials.Oncotarget 2018; 9(9): 8706-8715. 
15.  
Hudkins RL, Becknell NC, Zulli AL, et al. Synthesis and biological profile of the pan-vascular 
endothelial growth factor receptor/tyrosine kinase with immunoglobulin and epidermal growth 
factor-like homology domains 2 (VEGF-R/TIE-2) inhibitor 11-(2-methylpropyl)-12,13-dihydro-2-
methyl-8-(pyrimidin-2-ylamino)-4H-indazolo[5, 4-a]pyrrolo[3,4-c]carbazol-4-one (CEP-11981): a 
novel oncology therapeutic agent. J Med Chem 2012; 55(2): 903-13. 
16. 
Pili R, Carducci M, Brown P, Hurwitz H. An open-label study to determine the maximum tolerated 
dose of the multitargeted tyrosine kinase inhibitor CEP-11981 in patients with advanced cancer. 
Invest New Drugs 2014; 32(6): 1258-68. 
17. 
Yang ZJ, Chee CE, Huang S, Sinicrope FA. The role of autophagy in cancer: therapeutic 
implications. Mol Cancer Ther 2011; 10(9): 1533-41. 
18. 
Qu X, Yu J, Bhagat G, et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 


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1 autophagy gene. J Clin Invest 2003; 112(12): 1809-20. 
19. 
Saltz, L.B., et al., Phase II trial of sunitinib in patients with metastatic colorectal cancer after failure 
of standard therapy. J Clin Oncol, 2007. 25(30): p. 4793-9. 
20. 
Motzer, R.J., et al., Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J 
Med, 2015. 373(19): p. 1803-13. 
21. 
Wallin, J.J., et al., Atezolizumab in combination with bevacizumab enhances antigen-specific T-
cell migration in metastatic renal cell carcinoma. Nat Commun, 2016. 7: p. 12624. 
22. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45(2): 228-47. 
23.   
PASS 16:  Power and Analysis Sample Size Software (2018).  NCSS, LLC.  Kaysville, Utah, USA. 
ncss.com/software/pass. 
24. 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ 
DrugInteractionsLabeling/ucm093664.htm#inVitro 
25.      https://media4.asco.org/237/14161/170195/170195_poster_big_1.jpg 
 
 
 


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


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Appendix B: Medications with the Potential for Drug-Drug Interactions 
Please refer to Tables 3-2 and 3-3 of the FDA drug interactions labeling website for examples of clinical 
inhibitors and clinical inducers of P450, respectively.24
Potent Inhibitors of CYP1A2, CYP2C8, or 
CYP3A4 
Potent inhibitors of the CYP1A2, 2C8, or 3A4 
include, but are not limited to, the following: 
 
CYP1A2 
CYP2C8 
CYP3A4 
Fluvoxamine 
Gemfibrozil 
Ketoconazole 
Ciprofloxacin 
 
Indinavir 
Mexiletine 
 
Ritonavir 
Propafenone 
 
Itraconazole 
Zileuton 
 
Clarithromycin 
 
 
Telithromycin 
 
 
Aprepitant 
 
 
Diltiazem 
 
 
Erythromycin 
 
 
Fluconazole 
 
 
Grapefruit 
juice 
 
 
Verapamil 
This list is not comprehensive as new 
information is continually being identified. 
 
Potent Inducers of CYP1A2, CYP2C8, or 
CYP3A4 
Potent inducers of the CYP1A2, 2C8, or 3A4 
include, but are not limited to, the following: 
 
CYP1A2 
CYP2C8 
CYP3A4 
Smoking 
Rifampicin 
Rifampicin 
 
 
Carbamazepine 
 
 
Griseofulvin 
This list is not comprehensive as new 
information is continually being identified. 
 
Substrates of CYP3A4/5 with a Narrow 
Therapeutic Range 
Substrates of CYP3A4/5 with a narrow 
therapeutic range include, but are not limited to: 
 
CYP3A4/5 
Alfentanil 
Astemizole 
Cisapride 
Cyclosporine 
Diergotamine 
Ergotamine 
Fentanyl 
Pimozide 
Quindine 
Sirolimus 
Tacrolimus 
Terfenadine 
This list is not 
comprehensive as 
new information is 
continually being 
identified. 


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Page 65 of 67                                                              Version date: 06/24/2020 
 
 
 
 
 
Appendix C: Study Calendar  
 
 
 
 
Screening 
Treatment/Intervention Period 
End of Tx 
(30 Days 
from last 
dose) 
Follow-
up 
Q 3 
mos 
Cycle 1 
Cycle 2  
+ beyond 
 
Day -28 to 
Day -1 
Day 1  
 
Day 
8  
(±3 
d) 
Day 
15 
(±3 
d) 
Day 
22  
(±3 d) 
Day 1 
 (±3 d) 
(±3 d) 
 
Informed 
consent and 
research 
authorization/ 
HIPAA form 
Xa 
 
 
 
 
 
 
 
Demographics, 
medical history, 
histologic and 
radiologic 
confirmation 
of disease 
X 
 
 
 
 
 
 
 
Physical 
examination, 
vitals, weight, 
blood pressure 
X 
X 
X 
X 
X 
X 
X 
 
EKG 
X 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
Performance 
status 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant 
meds 
X 
X 
X 
X 
X 
X 
X 
 
Toxicity 
assessment 
X 
X 
X 
X 
X 
X 
X 
 
Tumor 
measurementsb 
X 
Tumor measurements will be repeated every 2 
cycles x3, then q 3 cycles (- 10 d) 
 
 
Laboratory 
testsc 
X 
Xh 
X 
X 
X 
X 
X 
 
PT/INR, PTTg 
X 
 
 
 
 
Xg 
Xg 
 
Correlative 
samples 
X 
 
 
 
 
Xd 
X 
 
Tumor Biopsies 
Xe 
 
 
 
 
Xe 
 
 
Follow-up 
 
 
 
 
 
 
 
Xf 
a. 
May be obtained up to 60 days prior to initiation of study treatment. 
b. 
Radiographic evaluations will include a CT or MRI abd/pel and a bone scan. Chest x-ray or Chest CT should 
be done if necessary for tumor assessment.  
c. 
Complete blood count, comprehensive chemistry panel, TSH, Free/Total T3, Free/Total T4,  PSA,  
testosterone (at baseline). Free/Total T3 & Free/Total T4 will be drawn when TSH is abnormal for the rest  
of the study. 
d. 
Whole blood samples will be collected every 4 weeks from screening to end of treatment (see lab manual). 
e. 
Tumor biopsies performed at the Cycle 3 visit (week 8, - 10 d) (see lab manual), collect one 10 mL EDTA  
tube prior to Cycle 1Day 1 (or anytime while the patient is on study). 
f. 
Patients will be followed every three months for 5 years from end of treatment for survival and subsequent 
treatment. 
g. 
 PT/INR, PTT to be done at screening and then will need to be done at least once every month, only if patient 
is on therapeutic Coumadin 
h. 
If labs done within 7 days prior to C1D1, they don’t need to be repeated  
 


ESK981/Nivolumab 
 
 
 
 
2019-031 
Karmanos Cancer Institute 
 
Page 66 of 67                                                              Version date: 06/24/2020 
 
 
 
Appendix D: Pill Diary Phase II Multi-center Trial of ESK981 in Combination with Nivolumab in 
Patients With Metastatic Castrate Resistant Prostate Cancer 
 
 
 


ESK981/Nivolumab 
 
 
 
 
2019-031 
Karmanos Cancer Institute 
 
Page 67 of 67                                                              Version date: 06/24/2020 
 
 
 
Appendix E. DSM Report Form 
 
1. Grade: 1-Mild, 2-Moderate, 3- Severe, 4-Life-threatening, or 5- Death. 
2. Attribution: 1-unrelated, 2 - unlikely, 3 - possibly, 4 - probably, or 5 - definitely   
 
 
 
PROTOCOL#:  
 
REPORT DATE:  
     
                                                                                      
PROTOCOL TITLE 
 
PROTOCOL ACTIVITY SINCE LAST REPORT 
Accrual Goal:  
Eligible: 
 
Total number of AE’s to date:  
 
Accrual to Date:  
 Ineligible:  
(provide reason):  
Accrual Since  
Last Monthly Report:    
 
Specifically for Phase I Trial &/or Dose Escalating Trials: 
Dose Level 
Accrual   
 
 
 
 
Record all Grade 3, 4, and 5 Adverse Events (AE). Group by category of AE. Record the date OF the 
occurrence, attribution and if reportable to the IRB.   Shade the rows of the AE’s that have occurred for 
this Report. Attach the HIC UP report form for these reportable events that occurred on this report. 
Pt. ID# 
Category and type of adverse 
reaction 
 
Date of 
Occurren
ce 
Grade
1 
Attributio
n2 
Reportable to IRB 
(Y/N) 
Yes with date 
 
 
 
 
 
 
 
 
 
 
 
 
OFF TREATMENT  Provide reason [progression, death, toxicity, completed therapy, etc.] 
 
PROTOCOL VIOLATIONS  Deviations from protocol treatment, monitoring, or study calendar. 
  
PROTOCOL AMENDMENTS  Include date submitted to regulatory bodies and date approved. 
 
OTHER COMMENTS 
 
 
Investigator 
Signature: 
 
Data Manager 
Signature: