Conditions: Castration Levels of Testosterone Castration-Resistant Prostate Carcinoma Metastatic Prostate Carcinoma PSA Progression Stage IV Prostate Adenocarcinoma AJCC v7
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 13
Healthy volunteers: no

Brief summary:
This phase II trials studies the side effects and how well ESK981 works in treating patients with castration-resistant prostate cancer that has spread to other places in the body. ESK981 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the PSA \>= 50% response rate (PSA50) from baseline using the Prostate Cancer Working Group 3 (PCWG3) criteria to pan-VEGFR/TIE2 tyrosine kinase inhibitor CEP-11981 (ESK981) as a single agent in men with castration-resistant prostate cancer (CRPC) who have progressed on enzalutamide (an oral androgen-receptor inhibitor) and/or abiraterone acetate (an androgen synthesis inhibitor).

II. To assess the safety and tolerability of ESK981 as a single agent.

SECONDARY OBJECTIVES:

I. To determine the time to PSA response to ESK981 in metastatic CRPC patients. II. To determine the duration of PSA response to ESK981 in metastatic CRPC patients.

III. To determine PSA progression rates and PSA progression free survival (PFS), as defined by the PCWG3 criteria.

TERTIARY OBJECTIVES:

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

OUTLINE:

Patients receive pan-VEGFR/TIE2 tyrosine kinase inhibitor CEP-11981 orally (PO) once daily (QD) for 5 days (Monday-Friday). Treatment repeats for up to 8 weeks in the absence of disease progression or unacceptable toxicity. If treatment is successful after 8 weeks, patients may receive up to 6 months of pan-VEGFR/TIE2 tyrosine kinase inhibitor CEP-11981.

After completion of study treatment, patients are followed up periodically.

Arms:
arm 1: Patients receive pan-VEGFR/TIE2 (Vascular Endothelial Growth Factor Receptor/angopoeitin receptor2) tyrosine kinase inhibitor CEP-11981 PO QD for 5 days (Monday-Friday). Treatment repeats for up to 8 weeks in the absence of disease progression or unacceptable toxicity. If treatment is successful after 8 weeks, patients may receive up to 6 months of pan-VEGFR/TIE2 tyrosine kinase inhibitor CEP-11981.

Interventions: intervention 1: ESK981
Intervention descriptions: intervention 1: Treatment with ESK981 for patients with metastatic castrate resistant prostate cancer

Protocol document:
Prot_SAP_000.pdf: 
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An Open-Label, Parallel, Phase II Study of Single-Agent Oral ESK981 in 
Men with Metastatic Castration-Resistant Prostate Cancer (mCRPC) 
Prostate Cancer Clinical Trials Consortium, LLC (PCCTC) 
PCCTC #: c16-178 
IND #: 136687 
Karmanos Cancer Institute/Esanik Therapeutics 
 
Principal Investigator 
Biostatistician 
 
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 
 
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 
Co-investigators 
 
Ulka Vaishampayan, MD 
Karmanos Cancer Institute 
4100 John R 
Detroit, MI 48201 
Phone: 313-576-8718 
Fax: 313-576-8767 
Email: vaishamu@karmanos.org 
 
Joseph Fontana, MD, PhD 
Karmanos Cancer Institute 
4100 John R 
Detroit, MI 48201 
Phone: 313-576-8022 
Fax: 313-576-8767 
Email: fontanaj@karmanos.org 
 
Laboratory 
 
University of Michigan: 
Pathology/MCTP 
c/o Erica Rabban 
1400 E. Medical Center Dr., 5309 CCC 
Ann Arbor, MI 48109-5940 
Email: ericafw@med.umich.edu  
Phone: 1-734-763-2826 
 
 
 
 
 
Protocol Date: September 25, 2017 
Amendment 1: January 4, 2018 
Amendment 2: February 26, 2018 
Amendment 3: April 24, 2018 
Amendment 4: July 27, 2018 
Amendment 5: November 27, 2018 


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Amendment 7: July 2, 2019 
 
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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PROTOCOL AGREEMENT 
I have read the protocol specified below. In my formal capacity as Investigator, my duties include 
ensuring the safety of the study subjects enrolled under my supervision and providing Esanik 
Therapeutics with complete and timely information, as outlined in the protocol.  It is understood 
that all information pertaining to the study will be held strictly confidential and that this 
confidentiality requirement applies to all study staff at this site. Furthermore, on behalf of the study 
staff and myself, I agree to maintain the procedures required to carry out the study in accordance 
with accepted good clinical practice (GCP) principles and to abide by the terms of this protocol. 
 
 
 
 
 
Principal Investigator Signature:  
_______________________________________________________ 
Principal Investigator Print:  
_______________________________________________________ 
Date:   
 
 
 
_______________________________________________________ 
 
 
 


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TABLE OF CONTENTS 
1. INTRODUCTION ..................................................................................................................................................................... 6 
 1.1 Disease Background........................................................................................................................................................................ 6 
 1.2 Treatment Background ................................................................................................................................................................. 7 
 
1.3 Rationale………………………………………………………………………………………………………..………………..……….......15 
 
1.4 Rationale for Correlative Studies……………………………………………………………………………………...….…………16 
2. OBJECTIVES .......................................................................................................................................................................... 17 
 2.1 Primary Objective .......................................................................................................................................................................... 17 
 2.2 Secondary Objectives ................................................................................................................................................................... 17 
 2.3 Correlative/Exploratory/Tertiary Objectives ................................................................................................................... 18 
3. PATIENT SELECTION ....................................................................................................................................................... 18 
 3.1 Inclusion Criteria............................................................................................................................................................................ 18 
 3.2 Exclusion Criteria ........................................................................................................................................................................... 19 
 3.3 Screen Failures ................................................................................................................................................................................ 20 
4. ENROLLMENT PLAN AND SUBJECT REGISTRATION ............................................................................................. 20 
 4.1 Registration Procedure ............................................................................................................................................................... 20 
 4.2 Survival Followup .......................................................................................................................................................................... 21 
5.  TREATMENT/INTERVENTION PLAN……………………………………………..…………………………………….………….20 
 
5.1 Removing Subjects from the Protocol…………………………………………………………………………………..………...21 
 
5.2 Definition of Compliance with Self-Adjusted Oral Agent ESK981…………………………………………………..…22 
6. THERAPEUTIC AGENT ..................................................................................................................................................... 22 
 6.1 Description of Treatments ......................................................................................................................................................... 22 
 
6.2 ESK981 Drug Supply and Return.………………………….………………….……..……………………………..……..…........…22  
 
6.3 Drug Accountability…………………………………………………………………………………...…………………………….……23 
ATTACHMENTS ..................................................................................................................................................................... 24 
  
 Attachment 1: .............................................................................................................................................................................. 25 
  
 Attachment 2: .............................................................................................................................................................................. 26 
  
 Pharmacokinetics ...................................................................................................................................................................... 27 
 6.4 Dosage Selected, Preparation, and Schedule of Administration ............................................................................... 31 
 6.5 Dose Modifications ........................................................................................................................................................................ 32 
 6.6 Management of Expected Toxicities ...................................................................................................................................... 32 
 6.7 Concomitant Medications and Supportive Care ............................................................................................................... 34 
7. SAFETY EVALUATION ...................................................................................................................................................... 35 
 7.1 Definitions ......................................................................................................................................................................................... 35 
 7.2 Recording and Grading of Adverse Events ......................................................................................................................... 37 
 7.3 Adverse Events Reporting ......................................................................................................................................................... 38 
 7.4   Serious Adverse Event Reporting ........................................................................................................................................... 40 
 7.5   Procedure in case of Pregnancy .............................................................................................................................................. 41 
8. CRITERIA FOR OUTCOME ASSESSMENT/THERAPEUTIC RESPONSE.............................................................. 42 
 8.1 Outcome Assessment ................................................................................................................................................................... 42 
 8.2 Therapeutic Response ................................................................................................................................................................. 43 
 8.3 Response Criteria ........................................................................................................................................................................... 45 
 8.4 Confirmatory Measures/Duration of Response ............................................................................................................... 48 
9.   CORRELATIVES ................................................................................................................................................................. 51 
10. DATA REPORTING AND REGULATORY REQUIREMENTS .................................................................................. 52 
 10.1 Data Collection and Management ....................................................................................................................................... 52 
 10.2 Data Safety and Monitoring Board ..................................................................................................................................... 54 
11. STATISTICAL CONSIDERATIONS ............................................................................................................................... 54 
 11.1 Objectives ...................................................................................................................................................................................... 54 
 11.2 Endpoints ...................................................................................................................................................................................... 55 
11.3 Design………………………………………………………………………...……………………………………………………………..55 
 11.4 Analysis……………........................................................................................................................................................................ 56 
 11.5 Expected Accrual Rate, Accrual Duration, and Total Study Duration ................................................................ 57 
12. REGULATORY AND PROTECTION OF HUMAN SUBJECTS .................................................................................. 57 


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 12.1 Roles and Responsibilities ..................................................................................................................................................... 57 
 12.2 Ethical Considerations ............................................................................................................................................................ 57 
 12.3 Written Informed Consent .................................................................................................................................................... 57 
 12.4 Protection of Privacy ................................................................................................................................................................ 58 
 12.5 Terminating or Modifying the Study ................................................................................................................................. 58 
13. REFERENCES ..................................................................................................................................................................... 59 
APPENDIX A: PERFORMANCE STATUS CRITERIA ....................................................................................................... 60 
APPENDIX B: MEDICATIONS WITH THE POTENTIAL FOR DRUG-DRUG INTERACTION..……………......…….61 
APPENDIX C: STUDY CALENDAR ....................................................................................................................................... 63 
APPENDIX D: GLOSSARY OF ABBREVIATIONS AND ACRONYMS............................................................................ 64 
APPENDIX E. PILL DIARY ..................................................................................................................................................... 66 
APPENDIX F. DSM REPORT FORM ..................................................................................................................................... 67 
 
 
  
 


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1.  INTRODUCTION 
1.1 Disease Background 
Prostate cancer is the second leading cause of cancer deaths in men. According to 
American Cancer Society estimates, in 2016 as many as 180,890 American men will be 
diagnosed with prostate cancer, and nearly 26,120 will die of the disease.2 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 (Figure 1).3 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. 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 most CRPC remains AR signaling intact.4-6 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,7 a recently presented Phase III trial 
evaluating the multi-tyrosine kinase inhibitor (MTKI) cabozantinib in CRPC did not meet 
its primary survival endpoint.8 Although the AR signaling status was unknown in trial 
participants, the majority of men with CRPC retain active AR signaling.9,10 Our preclinical 
study provided a mechanistic basis and rationale of combining cabozantibib 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.11 
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 piqued our further interest in deciphering the molecular basis for the log-fold 
increased sensitivity to ESK981 relative to other MTKIs in prostate cancer cells.   


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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. Our observation of a direct activity of ESK981 on prostate cancer 
cell autophagy coupled with its anti-angiogenesis activities provides a compelling rationale 
to investigate this MTKI in the treatment of mCRPC patients.   
1.2 
Treatment Background 
 
ESK981, formerly known as CEP-11981, is a novel oral MTKI originally developed by 
Cephalon12 and currently being developed by Esanik Therapeutics. 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.13 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


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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 cabozantib 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). 
Interestingly, 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.1 
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 to 75% of human breast, prostate, and 
ovarian cancers.1,14 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.1    
 
Figure 3. Overview of the autophagy pathway 
Adapted from Yang et al.1 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   Description and mechanism of action 
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 
nonredundant 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. 
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 
(qd) and twice daily (bid) dosing regimens demonstrate significant anti-tumor efficacy 
(tumor growth inhibition and partial and complete regressions). In both solid and 
hematologic tumor models, however, qd and bid continuous administration are 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 nonobese diabetic/severe 
immunocompromised mice (NOD-SCID) severely immunocompromised tumor-bearing 
mice.   
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).13 After daily oral 


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administration of ESK981 to cancer patients, the median tmax values for ESK981 were 
typically in the range of 2 to 4 hr. (Table 1 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).  
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 


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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 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.  
1.2.2 
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.  
One patient with an unrelated serious adverse event was a 76-year-old white man with 
metastatic prostate cancer. He started open-label treatment with CEP-11981 on 21 January 
2010. He had a history of being heavily pretreated with bicalutamide, leuprolide, 
ketoconazole, GVAX vaccine, CNTO, docetaxel, cyclophosphamide, mitoxantrone, and 
several other agents in clinical trials.  Relevant medical history included lumbar 


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laminectomies, osteoarthritis, lower back pain, pelvic pain, and intermittent right hand 
cramping. On 04 February 2010 (day 15), the patient had an elevated creatine 
phosphokinase laboratory value of 241 U/L (normal range, 25-195 U/L); study drug was 
interrupted from 05-10 February 2010. The laboratory value was back to normal at 165 
U/L on 09 March 2010 (day 48).  
The last dose of study drug was administered on 23 February 2010 (day 34). On 25 
February 2010 (day 36), the patient experienced serious adverse events of back pain, 
musculoskeletal pain, and abdominal pain, all Grade 3 in severity. Pain reduction was 
achieved by treatment with oxycodone and intravenous dexamethasone and morphine. 
The patient was hospitalized for pain control and a magnetic resonance imaging (MRI) 
scan of the thoracic spine to rule out cord compression. The MRI scan was negative for 
cord compression. All 3 serious adverse events resolved on day 37, with residual effects, 
and the patient was discharged from the hospital. The investigator considered the serious 
adverse events of back pain, musculoskeletal pain, and abdominal pain unlikely related to 
the study drug. The patient was withdrawn from the study on 09 March 2010 (day 48) 
because of disease progression. 
Another patient with experienced pyrexia, hemolytic anemia, and hyperbilirubinemia.  The 
patient was a 26 year-old African American woman with advanced lung cancer.  The 
patient started open-label treatment with CEP-11981 on 25 August 2010. Relevant medical 
history included migraine headaches, cough, nausea, shortness of breath, and fatigue. 
Concurrent medications included oxycodone, lorazepam, guaifenesin, and oxycocet. On 30 
August 2010 (day 6), the patient was hospitalized for Grade 3 serious adverse events of 
pyrexia (102°F), hyperbilirubinemia, and hemolytic anemia. She also had a urinary tract 
infection, pain in bilateral lower extremities, blurry vision, sinus tachycardia, lethargy and 
thrush. The study drug was held during admission. The patient's laboratory tests 
performed on days 6 and 7 showed an elevated bilirubin at 5.2 mg/dL and hemoglobin at 
9.6 g/dL, a concern for hemolytic anemia; the patient's haptoglobin was 315 mg/dL.  
Blood cultures were negative, but the urine culture was positive for E. coli. The patient was 
treated with ciprofloxacin for the urinary tract infection and fluconazole for thrush. On 02 
September 2010 (day 9), the patient's blood lactate dehydrogenase (LDH) was 618 U/L. 
The events of pyrexia and hyperbilirubinemia resolved by day 10, with a temperature of 
97.1°F, total bilirubin of 1.3 mg/dL and a hemoglobin of 10.6 mg/dL. The patient did not 
require a transfusion, and her bilirubin, hemoglobin, and hematocrit resolved during 
hospitalization. The patient was discharged from the hospital on day 9 (data on file). The 
investigator considered the serious events of pyrexia, hemolytic anemia, and 
hyperbilirubinemia as possibly related to the study drug. On 08 September 2010 (day 15), 
the patient had Grade 3 serious adverse events of nausea and vomiting that required 
hospitalization. An x-ray of the kidneys, ureters, and bladder was negative for obstruction 
or ileus, but indicated constipation. Her constipation was treated with docusate/senna, 
which improved the nausea and vomiting. The investigator considered the serious adverse 
events of nausea and vomiting, which resolved on 10 September 2010 (day 17), to be not 
related to the study drug. The last dose of study drug administered was on 29 August 2010 
(day 5). The patient was withdrawn from the study on 08 September 2010 (day 15) 
because 
of 
the 
serious 
adverse 
events 
of 
pyrexia, 
hemolytic 
anemia, 
and 
hyperbilirubinemia. 
Another patient experienced dyspnea, electrocardiogram changes, chest discomfort.  The 
patient was a 57 year-old white woman with colorectal cancer. She started open-label 
treatment with CEP-11981 on 08 December 2010. On 15 December 2010 (day 8), the 


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patient experienced serious adverse events of dyspnea (Grade 2), electrocardiogram (EKG) 
change (Grade 3), and chest discomfort (Grade 2). The EKG showed a t-wave inversion that 
was not present on previous EKGs. She was subsequently hospitalized for cardiac workup 
(data on file). The last dose of study drug was administered on 14 December 2010 (day 7). 
The events of EKG change and chest discomfort resolved with no residual effects on 20 
December 2010 (day 13). The event of dyspnea did not resolve. On 29 December 2010 
(day 22), the patient had a nonserious adverse event of Grade 1 chest discomfort that did 
not resolve and was withdrawn from the study because of the nonserious chest discomfort 
and serious adverse events of dyspnea and EKG change. The investigator considered the 
serious adverse events of dyspnea and EKG change and both the serious and nonserious 
chest discomfort to be possibly related to the study drug. 
In the Phase I study, 19/43 patients received more than 28 days (range 33-504 days) of 
treatment. Table 3 provides the patient’s dose level, number of days on treatment, and 
adverse events reported.  There were no Grade 4 toxicities in this group.  Six patients had 
at least one Grade 3 toxicity. 


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Table 3. Adverse Events Occurring On or After Day 28 in Patients that Received more than 
28 days of Treatment
 
 
 
 
 
 
Pts treated >27 
days
Days on 
Treatmen
t
Dose 
(mg/m2
)
Grade 1
Grade 2
Grade 3
001002/K-M
110
3.0
Dry skin, Nausea, Sinus headache, Gamma-
glutamyltransferase increased, Abdominal tenderness, 
Hypercalcaemia, Blood lactate dehydrogenase increased 
Hyperglycaemia, Vulvovaginal pruritus, Fatigue 
Abdominal pain
001001/RAM
322
3.0
Rhinitis, Wheezing, Hypoalbuminaemia, Nasopharyngitis, 
Sinus headache, Gamma-glutamyltransferase increased, 
Dyspnoea, Nausea, Oedema peripheral, Hypokalaemia, 
Burning sensation, Hyperglycaemia, Headache, 
Hypercholesterolaemia, Blood creatine phosphokinase 
increased, Vomiting, Pain in extremity, Hypoglycaemia, 
Blood creatinine increased, Back pain
Abdominal pain, Fatigue 
002003/CEC
69
4.2
Hyperkalaemia, Wheezing, Dyspnoea, Oral discomfort, 
Blood alkaline phosphatase increased, Constipation, 
Decreased appetite, Tachycardia, Oedema peripheral, 
Hyperglycaemia
 
002005/DNH
70
5.9
Gamma-glutamyltransferase increased, Hypoglycaemia, 
Dyspepsia, Incontinence, Dizziness, Bradycardia, 
Decreased appetite, Hyperglycaemia, Nausea, Chest 
discomfort, Asthenia, Hyperhidrosis 
Fatigue, Nocturia 
Hyperkalaemia
002008/DLH
70
11.8
Groin Pain, Decreased appetite, Nasopharyngitis, Myalgia, 
Hyperuricaemia, Urinary incontinence, Haemoglobin 
decreased
Hyperglycaemia, Neuropathy peripheral, Tongue 
ulceration 
002009/RMH
70
19.7
Hot flush, Gastrooesophageal reflux disease, 
Rhinorrhoea, Fatigue, Eye pain 
 
001015/SRG
110
19.7
Hyperglycaemia, Upper respiratory tract infection, 
Hyponatraemia, Oedema peripheral, Erythema, Cough, 
Dyspnoea, International normalised ratio increased, 
Proteinuria 
Ureteric obstruction, Abdominal pain, Proteinuria 
001017/D-F
41
29.6
None (All AEs had onset before day 28),
 
003002/MAR
90
29.6
Decreased appetite 
Anaemia, Myocardial ischaemia 
002010/EJB
217
29.6
Hypoaesthesia, Lip pain, Colonic polyp, Dry skin, Nausea, 
Decreased appetite, Asthenia, Constipation 
Cough 
002011/KJD
111
41.4
Dyspnoea, Musculoskeletal chest pain, Constipation, 
Bladder pain, Hot flush, Abdominal pain upper 
Night sweats, Upper respiratory tract infection 
002014/CSS
33
55.0
Decreased appetite 
Fatigue, Oedema peripheral 
Back pain, Musculoskeletal pain, Abdominal pain, Scrotal 
oedema
001018/ADM
152
55.0
Insomnia, Upper respiratory tract infection, Flushing, 
Lymph node pain, Skin nodule, Contusion, Stomatitis, 
Blister, Seasonal allergy, Neutropenia, 
Thrombocytopenia, Upper respiratory tract infection, 
Hyperuricaemia, Abdominal pain, Decreased appetite, 
Mood swings 
Pain in extremity, Presyncope, Mucosal inflammation, 
Blood bilirubin increased 
003003/MLK
504
55.0
Hiccups, Joint injury, Pain in extremity, Cheilitis, 
Stomatitis, Wheezing, Urinary retention, Incision site 
pain, Muscular weakness, Vision blurred, Vomiting, 
Headache, Erythema, Neuropathy peripheral, Chills, Rash 
macular, Stasis dermatitis, Rheumatoid arthritis, 
Joint effusion, Hypotension, Oedema peripheral, 
Anaemia, Weight increased, Urinary tract infection 
Somnolence, Arthralgia, Anxiety, Impaired healing, 
Cellulitis, Oedema peripheral,
001021/JBR
172
73.0
Chest pain, Muscle spasms, Abdominal pain, Pharyngitis 
streptococcal, Stomatitis, Sexual dysfunction, Dysuria, 
Pyrexia, Abdominal pain upper, Rales 
Back Pain, Abdominal distension, Urinary tract infection, 
Weight descreased, Tachycardia, Dehydration, Back pain, 
Flank pain, Oedema peripheral, Vomiting
Headache, Neck pain, Diarrhea, Decreased appetite, 
Anemia, Musculoskeletal pain,
001022/EDM
65
97.4
Chest pain, Pain in extremity 
 
001025/VGY
76
97.4
Neuropathy peripheral, Flank pain, Contusion, Insomnia 
 
002017/RWF
127
97.4
Rhinorrhoea, Pulmonary mass, Diarrhoea, Dysphonia 
 
002018/CRC
196
97.4
Musculoskeletal pain, Diarrhoea, Nasopharyngitis, 
Nausea, Dizziness, Onychoclasis, Abdominal pain, 
Vomiting, Dysphonia, Sinus congestion, Abdominal 
distension, Flatulence, Neuropathy peripheral, 
Oropharyngeal pain, Respiratory tract congestion, 
Decreased appetite, Diarrhoea, Insomnia
Cough, Pneumonia 
Chronic obstructive pulmonary disease


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Tumor response 
Out 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 4).  
 
 
Figure 4.  
Best overall tumor response per cohorta 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. In our preliminary studies, ESK981 appears to induce robust 
vacuolization associated with activation of the autophagy pathway in prostate cancer 
in vitro and in vivo and demonstrated dose-dependent inhibition of castrated VCaP 
xenograft growth (Figure 5).  


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Figure 5.  
ESK981 inhibits castrated VCaP tumor growth. Castrated VCaP-bearing mice received vehicle or ESK981 
(60 or 30mg/kg) as indicated. A, Tumor volume was measured twice per week over a 25-day course. B, 
Tumor weight was measured for each group after surgical resection. 
 
Thus, we are conducting a focused open-label Phase II study of ESK981 in men with 
mCRPC. The study will evaluate men with mCRPC who have progressed on 
enzalutamide and/or abiraterone acetate. Consenting patients will undergo a biopsy at 
baseline and after 8 weeks of treatment to assess gene expression and biomarkers. The 
primary objective will be to determine the PSA ≥ 50% response rate (PSA50) from 
baseline using the Prostate Cancer Working Group 3 (PCWG3) criteria to ESK981 as a 
single agent.  
Currently, CRPC patients receive either enzalutamide or abiraterone acetate as front-
line treatment for mCRPC without visceral metastases. If a patient has metastatic 
disease with visceral metastases he may also receive chemotherapy such as docetaxel. 
This study explores if ESK981, administered 5 days on and 2 days off can induce a high 
PSA response rate and/or if AR expression is induced or enhanced from baseline 
following a standard front-line treatment to determine the PSA50 response rate to 
ESK981. 
1.4 
Rationale for Correlative Studies 
1.4.1  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.  
1.4.2 
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.  
1.4.3 
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 patient.   
 


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1.4.4 
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.  
1.4.5 
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, 
immunohistochemistry to quantify PD-1 and PD-L1 expression and presence of CD8+ 
tumor infiltrating lymphocytes 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 11.3. 
2.  
OBJECTIVES 
2.1 
Primary Objective 
The primary objectives of this study are: 
 
To determine the PSA ≥ 50% response rate (PSA50) from baseline using the 
PCWG3 criteria to ESK981 as a single agent in men with mCRPC who have 
progressed on enzalutamide (an oral androgen-receptor inhibitor) and/or oral 
abiraterone acetate (an androgen synthesis inhibitor). 
 
To assess the safety and tolerability of ESK981 as a single agent. Adverse events of 
all grades will be captured by the National Cancer Institute - Common 
Terminology Criteria for Adverse Events, version 4.03 (NCI-CTCAE v4.03) and GCP 
standards.  
2.2 
Secondary Objectives 
 
To determine the time to PSA response to ESK981 in mCRPC patients. 
 
To determine the duration of PSA response to ESK981 in mCRPC patients. 
 
To determine PSA progression rates as defined by the PCWG3 criteria.  
 
To determine PSA progression free survival as defined by the PCWG3 criteria 


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2.3 
Correlative/Exploratory/Tertiary 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. 
3. 
PATIENT SELECTION 
A total of 27 patients with mCRPC 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 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 
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. 
3.1.2 
Be willing and able to adhere to the prohibitions and restrictions specified in this 
protocol. 
3.1.3 
Males 18 years of age and above. 
3.1.4 
Eastern Cooperative Group (ECOG) performance status ≤1. 
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 
Documented histologically confirmed adenocarcinoma of the prostate.   
3.1.7 
Metastatic prostate cancer (M1) as documented by appropriate medical imaging (i.e. 
CT-Scan, PET scan or bone scan). 
 


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3.1.8 
Treatment failure of either abiraterone and/or enzalutamide per PCWG3 criteria for 
PSA, measurable disease or non-measurable (bone) disease. 
 
3.1.9 
Willingness to use contraception by a method that is deemed effective by the 
Investigator throughout the treatment period and for at least 30 days following the last 
dose of therapy. 
 
3.1.10 Willingness and ability to comply with study procedures and follow-up examination. 
 
3.1.11 Able to swallow and retain oral medication. 
 
3.1.12 Willingness and ability to undergo mandatory tumor biopsy at baseline and week 
8/cycle 3. 
 
3.1.13 Willingness and ability to undergo mandatory whole blood sample collections at 
baseline, days 8, 15, and 22 in the first cycle, and then monthly. 
3.2 
Exclusion Criteria 
3.2.1  Current systemic therapy (other than a GnRH agonist/antagonist) for CRPC 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 chemotherapy (e.g. docetaxel, cabazitaxel) for CRPC. Prior docetaxel 
administered in the castrate-sensitive space is allowed.  
3.2.3 
Prior radiopharmaceutical therapy (e.g. radium-223, strontium-89, samarium-153, 
etc.) within the past year. 
3.2.4 
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. 
3.2.5 
The patient has any of the following hematologic values:  
 absolute neutrophil count (ANC) less than 1500/mm3 
 platelet count less than 100000/mm3 
 hemoglobin less than 9 g/dL. 
3.2.6 
The patient has any of the following hepatic function values: 
 bilirubin greater than 1.5 times the upper limit of normal (ULN) 
 alanine aminotransferase (ALT) greater than 2.0 times the ULN in the absence 
of known hepatic metastases 
 aspartate aminotransferase (AST) greater than 2.0 times the ULN in the 
absence of known hepatic metastases,  
  ALT or AST greater than 3.0 times the ULN in the presence of known hepatic 
metastases. 
3.2.7 
The patient has a serum creatinine value greater than 1.5 mg/dL. 
3.2.8 
The patient has active brain metastases. 
 


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3.2.9 
The patient is currently on warfarin or heparin therapy. 
 
3.2.10 The patient has any pre-existing coagulopathy, recent hemoptysis, gross hematuria or 
gastrointestinal bleeding. 
3.2.11 The patient has a history of a clinically significant cardiovascular or cerebrovascular 
event within 6 months prior to study entry. 
3.2.12 The patient has uncontrolled hypertension defined as a blood pressure measurement 
greater than 150 mm Hg systolic or 90 mm Hg diastolic with medication. 
3.2.13 The patient has received any investigational drug within the past 4 weeks. 
3.2.14 The patient has previously been enrolled in the study or received ESK981. 
3.2.15 The patient has known hypersensitivity to gelatin or lactose monohydrate. 
3.2.16 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. 
3.2.17 The patient has taken a medication known to be a potent inhibitor of CYP1A2, CYP2C8, 
or CYP3A4 within 2 weeks prior to the first dose of study drug. 
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. 
ENROLLMENT PLAN AND SUBJECT REGISTRATION 
4.1 
Registration Procedure 
 
All patients shall be registered with the Cancer Center Clinical Trials Office at (313) 
576-9837 (Kim Dobson). 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.  
4.2 
Survival Follow-up 
Subject survival information will be collected preferably via office visit or 
telephone contact every 3 months from the date of end of treatment visit until 5 
years post treatment.  
 The following information will be collected: The subject’s survival status, and 
if deceased, the date of death. 
 The method by which the survival status was assessed and the date it was 
assessed. 
 Any subsequent anti-cancer therapy received after discontinuation from 
study drug. 
 
The subject will be determined to be lost to follow-up only after at least 3 attempts to 
contact him have been made over a 4 month period. At least two of the attempts to 
contact must be made through certified letters. 
 
 


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5. 
TREATMENT/INTERVENTION PLAN 
This is an open-label, non-randomized single-stage Phase II design of ESK981 in 
patients with mCRPC who have had prior enzalutamide and/or abiraterone.  Patients 
will receive 8 weeks of ESK981, and then be evaluated for their rate of PSA decline of ≥ 
50% from baseline (PSA50), using the PCWG3 criteria.   
Assessments and procedures that will occur during the study are detailed in Appendix C. 
An overall study schema appears below: 
 
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. 
q4 weeks 
PSA 
Safety labs 
Plasma 
Until  the 
end of 
treatment  
PSA 
4 weeks 
PSA 
Safety  labs 
Plasma 
 
27 Pts with  
mCRPC who have 
received prior 
enzalutamide and 
/or abiraterone 


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Because an excessive rate of withdrawals can render the study uninterruptable, 
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 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 AGENT 
6.1 
Description of Treatments 
Patients will receive 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. Drugs can be taken in the fed or fasted state. If at the conclusion of the 8-week 
period, no disease progression has occurred, refer to section 5.1 to determine if 
participant can stay on trial.   
6.2 
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), 


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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. A temperature log is 
provided in Attachment 1; however, sites may use their own temperature log or the 
one provided in this manual. 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 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.   
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.    
6.3 
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 


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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.      
Attachments 
Attachment 1: Temperature Monitor Log 
Attachment 2: Site Investigational Drug Shipping Request Form 
 
 
 
 
 
 
 


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Attachment 1: 
TEMPERATURE MONITORING LOG 
Clinical Site: ___________________________________ 
Site Number: _________________ PI Name: _____________________ 
 Location of Refrigerator: ____________________________________________________________________________________ 
Record daily refrigerator temperatures on the log provided.  Temperatures must be maintained between 2-8oC.  If refrigerator 
fluctuates from the specified range, contact your CAP CRA for appropriate action and follow, if necessary. 
Month:  ________, 20_____ 
 
Day of Month 
1 
2 
3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 
Temp 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
<-4ºC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-3ºC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-2ºC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-1ºC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
0ºC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1ºC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2ºC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3ºC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4ºC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5ºC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6ºC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7ºC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8ºC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9ºC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10ºC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11ºC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12ºC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
13ºC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
>14ºC  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Attachment 2: 
 
 
SITE INVESTIGATIONAL DRUG SHIPPING REQUEST FORM 
Esanik Therapeutics, Inc.  
Protocol GT-001 
 
Please Email to: BRIAN WOOD 
 
EMAIL: Brian@esanik.com 
 
Protocol No./Investigational Agent:   
  ESK981 (CEP11981) 
Site No./Investigator: 
 
Request Date: 
Date Required On Site: 
Number of Vials Requested:   
Ship To: (include attention personnel, full mailing address, phone and email for receiving party) 
 
 
 
 
 
 
 
Comments/Special Instructions:  
Institutional Requestor: 
Name 
Signature 
Phone Number 
 
 
 
 
 
 
CAP Approval*: 
Name 
Signature 
Date 
 
 
 
 
 
 
The completed, original form must be filed in the Pharmacy Binder for this study. 


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Pharmacokinetics 
Note: CEP-11981 refers to the development name for ESK981. 
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 4. 
Table 4. 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 4. 


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Table 5. 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 AUC0-∞ were minimally affected by the fed/fasted state of the 
animals, but the 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 


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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 in the 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 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. 


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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 6. 
Table 6. 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 7. 


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Table 7. 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. 
6.4 
Dosage Selected, Preparation, and Schedule of Administration 
Treatment will be administered on an outpatient basis. 
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 


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high-density polyethylene (HDPE) bottle with a child resistant closure and an induction-
sealed inner seal. The formulation also contains lactose monohydrate. 
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. 
6.5 
Dose Modifications 
Patients with NCI-CTCAE Grade 3 or Grade 4 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 a reduced dose of 120mg (3 capsules) daily for 5 days, 2 days off. 
Following a dose reduction, patients who have a second NCI-CTCAE Grade 3 or Grade 4 
adverse event judged to be at least possibly related to ESK981 will be discontinued from the 
study.  If drug cannot be restarted within 3 weeks of being held, ESK981 should be 
discontinued. Patients will also be discontinued for any of the following reasons:   
1. Worsening symptoms that can be attributed to prostate cancer  
2. Unacceptable adverse event(s) including development of a urinary outlet 
obstruction requiring urinary catheterization and/or surgical intervention,  
3. Intercurrent illness that prevents further participation,  
4. Patient refuses further treatment through the study and/or withdraws consent to 
participate, 
5. Patient is noncompliant with respect to taking drugs, keeping appointments, or 
having tests required for the evaluation of drug safety and efficacy, or  
6. General or specific changes in the patient's condition that render the patient 
unacceptable for further treatment in this study in the judgment of the investigator.  
Under no circumstance will care of a withdrawn patient be adversely affected by a decision 
to withdraw or be withdrawn from the study  
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. 
 


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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 
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. 
 


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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 
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. 
 
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).
6.7.1 
Supportive Care Medications 
Patients should receive appropriate supportive care for CRPC and appropriate treatment 
for comorbidities, subject to the restrictions due to potential drug-drug interactions 
detailed in Section 6.7.3.   
6.7.2  Prohibited before enrollment and during administration of study treatment  
Concomitant systemic treatments for CRPC (other than a GnRH agonist/antagonist) 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 


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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. 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 
A safety review of the first six patients who have been observed for 8 weeks will occur.  
Enrollment will pause until all six patients have been assessed for toxicity 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 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.   


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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 § 
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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. Hospitalizations for administrative reasons or a nonworsening 
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 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 


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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, 
 
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 4.03.  If CTCAE 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 
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 .  
Table 8. 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 


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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.  
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.  


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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  
Within 24 hours of awareness of a serious adverse event, whether or not related to the study 
drug, the investigator will complete and submit a Medwatch 3500a form, containing all 
required information (reference CFR § 312.32). The investigator will submit a copy of this 
Medwatch 3500a form to the sponsor-investigator and Esanik 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 
Fax: 610-408-0321 
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: 


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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.  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.  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 
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 ESK981 in pregnant and lactating women is not known, and the exposure of a 
fetus or nursing infant is considered a potential risk. ESK981 can cause fetal harm when 
administered to a pregnant woman based on its mechanism of action. Subjects receiving 
ESK981 are advised to use two acceptable methods of birth control (one of which must 
include a condom as a barrier method of contraception) starting at the time of screening for 
an ESK981 study and continuing throughout the course of treatment and for at least three 
months after ESK981 is discontinued.  
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, 


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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 
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. PET scan will be used for bone scan if requested by 
physician. This applies to tumors of the chest, abdomen, pelvis and bone. 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 
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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) criteria15 and the guidelines for 
prostate cancer endpoints developed by the Prostate Cancer Clinical Trials Working Group 
(PCWG3).3 
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 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.3 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. 
8.2.2 
Measurable Disease 
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as ≥ 20 mm by chest x-ray, as ≥ 10 mm with CT 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 
might or might not be considered measurable. If the investigator thinks it appropriate to 


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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 t 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 or non-measurable) sine 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), 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. 
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). 


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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) 
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). 


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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). 


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8.3.3 Evaluation of New Lesions 
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 9). 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. 
 
 


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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 
 
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 10 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. 
Table 9. 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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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 10. 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 lead-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.  
†Particularly important when anticipated effect on PSA is delayed or for biologic therapies. 


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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. 


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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 screening to end of treatment). 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 
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. 


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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.  
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 


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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 as a single agent in men with mCRPC who have progressed on enzalutamide (an oral 
androgen-receptor inhibitor) and/or abiraterone acetate (an androgen synthesis inhibitor). 
2) To assess the safety and tolerability of ESK981 as a single agent.  
The secondary objectives of this study are: 
1) To determine the time to PSA response (TTPR) to ESK981 in patients with mCRPC 
2) To determine the duration of PSA response (PRD) to ESK981 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, 
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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 4.03 (NCI-CTCAE v4.03) 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 1.3. 
Duration of PSA response (PRD) is defined as the time from start of PSA50 until PSA 
progression (defined in Section 8.3.2). 
PSA progression free survival (PPFS) is defined in Section 8.3.2 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 
11.3.1  We will utilize a single group single-stage Phase II design for the study. Patients will receive 
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. After 8 weeks (2 cycles) of ESK981, 
patients will be evaluated for their rate of PSA decline of ≥ 50% from baseline (PSA50), 
using the PCWG3 criteria. Extrapolating from the data summarized on PSA50 response at 
any time by Cheng et al,16 we hypothesize that the 8-week PSA50 rate in patients similar to 
patients eligible for this protocol is approximately 20%. We also hypothesize that the 8-
week PSA50 rate for ESK981 treated patients will be approximately 30%.   
11.3.2  We seek preliminary evidence that the true 8-week PSA50 rate for patients on ESK981 
exceeds the hypothesized reference value of 20%. Having a directional hypothesis, the 
PSA50 rate will be estimated with a 1-sided Wilson type 90% lower confidence interval 
(CI).  With precision defined as a CI half-width (distance from the PSA50 estimate to the 
lower 90% confidence limit (CL)) of 0.100, a sample size of N=27 patients and a sample 
estimate of PSA50 = 30% would have a lower CL = 0.201. This would indicate that the 
true 8-week PSA50 rate was > 20%, with 90% confidence. 
11.3.3  The required sample size of N=27 was determined from the “Confidence Intervals for 
One Proportion” program within the PASS 15 software.17   
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 upon the 
PSA50 rate, safety, and tolerability. For each individual patient, we will allow for an 
ESK981 treatment non-compliance of up to 25% (i.e., up to 25% of 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).    


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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 27 ESK981 compliant patients (i.e., completely EEC) allowing for 
an overall attrition rate (“a”) of up to 15% of patients, we will need to enroll up to N’ = [N 
/ (1 – a)] = [27 / (1 – 0.15)] = 27 / 0.85 = 32 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. For example, that would 
focus on the patients who were “EE” but not compliant. Another effectiveness analysis 
would focus on the patients who were eligible, but neither evaluable or 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 
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 4.03.    
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 


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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 
Expected Accrual Rate, Accrual Duration, and Total Study Duration  
11.5.1 This will be a clinical trial involving Karmanos Cancer Institute (KCI) only. We expect to 
accrue  10-12 patients/year.   
11.5.2  At that rate, we can accrue  32 patients (to obtain 27 EEC patients) in  32-38 months. 
Allowing an additional 4 months to finish determining all biomarkers and correlatives in all 
patients yields an estimated total study duration of  36-42 months.   
12. 
REGULATORY 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 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. 


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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. 
 
 


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13.0 REFERENCES 
1. 
Yang ZJ, Chee CE, Huang S, Sinicrope FA. The role of autophagy in cancer: therapeutic 
implications. Mol Cancer Ther 2011; 10(9): 1533-41. 
2. 
American Cancer Society. Cancer Facts & Figures 2016. Atlanta, GA; 2016. 
3. 
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. 
4. 
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. 
5. 
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. 
6. 
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. 
7. 
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. 
8. 
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. 
9. 
Nelson PS. Targeting the androgen receptor in prostate cancer--a resilient foe. N Engl J Med 
2014; 371(11): 1067-9. 
10. 
Grasso CS, Wu YM, Robinson DR, et al. The mutational landscape of lethal castration-resistant 
prostate cancer. Nature 2012; 487(7406): 239-43. 
11. 
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. 
12. 
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. 
13. 
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. 
14. 
Qu X, Yu J, Bhagat G, et al. Promotion of tumorigenesis by heterozygous disruption of the 
beclin 1 autophagy gene. J Clin Invest 2003; 112(12): 1809-20. 
15. 
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. 
16. 
Cheng HH, Gulati R, Azad A, et al. Activity of enzalutamide in men with metastatic castration-
resistant prostate cancer is affected by prior treatment with abiraterone and/or docetaxel. 
Prostate Cancer Prostatic Dis 2015; 18(2): 122-7. 
17.    PASS 15:  Power and Analysis Sample Size Software (2017).   NCSS, LLC.   Kaysville, Utah, 
USA.  ncss.com/software/pass. 
18. 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ 
DrugInteractionsLabeling/ucm093664.htm#inVitro 


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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.18 
Potent Inhibitors of CYP1A2, CYP2C8, or CYP3A4 
Potent inhibitors of the CYP1A2, 2C8, or 3A4 include, but are not limited to, the following: 
CYP1A2 
Fluvoxamine 
Ciprofloxacin 
Mexiletine 
Propafenone 
Zileuton 
CYP2C8 
Gemfibrozil 
CYP3A4 
Ketoconazole 
Indinavir 
Ritonavir 
Itraconazole 
Clarithromycin 
Telithromycin 
Aprepitant 
Diltiazem 
Erythromycin 
Fluconazole 
Grapefruit juice 
Verapami 
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 
Smoking 
CYP2C8 
Rifampicin 
CYP3A4 
Rifampicin 
Carbamazepine 
Griseofulvin 
This list is not comprehensive as new information is continually being identified. 
 
 


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Substrates of CYP3A4/5 With a Narrow Therapeutic Range 
Substrates of CYP3A4/5 with a narrow therapeutic range include, but are not limited to: 
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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APPENDIX C: STUDY CALENDAR  
 
 
Screening 
Treatment/Intervention Period 
End of Tx (30 Days 
from last dose) 
 
Cycle 1 
Cycle 2 + beyond 
Follow-up 
Q 3 mos 
 
Day -28 to 
Day -1 
Day 1  
(±3 d) 
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 8 weeks (+/- 10 d) 
 
 
Laboratory testsc 
X 
 
X 
X 
X 
X 
X 
 
Correlative samples 
X 
 
 
 
 
Xd 
X 
 
Tumor Biopsies 
X 
 
 
 
 
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 or PET. Chest x-ray should be done if necessary for tumor assessment. Radiologic documentation will 
be provided for patients removed from study for progressive disease. 
c. Complete blood count, comprehensive chemistry panel including renal function (BUN, creatinine) and liver function tests (AST, ALT, total bilirubin), PSA, testosterone (at baseline). 
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). 
f. Patients will be followed every three months for 5 years from end of treatment for survival and subsequent treatment. 
 


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APPENDIX D: GLOSSARY OF ABBREVIATIONS AND ACRONYMS 
AE 
adverse event 
ALT 
alanine aminotransferase 
AR 
androgen receptor 
AST 
aspartate aminotransferase 
CFR 
Code of Federal Regulations 
CRF 
case report form 
CRPC 
castration resistant prostate cancer 
CT 
computerized tomography 
CTC 
circulating tumor cell 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
dose-limiting toxicity 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
FGFR1 
fibroblast growth factor receptor 1 
HIPAA 
Health Insurance Portability and Accountability Act 
IC50 
50% inhibition of activity  
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
intent-to-treat population 
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 
PCCTC 
Prostate Cancer Clinical Trials Consortium 
PCWG3 
Prostate Cancer Working Group 3 
PD 
progressive disease 
PFS 
progression-free survival 
PI 
principal investigator 
PR 
partial response 
PSA 
prostate-specific antigen 
PSA50 
PSA ≥ 50% response rate 


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RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SCID 
severe combined immunodeficiency 
SD 
stable disease 
TIE1, TIE2 
tyrosine kinase with immunoglobulin-like and EGF-like domains (1, 2) 
TMZ 
temozolomide 
ULN 
upper limit of normal 
VEGF 
vascular endothelial growth factor 


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APPENDIX E.  
 
 
 


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APPENDIX F. 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   
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: 
 
 
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 
Occurrence 
Grade1 
Attribution2 
Reportable to IRB (Y/N) 
Yes with date