Clinical trial NCT03837353
Conditions: Prostate Cancer
Sponsor: NYU Langone Health
Start date: 2019-04-01; Completion date: 2022-09-20
Enrollment: 18 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a non-randomized multi-center Phase 1b/2a dose escalation and dose expansion study testing DKN-01 as monotherapy or in combination with docetaxel in metastatic castration-resistant prostate cancer. Patients need to be biomarker positive (Dickkopf-1 \[DKK1\]) either in plasma or biopsy. Other biopsies for correlative studies are encouraged but not mandatory. Pharmacokinetic (PK) testing of one pre-treatment blood sample and one post-treatment blood sample will be mandatory on Day 1 of every cycle.

Detailed description:

Arms: arm 1: In dose-escalation Cohort 1A, the dose of docetaxel 75 mg/m2 will remain fixed. The DKN-01 dose level will start with 300 mg and be escalated to 600 mg or de-escalated to 150 mg depending on the absence or presence of identified DLTs. DKN-01 will be administered in combination with docetaxel on Day 1 and as monotherapy on Day 15 of each 21-day cycle. Patients will be treated with the combination of DKN-01 and Docetaxel until Prostate Cancer Working Group 3 (PCWG3) progression or unacceptable toxicity. arm 2: In dose-expansion Cohort 1B, either the maximum tolerated dose (MTD) or highest dose tested of DKN-01 in combination with docetaxel in Cohort 1A will be the dose used. The dose of docetaxel 75 mg/m2 will remain fixed. DKN-01 will be administered in combination with docetaxel on Day 1 and as monotherapy on Day 15 of each 21-day cycle. Patients will be treated with the combination of DKN-01 and Docetaxel until PCWG3 progression or unacceptable toxicity. arm 3: In dose-escalation Cohort 2A, DKN-01 dose level will start with 300 mg and be escalated to 600 mg or de-escalated to 150 mg depending on the absence or presence of identified DLTs. DKN-01 will be administered as monotherapy on Days 1 and 15 of each 28-day cycle. Patients will be treated with DKN-01 until PCWG3 progression or unacceptable toxicity. arm 4: In dose-expansion Cohort 2B, the MTD or highest dose tested of DKN-01 monotherapy in Cohort 2A will be the dose used. DKN-01 will be administered as monotherapy on Days 1 and 15 of each 28-day cycle. Patients will be treated with DKN-01 until PCWG3 progression or unacceptable toxicity.
Interventions: intervention 1: DKN-01 intervention 2: Docetaxel
Intervention descriptions: intervention 1: DKN-01 is a large molecular weight protein that will be given as a flat dose on a Days 1 and 15 of a 21-day cycle in Dose-Escalation Cohort 1A and Dose-Expansion Cohort 1B. DKN-01 will be given on Days 1 and 15 on a 28-day cycle in Dose-Escalation Cohort 2A and Dose-Expansion Cohort 2B. The dose of DKN-01 will be administered as an intravenous (IV) infusion over 60 (±) 15 minutes. intervention 2: Docetaxel will be administered as an IV infusion over approximately 60 (±15) minutes on day 1 of a 21-day cycle in Cohorts 1A and 1B. In Cohort 1A, docetaxel must be dosed at 75 mg/m2 on cycle 1 day 1. Docetaxel can be dosed at 75 mg/m2 or 60 mg/m2 in subsequent cycles depending on clinical discretion and dose modification guidelines. Regardless of dose, docetaxel must be dosed in 21-day cycles. In Cohort 1B, cycle 1 day 1 dosing of docetaxel will either be 75 mg/m2 or 60 mg/m2 depending on clinical discretion.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Official Title: 
A Parallel Arm Phase 1b/2a Study of DKN-01 as Monotherapy or in 
Combination With Docetaxel for the Treatment of Advanced Prostate 
Cancer With Elevated DKK1   
NCT Number: 
NCT03837353 
Study Number: 
17-01747 
Document Type:  
Study Protocol and Statistical Analysis Plan 
Date of the 
Document: 
• 
July 13, 2021  
 
 


Clinical Study Protocol DKN-01-Prostate Version 1.5 
Perlmutter Cancer Center at NYU Langone, David Wise, MD PhD 
page 1 
CONFIDENTIAL 
 
A Parallel Arm Phase 1b/2a Study of DKN-01 as Monotherapy or in 
Combination With Docetaxel for the Treatment of Advanced Prostate Cancer  
Protocol Version: DKN-01-Prostate Version 1.5 
This study will be conducted according to the protocol and in compliance with 
Good Clinical Practice, the ethical principles stated in the Declaration of Helsinki, 
and other applicable regulatory requirements. 
Study Sponsor and 
Principal Investigator: 
David R. Wise, MD, PhD 
Medical Oncologist 
Perlmutter Cancer Center at NYU Langone 
160 E 34TH Street, 10th Fl, Suite 1009 
New York, NY 10016 
 
Biostatistician: 
Andrea Troxel, PhD 
Protocol No: 
s17-01747 
IND: 
140254 
Coordinating Center: 
NYU Langone Health 
Perlmutter Cancer Center 
Clinical Trials Office 
PCC-QAU@nyulangone.org 
 
 
Document Version: 
Original Protocol  dtd 2018 May 22 
Protocol v1.2 dtd 2018 Aug 05 
Protocol v1.3 dtd 2019 May 21 
Protocol v1.4 dtd 2020 June 30 
Protocol v1.5 dtd 2021 April 19 
CONFIDENTIALITY NOTE: 
This document contains information that is confidential and proprietary to the Sponsor. This information is 
being provided to you solely for the purpose of evaluation and/or conducting a clinical study. You may 
disclose the contents of this document only to study personnel under your supervision and/or to your 
institutional review board(s) or ethics committee(s) who need to know the contents for this purpose and who 
have been advised on the confidential nature of the document. 


Clinical Study Protocol DKN-01-Prostate Version 1.5 
Perlmutter Cancer Center at NYU Langone, David Wise, MD PhD 
page 2 
CONFIDENTIAL 
 
SIGNTURE PAGE 
Protocol Title:  
A Parallel Arm Phase 1b/2a Study of DKN-01 as Monotherapy or 
in Combination With Docetaxel for the Treatment of Advanced 
Prostate Cancer  
Protocol Number: 
s17-01747 
 
REVIEWED/APPROVED BY: 
 
 
 
 
 
 
 
 
 
David R. Wise, MD, PhD 
 
 
 
 
Signature  
Date 
 


Clinical Study Protocol DKN-01-Prostate Version 1.5 
Perlmutter Cancer Center at NYU Langone, David Wise, MD PhD 
page 3 
CONFIDENTIAL 
 
INVESTIGATOR STATEMENT 
I understand that all documentation provided to me by the Sponsor or its designated 
representative(s) concerning this study that has not been published previously will be kept in the 
strictest confidence. This documentation includes the study protocol, Investigator’s Brochure, 
case report forms, and other scientific data. 
This study will not commence without the prior written approval of a properly constituted 
Institutional Review Board or Ethics Committee. No changes will be made to the study protocol 
without the prior written approval of the Sponsor and the Institutional Review Board or Ethics 
Committee, except where necessary to eliminate an immediate hazard to the patient. 
I have read, understood, and agree to abide by all the conditions and instructions contained in 
this protocol. 
Investigator Name 
 
Investigator Signature 
 
Date 
 
 
Name and address of investigational site / institution  
(please print) 


Clinical Study Protocol DKN-01-Prostate Version 1.5 
Perlmutter Cancer Center at NYU Langone, David Wise, MD PhD 
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CONFIDENTIAL 
 
STATEMENT OF COMPLIANCE 
This study will be conducted in accordance with the Code of Federal Regulations (CFR) on the 
Protection of Human Subjects (45 CFR Part 46), 21 CFR Parts 50, 56, 312, and 812 as 
applicable, any other applicable United States government research regulations, and institutional 
research policies and procedures. The International Council for Harmonization (“ICH”) 
Guideline for Good Clinical Practice (“GCP”) (sometimes referred to as “ICH-GCP” or “E6”) 
will be applied only to the extent that it is compatible with Food and Drug Administration (FDA) 
and Department of Health and Human Services regulations. The Principal Investigator (PI) will 
assure that no deviation from, or changes to the protocol will take place without prior agreement 
from the Sponsor and documented approval from the Institutional Review Board (IRB), except 
where necessary to eliminate an immediate hazard(s) to the study participants. All personnel 
involved in the conduct of this study have completed Human Subjects Protection Training. 


Clinical Study Protocol DKN-01-Prostate Version 1.5 
Perlmutter Cancer Center at NYU Langone, David Wise, MD PhD 
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CLINICAL STUDY SYNOPSIS 
Name of Sponsor: 
Perlmutter Cancer Center at NYU Langone Medical Center 
Name of Investigational 
Product: 
DKN-01 
Protocol Title: 
A Parallel-Arm Phase 1b/2a Study of DKN-01 as Monotherapy or in 
Combination With Docetaxel for the Treatment of Advanced Prostate Cancer  
Protocol Number: 
s17-01747 
Summary 
This is a non-randomized multi-center Phase 1b/2a dose escalation and dose 
expansion study involving up to 84 patients testing DKN-01 as monotherapy or 
in combination with docetaxel in metastatic castration-resistant prostate cancer. 
Biopsies for correlative studies are encouraged but not mandatory. 
Pharmacokinetic (PK) testing of one pre-treatment blood sample and one post-
treatment blood sample will be mandatory on Day 1 of every cycle. 
Study Phase: 
1b/2a 
Objectives: 
Primary Objectives: 
Part 1: Dose Escalation:  To determine the safety, tolerability, dose-limiting 
toxicities (DLTs), and maximum tolerated dose (MTD) of DKN-01 
administered alone and in combination with docetaxel in patients with advanced 
prostate cancer with elevated DKK1.  
Part 2: Dose Expansion: To evaluate the anti-tumor activity of DKN-01 in 
combination with docetaxel in patients with advanced prostate cancer with 
elevated DKK1. 
Secondary Objectives: 
1. To determine the anti-tumor activity of DKN-01 as monotherapy using 
immune-related response criteria (iRECIST) guidelines. 
2. To characterize the pharmacodynamics effects of DKN-01 administered 
as monotherapy or in combination with docetaxel.  
3. To characterize the PK of DKN-01 administered as monotherapy or in 
combination with docetaxel.  
4. To characterize the immunogenicity of DKN-01 administered as 
monotherapy or in combination with docetaxel.  
5. To determine the concordance between anti-tumor activity and DKK1 
expression in the monotherapy and combination cohorts.  
Exploratory Objectives: 
1. To determine the effect of DKN-01 monotherapy on peripheral and 
intratumoral immune cell abundance and activation. 


Clinical Study Protocol DKN-01-Prostate Version 1.5 
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2. To explore the association between DKN-01 exposure, peripheral and 
intratumoral immune cell abundance and activation, anti-tumor activity, 
and key safety measures.  
3. To determine the impact of docetaxel on peripheral and intratumoral 
immune cell abundance and activation. 
4. To determine the concordance between plasma and intratumoral DKK1 
levels and determine the association between DKK1 level, Wnt 
pathway, FGF, and, cell cycle gene alterations,  and anti-tumor activity 
5. To determine the effect of DKN-01 as monotherapy or in combination 
with docetaxel on ex-vivo intratumoral immune cell abundance and 
activation in a 3-dimensional organotypic culture model. 
6. To explore the association between response to study drug treatment and 
clinical evidence of “prostate-specific antigen (PSA)-high” (concordant 
radiographic and PSA progression) and “PSA-low” (radiographic 
evidence in the absence of PSA progression) prostate cancer. 
Endpoints: 
 
Primary Endpoints: 
Phase 1b, Cohort 1A and Cohort 2A: DLT observed during the DLT evaluation 
period (starting from Cycle 1, Day 1 [C1D1] until C2D1). 
Phase 2, Cohort 1B: Best overall response, based on iRECIST v1.1 soft tissue 
response. 
Secondary efficacy endpoints (apply to all cohorts): 
• 
Radiographic progression-free survival (PFS). 
• 
PSA PFS. 
• 
Overall survival (OS). 
• 
Duration of response (DR). 
• 
Time-to-tumor response (TTR). 
• 
≥50% decline in PSA. 
• 
Percentage change in PSA from baseline to 12 weeks post-treatment. 
• 
Maximal decline in PSA after treatment initiation. 
• 
CTC conversion from unfavorable (5 or greater CTC/7.5 mL) to 
favorable (4 or fewer CTC/7.5 mL) at 13 weeks 
• 
CTC ≥1 at baseline and 0 at 13 weeks (CTC0). 
• 
BOR stratified by tumoral DKK1 expression, Wnt pathway, FGF 
pathway, and/or cell cycle gene alteration 


Clinical Study Protocol DKN-01-Prostate Version 1.5 
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Exploratory Endpoints:  
• 
Baseline (for tumor tissue and peripheral blood) and on treatment (for 
tumor and peripheral blood) measurements related to genomic events 
that might predict outcome, including Wnt pathway alterations, genome 
scarring and mutational load, neoantigen analysis, ribonucleic acid 
(RNA) sequencing, and whole exome sequencing. Genomic studies will 
be done on tumor tissue and when feasible on cell-free deoxyribonucleic 
acid (DNA). 
• 
Baseline and on-treatment measurement of the viability of pre-treatment 
patient-biopsy-derived 3-dimensional organotypic cultures as well as the 
number and phenotype of the immune cells present within these cultures 
incubated ex-vivo with DKN-01 and docetaxel. 
• 
Baseline (for tumor tissue and peripheral blood) and on treatment (for 
tumor and peripheral blood) measurements related to target modulation 
and immune function that may include, but not be limited to, the 
number and phenotype of immune cells, gene expression profile, 
abundance and diversity of tumor infiltrating and peripheral blood T cell 
clones by high throughput T-cell receptor (TCR) sequencing, variation 
in proteomic signatures within peripheral blood and presence or absence 
of key driver mutations and quantitation of mutational load within 
tumor tissue. 
• 
Overall response stratified by “PSA-high” (concordant radiographic and 
PSA progression) and “PSA-low” (radiographic evidence in the absence 
of PSA progression) prostate cancer status. 
• 
Overall response stratified by plasma DKK1 “high” and “low” defined 
as above or below the DKK1 plasma level reference range in a cohort of 
healthy men. 
Study Design: 
This is a 2-arm, non-randomized, phase 1b/2a, multicenter, open-label study of 
DKN-01 as monotherapy or in combination with docetaxel in patients with 
advanced treatment-refractory prostate cancer.  
This study will be conducted in two parts: dose escalation and expansion. The 
dose escalation and expansion parts will each consist of cohorts in which DKN-
01 is combined with docetaxel (Cohorts 1A, 1B) and in which DKN-01 is 
administered as monotherapy (Cohorts 2A, 2B). Dose escalation (Part 1) will 
apply exclusively to the dose of DKN-01 in both cohorts.  
In dose escalation Cohort 1A, the dose of docetaxel 75 mg/m2 will remain fixed. 
The DKN-01 dose level will start with 300 mg and be escalated to 600 mg or 
de-escalated to 150 mg depending on the absence or presence of identified 
DLTs. DKN-01 will be administered in combination with docetaxel on Day 1 
and as monotherapy on Day 15 of each 21-day cycle. The DLT monitoring 
period will start with C1D1 and end on C2D1, but may be longer in the setting 
of a treatment delay. The maximum treatment delay is 28 days prior to 
necessitating withdrawal from study. The MTD or highest dose tested of DKN-
01 in combination with docetaxel will be the dose used Dose Expansion Cohort 
1B. 


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In dose escalation Cohort 2A, DKN-01 dose level will start with 300 mg and be 
escalated to 600 mg or de-escalated to 150 mg depending on the absence or 
presence of identified DLTs. DKN-01 will be administered as monotherapy on 
Days 1 and 15 of the 28-day cycle 1. The DLT monitoring period will start with 
C1D1 and end on C2D1, but may be longer in the setting of a treatment delay. 
The maximum treatment delay is 28 days prior to necessitating withdrawal from 
study. The MTD or highest dose tested of DKN-01 monotherapy will be the 
dose used Dose Expansion Cohort 2B. 
Doses of DKN-01 higher than 600 mg will not be tested because of the PK and 
pharmacodynamic data described Section 2.2. 
Dose expansion (Part 2) will include two cohorts. The dose of DKN-01 chosen 
for dose expansion cohorts 1B will be the MTD or highest dose tested in dose 
escalation cohort 1A. The dose of DKN-01 chosen for dose expansion cohorts 
2B will be the MTD or highest dose tested in dose escalation cohort 2A.  
Cohorts 1B will be restricted to patients who have had 1 or more prior 2nd 
generation AR targeting therapies 
(enzalutamide/abiraterone/apalutamide/darolutamide) and no prior docetaxel 
exposure. Cohort 1B will include patients with RECIST v1.1 measurable 
disease. Cohort 2B will be restricted to patients who have had 1 or more prior 
2nd generation AR targeting therapies and have had progression on 1 or more 
prior taxane chemotherapies or are intolerant of taxane-based chemotherapy or 
refusing taxane-based chemotherapy. In either cohort, Patients with pure 
neuroendocrine carcinoma do not need to have been previously treated with 
androgen receptor (AR) signaling inhibitors (abiraterone or enzalutamide or 
apalutamide or darolutamide) but must have castrate testosterone and have 
castration-resistant disease. Cohorts 1B will be treated with the combination of 
DKN-01 at the MTD or highest dose tested given on Days 1 and 15, and 
docetaxel 75 mg/m2 (or 60 mg/m2 depending on clinical discretion) given on 
Day 1 of every 3 weeks (21-day cycles). Cohort 2B will be treated with DKN-01 
monotherapy at the MTD or highest dose tested given on Days 1 and 15 of a 28-
day cycle. 
 
 


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Treatment Groups: 
Dose Escalation: 
Cohort 1A 
Dose Level 1: DKN-01 300 mg intravenously (IV) on Days 1 and 15, docetaxel 
75 mg/m2 on Day 1 every 3 weeks (21-day cycles). 
Dose Level 2: DKN-01 600 mg IV on Days 1 and 15, docetaxel 75 mg/m2 on 
Day 1 every 3 weeks (21-day cycles). 
Cohort 2A 
Dose Level 1: DKN-01 300 mg IV on Days 1 and 15 of a 28-day cycle. 
Dose Level 2: DKN-01 600 mg IV on Days 1 and 15 of a 28-day cycle. 
Dose Expansion: 
Cohort 1B:  DKN-01 at MTD or highest dose tested: Days 1 and 15, docetaxel 
75 mg/m2 Day 1 of every 3 weeks (21-day cycles) 
Cohort 2B:  DKN-01 at MTD or highest dose tested: Days 1 and 15 (28-day 
cycles) 
Number of Patients 
Planned: 
Dose Escalation:  
Cohort 1A: up to 12 patients (up to 6 per Dose Level) 
Cohort 2A: up to 12 patients (up to 6 per Dose Level) 
Dose Expansion:  
Cohort 1B: 33 patients 
Cohort 2B: 27 patients 
Diagnosis and Main 
Criteria for Inclusion: 
Inclusion 
Male patients who meet the following inclusion criteria and none of the 
exclusion criteria will be eligible for enrollment in the study: 
1) Age >18 years. 
2) Have a histologically or cytologically confirmed cancer of prostate origin 
(adenocarcinoma, poorly differentiated carcinoma, or neuroendocrine 
carcinoma are all allowed).  
I. 
Patients with pure neuroendocrine carcinoma must have had at 
least one line of platinum-based chemotherapy unless the 
patient is intolerant of or is refusing chemotherapy.  
II. 
Patients with pure neuroendocrine carcinoma do not need to 
have been previously treated with androgen receptor (AR) 
signaling inhibitors (abiraterone or enzalutamide or 
apalutamide or darolutamide) but must have castrate 
testosterone and have castration-resistant disease. 
 
3) Surgically or medically castrated, with testosterone levels of < 50 ng/dL 
(< 2.0 nM). If the patient is being treated with luteinizing hormone-releasing 
hormone (LHRH) agonists (patient who have not undergone orchiectomy), 
this therapy must have been initiated at least 4 weeks prior to C1D1 and 
must be continued throughout the study. 


Clinical Study Protocol DKN-01-Prostate Version 1.5 
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CONFIDENTIAL 
 
4) Cohorts 1A, 1B. Patients must have progressed despite 1 or more androgen 
receptor (AR) signaling inhibitors (abiraterone or enzalutamide or 
apalutamide or darolutamide) and have not received prior taxane-based 
chemotherapy for prostate cancer. Prior treatment with an AR signaling 
inhibitor for castration-sensitive disease will be allowed if the time to 
progression was within 1 year after starting drug. Prior treatment with a 
taxane-based chemotherapy for castration-sensitive disease will be 
exclusionary. (Prior treatment with an AR signaling inhibitor is not 
required for pure prostate neuroendocrine carcinoma as in inclusion 2.) 
5) Cohorts 2A and 2B. Patients must have progressed despite 1 or more AR 
signaling inhibitor (abiraterone or enzalutamide or apalutamide or 
darolutamide) and either had disease progression, were intolerant of, or 
refused 1 or more taxane-based chemotherapies for mCRPC. (Prior 
treatment with an AR signaling inhibitor is not required for pure prostate 
neuroendocrine carcinoma as in inclusion 2.) 
6) Cohort 1B. Patients must have measurable disease per RECIST v1.1 
guidelines AND must have either:  
a) PSA progression is defined by Prostate Cancer Working Group 3 
(PCWG3) criteria as a minimum of two consecutive rising levels, with 
an interval of ≥1 week between each determination with a minimum 
PSA of 1 ng/mL, if PSA is the sole evidence of progression, OR  
b) Radionuclide bone progression as defined by at least two new 
metastatic lesions (per PCWG3), OR 
c) Soft tissue progression on transaxial imaging: new or progressive soft 
tissue masses on computed tomography (CT) or magnetic resonance 
imaging (MRI) scans as defined by RECIST v1.1. 
7) Cohorts 1A, 2A, 2B. Patients must have baseline progression defined as 
one of the following:  
a) PSA progression is defined by PCWG3 criteria as a minimum of two 
consecutive rising levels, with an interval of ≥1 week between each 
determination with a minimum PSA of 2 ng/mL. 
b) Radionuclide bone progression as defined by at least two new 
metastatic lesions (per PCWG3). 
c) Soft tissue progression on transaxial imaging: new or progressive soft 
tissue masses on computed tomography (CT) or magnetic resonance 
imaging (MRI) scans as defined by RECIST v1.1. 
8) Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 
0 or 1.  
9) Estimated life expectancy of at least 3 months, in the judgment of the 
Investigator. 
10) Required initial laboratory values within 14 days of C1D1:  


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CONFIDENTIAL 
 
a) Total bilirubin within normal limits for the institution. (For Cohorts 
2A and 2B, total bilirubin < 3 × ULN is acceptable with known liver 
metastases). 
b) For Cohorts 1A, 1B transaminases [aspartate aminotransferase (AST) 
and alanine aminotransferase (ALT)] ≤1.5 × the upper limit of normal 
(ULN). For Cohorts 2A and 2B, AST and ALT ≤ 5.0 × ULN is 
acceptable with known liver metastases.  
c) Creatinine ≤2.0 or calculated creatinine clearance ≥50 mL/min using 
the Cockcroft and Gault Method (Cockroft and Gault 1976). 
d) Absolute neutrophil count ≥1000 cells/µl. 
e) Absolute lymphocyte count ≥500/µl. 
f) Hemoglobin ≥8.5 g/dL. 
g) Platelet count ≥100,000 cells/µl. (For Cohorts 2A and 2B, Platelet 
count ≥75,000 cells/µl). 
h) International normalized ratio (INR) (prothrombin time [PT])/partial 
thromboplastin time (PTT) ≤1.5 × ULN unless receiving 
anticoagulant, in which case INR ≤3.0 and no active bleeding, (ie, no 
clinically significant bleeding within 14 days prior to first dose of 
study therapy. 
11) Sexually active male patients must agree to use adequate contraception 
(hormonal or barrier method of birth control) during the study and for 
6 months after their last dose of study drug. Should a patient’s partner 
become pregnant or suspect she is pregnant while participating in the 
study, the Investigator should be immediately informed. 
12) Reliable and willing to make themselves available for the duration of the 
study and are willing to follow study-specific procedures. 
13) Provided written informed consent prior to any study-specific procedures. 
14) Submission of a next-generation sequencing report from prostate cancer 
tissue or ctDNA from a CLIA certified lab if available. If no such report is 
available, a statement attesting to the lack of such a report is sufficient for 
eligibility.   
Exclusion 
15) Any anti-cancer therapy (with the exception of luteinizing hormone-
releasing hormone [LHRH] analog or antagonist) within 2 weeks prior to 
initiation of study treatment. 
 
16) Any investigational anti-cancer therapy within 4 weeks of initiation of study 
treatment.  
17) New York Heart Association Class III or IV heart failure, or myocardial 
infarction within the past 6 months, or unstable arrhythmia within 3 months. 
18) Uncontrolled bacterial, viral, or fungal infections, within 7 days of study 
entry. 


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19) History of malignancy other than prostate cancer within 2 years prior to 
screening, except for malignancies with a negligible risk of metastasis or 
death (e.g., 5-year OS rate > 90%), such as non-melanoma skin carcinoma 
or ductal carcinoma in situ 
20) Known to be human immunodeficiency virus (HIV) positive, have positive 
hepatitis B surface antigen (HBSAg), or positive hepatitis C antibody 
(HCAb) test. (Hepatitis C antibody-positive patients with an undetectable 
hepatitis C virus (HCV) RNA will be eligible.) 
21) History of solid organ transplant (ie, heart, lungs, liver, or kidney). 
22) History of autologous/allogenic bone marrow transplant. 
23) Serious nonmalignant disease that could compromise protocol objectives in 
the opinion of the Investigator and/or Sponsor. 
24) Major surgical procedures or significant traumatic injury within 4 weeks 
prior to study entry (minor surgical procedures within 1 week of study 
entry). Note: Diagnostic cystoscopy is not exclusionary at any time during 
screening. History of osteonecrosis of the hip. Other hip pathology such as 
degenerative disease or malignant involvement are not exclusionary. 
Screening of asymptomatic patients is not required. 
25) Active or untreated central nervous system (CNS) malignancy or metastasis. 
Screening for CNS metastases of asymptomatic patients without a history of 
CNS metastases is not required. Patients with treated CNS metastases are 
eligible provided they meet all of the following criteria:  
a) Evaluable disease outside the CNS. 
b) No history of intracranial or intraspinal hemorrhage. 
c) No evidence of significant vasogenic edema. 
d) No ongoing requirement for corticosteroids as therapy for CNS disease. 
(Anti-convulsants at a stable dose for > one month is allowed.) 
e) No stereotactic radiation, whole brain radiation within 4 weeks of 
C1D1. 
f) Patients with CNS metastases treated by neurosurgical resection or brain 
biopsy within 3 month prior to C1D1 will not be allowed. 
g) Radiographic demonstration of interim stability (ie, no progression) 
between completion of CNS-directed therapy and the screening 
radiographic study. 
h) Screening CNS radiographic study ≥4 weeks since completion of 
radiotherapy or surgical resection and ≥2 weeks since discontinuation of 
corticosteroids. 
26) Any other condition, disease, metabolic dysfunction, physical examination 
finding, or clinical laboratory finding giving reasonable suspicion of a 
disease or condition that contraindicates the use of an investigational drug or 
that may affect the interpretation of the results or render the patient at high 
risk from treatment complications.  
27) Active substance abuse. 


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28) Receipt of any live vaccine within 30 days before the first dose of 
study treatment or anticipation that such a live vaccine will be 
required during study participation. 
29) Previously treated with an anti-DKK1 therapy. 
Study Treatment: 
Cohorts 1A, 1B: DKN-01 will be administered IV on Days 1 and 15 of each 
cycle without interruption. The duration of each cycle is 21 days. 
Docetaxel will be administered IV on Day 1 of each cycle without interruption. 
The duration of each cycle is 21 days. Patients will be pre-medicated with a 
standard institutional regimen as per standard institutional guidelines. 
Corticosteroids, whether in an IV or oral regimen, are allowed as part of the pre-
medication regimen. 
Prednisone 5 mg twice daily given for purposes other than pre-medication for 
infusion will not be allowed until C3D1, after which it will be optional and 
under the discretion of the Investigator. See Section 5.16 for further details on 
concomitant medications.  
Cohorts 2A, 2B: DKN-01 will be administered IV on Days 1 and 15 of a 28-day 
cycle. 
Dose Escalation Scheme 
(Part A): 
Dose escalation scheme Cohort 1A: 
Dose 
Level 
Dose of DKN-01 on 
Days 1 and 15 of each 
21-day cycle 
Dose of Docetaxel 
Level 1 
300 mg 
75 mg/m2 
Level 2 
600 mg 
75 mg/m2 
Level -1* 
150 mg 
75 mg/m2 
* if required 
Dose escalation scheme Cohort 2A: 
Dose 
Level 
Dose of DKN-01 on Days 1 and 15 
of each 28-day cycle 
Level 1 
300 mg 
Level 2 
600 mg 
Level -1* 
150 mg 
* if required 
Data from each cohort in Part A will be evaluated for safety and DLTs prior to 
dose escalation. 
At each dose level (cohort) in Part A, up to 4 patients will be screened 
simultaneously in order to ensure 3 patients will be treated and evaluable for 
DLT period. If all 4 patients in Screening are eligible, all will be permitted to 
enroll. Screening of patients will continue until 3 patients are evaluable for 
DLTs at each dose level.  If none of the treated patients per cohort (up to 4 
patients) develop a DLT after a minimum of 21 days (Cohort 1A) or 28 days 
(Cohort 2A) and 1 cycle of treatment beginning with cycle 1 Day 1, subsequent 
dose escalation will proceed according to the planned schedule. Prior to the start 


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of the next dosing cohort in Part A, a safety assessment will be performed to 
assess safety and DLTs. 
If a DLT is observed in 1 out of 3 patients (or 1 of 4 should 4 patients be 
enrolled) during C1 of any given dose level, the cohort will be expanded and up 
to an additional 3 patients (maximum of 6 patients per dose level) will be 
enrolled and treated at that dose level. If no further DLTs are observed within 
the expanded cohort, dose escalation will proceed. If 2 or more patients at that 
dose level have DLTs, the MTD will have been exceeded and dose escalation 
will cease. 
Study Procedures: 
Patients will complete up to 5 periods of the study: Screening, Treatment, 
Follow-up, and Survival/Long-term Follow-up. 
Screening Period: 
Up to 28 days: Patients will sign consent and be screened for study eligibility.  
Treatment Period: 
Cohort 1A, 1B (Dose escalation and Dose Expansion): Patients will be treated 
with the combination of DKN-01 and Docetaxel until PCWG3 progression or 
unacceptable toxicity.  
Cohort 2A and 2B: Patients will be treated with DKN-01 until PCWG3 
progression or unacceptable toxicity. 
Following 9 weeks (3 cycles), the decision to continue treatment with additional 
cycles of study drug(s) will be based on radiological assessments (performed at 
baseline, end of C3, and every 9 weeks for the first 27 weeks, then every 
12 weeks). Tumor progression or response endpoints will be assessed using 
iRECIST, and PCWG3 guidelines. 
Treatment beyond progression may be allowed in select patients after discussion 
and agreement with the Sponsor and Leap Therapeutics. The benefit/risk 
assessment needs to favors continued administration of study therapy 
(eg, patients are continuing to experience clinical benefit as assessed by the 
Investigator and tolerating treatment), and no treatment discontinuation criteria 
are met: 
1. Investigator-assessed clinical benefit, and not having rapid disease 
progression. 
2. Continue to meet all other study protocol eligibility criteria for continued 
treatment as per Section 5.10 (criteria for continued treatment). 
3. Tolerance of study drug; 
4. Stable performance status; 
5. Treatment beyond progression will not delay an imminent intervention to 
prevent serious complications of disease progression (eg, CNS 
metastases); 
6. Patient provides written informed consent prior to receiving any additional 
DKN-01/docetaxel treatment, using an informed consent form (ICF) 
describing any reasonably foreseeable risks or discomforts, or other 
alternative treatment options. 
Follow-up Period: 
Upon completion of study therapy (or upon completion of DKN-01 if further 
treatment is warranted), all patients will enter the Clinical/Safety Follow-up 


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period once the decision is made to discontinue the patient from treatment 
(eg, at end of treatment [EOT]).   At the time of discontinuation, the most recent 
on-treatment visit will be the EOT visit.  Any assessments required for EOT that 
were completed within 14 days of the last on-treatment visit do not need to be 
re-completed.  This visit will be considered the start of the Week 1 
Clinical/Safety Follow-up visit. Patients who discontinue the treatment phase 
will enter the Clinical/Safety Follow-up period. Patients must be followed for at 
least 100 days (representing approximately 5 half-lives for DKN-01) after the 
last dose of study drug. Follow-up visits should occur at Days 30, 60, and 100 
(±10 days) after the last dose of study drug or should coincide with the date of 
discontinuation (±10 days) if date of discontinuation is greater than 30 days after 
the last dose of study drug to monitor for adverse events (AEs). All patients will 
be required to complete 3 Clinical/Safety Follow-up visits regardless of whether 
they start new anti-cancer therapy, except those patients who withdraw consent 
for study participation. 
After completion of the Clinical/Safety Follow-up period, all patients will then 
enter the Survival/Long-term Follow-up period. During this period, clinic visits 
or telephone contact every 3 months will be performed to assess survival status. 
The duration of the Survival/Long-term Follow-up period will be approximately 
2 years following the first dose of study drug, and a minimum of 12 months 
following the last dose of study drug. After completion of the Safety Follow-up 
period, patients who discontinue study with ongoing stable disease (SD), partial 
response (PR), or complete response (CR) at the EOT visit will enter the 
Response Follow-up period. These periods will occur simultaneously with the 
Survival Follow-up period for mentioned patients. These patients will continue 
to have tumor radiological and clinical tumor assessments (PSA, CgA, and 
CEA) every 3 months (every 12 weeks) during the Response Follow-up period 
or until progressive disease (PD), withdrawal from the study, or initiation of 
new treatment. Radiological tumor assessments for patients who have ongoing 
clinical benefit may continue to be collected after completing the survival phase 
of the study. 
Study Evaluations: 
Every effort should be made to ensure that the protocol-required tests and 
procedures are completed as described. However, it is anticipated that from time 
to time there may be circumstances, outside of the control of the Investigator 
that may make it unfeasible to perform the test. In these cases the Investigator 
will take all steps necessary to ensure the safety and well-being of the patient. 
When a protocol-required test cannot be performed, the Investigator will 
document the reason for this and any corrective and preventive actions that he or 
she has taken to ensure that normal processes are adhered to as soon as possible. 
The study team will be informed of these incidents in a timely manner. For 
samples being collected and shipped, detailed collection, processing, storage, 
shipment instructions and contact information will be provided to the study 
center prior to initiation of the study. 
Safety: 
Safety will be evaluated by assessment of AEs, physical examination, ECOG 
PS, vital signs, electrocardiograms (ECGs), and clinical and laboratory values. 
Toxicities will be graded and documented according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v 5 
guidelines). DLTs will be evaluated in the dose escalation phase from cycle 1 


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Day 1 until cycle 2 Day 1 in each Part (DKN-01 in combination with docetaxel 
and DKN-01 monotherapy) independently and in parallel for Cohort 1A and 
Cohort 2A. DLT is defined as an AE that is at least possibly related to the study 
drug and fulfills at least 1 of the following:  
• 
Grade 4 neutropenia lasting >5 days or Grade 4 neutropenic fever 
• 
Grade 4 thrombocytopenia (or Grade 3 with bleeding) 
• 
Grade 4 anemia 
• 
Grade 3 or 4 non-hematological toxicity (excluding Grade 3 vomiting 
and Grade 3 diarrhea lasting > 72 hours including the clinical sequelae 
(eg, electrolyte abnormalities) despite optimal supportive care and 
excluding alopecia 
• 
Dosing delay greater than 14 days due to treatment-emergent AEs or 
treatment related severe laboratory abnormalities 
• 
Grade 3 hypersensitivity reaction to DKN-01 with premedication 
(Grade 3 hypersensitivity reaction to DKN-01 without premedication is 
not considered a DLT) 
• 
Grade 4 hypersensitivity reaction to DKN-01 with or without 
premedication 
• 
Any Grade 5 AE 
• 
Any treatment-related AE that causes the patient to discontinue 
treatment during C1 
A drug-related fever ≤Grade 3 will not be considered a DLT. 
The MTD is defined as the highest tested dose level below the dose level at 
which a DLT is seen in 2 or more patients.  
Pharmacokinetic: 
Samples for DKN-01 and docetaxel PK studies will be collected pre-dose and 
post-infusion on Day 1 of each cycle and at EOT.  
Efficacy: 
Dose escalation in the Phase 1b cohort will be based on DLT assessment and 
will follow a 3+3 design. 
For all cohorts, soft tissue (visceral and nodal) radiographic response, PSA, and 
circulating tumor cells will be evaluated based on PCWG3 guidelines. Bone 
lesions will be followed and evaluated for evidence of radiologic progression 
based on PCWG3 criteria.  
Tumor assessments will be performed during Screening (baseline), at the end of 
every 9 calendar weeks (±7 days) relative to Study Day 1 (Week 1) up to 
27 weeks, then every 12 calendar weeks (±7 days), until confirmed radiologic 
measurable disease progression by iRECIST or bone progression by PCWG3 
criteria, as assessed by the Investigator, loss to follow-up, withdrawal, initiation 
of new treatment, or study closure.  
Tumor assessments should be performed at the time of treatment discontinuation 
if the reason was other than radiologically confirmed disease progression and it 
has been ≥8 weeks since the last assessment. Tumor assessments should consist 
of clinical examination, serum PSA, and appropriate imaging techniques (i.e., 
CT scans of the chest, abdomen, and pelvis with appropriate slice thickness per 


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iRECIST); other studies (MRI, X-ray, PET/CT, and ultrasound) may also be 
performed if required.  
If a site can document that the CT performed as part of a PET/CT is of identical 
diagnostic quality to a diagnostic CT (with IV and oral contrast) then the CT 
portion of the PET/CT can be used for iRECIST measurements. Radionuclide 
bone scanning (whole body) should be performed using 99mTc-methylene. All 
sites of disease should be followed and the same methods used to detect lesions 
at baseline are to be used to follow the same lesions throughout the clinical 
study. If a patient has known brain metastases, this disease should be evaluated 
at each required assessment time. Copies of CT scans (and other imaging, as 
appropriate) If a response is noted, a follow-up radiographic assessment at a 
minimum of 4 weeks later to confirm response is to be done. 
Pharmacodynamics: 
Blood sample collection for pharmacodynamic studies will be mandatory and 
will be collected at the Screening visit and at Days 1 and 15 of each cycle and at 
the EOT visit. Pre-treatment, on-treatment, and progression tumor samples will 
also be utilized for pharmacodynamic analysis.  
Immunogenicity: 
Blood samples will be drawn for assessment of DKN-01 anti-drug antibodies 
(ADA) as per the Schedule of Events. Immunogenicity blood samples will be 
assayed for ADA using a validated assay. The testing process will follow a 
tiered approach of Screening, confirmation, and titer determination. Details 
regarding the collection, processing, storage, and shipping of the blood samples 
will be provided in the Laboratory Manual to maintain sample integrity. Any 
deviations from the processing steps (eg, sample collection and processing steps, 
interim storage or shipping conditions), including any actions taken, must be 
documented and reported to the Sponsor. On a case by case basis, the Sponsor 
may make a determination as to whether sample integrity has been 
compromised. Any deviation from the specified sample handling procedure 
resulted in compromised sample integrity, will be considered a protocol 
deviation. 
Tumor Biopsy Samples: 
Tumor biopsy for DKK1 Testing:  
Retrospective correlation of anti-tumor activity with tumoral DKK1 expression 
is a key secondary endpoint of this study. Submission of a tumor sample 
(archival or fresh) is recommended but not required. Tumor samples will be 
tested for DKK1 expression but the results of this testing are not required for 
protocol eligibility.  Archival tumor tissue can be from a biopsy/surgery 
performed within 5 years prior to study enrollment Provision of a formalin-fixed 
paraffin–embedded (FFPE) tumor tissue block, or of at least 15 unstained slides 
(if the block cannot be submitted due to documented local/institutional 
regulations) is requested.  
Patients in Dose Expansion Cohort 1B can have their fresh biopsy from a locally 
recurrent or metastatic tumor site amenable to biopsy that is not the only 
RECIST v1.1 target lesion. Patients in Dose escalation Cohort 1A, 2A and Dose 
expansion Cohort2B can have their required fresh biopsy from any locally 
recurrent or metastatic tumor site amenable to biopsy regardless of whether this 
site is the only RECIST v1.1 target lesion. A core biopsy, using a minimum 18-
gauge needle should be performed, in order to maximize the quality and value of 
obtained tissue. A minimum of 3 separate cores are requested for each biopsy 


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procedure. Tumor tissue from soft tissue or effusion cytologic sampling (fine 
needle aspiration provided as an FFPE cell pellet material) can be submitted, 
however, we recommend an FFPE tumor tissue block to maximize the chance of 
identifying DKK1 positive cells. If a block cannot be provided due to 
documented local/institutional regulations, at least 15 unstained slides are 
required. Bone biopsy material is acceptable provided that a gentle 
decalcification protocol was used. Bone core biopsy or bone fine needle 
aspiration provided as an FFPE cell pellet material (bone FNA is preferred) can 
be submitted.  
Tumor Biopsy for Exploratory Studies: 
Archival tumor tissue samples and tissue from biopsies of the primary and/or 
metastatic lesions will be used to analyze candidate DNA, RNA, or protein 
markers, or a relevant signature of markers, for their ability to identify those 
patients who are most likely to benefit from treatment.  On-treatment tumor 
biopsies are encouraged and tumor tissue is requested for those patients who 
undergo a biopsy or tumor resection as part of routine clinical care at any time 
during the treatment period. For patients on the combination arm, this biopsy 
can be obtained from C2D15 through C3D1 or C3D15 through C4D1 at the 
discretion of the treating investigator and after consideration of the risk of 
neutropenia related to docetaxel. Patients on monotherapy arms can have their 
biopsy at any point in C2 or C3 at the discretion of the treating investigator. 
Every effort should be made to perform a tumor biopsy at the time of iRECIST 
or PCWG3 confirmed disease progression if a patient discontinues study 
treatment due to disease progression, except in instances where the procedure 
poses an unacceptable risk to patients in the clinical research setting. A 14-day 
window from the EOT visit is permitted.  
Candidate markers of interest include, but may not be limited to: 
• 
Abundance and enrichment of infiltrating CD8+ T cells, CD4+ T cells, 
granulocytic and monocyte myeloid-derived suppressor cells, natural 
killer (NK) cells, Regulatory T cells, and Monocyte-derived cells as 
determined by flow cytometry from peripheral blood and 
immunohistochemistry (IHC)/immunofixation of FFPE. 
• 
Inhibitory ligand and co-receptor expression on tumor and infiltrating 
immune cells measured by IHC. 
• 
Expression of genes associated with active antitumor immunity. 
• 
Frequency and diversity of different TCR sequences. 
• 
Expression of genes associated with activated Wnt signaling 
• 
Expression of genes associated with basal-type prostate cancer 
• 
Neutrophil/lymphocyte ratio 
Sample Size 
Determination: 
Simon’s two-stage design (Simon, 1989) will be used for the power calculation. 
A 3+3 design will be used for the dose escalation design.  
Statistical Methods: 
Dose expansion Cohort 1B. Efficacy will be evaluated for the primary endpoint 
in Dose expansion Cohort 1B only. The null hypothesis that the true response 
rate is 0.2 will be tested against a one-sided alternative. In the first stage, 18 
patients will be accrued. If there are 4 or fewer responses in these 18 patients, 


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the study will be terminated. Otherwise, an additional 15 patients will be 
accrued for a total of 33. The null hypothesis will be rejected if 11 or more 
responses are observed in 33 patients. This design yields a Type I error rate of 
0.05 and a power of 0.8 when the true response rate is 0.4.  
Dose escalation and expansion Cohort 2B. Efficacy will be evaluated in all 
patients receiving the recommended phase 2 dose.  
 
Simon's two-stage design (Simon, 1989) will be used to evaluate Dose 
Expansion Cohorts 2B. The null hypothesis that the true response rate 
is 0.05 will be tested against a one-sided alternative. In the first stage, 13 
patients will be accrued. If there are 0 responses in these 13 patients, the study 
will be stopped. Otherwise, 14 additional patients will be accrued for a total of 
27. The null hypothesis will be rejected if 4 or more responses are observed in 
27 patients. This design yields a type I error rate of 0.05 and a power of 0.8 
when the true response rate is 0.2. 
 
Descriptive statistics will be performed to assess the endpoint of best overall 
response as a composite endpoint consisting of a decrease in PSA >50%, 
conversion of CTCs, or iRECIST soft tissue response. 
 


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SCHEMATIC OF STUDY DESIGN 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
18F-DHT PET 
18F dihydro-testosterone positron emission tomography 
2GHA 
2nd-Generation hormonal agents 
ADA 
Anti-drug antibody 
AEs 
Adverse events 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AR 
Androgen-receptor  
AST 
Aspartate aminotransferase 
BICR 
Blinded Independent Central Review 
BOR 
Best overall response 
BUN 
Blood urea nitrogen 
C 
CEA 
Cycle 
Carcinoembryonic antigen 
CFR 
CgA 
Code of Federal Regulations 
Chromogranin A 
CI 
Confidence interval 
CK 
Creatine kinase 
CNS 
Central nervous system 
CR 
Complete response 
CT 
Computed tomography 


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Abbreviation 
Definition 
CTC 
Circulating Tumor Cell 
CTO 
Clinical Trials Office 
D 
Day 
DKK1 
Dickkopf-1 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
DR 
Duration of response 
DSMC 
Data Safety Monitoring Committee 
EAS 
Evaluable analysis set 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
ELISA 
Enzyme-linked immunosorbent assay 
EOT 
End-of-treatment 
FDA 
Food and Drug Administration 
FFPE 
Formalin-fixed paraffin–embedded 
GCP 
Good Clinical Practice 
gem/cis 
Gemcitabine/cisplatin 
GGT 
Gamma-glutamyl transferase 
HBSAg 
hepatitis B surface antigen 
HCAb 
Hepatitis C antibody 


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Abbreviation 
Definition 
HCV 
Hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
iCPD 
Confirmed radiographic progression 
iCR 
Complete response per iRECIST 
IDE 
Investigational Device Exemption 
IHC 
Immunohistochemistry 
IND 
Investigational New Drug Application 
INR 
International normalized ratio 
iPD 
Confirmed progressive disease per iRECIST 
iPR 
Partial response per iRECIST 
IRB 
Institutional Review Board 
iRECIST 
Immune-related Response Evaluation Criteria in Solid Tumors 
iSD 
Stable disease per iRECIST 
iUPD 
Unconfirmed progressive disease per iRECIST 
IV 
Intravenous(ly) 
LDH 
Lactate dehydrogenase 
len/dex 
Lenalidomide and dexamethasone 
LHRH 
Luteinizing hormone-releasing hormone 
mCRPC 
Metastatic castration-resistant prostate cancer 


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Abbreviation 
Definition 
MCV 
Mean cell volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
RECIST v1.1 
Modified Response Evaluation Criteria in Solid Tumors, version 1.1 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NE 
Neuroendocrine 
NK 
Natural killer 
NSCLC 
Non-small cell lung cancer 
NYU 
New York University 
OR 
Overall response 
OS 
Overall survival 
PCC 
Perlmutter Cancer Center 
PCWG3 
Prostate Cancer Working Group 3 
PD 
Progressive disease 
PFS 
Progression-free survival 
PI 
Principal Investigational 
PK 
Pharmacokinetic 
PP 
Per-protocol 
PR 
Partial response 
PS 
Performance status 
PSA 
Prostate-specific antigen 


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Abbreviation 
Definition 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
Q2W 
Every 2 weeks 
RBC 
Erythrocyte count 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Stable disease 
SUV 
Standardized uptake values 
TCR 
T-cell receptor 
TEAE 
Treatment-emergent adverse event 
TSH 
Thyroid-stimulating hormone 
TTR 
Time-to-tumor response 
ULN 
Upper limit of normal 
WBC 
Leukocytes 
 


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TABLE OF CONTENTS 
1. 
Key Roles ........................................................................................................................ 33 
2. 
Introduction .................................................................................................................... 34 
2.1. 
Background and Study Rationale..................................................................... 34 
2.1.1. 
Prostate Cancer ..................................................................................... 34 
2.1.2. 
Dickkopf-1 (DKK1) .............................................................................. 36 
2.1.3. 
DKN-01 ................................................................................................ 36 
2.2. 
Rationale for the Dose Selection ....................................................................... 39 
2.2.1. 
Rationale for the DKN-01 Dose Selected ............................................. 39 
2.2.2. 
Rationale for the Combination with Docetaxel 75mg/m2 ..................... 43 
2.3. 
Justification of the Study Design ...................................................................... 43 
 
 
2.3.1       Rationale for Retrospective DKK1/Wnt Biomarker Analysis………...43  
3. 
Study Objectives and Endpoints................................................................................... 45 
3.1. 
Study Objectives................................................................................................. 45 
3.1.1. 
Primary Objective ................................................................................. 45 
3.1.2. 
Secondary Objectives ........................................................................... 45 
3.1.3. 
Exploratory Objectives ......................................................................... 45 
3.2. 
Study Endpoints ................................................................................................. 46 
3.2.1. 
Primary Endpoints ................................................................................ 46 
3.2.2. 
Secondary Endpoints ............................................................................ 46 
3.2.3. 
Safety Endpoint..................................................................................... 46 
3.2.4. 
Exploratory Endpoints .......................................................................... 46 
4. 
Investigational Plan ....................................................................................................... 48 
4.1. 
Overall Design and Plan of the Study .............................................................. 48 
4.1.1. 
Study Periods ........................................................................................ 50 
4.1.1.1. Pre-Screening Period ............................................................. 50 
4.1.1.2. Screening Period (Up to 28 Days) ......................................... 50 
4.1.1.3. Treatment Period .................................................................... 50 
4.1.1.4. Follow-up Period ................................................................... 50 
4.1.1.5. Survival/Long-term Follow-up Period ................................... 51 
4.2. 
Study Termination ............................................................................................. 51 
5. 
Study Population ............................................................................................................ 52 


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5.1. 
Number of Patients ............................................................................................ 52 
5.1.1. 
Dose Escalation..................................................................................... 52 
5.1.2. 
Dose expansion ..................................................................................... 52 
5.2. 
Inclusion Criteria ............................................................................................... 52 
5.3. 
Exclusion Criteria .............................................................................................. 54 
5.4. 
Clinical Trial Materials ..................................................................................... 56 
5.4.1. 
DKN-01 ................................................................................................ 56 
5.4.2. 
Docetaxel .............................................................................................. 56 
5.5. 
Blinding, Packaging and Labeling ................................................................... 56 
5.5.1. 
Blinding and Breaking the Blind .......................................................... 56 
5.5.2. 
Packaging and Labeling ........................................................................ 56 
5.6. 
Method of Assigning Patients to Treatment .................................................... 56 
5.7. 
Study Drug Accountability and Disposal ......................................................... 56 
5.8. 
Assessment of Treatment Compliance ............................................................. 57 
5.9. 
Administration of Study Drug(s) ...................................................................... 57 
5.9.1. 
DKN-01 Administration ....................................................................... 57 
5.9.2. 
Docetaxel Administration ..................................................................... 58 
5.10. Criteria for Initiation of a New Treatment Cycle ........................................... 58 
5.11. Criteria for Treatment on Day 15 of a Treatment Cycle ............................... 59 
5.12. Dosing Modifications, Reductions and Re-escalations, and Delays .............. 59 
5.12.1. 
DKN-01 Dosing and Dose Adjustments ............................................... 61 
5.12.2. 
Combination Dosing and Dose Adjustments, if applicable .................. 62 
5.13. Definition of Dose-limiting Toxicity ................................................................. 62 
5.14. Duration of Study Participation and Treatment............................................. 64 
5.15. Withdrawal and Replacement of Patients ....................................................... 64 
5.15.1. 
Withdrawal from Treatment or the Study ............................................. 64 
5.15.2. 
Replacement of Study Patients ............................................................. 65 
5.16. Concomitant Medications, Therapies and Supportive Care.......................... 65 
5.16.1. 
Prohibited Concomitant Medications ................................................... 65 
5.16.2. 
Rescue Medications, Supportive Care, and Allowed 
Concomitant Medications ..................................................................... 66 
5.16.3. 
Diet/Activity/Other Considerations ...................................................... 66 


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5.16.3.1. Diet ......................................................................................... 66 
5.16.3.2. Contraception ......................................................................... 67 
6. 
Study Assessments ......................................................................................................... 68 
6.1. 
Clinical Procedures and Safety Assessments ................................................... 68 
6.1.1. 
Informed Consent ................................................................................. 68 
6.1.2. 
Inclusion / Exclusion Criteria Review .................................................. 68 
6.1.3. 
Demographics, Medical and Disease History ....................................... 68 
6.1.4. 
Physical Examination ........................................................................... 68 
6.1.5. 
Vital Signs and Weight ......................................................................... 69 
6.1.6. 
Electrocardiograms ............................................................................... 69 
6.1.7. 
Eastern Cooperative Oncology Group Performance Status 
(ECOG PS) ........................................................................................... 69 
6.1.8. 
Clinical Laboratory Evaluations ........................................................... 69 
6.1.9. 
Concomitant Medications / Procedures Review ................................... 70 
6.1.10. 
Adverse Event Monitoring.................................................................... 70 
6.1.11. 
Medical Events of Interest .................................................................... 71 
6.1.11.1. Infusion-related Reactions ..................................................... 71 
6.2. 
Efficacy and Response Assessments ................................................................. 71 
6.2.1. 
Tumor Measurement and Disease Response Assessment by 
iRECIST................................................................................................ 71 
6.2.2. 
iRECIST Assessment of Disease .......................................................... 72 
6.3. 
Post-Treatment Follow-up and Mortality Assessments ................................. 75 
6.4. 
Pharmacodynamics ............................................................................................ 76 
6.5. 
Immunogenicity.................................................................................................. 76 
6.5.1. 
Immunogenicity in Blood ..................................................................... 76 
6.5.2. 
Tumor Biopsy Samples ......................................................................... 76 
6.5.2.1. Tumor biopsy for DKK1 Testing ........................................... 76 
6.5.2.2. Tumor Biopsy for Exploratory Studies .................................. 77 
7. 
Adverse Events ............................................................................................................... 78 
7.1. 
Definitions, Documentation, and Reporting .................................................... 78 
7.1.1. 
Adverse Event Definition ..................................................................... 78 
7.1.2. 
Serious Adverse Event Definition ........................................................ 78 
7.1.2.1. Reporting of Pregnancy to the Sponsor ................................. 79 


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7.2. 
Procedures for Recording and Reporting AEs and SAEs .............................. 79 
7.3. 
Monitoring of Adverse Events and Period of Observation ............................ 82 
7.1. 
Reporting Procedures – Notifying the FDA .................................................... 82 
7.2. 
Reporting Procedures – Participating Investigators ...................................... 83 
7.1. 
Safety Oversight ................................................................................................. 83 
7.2. 
Data and Safety Monitoring Plan (DSMP) ...................................................... 84 
7.3. 
Study Monitoring Plan ...................................................................................... 85 
7.3.1. 
Subsite Monitoring ............................................................................... 85 
7.4. 
Data Quality Oversight Activities..................................................................... 86 
7.5. 
Onsite Monitoring .............................................................................................. 87 
7.6. 
Compliance with Study Registration and Results Posting 
Requirements...................................................................................................... 87 
8. 
Statistical Considerations .............................................................................................. 88 
8.1. 
Sample Size Determination ............................................................................... 88 
8.2. 
Randomization ................................................................................................... 88 
8.3. 
Populations for Analysis .................................................................................... 88 
8.4. 
Procedures for Handling Missing, Unused and Spurious Data ..................... 89 
8.5. 
Interim Analyses ................................................................................................ 89 
8.6. 
Statistical Methods ............................................................................................. 89 
8.6.1. 
General Methods ................................................................................... 89 
8.6.2. 
Disposition of Patients .......................................................................... 89 
8.6.3. 
Baseline Characteristics ........................................................................ 90 
8.6.4. 
Efficacy Analysis .................................................................................. 90 
8.6.4.1. Primary Efficacy Endpoint and Analysis ............................... 90 
8.6.4.2. Secondary Efficacy Endpoints and Analysis ......................... 90 
8.6.5. 
Safety Analysis ..................................................................................... 91 
8.6.5.1. Study Drug Exposure ............................................................. 92 
8.6.5.2. Adverse Events ...................................................................... 92 
8.6.5.3. Clinical Laboratory Data........................................................ 92 
8.6.5.4. Other Safety Parameters ........................................................ 93 
8.6.6. 
Analysis of Exploratory Endpoints ....................................................... 93 


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8.6.7. 
Procedures for Reporting Deviations to the Original 
Statistical Analysis Plan........................................................................ 93 
9. 
Administrative Requirements ....................................................................................... 94 
9.1. 
Good Clinical Practice ....................................................................................... 94 
9.2. 
Ethical Considerations....................................................................................... 94 
9.3. 
Patient Information and Informed Consent .................................................... 94 
9.3.1. 
Consent Procedures and Documentation .............................................. 94 
9.3.1.1. Informed Consent................................................................... 94 
9.3.1.2. Documentation of Consent .................................................... 95 
9.3.2. 
Registration Procedures ........................................................................ 95 
9.3.3. 
Multi-Site Surveillance ......................................................................... 96 
9.3.4. 
Patient Registrations at Additional Sites .............................................. 96 
9.4. 
Patient Confidentiality....................................................................................... 97 
9.5. 
Protocol Compliance .......................................................................................... 97 
9.6. 
Direct Access to Source Data ............................................................................ 97 
9.7. 
Case Report Form Completion ......................................................................... 98 
9.8. 
Record Retention ............................................................................................... 98 
9.9. 
Liability and Insurance ..................................................................................... 99 
9.10. Publication of Study Findings and Use of Information .................................. 99 
9.11. Research Use of Stored Human Samples, Specimens, or Data ...................... 99 
9.12. Future Use of Stored Specimens ....................................................................... 99 
9.13. Conflict of Interest Policy ................................................................................ 100 
11. 
References ..................................................................................................................... 101 
12. 
Appendices .................................................................................................................... 105 
12.1. Schedule of Assessments .................................................................................. 105 
12.2. Response Evaluation Criteria in Solid Tumors (RECIST) Quick 
Reference Guide ............................................................................................... 109 
12.3. Description of iRECIST Process for Assessment of Disease 
Progression ....................................................................................................... 116 
12.4. NCI-CTCAE v 5 Infusion-related Reactions ................................................. 120 
12.5. Management of DKN-01 Infusion-related Reactions ................................... 121 
12.6. Declaration of Helsinki .................................................................................... 122 
12.7. PCWG3 Criteria for Disease Assessment ...................................................... 127 


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LIST OF TABLES IN THE TEXT 
Table 1: 
All DKN-01-Related Adverse Events by MedDRA SOC and Preferred Term 
and CIOMS Frequency in DEK-DKK1-P100 and the Monotherapy Arm of 
Study DEK-DKK1-P102 ................................................................................................. 38 
Table 2: 
Management of DKN-01-related Adverse Reactions ...................................................... 59 
Table 3 
DKN-01 Dose Adjustments ............................................................................................. 62 
Table 4: 
Imaging and Treatment after First Radiologic Evidence of  Progressive 
Disease ............................................................................................................................. 74 
Table 5 
Schedule of Assessments ............................................................................................... 105 
 
LIST OF FIGURES IN THE TEXT 
Figure 1: 
Free DKK1 Concentrations in Studies P102 and P103 .................................................... 41 
Figure 2: 
Imaging and Treatment after First Radiologic Evidence of  Progressive 
Disease ............................................................................................................................. 75 
 
 


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1. 
KEY ROLES 
Principle Investigator: 
David Wise, MD PhD 
Perlmutter Cancer Center at NYU Langone 
160 E 34TH Street, 10th Fl, Suite 1009 
New York, NY 10016 
212-731-6366 
David.Wise@nyulangone.org 
Biostatistician: 
Andrea Troxel  
650 First Avenue, 5th Fl, 521 
New York, NY 10016 
Andrea.Troxel@nyulangone.org 


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2. 
INTRODUCTION 
2.1. 
Background and Study Rationale 
2.1.1. 
Prostate Cancer 
Metastatic castration-resistant prostate cancer (mCRPC) is an incurable illness that requires 
innovative clinical studies (Scher et al. 2016). Five life-prolonging drugs, approved in the past 
decade, were developed in-parallel and exhibit cross-resistance (Lorente et al. 2016). The 
2nd-generation hormonal agents (2GHA), enzalutamide and abiraterone, both prolong survival 
and have an excellent tolerability profile and have become de facto first-line agents for the 
treatment of mCRPC (Gillessen et al. 2015). The recent LATITUDE (Fizazi et al. 2017) and 
STAMPEDE (James et al. 2017) results demonstrate the efficacy of abiraterone in the castration-
sensitive setting and will likely lead to an increase in the utilization of abiraterone in this setting 
and increase prevalence of mCRPC that is resistance to an 2GHA. Novel treatments for 2GHA-
resistant mCRPC are increasingly needed. 
Unfortunately, the available agents for these 2GHA-resistant patients have a relatively poor side 
effect profile and are limited in their efficacy. Docetaxel and cabazitaxel are the available 
taxanes that are FDA-approved for the treatment of mCRPC. Recent data failed to demonstrate 
the superiority of cabazitaxel over docetaxel (Oudard et al. 2017). This suggests that docetaxel 
will continue to be the first-line taxane used for the majority of patients with mCRPC that has 
progressed on a 2GHA. The efficacy of docetaxel in the post-2GHA setting has not been 
published in large patient cohorts. The Tax327 study demonstrated the overall survival (OS) 
benefit of docetaxel in the pre-2GHA era showed a soft-tissue response rate of 12% and a 
prostate-specific antigen (PSA) response rate of 45% (Tannock et al. 2004). The FIRSTANA 
study, which randomized pre-2GHA patients to cabazitaxel or docetaxel, showed that the soft-
tissue response rate to docetaxel was 30% and the PSA response rate was 68% (Oudard et al. 
2017). In a retrospective study of post-abiraterone patients treated on a phase II study, the soft 
tissue response rate was 11% and the PSA response rate was 26% (Mezynski et al. 2012). In a 
larger retrospective study of patients treated on the phase III study of abiraterone naïve to 
chemotherapy, the subsequent rate of PSA response was 27% (whereas the soft tissue response 
rate was not reported) (de Bono et al. 2017).  
In sum, the available data suggest that the soft tissue response rate of docetaxel in patients 
previously treated with a 2GHA is likely significantly lower than 30%. 
Identification of DKK1 as a biomarker of AR-null/NE-null mCRPC  
There is a critical need to identify druggable mechanisms that promote mCRPC resistance to 
2GHA therapy. Recent work has demonstrated that prostate cancer can develop resistance to 
2GHA through an androgen-receptor (AR)-independent escape mechanism reflected by prostate 
cancers with low or absent AR expression (Bluemn et al. 2017). These AR-null prostate cancers 
exist as two subtypes determined by the expression of neuroendocrine (NE) markers – AR-
null/NE-high and AR-null/NE-null. Further work has shown that dickkopf-1 (DKK1) is 
specifically upregulated in AR-null/NE-null prostate cancers (Wise et al. 2020). DKK1 can be 


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measured in the tumor specimen but it can also be measured in a plasma-based assay (Wise et al. 
2020). DKK1-high prostate cancers show loss of CD8+ T cells and reduction in activated natural 
killer (NK) cells.  
Rationale for Targeting DKK1 in mCRPC 
Targeted inhibition of DKK1 in an AR-null/NE-null prostate cancer model has been shown to 
delay the growth of these tumors in a mouse-xenograft model (Hall et al. 2010). Targeted 
inhibition of DKK1 in patient-derived organoids leads to the upregulation of pro-inflammatory 
molecules. These studies suggest that targeted inhibition of DKK1 might provide therapeutic 
benefit for AR-null/NE-null DKK1-high mCRPC patients through upregulating anti-tumor 
immunity. A further hypothesis is that AR-high/NE-null or AR-null/NE-high patients who have 
abnormally high plasma DKK1 might also derived benefit from DKK1 blockade.  
We have chosen to combine DKK1 blockade with docetaxel in Cohort 1A and 1B because 
durable treatment responses were seen with DKN-01 in combination with another taxane, 
paclitaxel, in advanced gastroesophageal cancer. Furthermore, docetaxel likely has broad activity 
against mCRPC across a broad spectrum of AR activity. The utility of docetaxel in this trial is to 
synergize with DKN01 in targeting AR-null prostate cancer clones and to target AR-high clones 
that might be resistant to DKN01. 
Patients with mCRPC who have progressed on 2GHA and a taxane-based chemotherapy have 
limited treatment options that are associated with significant toxicity. The National 
Comprehensive Cancer Network guidelines offer enrollment on a clinical study as an option for 
these patients given the significant toxicity associated with treatment with cabazitaxel or radium-
223. This population will serve as the patients in Cohort 2A/B/C of this study which will test the 
hypothesis that DKN-01 monotherapy is active in DKK1-expressing mCRPC through re-
activation of anti-tumor immunity. 
To summarize, patients with mCRPC that has progressed despite 2GHA therapy represents a 
population of patients whose main therapeutic options are cytotoxic chemotherapy, which have a 
poor side effect profile and modest clinical activity. We propose to test DKK1 blockade using 
DKN-01 either as monotherapy or as a novel combination partner with docetaxel chemotherapy 
as an immunomodulatory therapeutic strategy for advanced 2GHA-resistant mCRPC. 
Correlating DKN01-mediated anti-tumor activity with pathogenic Wnt signaling  
Wnt mutations correlate with elevated DKK1 
The canonical Wnt signaling pathway refers to a cell signal transduction pathway that leads to 
stabilization of the transcription factor β-Catenin and ultimately activation of a host of β-Catenin 
target genes involved in cancer pathogenesis. Recurrent mutations in the genes involved in 
canonical Wnt signaling are among the most common mutations in human cancer and include 
mutations and/or genomic alterations in the following genes: APC, CTNNB1, RNF43, ZNRF3, 
RSPO2, RSPO3 AXIN1, and AXIN2. Mutations in these genes can lead to the constitutive 
activation of Wnt/b-catenin signaling. DKK1 is a known β-Catenin target gene (Chamorro et al. 
2005) and the correlation between Wnt signaling mutations and elevated DKK1 in mCRPC has 


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been confirmed (Wise et al. 20). Retrospective analysis of patients with a detectable Wnt family 
gene alteration in tumor or blood will be undertaken to investigate whether these alterations 
predict response.  
Wnt mutations correlate with response to DKN-01 
Leap Therapeutics preliminary data indicates that tumors from patients with a Wnt/b-catenin 
signaling activating mutation are more likely to express elevated levels of DKK1 and therefore 
may be more likely to respond to a DKK1 neutralizing therapy.  As such, endometrial patients 
with a Wnt/b-catenin signaling activating mutation appear to be more likely to derived clinical 
benefit from DKN-01 based therapies (Arend et al. 2019).  
 
2.1.2. 
Dickkopf-1 (DKK1) 
DKK1 protein, is over-expressed in a variety of tumor types and this is associated with a poor 
prognosis such as decreased OS of cancer patients, including NSCLC, esophageal cancer, breast 
cancer, cholangiocarcinoma, liver cancer, and ovarian cancer as well as multiple myeloma 
(Shizhuo et al. 2009; Tung et al. 2011; Xu et al. 2012; Sezer 2009; Shi et al. 2013; Hiss 2012). 
DKK1 has direct tumor effects by increasing tumor growth, metastasis, and angiogenesis and 
through favoring a stem cell-like phenotype (Smadja et al. 2010; Krause et al. 2014; Malladi et 
al. 2016; Thudi et al. 2011). Furthermore, DKK1 has been implicated in promoting an 
immunosuppressive tumor microenvironment by activating myeloid derived suppressor cells and 
through the downregulation of NK activating ligands on cancer cells (D’Amico et al. 2016; 
Malladi et al. 2016). Based on these data, neutralizing DKK1 has been hypothesized to not only 
directly impede tumor growth but also promote an anti-tumor immune response.  
Wnt signaling is a multifaceted pathway that regulates stem cell maintenance, cell fate decisions, 
cell proliferation, survival, migration, and polarity determination during development and adult 
tissue homeostasis (Logan and Nusse 2004; MacDonald et al. 2009; Clevers and Nusse 2012; 
Clevers et al. 2014; Sedgwick and D'Souza-Schorey 2016). DKK1 is a secreted modulator of 
Wnt signaling and is best characterized as an antagonist of the canonical Wnt/β-catenin signaling 
pathway, however it has also been implicated in the activation of noncanonical Wnt signaling 
pathways and PI3K/AKT signaling (Niehrs et al. 2006; Wang and Zang 2011; Kimura et al. 
2016).  
DKK1 is expressed in basal cells of the normal human prostate (Zhang et al. 2016). 
Overexpression of AR and treatment with DHT in the AR-negative cancer cell line DU145 leads 
to downregulation of DKK1 (Wise et al. 2020). Serum DKK1 levels inversely correlate and 
serum PSA positive correlate with 18F dihydro-testosterone positron emission tomography (18F-
DHT PET) uptake in patients (Wise DR et al. 2020). These data suggest that activation of AR is 
one potential upstream repressor of DKK1 expression.  
2.1.3. 
DKN-01 
DKN-01 (formerly known as LY2812176) is a potent humanized monoclonal antibody 
(immunoglobulin G4) with neutralizing activity against DKK1, a modulator of Wnt signaling 


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pathways that influences a number of important processes such as cell growth and 
differentiation, bone development, adult bone homeostasis, and anti-tumor immunity (Sato et al. 
2010; Gavriatopoulou et al. 2009; Vallet et al. 2010; Pinzone et al. 2009). DKN-01 is in 
development as an anti-cancer agent and is being investigated in a variety of solid tumors. 
As of 21 August 2017, DKN-01 has been evaluated in 30 healthy subjects and 167 patients with 
cancer in 5 clinical studies. All 30 healthy subjects received a single dose of DKN-01. Among 
the 167 patients with cancer treated with DKN-01, 55 received DKN-01 monotherapy; 
7 received DKN-01 in combination with lenalidomide/dexamethasone (len/dex); 54 received 
DKN-01 in combination with paclitaxel; and 51 patients received DKN-01 in combination with 
gemcitabine/cisplatin (gem/cis). In addition, as controls in 2 clinical studies, 18 healthy subjects 
received a single dose of placebo and 1 patient with MM received len/dex. Safety data for DKN-
01 are available from 30 healthy subjects treated with a single dose of DKN-01 monotherapy and 
164 patients with cancer treated with DKN-01, of whom 55 received DKN-01 monotherapy, 
7 received DKN-01+len/dex, 54 received DKN-01+paclitaxel, and 48 received DKN-
01+gem/cis. 
Results from completed Phase 1 Study DEK-DKK1-P100, in which DKN-01 was administered 
as monotherapy to patients with cancer at doses up to 600 mg every other week, demonstrated an 
acceptable safety profile. Based on these results, clinical evaluation of DKN-01 in combination 
was initiated, with DKN-01 also shown to be well tolerated when administered in combination 
with commercially available anti-neoplastic agents. Across all studies, there have been no safety 
concerns identified that relate to significant injection site reactions or systemic infusion 
reactions. Furthermore, there have been no known undesirable effects identified with 
administration of DKN-01. DKN-01 has been observed to be well-tolerated over multiple 
treatment cycles.  
Table 1 describes the cumulative DKN-01 monotherapy cancer treatment experience at doses 
ranging from 75 mg to 600 mg, and includes all DKN-01-related treatment-emergent adverse 
events (TEAEs) by SOC and preferred term from DEK-DKK1-P100 (N=32) and the 
Monotherapy Arm of Study DEK-DKK1-P102 (N=23). 


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Table 1: 
All DKN-01-Related Adverse Events by MedDRA SOC and Preferred Term 
and CIOMS Frequency in DEK-DKK1-P100 and the Monotherapy Arm of 
Study DEK-DKK1-P102 
MedDRA Preferred Term3 
Monotherapy 
DKN-01 
(n=55)1,2 
CIOMS 
Frequency 
n 
% 
Fatigue 
12 
21.8% 
Very Common 
Nausea 
4 
7.3% 
Common 
Decreased appetite 
3 
5.5% 
Anaemia 
3 
5.5% 
Vomiting 
2 
3.6% 
Arthralgia 
2 
3.6% 
Dysgeusia 
2 
3.6% 
Asthenia 
2 
3.6% 
Constipation 
1 
1.8% 
Stomatitis 
1 
1.8% 
Oral pain 
1 
1.8% 
Dehydration 
1 
1.8% 
Hypocalcaemia 
1 
1.8% 
Muscle Spasms 
1 
1.8% 
Musculoskeletal chest pain 
1 
1.8% 
Myalgia 
1 
1.8% 
Depression 
1 
1.8% 
Night sweats 
1 
1.8% 
Onychoclasis 
1 
1.8% 
Paraesthesia 
1 
1.8% 
Periorbital oedema 
1 
1.8% 
Weight decreased 
1 
1.8% 
1 Events reported from Study DEK-DKK1-P100 (n=32) and the monotherapy arm of Study DEK-DKK1-P102 (n=23). 
2 Of these 55 patients, 3 received DKN-01 75 mg, 3 received DKN-01 150 mg, 46 received DKN-01 300 mg, and 3 received DKN-
01 600 mg. 
3 MedDRA Version 14.1 used for Study DEK-DKK1-P100 and Version 18.0 used for Study DEK-DKK1-P102. 
Evidence of an anti-tumor effect of DKN-01 as a monotherapy has been seen in patients with 
non-small cell lung cancer (NSCLC). No patient in the study achieved an overall best response 
of complete response (CR). For patients with NSCLC in Part B, 1 patient (5.3%) had an overall 
best response of partial response (PR) and 8 (42.1%) achieved stable disease (SD). The overall 
clinical benefit (PR+SD) was 47.4% (9/19 patients) and overall response (OR) rate was 5.3% 
(1/19 patients; 95% CI, 0.1, 26.0). For the 19 patients with advanced NSCLC receiving DKN-01 


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at 300 mg every 2 weeks (Q2W) in Part B, median progression-free survival (PFS) was 2.2 
months (95% confidence interval [CI], 1.5, 2.9). Additionally, evidence of an anti-tumor effect 
has been seen with DKN-01 in combination with paclitaxel in patients with esophagogastric 
cancer, and in combination with gemcitabine/cisplatin in patients with biliary tract cancer.  
Overall, among all 77 esophagogastric cancer patients enrolled, 62 were male and 15 were 
female, and most (69 patients) were white. The mean age of patients was 62 years (range 34 to 
82 years). Patients were required to have esophagogastric cancer to be eligible for the study; 
41 patients had a primary diagnosis of esophageal cancer, with 35 patients having a primary 
diagnosis of gastroesophageal junction cancer; primary cancer type was not reported for 1 
patient. The histological type was adenocarcinoma for 64 patients and squamous cell carcinoma 
for 13 patients. At the time of diagnosis, most (42 patients) had Stage IV disease, with 25 having 
Stage III disease and 10 having Stage II disease. The median time since diagnosis was 
17.2 months (range 2.1 to 70.4 months). All 77 patients had received prior chemotherapy, with 
44 having received a prior taxane, 26 in the adjuvant/neo-adjuvant setting and 21 in the 
metastatic/palliative setting. The median number of prior systemic therapy regimens was 
2 (range 1 to 7). Overall, 20 (26.0%) patients had received prior Herceptin (trastuzumab) and 
12 (15.6%) patients had received prior ramucirumab. To be evaluable for response according to 
the modified Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1), patients 
were required to have received at least 1 dose of DKN-01 and have at least 1 evaluable tumor 
response assessment or have discontinued treatment due to death, toxicity, or clinical 
progression; as of 21 August 2017, 64 of 77 patients were evaluable for response. 
Overall, among all 64 patients evaluable for response, the OR rate was 20.3% (13/64 patients), 
with all 13 patients experiencing a PR. Twenty-three (30.3%) patients experienced SD; thus, the 
disease control rate was 56.3% (36/64 patients). With DKN-01 300 mg +paclitaxel, the OR rate 
was 26.1% (12/46 patients) and the disease control rate was 58.7% (27/46 patients). The OR rate 
among those treated with DKN-01 300 mg + paclitaxel with prior taxane exposure (N=24) and 
those without (N=22) was 12.5% (3/24 patients) and 40.9% (9/22 patients) and the disease 
control rate in each of these groups was 45.8% (11/24 patients) and 72.7% (16/22 patients), 
respectively. 
Full information on DKN-01 is provided in the Investigator’s Brochure. 
2.2. 
Rationale for the Dose Selection 
2.2.1. 
Rationale for the DKN-01 Dose Selected 
DKN-01 will be administered at a dose of 300 mg or 600 mg intravenously (IV) on Days (D) 1 
and 15 every 21 days (Cohorts 1A/1B) and every 28 days (Cohorts 2A/2B).  
These DKN-01 doses were selected based on the results of two ongoing Phase 1, multi-part, 
dose-escalation studies of DKN-01 in combination with other anticancer agents, including 
paclitaxel (Study DEK-DKK1-P102 [Study P102]) and gem/cis (Study DEK-DKK1-P103 [Study 
P103]).  


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DKN-01 is selective for the DKK1 member of the dickkopf family. It binds human DKK1 with 
high affinity and, as a consequence, potently neutralizes DKK1. The levels of the protein DKK1 
are elevated in a variety of tumor types and have been implicated in tumor growth and disease 
progression. A preclinical NSCLC A549 xenograft model study demonstrated that suppression of 
free (unbound) DKK1 concentrations correlated with an inhibition of tumor growth. A 
pharmacokinetic (PK)/pharmacodynamic model was fit to the data in this study and it was found 
that a 50% reduction in free DKK1 by DKN-01 binding approximately correlated with 50% 
maximal tumor growth inhibition (Leap Therapeutics, data on file, 2012). 
Several ongoing clinical studies have been conducted to determine the effect of DKN-01 on a 
variety of cancers. In Study DEK-DKK1-P102 (P102), DKN-01 was dosed in combination with 
paclitaxel as well as in a separate monotherapy substudy. In this study, patients were 
administered DKN-01 at doses of 150 or 300 mg Q2W over a 28-day cycle. Patients in Study 
DEK-DKK1-P103 (P103) were administered DKN-01 at doses of 150 or 300 mg in combination 
with gemcitabine and cisplatin on Days 1 and 8 of each 21-day cycle.  
In both of these studies, PK/Pharmacodynamic modeling showed a dose-dependent decrease in 
free DKK1 concentrations. In Study P102, the median free DKK1 at the 150 mg dose was 
2.27 ng/mL (concentration after the last dose for each patient), whereas the median value was 
1.27 ng/mL in the 300 mg group. Preliminary modeling suggested that efficacy was more likely 
to be observed if the maximal concentration of free DKK1 was below 1 to 1.5 ng/mL 
(Figure 1[a] and [b]). In the current study, a dose of 600 mg is proposed in order to increase the 
number of patients that have free DKK1 in the target range (<1 - 1.5 ng/mL). Based on modeling 
analysis, a 600 mg dose is expected to reduce free DKK1 concentrations to half of that observed 
at 300 mg dose levels. 


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Figure 1: 
Free DKK1 Concentrations in Studies P102 and P103 
(a) 
C m a x
C m a x
0
5
1 0
P 1 0 2  F r e e  D K K 1  C o n c e n t r a t i o n
D o s e  =  3 0 0  m g
D K K 1   ( n g / m L )
B l a c k  -  n o n r e s p o n d e r
B l u e  -  r e s p o n d e r
 
(a) the responder population was observed to have free DKK1 concentrations below ~1.5 ng/mL  
(b) 
 C m a x
 C m a x
0
5
1 0
1 5
P 1 0 3   F r e e  D K K 1  C o n c e n t r a t i o n
D o s e  =  3 0 0  m g
F r e e  D K K 1   ( n g / m L )
B l a c k  -  n o n r e s p o n d e r
B l u e  -  r e s p o n d e r
 
(b) the responder population was observed to have free DKK1 concentrations below ~1 ng/mL. 


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Preliminary results from ongoing Study P102, conducted in patients with esophagogastric 
cancer, show DKN-01 to be well tolerated in combination with weekly paclitaxel 80 mg/m2. The 
maximum tolerated dose (MTD) of DKN-01 in combination was determined to be 300 mg, the 
highest dose evaluated. Overall, the most common individual treatment-emergent adverse events 
(TEAEs) in Study DEK-DKK1-P102 were fatigue (26 patients; 33.8%), anemia (22 patients; 
28.6%), alopecia (19 patients; 24.7%), neutropenia (15 patients; 19.5%), vomiting and dyspnea 
(each 13 patients; 16.9%); and constipation, nausea, and cough (each 12 patients; 15.6%). With 
DKN-01 monotherapy, the most common TEAEs also was fatigue (7 patients; 30.4%). Other 
common TEAEs with DKN-01 monotherapy in this patient population were dehydration (6 
patients; 26.1%), vomiting and constipation (5 patients; 21.7%), and ascites (4 patients; 17.4%).  
Forty (51.9%) patients overall experienced at least 1 TEAE that was considered by the 
Investigator to be DKN-01-related, with the most common such events including fatigue 
(13 patients; 16.9%), anemia, decreased appetite, and nausea (each 7 patients; 9.1%), diarrhea 
(6 patients; 7.8%), and arthralgia, constipation, and vomiting (each 4 patients; 5.2%). 
Given the disparity in the numbers of patients treated with 150 mg and 300 mg (3 versus 74, 
respectively), TEAE incidence rates are not compared by dose. 
Thirty-five (45.5%) patients experienced at least 1 Grade 3/4 TEAE. Grade 3 TEAEs reported 
for >1 patient overall included anemia, hypophosphatemia, and neutropenia (3 patients; 3.9%) 
and ascites, lung infection, and pneumonia (each 2 patients; 2.6%). All other Grade 3 TEAEs 
were reported for 1 patient only. Grade 4 TEAEs included neutropenia (2 patients; 2.6%) and 
gastrointestinal hemorrhage and leukopenia (each 1 patient; 1.3%). 
Most Grade 3 TEAEs and all Grade 4 TEAEs were considered to be unrelated to DKN-01. Four 
(5.2%) patients experienced a Grade 3 TEAE that was considered by the Investigator to be DKN-
01-related, including anemia, fatigue, hypophosphatemia, and peripheral neuropathy (each 1 
patient; 1.3%). 
Similarly, in ongoing Study P103, in which DKN-01 is administered in combination with 
gemcitabine + cisplatin in patient with advanced carcinoma primary to the intra- or extra-hepatic 
biliary system or gallbladder, the 300 mg dose of DKN-01 also was determined to be the MTD, 
the highest dose evaluated, with no dose-limiting toxicities (DLTs) reported. Enrollment in the 
study is complete, with a total of 51 patients enrolled. Of these 51 patients, 7 patients were 
enrolled in Part A, of whom 4 received DKN-01 150 mg and 3 received DKN-01 300 mg, and 
44 patients were enrolled in Part B, with all 44 patients assigned to receive DKN-01 300 mg. All 
patients receive DKN-01 in combination with gem/cis. As of 21 August 2017, safety data were 
available for 48 patients. 
As was the case in Study P102, the 300 mg dose of DKN-01 was well tolerated in Study P103. 
Overall, 46 (95.8%) of 48 patients in the Safety Population patients experienced at least 1 TEAE. 
Overall, the most common TEAEs in Study DEK-DKK1-P103 were thrombocytopenia 
(32 patients; 66.7%), neutropenia (28 patients; 58.3%), aspartate aminotransferase (AST) 
increased (26 patients; 54.2%), fatigue (25 patients; 52.1%), and anemia (23 patients; 47.9%).  


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Thirty-four (70.8%) patients experienced a Grade 3/4 TEAE. Grade 3 TEAEs reported by 
>1 patient, regardless of relationship to study drug, included neutropenia (14 patients; 29.2%), 
leukopenia (10 patients; 20.8%), hypertension and thrombocytopenia (each 8 patients; 16.7%) 
anemia (6 patients; 12.5%), hyperbilirubinemia (5 patients; 10.4%), AST increased, gamma-
glutamyl transferase (GGT) increased, hyponatremia, and hypophosphatemia (each 4 patients; 
8.3%), alanine aminotransferase (ALT) increased, blood alkaline phosphatase increased, and 
leukocytosis (each 3 patients; 6.3%), and abdominal pain, ascites, cholangitis, muscular 
weakness, upper gastrointestinal hemorrhage, and urinary tract infection (each 2 patients; 4.2%). 
Twelve (25.0%) patients experienced at least 1 Grade 4 TEAE, with such events including 
neutropenia (9 patients; 18.8%), thrombocytopenia (2 patients; 4.2%), and aspiration pneumonia, 
blood uric acid increased, Escherichia bacteremia, GGT increased, hyperbilirubinemia, 
hypoglycemia, and respiratory distress (each 1 patient; 2.1%). 
Twenty-three (47.9%) patients experienced at least 1 Grade 3/4 TEAE that was considered by 
the Investigator to be DKN-01-related. DKN-01-related Grade 3 TEAEs reported for >1 patient 
included neutropenia (13 patients; 27.1%), thrombocytopenia (5 patients; 10.4%), AST increased 
and leukopenia (each 4 patients; 8.3%), ALT increased and anemia (each 3 patients; 6.3%), and 
hyperbilirubinemia and hyponatremia (each 2 patients; 4.2%). DKN-01-related Grade 4 TEAEs 
included neutropenia (5 patients; 10.4%) and thrombocytopenia (1 patient; 2.1%). 
The 300 mg dose of DKN-01 also is supported by PK data. DKN-01 exhibits dose proportional 
PK. Population PK/pharmacodynamic simulation model identified that at a dose of 300 mg, 
more than 95% of patients are expected to experience a more than 90% reduction in free serum 
DKK1 levels (Leap Therapeutics, data on file, 2012). 
2.2.2. 
Rationale for the Combination with Docetaxel 75mg/m2  
DKN-01 will be combined with docetaxel in this study based on previously reported synergism 
between DKN-01 and another taxane, paclitaxel, in gastroesophageal cancer. Docetaxel, rather 
than paclitaxel was chosen for the current study because it is the standard first-line taxane in 
mCRPC. Finally, the response rate to docetaxel in the post-2GHA setting is low (10-30%) 
making this an appropriate context for novel drug combinations. 
2.3. 
Justification of the Study Design 
The phase 1b/2 non-randomized design is most appropriate because of the following: 
1. MTD determination will be needed because of novel combination with docetaxel. 
2. Single-arm design in phase 2 is appropriate because no activity of DKN-01 has yet been 
demonstrated in prostate cancer. 
2.3.1 
Rationale for Retrospective Correlation of DKK1 / WNT Status with DKN01 Response 
In the prior version of this protocol, patient eligibility was dependent upon the finding of elevated tumoral 
DKK1 as determined by RNA expression in-situ or a pathogenic genomic alteration in a Wnt family gene. 
In this amendment, these biomarker results will no longer be required for eligibility, but rather, will be 
investigated retrospectively to test the hypothesis that DKK1 and or activated Wnt signaling correlate with 


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response to DKN01. The primary rationale for this change in inclusion is that we have observed clinical 
activity of DKN01 in combination with Docetaxel even in patients with very low or zero DKK1 expression. 
For example, we observed a dramatic partial response in a patient whose tumor exhibited a DKK1 H-score 
of 2 (1+ expression in 2% of cells) and without Wnt gene mutation. We also observed a confirmed partial 
response in a patient with a circulating Wnt alteration but undetectable DKK1 expression in a tumor biopsy. 
These data suggest that our biomarkers may be excluding patients who could benefit from the study 
treatments. We have also observed that the time required for tumor procurement and biomarker testing 
poses a significant barrier to enrollment in a population of patients who are typically symptomatic. These 
factors provided the rationale for the proposed protocol amendment to no longer require DKK1/Wnt testing 
results as a study inclusion criterion. Rather, anti-tumor activity of DKN01 with or without Docetaxel will 
be retrospectively correlated with these biomarkers to better define a threshold to determine the patient 
population that will be most likely benefit. 
The current amendment also clarifies that patients with treatment-emergent neuroendocrine 
prostate cancer (te-NEPC) are eligible for study regardless of prior exposure to an androgen 
receptor (AR) signaling inhibitors (abiraterone or enzalutamide or apalutamide or darolutamide), 
which is consistent with standard of care guidelines that do not recommend AR signaling inhibitors 
this histologic variant. Furthermore, we have observed increased DKK1 expression in a subset of 
these patients (Wise DR et al. JCO Precision Oncology 2020), which provides the biological 
rationale to include this patient population.  
 
 
The Sponsor, Monitor, and Investigators will perform this study in compliance with the protocol, 
GCP, and ICH guidelines, and applicable regulatory requirements. 
 


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3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Study Objectives 
3.1.1. 
Primary Objective 
• Part 1: Dose Escalation:  To determine the safety, tolerability, DLTs, and MTD of 
DKN-01 administered alone and in combination with docetaxel in patients with advanced 
prostate cancer with elevated DKK1.  
• Part 2, Dose Expansion: To evaluate the anti-tumor activity of DKN-01 in combination 
with docetaxel in patients with advanced prostate cancer with elevated DKK1. 
3.1.2. 
Secondary Objectives 
1. To determine the anti-tumor activity of DKN-01 as monotherapy using Immune-related 
Response Evaluation Criteria in Solid Tumors (iRECIST). 
2. To characterize the pharmacodynamics effects of DKN-01 administered as monotherapy 
or in combination with docetaxel.  
3. To characterize the PK of DKN-01 administered as monotherapy or in combination with 
docetaxel.  
4. To characterize the immunogenicity if DKN-01 administered as monotherapy or in combination 
with docetaxel.  
5. To determine the concordance between anti-tumor activity and DKK1 expression in the 
monotherapy and combination cohorts.  
 
3.1.3. 
Exploratory Objectives 
1. To determine the effect of DKN-01 monotherapy on peripheral and intratumoral immune 
cell abundance and activation. 
2. To explore the association between DKN-01 exposure, peripheral and intratumoral 
immune cell abundance and activation, anti-tumor activity, and key safety measures.  
3. To determine the impact of docetaxel on peripheral and intratumoral immune cell 
abundance and activation. 
4. To determine the concordance between plasma and intratumoral DKK1 levels and 
determine the association between DKK1 level, Wnt pathway, FGF, cell cycle 
alterations, and anti-tumor activity. 
5. To determine the effect of DKN-01 as monotherapy or in combination with docetaxel on 
ex-vivo intratumoral immune cell abundance and activation in a 3-dimensional 
organotypic culture model. 


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6. To explore the association between response to study drug treatment and clinical 
evidence of “PSA-high” (concordant radiographic and PSA progression) and “PSA-low” 
(radiographic evidence in the absence of PSA progression) prostate cancer. 
3.2. 
Study Endpoints 
3.2.1. 
Primary Endpoints 
The primary efficacy endpoints are: 
• Phase 1b, Cohort 1A and Cohort 2A: DLT observed during the DLT evaluation period 
(starting from C1D1 until C2D1). 
• Phase 2, Cohort 1B: Best overall response, based on iRECIST soft tissue response. 
3.2.2. 
Secondary Endpoints 
Secondary efficacy endpoints are:  
• Radiographic PFS. 
• PSA PFS. 
• OS. 
• Duration of response (DR). 
• Time-to-tumor response (TTR). 
• ≥50% decline in PSA. 
• Percentage change in PSA from baseline to 12 weeks post-treatment. 
• Maximal decline in PSA after treatment initiation. 
• Circulating tumor cell (CTC) conversion from unfavorable (5 or greater CTC/7.5 mL) to 
favorable (4 or fewer CTC/7.5 mL) at 13 weeks. 
• CTC ≥1 at baseline and 0 at 13 weeks (CTC0). 
• BOR stratified by tumoral DKK1 expression, Wnt pathway, FGF pathway, and/or cell 
cycle gene alteration 
3.2.3. 
Safety Endpoint 
The safety endpoint is: 
• Adverse events (AEs) as characterized by type, severity (as graded by National Cancer 
Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] v 5.0), 
timing, seriousness, and relationship to study therapy.  
3.2.4. 
Exploratory Endpoints 
The exploratory endpoints are: 
• Baseline (for tumor tissue and peripheral blood) and on treatment (for tumor and 
peripheral blood) measurements related to genomic events that might predict outcome, 


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including Wnt pathway alterations, genome scarring and mutational load, neoantigen 
analysis, ribonucleic acid (RNA) sequencing, and whole exome sequencing. Genomic 
studies will be done on tumor tissue and when feasible on cell-free deoxyribonucleic acid 
(DNA). 
• Baseline and on-treatment measurement of the viability of pre-treatment patient-biopsy-
derived 3D organotypic cultures as well as the number and phenotype of the immune 
cells present within these cultures incubated ex-vivo with DKN-01 and docetaxel. 
• Baseline (for tumor tissue and peripheral blood) and on treatment (for tumor and 
peripheral blood) measurements related to target modulation and immune function that 
may include, but not be limited to, the number and phenotype of immune cells, gene 
expression profile, abundance and diversity of tumor infiltrating and peripheral blood T 
cell clones by high throughput T-cell receptor (TCR) sequencing, variation in proteomic 
signatures within peripheral blood and presence or absence of key driver mutations and 
quantitation of mutational load within tumor tissue. 
• Overall response stratified by “PSA-high” (concordant radiographic and PSA 
progression) and “PSA-low” (radiographic evidence in the absence of PSA progression) 
prostate cancer status. 
• Overall response stratified by plasma DKK1 “high” and “low” defined as above or below 
the DKK1 plasma level reference range in a cohort of healthy men. 


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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Design and Plan of the Study 
This is a 2-arm, non-randomized, phase 1b/2a, multicenter, open-label study of DKN-01 as 
monotherapy or in combination with docetaxel in patients with advanced treatment-refractory 
prostate cancer with elevated DKK1.  
This study will be conducted in two parts: dose escalation and expansion. The dose escalation 
and expansion parts will each consistent of cohorts in which DKN-01 is combined with 
docetaxel (Cohorts 1A, 1B) and in which DKN-01 is administered as monotherapy (Cohorts 2A, 
2B). Dose escalation (Part 1) will apply exclusively to the dose of DKN-01 in both cohorts.  
In dose escalation Cohort 1A, the dose of docetaxel 75 mg/m2 will remain fixed. The DKN-01 
dose level will start with 300 mg and be escalated to 600 mg or de-escalated to 150 mg 
depending on the absence or presence of identified DLTs. DKN-01 will be administered in 
combination with docetaxel on Day 1 and as monotherapy on Day 15 of each 21-day cycle. The 
DLT monitoring period will start with C1D1 and end on C2D1, but may be longer in the setting 
of a treatment delay. The maximum treatment delay is 28 days prior to necessitating withdrawal 
from study. The MTD is defined as the highest tested dose level below the dose level at which a 
DLT is seen in 2 or more patients (see Section 8.1). The MTD or highest dose tested of DKN-01 
in combination with docetaxel will be the dose used Dose Expansion Cohort 1B.  
In dose escalation Cohort 2A, DKN-01 dose level will start with 300 mg and be escalated to 
600 mg or de-escalated to 150 mg, depending on the absence or presence of identified DLTs. 
DKN-01 will be administered as monotherapy on Days 1 and 15 of the 28-day C1. The DLT 
monitoring period will start with C1D1 and end on C2D1, but may be longer in the setting of a 
treatment delay. The maximum treatment delay is 28 days prior to necessitating withdrawal from 
study. The MTD or highest dose tested of DKN-01 monotherapy will be the dose used Dose 
Expansion Cohorts 2B. 
At each dose level (cohort) in Cohorts 1A and 2A, up to 4 patients will be screened 
simultaneously in order to ensure 3 patients will be treated. If all 4 patients in Screening are 
eligible, all will be permitted to enroll. If none of the treated patients per cohort (up to 4 patients) 
develop a DLT, subsequent dose escalation will proceed according to the planned schedule. 
Screening of patients will continue until 3 patients are evaluable for DLTs at each dose level.  Prior to 
the start of the next dosing cohort in Part A, a safety assessment will be performed to assess 
safety and DLTs. Doses of DKN-01 higher than 600 mg will not be tested because of the PK and 
pharmacodynamic data described Section 2.2.  
If a DLT is observed in 1 out of 3 patients (or 1 of 4 should 4 patients be enrolled) during C1 of 
any given dose level, the cohort will be expanded and up to an additional 3 patients (maximum 
of 6 patients per dose level) will be enrolled and treated at that dose level. If no further DLTs are 
observed within the expanded cohort, dose escalation will proceed. If 2 or more patients at that 
dose level have DLTs, the MTD will have been exceeded and dose escalation will cease. The 
dose of DKN-01 chosen for dose expansion cohort 1B will be the MTD or highest dose tested in 


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dose escalation cohort 1A. The dose of DKN-01 chosen for dose expansion cohorts 2B will be 
the MTD or highest dose tested in dose escalation cohort 2A. Doses of DKN-01 higher than 600 
mg will not be tested because of the PK and pharmacodynamic data described Section 2.2.  
  
Dose escalation scheme Cohort 1A: 
Dose 
Level 
Dose of DKN-01 on Days 1 and 15 
of each 21-day cycle 
Dose of Docetaxel 
Level 1 
300 mg 
75 mg/m2 
Level 2 
600 mg 
75 mg/m2 
Level -1* 
150 mg 
75 mg/m2 
* if required 
Dose escalation scheme Cohort 2A: 
 
Data from each cohort in Part A will be evaluated for safety and DLTs prior to dose escalation. 
Dose expansion (Part 2) will include two cohorts. Cohort 1B will be restricted to patients who 
have had 1 or more prior 2nd generation AR targeting therapies 
(enzalutamide/abiraterone/apalutamide/darolutamide) and no prior docetaxel. Cohort 1B will 
include patients with RECIST v1.1 measurable disease. The dose of docetaxel in Cohorts 1B will 
either be 75 mg/m2 or reduced to 60 mg/m2 at the discretion of the treating investigator. Cohort 
1B will include patients with RECIST v1.1 measurable disease. Cohort 2B will be restricted to 
patients who have had 1 or more prior 2nd generation AR targeting therapies and have had 
progression on 1 or more prior taxane chemotherapies or are intolerant of taxane-based 
chemotherapy or refusing taxane-based chemotherapy. Cohort 1B will be treated with the 
combination of DKN-01 at the MTD or highest dose tested given on Days 1 and 15, and 
docetaxel 75 mg/m2 (or 60 mg/m2 depending on clinical discretion)  given on Day 1 of every 3 
weeks (21-day cycles). Cohort 2B will be treated with DKN-01 monotherapy at the MTD or 
highest dose tested given on Days 1 and 15 of a 28-day cycle. The requirement for prior AR 
targeting therapies does not apply to patients in any cohort with prostate pure neuroendocrine 
carcinoma. 
A schematic of the study design follows: 
Dose 
Level 
Dose of DKN-01 on Days 1 and 15 of each 
28-day cycle 
Level 1 
300 mg 
Level 2 
600 mg 
Level -1* 
150 mg 


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4.1.1. 
Study Periods 
Patients will complete up to 5 periods of the study: Screening, Treatment, Follow-up, and 
Survival/Long-term Follow-up. 
4.1.1.1. 
Pre-Screening Period  
 
This study will not entail any pre-screening period since there is no required testing for Wnt 
pathway gene alterations or DKK1 expression to confirm eligibility.    
4.1.1.2. 
Screening Period (Up to 28 Days) 
Patients will sign consent and be screened for study eligibility.  
4.1.1.3. 
Treatment Period 
Cohort 1A, 1B (Dose escalation and Dose Expansion): Patients will be treated with the 
combination of DKN-01 and Docetaxel until PCWG3 progression or unacceptable toxicity. 
Treatment with docetaxel beyond 10 cycles can be considered after consultation with the Study 
Sponsor.  
Cohort 2A, 2B (Dose escalation and Dose expansion): Patients will be treated with DKN-01 until 
PCWG3 progression or unacceptable toxicity. 
4.1.1.4. 
Follow-up Period 
Upon completion of study therapy (or upon completion of DKN-01 if further treatment is 
warranted), all patients will enter the Clinical/Safety Follow-up period once the decision is made 
to discontinue the patient from treatment (eg, at end-of-treatment [EOT]). At the time of 
discontinuation, the most recent on-treatment visit will be the EOT visit. Any assessments 
required for EOT that were completed within 14 days of the last on-treatment visit do not need to 
be re-completed.  This visit will be considered the start of the Week 1 Clinical/Safety Follow-up 
visit. Patients who discontinue the treatment phase will enter the Clinical/Safety Follow-up 
period. Patients must be followed for at least 100 days (representing approximately 5 half-lives 
 
 


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for DKN-01) after the last dose of study drug. Follow-up visits should occur at Days 30, 60, and 
100 (±10 days) after the last dose of study drug or should coincide with the date of 
discontinuation (±10 days) if date of discontinuation is greater than 30 days after the last dose of 
study drug to monitor for AEs. If the patient starts a new treatment than only pre-existing 
treatment-related AEs that started prior the patient enrolling on the new treatment will need to be 
followed. All patients will be required to complete 3 Clinical/Safety Follow-up visits regardless 
of whether they start new anti-cancer therapy, except those patients who withdraw consent for 
study participation. 
4.1.1.5. 
Survival/Long-term Follow-up Period 
After completion of the Clinical/Safety Follow-up period, all patients will then enter the 
Survival/Long-term Follow-up period. During this period, clinic visits or telephone contact every 
3 months will be performed to assess survival status. The duration of the Survival/Long-term 
Follow-up period will be approximately 2 years following the first dose of study drug, and a 
minimum of 12 months following the last dose of study drug. After completion of the Safety 
Follow-up period, patients who discontinue study with ongoing SD, PR, or CR at the EOT visit 
will enter the Response Follow-up period. These periods will occur simultaneously with the 
Survival Follow-up period for mentioned patients. These patients will continue to have tumor 
radiological and clinical tumor assessments (PSA, CgA, and CEA) every 3 months (every 12 
weeks) during the Response Follow-up period or until PD, initiation of new therapy, or 
withdrawal of study. Radiological tumor assessments for patients who have ongoing clinical 
benefit may continue to be collected after completing the survival phase of the study. 
4.2. 
Study Termination 
The study may be prematurely terminated if, in the opinion of the Investigator or Sponsor, there 
is sufficient reasonable cause. Written notification documenting the reason for study termination 
will be provided to the Investigator or Sponsor by the terminating party.  
Circumstances that may warrant termination of the study or discontinuation of a study site 
include, but are not limited to, the following: 
• Determination of unexpected, serious, or unacceptable risk to patients enrolled in the 
study. 
• Failure to enter patients at an acceptable rate. 
• Failure to comply with pertinent regulations of appropriate regulatory authorities. 
• Submission of knowingly false information from the research facility to the Sponsor. 
• Insufficient adherence to protocol requirements. 
• Insufficient complete and/or evaluable data. 
• Plans to modify suspend or discontinue the development of the study drug. 
Should the study be closed prematurely, all study materials must be returned to the Sponsor or its 
designee. 


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5. 
STUDY POPULATION 
The study population will consist of men with advanced castration-resistant metastatic or locally-
recurrent prostate cancer. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted. 
5.1. 
Number of Patients 
5.1.1. 
Dose Escalation 
Cohort 1A: up to 12 patients. 
Cohort 2A: up to 12 patients  
5.1.2. 
Dose expansion 
Cohort 1B: 33 patients 
Cohort 2B: 27 patients 
5.2. 
Inclusion Criteria 
Male patients who meet the following inclusion criteria and none of the exclusion criteria will be 
eligible for enrollment in the study:  
1) Age >18 years. 
2) Have a histologically or cytologically confirmed cancer of prostate origin (adenocarcinoma, 
poorly differentiated carcinoma, or neuroendocrine carcinoma are all allowed).  
I. Patients with pure neuroendocrine carcinoma must have had at least one line of 
platinum-based chemotherapy unless the patient is intolerant of or is refusing 
chemotherapy.  
II. Patients with pure neuroendocrine carcinoma do not need to have been previously 
treated with an androgen receptor (AR) signaling inhibitors (abiraterone or 
enzalutamide or apalutamide or darolutamide) but must have castrate testosterone and 
have castration-resistant disease. 
3) Surgically or medically castrated, with testosterone levels of < 50 ng/dL (< 2.0 nM). If the 
patient is being treated with luteinizing hormone-releasing hormone (LHRH) agonists 
(patient who have not undergone orchiectomy), this therapy must have been initiated at least 
4 weeks prior to C1D1 and must be continued throughout the study. 
4) Cohorts 1A, 1B. Patients must have progressed despite 1 or more AR signaling inhibitors 
(abiraterone or enzalutamide or apalutamide or darolutamide) and have not received prior 
taxane-based chemotherapy for prostate cancer. Prior treatment with an AR signaling 
inhibitor for castration-sensitive disease will be allowed if the time to progression was within 
1 year after starting drug. Prior treatment with a taxane-based chemotherapy for castration-


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sensitive disease will be exclusionary. (Prior treatment with an AR signaling inhibitor is not 
required for pure prostate neuroendocrine carcinoma as in inclusion 2.) 
5) Cohorts 2A and 2B. Patients must have progressed despite  1 or more AR signaling inhibitor 
(abiraterone or enzalutamide or apalutamide or darolutamide) and either had disease 
progression, were intolerant of, or refused 1 or more taxane-based chemotherapies for 
mCRPC. (Prior treatment with an AR signaling inhibitor is not required for pure prostate 
neuroendocrine carcinoma as in inclusion 2.) 
6) Cohort 1B. Patients must have measurable disease per RECIST v1.1 guidelines AND must 
have either:  
I. PSA progression is defined by Prostate Cancer Working Group 3 (PCWG3) criteria as a 
minimum of two consecutive rising levels, with an interval of ≥1 week between each 
determination with a minimum PSA of 1 ng/mL, if PSA is the sole evidence of 
progression, OR  
II. Radionuclide bone progression as defined by at least two new metastatic lesions (per 
PCWG3), OR 
III. Soft tissue progression on transaxial imaging: new or progressive soft tissue masses on 
computed tomography (CT) or magnetic resonance imaging (MRI) scans as defined by 
RECIST v1.1. 
7) Cohorts 1A, 2A, 2B. Patients must have baseline progression defined as one of the 
following:  
I. PSA progression is defined by PCWG3 criteria as a minimum of two consecutive rising 
levels, with an interval of ≥1 week between each determination with a minimum PSA of 
1 ng/mL. 
II. Radionuclide bone progression as defined by at least two new metastatic lesions (per 
PCWG3) 
III. Soft tissue progression on transaxial imaging: new or progressive soft tissue masses on 
computed tomography (CT) or magnetic resonance imaging (MRI) scans as defined by 
RECIST v1.1 
8) Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.  
9) Estimated life expectancy of at least 3 months, in the judgment of the Investigator. 
10) Required initial laboratory values within 14 days of C1D1:  
I. Total bilirubin within normal limits for the institution (For Cohorts 2A and 2B, total 
bilirubin < 3 × upper limit of normal (ULN) is acceptable with known liver metastases). 
II. For Cohorts 1A, 1B transaminases [aspartate aminotransferase (AST) and ALT] ≤1.5 × 
ULN (For Cohorts 2A and 2B, AST and ALT ≤ 5.0 × ULN is acceptable with known 
liver metastases). 


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III. Creatinine ≤2.0 or calculated creatinine clearance ≥50 mL/min using the Cockcroft and 
Gault Method (Cockroft and Gault 1976). 
IV. Absolute neutrophil count (ANC) ≥1000 cells/µl. 
V. Absolute lymphocyte count ≥500/µl. 
VI. Hemoglobin ≥8.5 g/dL. 
VII. 
Platelet count ≥100,000 cells/µl. (For Cohorts 2A and 2B, Platelet count 
≥75,000 cells/µl). 
VIII. 
International normalized ratio (INR) (prothrombin time [PT])/partial 
thromboplastin time (PTT) ≤1.5 × ULN unless receiving anticoagulant, in which case 
INR ≤3.0 and no active bleeding, (ie, no clinically significant bleeding within 14 days 
prior to first dose of study therapy 
11) Sexually active male patients must agree to use adequate contraception (hormonal or barrier 
method of birth control) during the study and for 6 months after their last dose of study 
drug. Should a patient’s partner become pregnant or suspect she is pregnant while 
participating in the study, the Investigator should be immediately informed. 
12) Reliable and willing to make themselves available for the duration of the study and are 
willing to follow study-specific procedures. 
13) Provided written informed consent prior to any study-specific procedures. 
14) Submission of a next-generation sequencing report from prostate cancer tissue or ctDNA 
from a CLIA certified lab if available. If no such report is available, a statement attesting to 
the lack of such a report is sufficient for eligibility.   
 
5.3. 
Exclusion Criteria 
Patients who meet any of the following criteria are not eligible for enrollment in the study: 
1) Any anti-cancer therapy (with the exception of LHRH analog) within 2 weeks prior to 
initiation of study treatment. 
2) Any investigational anti-cancer therapy within 4 weeks of initiation of study treatment.  
3) New York Heart Association Class III or IV heart failure, or myocardial infarction within 
the past 6 months, or unstable arrhythmia within 3 months. 
4) Uncontrolled bacterial, viral, or fungal infections, within 7 days of study entry. 
5) Known to be human immunodeficiency virus (HIV) positive, have positive hepatitis B 
surface antigen (HBSAg), or positive hepatitis C antibody (HCAb) test. (Hepatitis C 
antibody-positive patients with an undetectable hepatitis C virus (HCV) RNA will be 
eligible.) 


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6) History of malignancy other than prostate cancer within 2 years prior to screening, 
except for malignancies with a negligible risk of metastasis or death (e.g., 5-year OS 
rate > 90%), such as non-melanoma skin carcinoma or ductal carcinoma in situ  
7) History of solid organ transplant (ie, heart, lungs, liver, or kidney). 
8) History of autologous/allogenic bone marrow transplant. 
9) Serious nonmalignant disease that could compromise protocol objectives in the opinion 
of the Investigator and/or Sponsor. 
10) Major surgical procedures or significant traumatic injury within 4 weeks prior to study entry 
(minor surgical procedures within 1 week of study entry). Note: Diagnostic cystoscopy is not 
exclusionary at any time during screening.) 
11) History of osteonecrosis of the hip. Other hip pathology such as degenerative disease or 
malignant involvement are not exclusionary. Screening of asymptomatic patients is not 
required. 
12) Active or untreated central nervous system (CNS) malignancy or metastasis. Screening 
for CNS metastases of asymptomatic patients without a history of CNS metastases is not 
required. Patients with treated CNS metastases are eligible provided they meet all of the 
following criteria:  
a. Evaluable disease outside the CNS. 
b. No history of intracranial or intraspinal hemorrhage. 
c. No evidence of significant vasogenic edema. 
d. No ongoing requirement for corticosteroids as therapy for CNS disease. (Anti-
convulsants at a stable dose for > one month is allowed.) 
e. No stereotactic radiation, whole brain radiation within 4 weeks of C1D1. 
f. Patients with CNS metastases treated by neurosurgical resection or brain biopsy 
within 3 month prior to C1D1 will not be allowed. 
g. Radiographic demonstration of interim stability (ie, no progression) between 
completion of CNS-directed therapy and the screening radiographic study. 
h. Screening CNS radiographic study ≥4 weeks since completion of radiotherapy or 
surgical resection and ≥2 weeks since discontinuation of corticosteroids. 
13) Any other condition, disease, metabolic dysfunction, physical examination finding, or 
clinical laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of an investigational drug or that may affect the interpretation of 
the results or render the patient at high risk from treatment complications.  
14) Active substance abuse. 


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15) Receipt of any live vaccine within 30 days before the first dose of study treatment 
or anticipation that such a live vaccine will be required during study participation. 
16) Previously treated with an anti-DKK1 therapy. 
5.4. 
Clinical Trial Materials 
5.4.1. 
DKN-01 
DKN-01 supplied for this study is for investigational use and only to be used within the context 
of this clinical study. DKN-01 will be supplied to the Investigator by the Sponsor or its designee. 
DKN-01 is provided in a glass vial as a lyophilized powder for reconstitution. Each vial is 
manufactured to deliver 20 mg of DKN-01 and contains the inactive ingredients sucrose, 
polysorbate 80, sodium chloride, citric acid, and sodium citrate. DKN-01 vials should be stored 
refrigerated at 2º – 8ºC. 
Detailed instructions for the preparation and handling of DKN-01 will be provided by the 
Sponsor or its designee in the pharmacy manual.  
5.4.2. 
Docetaxel 
Docetaxel will be provided as part of a standard of care standard operating procedure. 
5.5. 
Blinding, Packaging and Labeling 
5.5.1. 
Blinding and Breaking the Blind 
This is an open-label study; no blinding methods will be employed. 
5.5.2. 
Packaging and Labeling 
Vials of DKN-01 vials are manufactured in accordance with Good Manufacturing Practices and 
packaged and labeled to meet applicable regulatory requirements.  
Study drug labels will not bear any statement that is false or misleading in any manner or 
represent that the study drug is safe or effective for the purposes for which it is being 
investigated.  
5.6. 
Method of Assigning Patients to Treatment 
This study consists of dose escalation and dose expansion cohorts. The dose expansion cohorts 
consists of non-randomized parallel arms. Assignment to treatment arms will be based on cohort 
specific eligibility criteria.  
5.7. 
Study Drug Accountability and Disposal 
All study drug will be stored, inventoried, reconciled, and destroyed according to applicable 
regulations. 
Accountability for the study drug at the study site is the responsibility of the Investigator. The 
Investigator will ensure that the study drug is used only in accordance with this protocol. Where 
allowed, the Investigator may choose to assign drug accountability responsibilities to a 
pharmacist or other appropriate individual. Drug accountability records indicating the date of 


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delivery of the study drug to the site, inventory at the site, amount dispensed to and returned by 
each patient, and return to the Sponsor (or disposal of the study drug, if approved by the 
Sponsor) will be maintained by the clinical site. These records will adequately document that the 
patients were provided the study drug as specified in the protocol and should reconcile all study 
drug received from the Sponsor. Accountability records will include dates, quantities, 
batch/serial numbers, expiration dates (if applicable), and patient numbers. The Sponsor (or 
designee) will review drug accountability at the site during monitoring visits. 
All unused study drug will be retained at the site until inventoried by the monitor. All unused or 
expired study drug will be returned to the Sponsor or, if authorized, disposed of at the study site 
and documented. 
5.8. 
Assessment of Treatment Compliance 
All study drug will be administered IV at the investigational site, under the direction of the 
Investigator. As a result, a patient’s compliance with study drug administration is ensured. Any 
deviation(s) from the prescribed dosage regimen or problems with administering the IV infusion 
should be recorded on the electronic case report form (eCRF).  
Patients should attend scheduled clinic visits and must comply with study criteria under their 
control. Deviation(s) from the prescribed dosage regimen should be recorded in the eCRF.  
5.9. 
Administration of Study Drug(s) 
The Investigator or designee is responsible for: 
• Explaining the correct use of the investigational agent(s) and planned duration of each 
individual’s treatment to the site personnel, 
• Verifying that instructions are followed properly,  
• Maintaining accurate records of study drug dispensation, destruction, and collection, and 
• Returning or destroying all unused medication to the Sponsor or its designee at the end of 
the study. 
Patients will be instructed to contact the Investigator as soon as possible if they have an issue 
with the study drug(s) so that the situation can be assessed. 
5.9.1. 
DKN-01 Administration 
DKN-01 is a large molecular weight protein that will be given as a flat dose on a Days 1 and 15 
of a 21-day cycle in Dose Escalation Cohort 1A and Dose Expansion Cohorts 1B. DKN-01 will 
be given on Days 1 and 15 on a 28-day cycle in Dose Escalation and Expansion Cohort 2A and 
2B. The dose of DKN-01 will be administered as an IV infusion over 60 (±) 15 minutes. If the 
first infusion is well-tolerated without infusion-associated adverse events, the second infusion 
may be delivered over 30 (±10) minutes. If the 30-minute infusion well tolerated, all subsequent 
infusions may be delivered over 30 (±) 10 minutes.  
If the patient experiences an infusion reaction following administration of DKN-01 over 
60 minutes, the infusion time should be increased to 120 (±30) minutes. If the patient 


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experiences an infusion reaction following administration of DKN-01 over 30 minutes, the 
infusion time should be increased to 60 (±15) minutes and all subsequent doses should be 
administered over this amount of time. 
5.9.2. 
Docetaxel Administration 
Docetaxel will be administered as an IV infusion over approximately 60 (±15) minutes on D1 of 
a 21-day cycle. In Cohort 1A, docetaxel must be dosed at 75 mg/m2 on cycle 1 day 1. Docetaxel 
can be dosed at 75 mg/m2 or 60 mg/m2 in subsequent cycles depending on clinical discretion and 
the dose modification guidelines in section 5.12.2. Regardless of dose, docetaxel must be dosed 
in 21-day cycles. In Cohort 1B, cycle 1 day 1 dosing of docetaxel will either be 75 mg/m2 or 60 
mg/m2 depending on clinical discretion. Patients will be pre-medicated as per standard 
institutional guidelines.  
On days in which both DKN-01 and docetaxel are given, the order of administration will be:  
1. Pre-medication for Docetaxel 
2. DKN-01 Infusion 
3. Docetaxel Infusion 
A minimum of 5 minutes is required between completion of DKN-01 infusion and initiating 
docetaxel infusion dosing. 
 
5.10. 
Criteria for Initiation of a New Treatment Cycle 
A new cycle may be initiated for patients meeting the following criteria:  
• ANC ≥1000/mm3 (≤Grade 2). 
• Platelet count ≥100×109/L (≤Grade 1) (≥75×109/L in dose escalation and expansion 
Cohort 2A and 2B). 
• Total bilirubin within normal limits for the institution (For Cohorts 2A and 2B, or in 
Cohort 1A and 1B if the patient is to receive DKN01 monotherapy, total bilirubin < 3 × 
upper limit of normal (ULN) is acceptable with known liver metastases). 
• Transaminases [aspartate aminotransferase (AST) and ALT] ≤1.5 × ULN (For Cohorts 
2A and 2B, or in Cohort 1A and 1B if the patient is to receive DKN01 monotherapy, 
AST and ALT ≤ 5.0 × ULN is acceptable with known liver metastases). 
If these conditions are not met on D1 of a new cycle, the administration of both docetaxel and 
DKN-01 will be held, and the patient will be evaluated weekly and a new cycle of treatment will 
not be initiated until the toxicity has resolved as described above. The maximum treatment delay 
is 28 days prior to necessitating withdrawal from study. Treatment windows of +/- 3 days are 
allowable for day 1 and day 15 starting with cycle 2, however at least 7 days must elapse 
between Day 15 and the Day 1 treatment of the subsequent cycle. 


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If, in the opinion of the Investigator, a patient is receiving clinical benefit from continued 
treatment with DKN-01 alone, patients may discontinue docetaxel and continue with DKN-01 
monotherapy until developing documented progressive disease (PD) or otherwise meeting 
criteria for treatment discontinuation (Section 5.15.1) and patients can be dosed with DKN-01 on 
D1 and D15 of a 21-day cycle or D1 and D15 of a 28 day cycle. 
Patients for whom the Investigator decides it is in their best interest to stop DKN-01 treatment 
are discontinued and complete the EOT procedures. 
5.11. 
Criteria for Treatment on Day 15 of a Treatment Cycle 
Treatment may be administered on D15 for patients meeting the following criteria: 
• ANC ≥900 cells/mm3. 
• Platelet count ≥70×109/L. 
• Total bilirubin within normal limits for the institution (For Cohorts 2A and 2B, or in 
Cohort 1A and 1B if the patient is to receive DKN01 monotherapy, total bilirubin < 3 × 
upper limit of normal (ULN) is acceptable with known liver metastases). 
• Transaminases [aspartate aminotransferase (AST) and ALT] ≤1.5 × ULN (For Cohorts 
2A and 2B, or in Cohort 1A and 1B if the patient is to receive DKN01 
monotherapy,tumorAST and ALT ≤ 5.0 × ULN is acceptable with known liver 
metastases). 
If these criteria are not met, the dose will be skipped, and the patient will return for D1 of the 
next cycle. Treatment windows of +/- 3 days are allowable for day 1 and day 15 starting with 
cycle 2, however at least 7 days must elapse between Day 15 and the Day 1 treatment of the 
subsequent cycle. 
5.12. 
Dosing Modifications, Reductions and Re-escalations, and Delays 
Management procedures for DKN-01-related toxicities are summarized in Table 2. Docetaxel 
should be continued in the setting of DKN-01 related toxicities at the Investigator’s discretion. 
Table 2: 
Management of DKN-01-related Adverse Reactions 
System Monitoring 
Severity 
Management 
Follow-up 
Gastrointestinal 
Any changes in normal 
bowel habits or changes 
from BL: 
Diarrhea 
Abdominal pain 
Grade 2 
Withhold DKN-01 
Administer antidiarrheal 
treatment while etiology is 
investigated. 
Symptoms Resolve to 
≤Grade 1 or baseline: 
Resume DKN-01 as per 
Table 3 if symptoms have 
improved to mild severity 
or resolution. 


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System Monitoring 
Severity 
Management 
Follow-up 
Blood or mucus in stool 
with or without fever 
Peritoneal signs consistent 
with bowel perforation 
Ileus 
 
Grade 3 or higher 
Permanently discontinue 
DKN-01 
Rule out bowel perforation 
Consider endoscopic 
evaluation 
 
 
Liver 
 
 
 
Elevations in liver function 
tests: 
AST  
ALT  
Total bilirubin  
 
*Patients in Cohorts 2A or 
2B with documented liver 
metastases and grade 1 or 2 
LFT abnormalities 
(ALT/AST/Total bilirubin) 
may continue to receive 
study drug per protocol. 
 
Grade 2 
*Withhold DKN-01 
Rule out infectious or 
malignant causes 
Increase frequency of liver 
function test monitoring 
until resolution 
Symptoms Resolve to 
≤Grade 1 or baseline: 
Resume DKN-01 as per 
Table 3  
Symptoms Ongoing: 
If AST or ALT elevation 
continues to be >5 × 
ULN OR total bilirubin 
>3 × ULN, see below. 
Grade 3 or higher 
Permanently discontinue 
DKN-01 
Rule out infectious or 
malignant causes 
Increase frequency of liver 
function test monitoring 
until resolution 
 
 
Skin 
Pruritus 
Rash (acneiform, maculo-
papullar, pustular, 
papulopustular) 
Grade 2 
Withhold DKN-01 
Administer topical 
corticosteroids if there is 
no improvement of 
symptoms within 1 week. 
Symptoms Resolve to 
≤Grade 1 or baseline: 
Resume DKN-01 as per 
Table 3 if dermatitis 
resolves or improves to 
mild (localized) 
symptoms. 
Symptoms Ongoing: 
If symptoms worsen, see 
below. 
Grade 3 or higher 
Permanently discontinue 
DKN-01 
Administer systemic 
corticosteroid therapy 
 
Neurologic 


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System Monitoring 
Severity 
Management 
Follow-up 
Monitor for symptoms of 
motor or sensory 
neuropathy 
Unilateral or bilateral 
weakness 
Sensory alterations 
Grade 2 
Withhold DKN-01 
Introduce appropriate 
medical intervention 
Symptoms Resolve to 
≤Grade 1 or baseline: 
Resume DKN-01 as per 
Table 3 when symptoms 
resolve or return to BL 
Symptoms Ongoing: 
If symptoms worsen, see 
below 
Grade 3 or higher 
Permanently discontinue 
DKN-01 
Institute appropriate 
medical intervention 
 
Endocrine 
Adrenal insufficiency 
 
Abnormal thyroid function 
tests and/or serum 
chemistries 
 
Hypophysitis 
 
Type 1 Diabetes 
Grade 2 or higher 
Withhold DKN-01 
Document signs and/or 
symptoms of dysfunction 
Evaluate endocrine 
function 
Consider radiographic 
pituitary gland imaging 
Continue to assess as 
indicated 
Initiate appropriate 
hormone-replacement 
therapy 
Symptoms Resolve to 
≤Grade 1 or baseline: 
Resume DKN-01 as per 
Table 3 when: 
Patient is stable on 
hormone-replacement 
therapy (as indicated) 
Symptoms Ongoing: 
Permanently discontinue 
DKN-01  
 
5.12.1. 
DKN-01 Dosing and Dose Adjustments 
DKN-01 will be administered via IV infusion on D1 and 15 in each 21-day treatment cycle 
(Cohort 1A, 1B) or 28-day cycle (Cohort 2A and 2B).  
After the first occurrence of a toxicity necessitating withholding of study treatment, the 
Investigator may elect to restart DKN-01 treatment for the patient at the previously received dose 
once the toxicity resolves to ≤Grade 1 or baseline. For subsequent recurrence of the toxicity, 
DKN-01 treatment, per Investigator discretion, may be resumed at the next lower dose after the 
toxicity resolves to ≤Grade 1 or baseline (see Table 3).  


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Table 3 
DKN-01 Dose Adjustments 
Toxicity Occurrence 
DKN-01 
First*  
Restart at assigned dose level after toxicity resolves to ≤Grade 1 or baseline. 
Second  
Restart at reduced dose (-1) after toxicity resolves to ≤Grade 1 or baseline. 
Dose level 1 (300 mg): resume at 150 mg 
Dose level 2 (600 mg): resume at 300 mg 
Third  
Restart at reduced dose (-2) after toxicity resolves to ≤Grade 1 or baseline. 
Dose level 1 (300 mg): resume at 75 mg 
Dose level 2 (600 mg): resume at 150 mg 
Fourth 
Discontinue  
*If the toxicity is judged to be significant in the opinion of the Investigator or the Investigator does not wish to dose at the same 
dosing level, he/she may contact the Medical Monitor to consider a one dose reduction level with the first occurrence of toxicity. 
Once a patient’s DKN-01 dose has been reduced, no re-escalation to a previously received dose 
is allowed at any time during the study. Intra-patient dose escalation is not permitted at any time 
during the study. Docetaxel should be continued in the setting of DKN-01 related toxicities at the 
Investigator’s discretion. 
DKN-01-related infusion reactions are to be managed as described in Appendix 12.5. 
5.12.2. 
Combination Dosing and Docetaxel Dose Adjustments, if applicable 
Toxicities attributable to docetaxel, such as febrile neutropenia, neutrophils <500/mm3 for 
>1 week, severe or cumulative cutaneous reactions, platelet nadir <25,000/mm3 and other 
Grade 3/4 non-hematologic toxicities, will necessitate holding docetaxel and DKN-01 until the 
criteria in 5.1 are satisfied followed by a dose reduction to docetaxel 60 mg/m2. Persistence or 
recurrence of symptoms will necessitate discontinuation of docetaxel. Once docetaxel is 
discontinued, the decision to restart DKN-01 as monotherapy will be at the Investigator’s 
discretion and following discussion with the Sponsor. 
5.13. 
Definition of Dose-limiting Toxicity 
The DLT period is exclusively in the dose escalation cohort and starts with C1D1 and concludes 
on C2D1. The dose escalation cohorts will remain independent with respect to DLT assessment 
and dose modification. A DLT is defined as an AE that is at least possibly related to the study 
drug (DKN-01) and fulfills at least 1 of the following:  
• Grade 4 neutropenia lasting >5 days or Grade 4 neutropenic fever 
• Grade 4 thrombocytopenia (or Grade 3 with bleeding) 
• Grade 4 anemia 
• Grade 3 or 4 non-hematological toxicity (excluding Grade 3 vomiting and Grade 3 
diarrhea lasting < 72 hours including the clinical sequelae (eg, electrolyte abnormalities) 
despite optimal supportive care and excluding alopecia 


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• Dosing delay greater than 14 days due to treatment-emergent AEs or related severe 
laboratory abnormalities 
• Grade 3 hypersensitivity reaction to DKN-01 with premedication (Grade 3 
hypersensitivity reaction to DKN-01 without premedication is not considered a DLT) 
• Grade 4 hypersensitivity reaction to DKN-01 with or without premedication 
• Any Grade 5 AE 
• Any treatment-related AE that causes the patient to discontinue treatment during C1 
A drug-related fever ≤Grade 3 will not be considered a DLT. 
The MTD is defined as the highest tested dose level below the dose level at which a DLT is seen 
in 2 or more patients (see Section 8.1). 
 


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5.14. 
Duration of Study Participation and Treatment 
Cohort 1A, 1B (Dose escalation and Dose Expansion): Patients will be treated with the 
combination of DKN-01 and Docetaxel until PCWG3 progression or unacceptable toxicity. 
Treatment with docetaxel beyond 10 cycles can be considered after consultation with the Study 
Sponsor.  
Cohort 2A, 2B (Dose escalation and Dose expansion): Patients will be treated with DKN-01 
until PCWG3 progression or unacceptable toxicity. 
Following 9 weeks (3 cycles), the decision to continue treatment with additional cycles of 
DKN-01 and docetaxel will be based on radiological assessments (performed at baseline, end of 
C3, and every 9 weeks for the first 27 weeks, then every 12 weeks). Tumor progression or 
response endpoints will be assessed using iRECIST (measurable disease) and the PCWG3 
guidelines (non-target bone progression). 
Treatment beyond PD may be allowed in select patients after discussion and agreement with the 
Sponsor and Leap Therapeutics (Leap). The benefit/risk assessment needs to favors continued 
administration of study therapy (eg, patients are continuing to experience clinical benefit as 
assessed by the Investigator and tolerating treatment), and no treatment discontinuation criteria 
are met: 
1) Investigator-assessed clinical benefit, and not having rapid disease progression 
2) Continue to meet all other study protocol eligibility criteria; 
3) Tolerance of study drug; 
4) Stable performance status; 
5) Treatment beyond PD will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, CNS metastases); 
6) Patient provides written informed consent prior to receiving any additional nivolumab or 
DKN-01/docetaxel treatment, using an informed consent form (ICF) describing any 
reasonably foreseeable risks or discomforts, or other alternative treatment options. 
5.15. 
Withdrawal and Replacement of Patients 
5.15.1. 
Withdrawal from Treatment or the Study 
Patients will be informed that they have the right to withdraw from the study at any time for any 
reason without prejudice to their medical care. The Sponsor and Investigators also have the 
right to withdraw patients from the study.  
All patients who withdraw from the study prematurely will undergo all end of treatment 
assessments. Regardless of the reason for withdrawal, efforts should be made to follow safety 
events from the time of withdrawal through resolution or until the event stabilizes.  
Study drug should be discontinued for any of the following reasons: 
• AEs/unacceptable toxicity justifying treatment or study withdrawal. 
• Non-adherence to the study drug regimen or protocol requirements. 


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• Non-compliance with instructions or failure to return for follow-up. 
• Investigator decides that study termination is in the patient’s best medical interest. 
• Lost to follow-up. 
• Enrollment in any other clinical study involving use of an investigational drug or device 
or enrollment in any other type of medical research judged not to be scientifically or 
medically compatible with this study. 
• Dosing delay of ≥28 days. 
• Development of radiographically-documented PD, as determined by the Investigator 
using iRECIST (Appendix 12.3). 
• An isolated PSA rise in the absence of radiographic progression is not an indication for 
study drug discontinuation provided that the Investigator deems the patient to be 
clinically benefitting from the study drug(s). 
With the consent of the patient or the legally authorized representative the Investigator may 
determine that limited data collection may be continued (eg, through medical record review) for 
the duration of the study after a patient has withdrawn. 
5.15.2. 
Replacement of Study Patients 
Patients in the dose escalation phase of the study who discontinue during the DLT period for 
non-safety related issues will be replaced. Patients in the dose expansion cohorts who 
discontinue from the study will not be replaced.  
5.16. 
Concomitant Medications, Therapies and Supportive Care 
5.16.1. 
Prohibited Concomitant Medications 
Patients are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this study: 
• Antineoplastic systemic chemotherapy or biological therapy 
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Concomitant systemic corticosteroids given with docetaxel prior to C3D1 other than as 
part of a standard institutional pre-medication regimen or to treat infusion-related 
allergic reactions or cytokine release syndromes as described below. 
• Investigational agents other than DKN-01 
• Radiation therapy  
- 
Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be 
considered on an exceptional case by case basis after consultation with Sponsor. The 
patient must have clear measurable disease outside the radiated field. Administration 
of palliative radiation therapy will be considered clinical progression for the 
purposes of determining PFS. 


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• Live vaccines within 30 days prior to the first dose of study treatment and while 
participating in the study. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, yellow fever, rabies, Bacillus 
Calmette–Guérin, and typhoid (oral) vaccine. Seasonal influenza vaccines for injection 
are generally killed virus vaccines and are allowed. However, intranasal influenza 
vaccines (eg, Flu - Mist®) are live attenuated vaccines, and are not allowed. 
Patients who, in the assessment by the Investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the study. Patients may receive 
other medications that the Investigator deems to be medically necessary. 
The Exclusion Criteria (Section 5.3) describe other medications that are prohibited in this study. 
5.16.2. 
Rescue Medications, Supportive Care, and Allowed Concomitant Medications 
Necessary supportive measures for optimal medical care will be given throughout the study, 
including IV antibiotics to treat infections, growth factor support, blood components, and 
standard of care bone-targeted agents, etc. Additional care, including palliative radiotherapy 
(excluding target lesions and lesions representing progressive disease) (see Section 5.16.1 for 
exceptions), may be administered as indicated by the treating physician, patient’s medical need, 
and after discussion with the Sponsor. 
Concomitant medications refers to any over-the-counter or prescription medications taken by 
the patient during the period starting 7 days prior to Screening until the EOT visit.  
Patients who experience infusion-associated symptoms may be treated symptomatically with 
acetaminophen, ibuprofen, diphenhydramine, and/or famotidine or another H2 receptor 
antagonist, or glucocorticoids as per standard practice. Serious infusion-associated events 
manifested by dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen 
saturation, or respiratory distress should be managed with supportive therapies as clinically 
indicated (eg, supplemental oxygen and ß2-adrenergic agonists). Systemic corticosteroids 
administered prior to C3 may attenuate the beneficial immunological effects of DKN-01 but 
may administered at the discretion of the treating physician. Tumor necrosis factor-alpha 
inhibitors may be administered at the discretion of the treating physician in consultation with 
the Sponsor. Inhaled steroids are allowed for management of asthma and/or chronic obstructive 
pulmonary disease. Topical steroids also are allowed. 
Influenza vaccination should be given during influenza season only (approximately October to 
March).  
5.16.3. 
Diet/Activity/Other Considerations 
5.16.3.1. 
Diet 
Patients should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea, or vomiting. 


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5.16.3.2. 
Contraception  
DKN-01 may have adverse effects on a fetus in utero. Furthermore, it is not known if DKN-01 
has transient adverse effects on the composition of sperm. Patients should be informed that 
taking the study drug may involve unknown risks to the fetus (unborn baby) if pregnancy were 
to occur during the study. In order to participate in the study patients of childbearing potential 
must adhere to the contraception requirement (described above) from the day of study drug 
initiation (or 14 days prior to the initiation of study drug for oral contraception) throughout the 
study period up to 6 months after the last dose of study therapy. If there is any question that a 
patient of childbearing potential will not reliably comply with the requirements for 
contraception, that patient should not be entered into the study. 


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6. 
STUDY ASSESSMENTS 
The Schedule of Assessments for the study is provided in Table 5 in Appendix 12.1. Detailed 
descriptions of the study assessments to be conducted during this study are described in the 
following sub-sections.  
6.1. 
Clinical Procedures and Safety Assessments 
6.1.1. 
Informed Consent 
A complete description of the study is to be presented to each potential study patient. Signed 
and dated informed consent is to be obtained before any study-specific procedures are 
performed. 
6.1.2. 
Inclusion / Exclusion Criteria Review 
The inclusion and exclusion criteria will be reviewed during the Screening Period as 
assessments are performed to confirm patient eligibility for the study. The criteria will be 
reviewed prior to administration of the first dose of study drug in C1D1 to confirm continued 
study eligibility. 
6.1.3. 
Demographics, Medical and Disease History 
Demographic data and medical and disease histories will be obtained for all patients during the 
Screening Period. Demographic data to be recorded in the source document/eCRF includes 
gender, race, and date of birth. Information on significant medical and surgical history including 
dates, outcome, and whether or not ongoing or currently treated will be recorded. The date of 
original cancer diagnosis will be recorded along with any known cancer genomics profile 
results and previous treatments, including chemotherapy, radiation therapy, surgery, and use of 
blood products, including red cell and platelet transfusions and growth factors, within the 
previous 3 months. In addition, all other medications taken within 28 days of the initial 
Screening visit will be recorded.  
The medical history will be reviewed prior to dosing on C1D1 to assess continued study 
eligibility and adherence to final inclusion/exclusion criteria. This recent medical history 
includes a review for changes from Screening as well as a review of the patient’s recent 
medication use to assess whether or not any changes have occurred since the previous study 
visit. 
6.1.4. 
Physical Examination 
A complete physical examination (general appearance, head/ears/eyes/nose/throat, lungs/chest, 
heart, abdomen, lymph nodes, musculoskeletal, extremities, and neurological examination) will 
be conducted at the time points designated in Table 5. During Screening, the physical 
examination is to include measurement of height. 
Abbreviated (ie, symptom-directed) physical examinations will be conducted at the time points 
designated in Table 5 to address any complaints or concerns verbalized by the patient at all 
other study visits. 


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6.1.5. 
Vital Signs and Weight 
Vital signs are to be measured at the time points designated in Table 5. Vital signs to be 
measured include systolic and diastolic blood pressure (mmHg; measured in the same arm), oral 
temperature (°C), pulse (bpm), and respiration rate (breaths/minute). 
Weight will be measured on Day 1 of each treatment cycle and at the EOT visit. Body surface 
area (BSA) is to be calculated on Day 1 of each treatment cycle using the weight from that cycle 
and the Screening height measurement. 
6.1.6. 
Electrocardiograms 
A 12-lead electrocardiogram (ECG) will be obtained at the time points designated in Table 5. 
Additional ECGs may be obtained as clinically warranted and judged by the Investigator.  
Patients must be supine for approximately 5 to 10 minutes before ECG collection and remain 
supine but awake during ECG collection.  
ECGs will be interpreted by a qualified physician (the Investigator or qualified designee) at the 
site as soon after the time of ECG collection as possible, and ideally while the patient is still 
present, to determine whether the patient meets entry criteria at the relevant visit(s) and for 
immediate patient management, should any clinically relevant findings be identified.  
If a clinically significant quantitative or qualitative change from baseline is identified after 
enrollment, the Investigator will assess the patient for symptoms (for example, palpitations, near 
syncope, syncope) to determine whether the patient can continue in the study. The Investigator 
or qualified designee is responsible for determining if any change in patient management is 
needed and must document his/her review of the ECG printed at the time of evaluation. 
The machine-read ECG intervals and heart rate may be used for data analysis and report writing 
purposes.  
6.1.7. 
Eastern Cooperative Oncology Group Performance Status (ECOG PS) 
The ECOG PS (Oken et al. 1982) will be determined at the time points designated in Table 5. 
Patients must have an ECOG PS of 0-1 to be enrolled into the study. Patients with an ECOG PS 
of 2 may be entered upon review and approval for study participation by the Medical Monitor. 
6.1.8. 
Clinical Laboratory Evaluations 
Routine clinical laboratory evaluations will be performed locally by a certified laboratory 
selected for the study. Prior to starting the study, the Investigator will provide copies of all 
laboratory certifications and normal ranges for all laboratory parameters to be assessed by the 
local laboratory. 
Clinical laboratory evaluations are to be performed at the time points designated in Table 5. 
Final clinical laboratories are to be performed at EOT. 
All clinically significant laboratory abnormalities noted on testing will be followed up by repeat 
testing and further investigated according to the judgment of the Investigator. 
The Investigator must review all the patient’s laboratory reports in a timely manner. 
Investigators must document their review of each laboratory report and must assess whether or 


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not any abnormal test results are clinically significant. The Investigator must complete an 
appropriate AE form for any abnormal test results that are identified as clinically significant. 
Specific tests to be performed are described below: 
Hematology 
Hemoglobin, hematocrit, erythrocyte count (RBC), mean cell volume (MCV), mean cell 
hemoglobin concentration (MVHC), platelets, leukocytes (WBC) and differential [absolute 
counts of] neutrophils (segmented and banded), lymphocytes, monocytes, eosinophils, and 
basophils. Neutrophil/lymphocyte ratio (a calculated ratio) also is to be determined. 
Chemistry 
Sodium, potassium, total bilirubin, direct bilirubin, lactate dehydrogenase (LDH), alkaline 
phosphatase (ALP), ALT, AST, blood urea nitrogen (BUN), creatinine, creatine kinase (CK), 
uric acid, calcium, glucose (random), albumin, cholesterol, serum chloride, phosphorus, carbon 
dioxide, and total protein. 
Coagulation Studies 
PT, PTT, and INR. 
Tumor Markers 
Serum Prostate-Specific Antigen (PSA), Carcinoembryonic antigen (CEA), and Chromogranin A 
(CgA) 
Other Clinical Laboratory Tests 
25-hydroxyvitamin D is to be collected at the screening visit. 
Circulating Tumor Cell Enumeration:  
CTCs will be enumerated using Menarini Silicon Biosystems CellSearch™ platform. CTC 
samples in all patients will be used to enumerate CTC counts. Refer to the study laboratory 
manual for specific details on sample collection, handling, storage, and shipping requirements. 
6.1.9. 
Concomitant Medications / Procedures Review 
A review of concomitant medications and procedures will be conducted at each study visit. Any 
medications taken by study participants or concomitant procedures (eg, transfusions, radiation, 
surgery, or other palliative care) are to be recorded in the eCRF and reviewed for compliance 
with protocol requirements.  
6.1.10. 
Adverse Event Monitoring 
Each participant must be carefully monitored for the development of any AEs, including 
infusion-related AEs and immune-related AEs (see Section 6.1.11), throughout the study from 
signing of the informed consent through 100 days after the last dose of DKN-01, when end of 
treatment procedures are performed. This information should be obtained in the form of non-
leading questions (eg, “How are you feeling?”), and from signs and symptoms detected during 
each examination, from laboratory evaluation, observations of study personnel, participant 


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diary, and spontaneous reports from participants. If, after study drug discontinuation, patients 
initiate a new treatment, only study drug-related AEs need to be followed.  
During post-treatment follow-up, any serious adverse events (SAEs) which the Investigator 
considers related to study treatment are to be reported. 
All AEs will be graded using the NCI CTCAE, version 5.0, grading system (available at:  
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_
Reference_8.5x11.pdf). The Investigator will assess and grade all AEs. Details of AE 
monitoring and reporting are provided in Section 7.1 of this protocol. 
6.1.11. 
Medical Events of Interest 
The following sections describe the assessment and management of DKN-01 infusion-related 
AEs. Details for the management and assessment of these events are found in Appendix 11.5 
through Appendix 11.6.  
6.1.11.1. 
Infusion-related Reactions 
The NCI CTCAE, version 5, definition of infusion-related reactions will be used in this study 
(see Appendix 12.4), and any reactions will be graded using these same criteria. The Sponsor or 
designee should be contacted immediately if questions arise concerning the grade of the 
reaction. 
Infusion-related reactions are temporally associated with the infusion of DKN-01 (≤24 hours 
post-infusion). Symptoms occurring during or following infusion of study drug may also be 
defined according to AE categories such as allergic reaction, anaphylaxis, or cytokine release 
syndrome. In the setting of symptoms occurring during or following infusion of investigational 
therapy, Investigators are encouraged to use the AE term “Infusion-related reaction” and any 
additional terms (including those not listed in the NCI CTCAE) that best describe the event. 
Guidelines for the management of DKN-01 related reactions are summarized in Appendix 11.5 
and Appendix 11.6. 
6.2. 
Efficacy and Response Assessments 
6.2.1. 
Tumor Measurement and Disease Response Assessment by iRECIST 
Soft tissue response and evaluation of PD will be determined according to the iRECIST 
guidelines (Appendix 12.3). Progression in bone will be evaluated according to PCWG3 
guidelines. Refer to the Schedule of Assessments (Table 5) for details regarding the timing of 
specific efficacy measures.  
For all cohorts soft tissue (visceral and nodal) disease will be evaluated for evidence of 
radiographic response based on iRECIST guidelines. Bone lesions will be followed and 
evaluated for evidence of radiologic progression based on PCWG3 criteria. PSA response will 
also be evaluated.  
Tumor assessments will be performed during Screening (baseline), at the end of every 
9 calendar weeks (±7 days) relative to Day 1 (Week 1) up to 27 weeks, then every 12 calendar 
weeks (±7 days), until confirmed radiologic disease progression by iRECIST (measurable 


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disease) or PCWG3 criteria (non-target bone lesions), as assessed by the Investigator, loss to 
follow-up, withdrawal, or study closure.  
Tumor assessments should be performed at the time of treatment discontinuation if the reason 
was other than radiologically confirmed disease progression and it has been ≥8 weeks since the 
last assessment. Tumor assessments should consist of clinical examination, serum PSA, and 
appropriate imaging techniques (ie, CT scans of the chest, abdomen, and pelvis with appropriate 
slice thickness per RECIST v1.1); other studies (MRI, X-ray, positron emission 
tomography[PET]/CT, and ultrasound) may also be performed if required.  
If a site can document that the CT performed as part of a PET/CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast) then the CT portion of the PET/CT can be 
used for RECIST measurements. Radionuclide bone scanning (whole body) should be 
performed using 99mTc-methylene. All sites of disease should be followed and the same 
methods used to detect lesions at baseline are to be used to follow the same lesions throughout 
the clinical study. If a patient has known brain metastases, this disease should be evaluated at 
each required assessment time. Copies of CT scans (and other imaging, as appropriate) If a 
response is noted, a follow-up radiographic assessment at a minimum of 4 weeks later to 
confirm response is to be done. 
6.2.2. 
iRECIST Assessment of Disease 
iRECIST is based on RECIST v1.1, but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs. iRECIST will be used by the Investigator to assess tumor 
response and progression, and make treatment decisions. When clinically stable, participants 
should not be discontinued until progression is confirmed by the Investigator, working with 
local radiology, according to the rules outlined in Appendix 12.3. This allowance to continue 
treatment despite initial radiologic PD takes into account the observation that some participants 
can have a transient tumor flare in the first few months after the start of immunotherapy, and 
then experience subsequent disease response. This data will be captured in the clinical database. 
Clinical stability is defined as the following:  
• Absence of symptoms and signs indicating clinically significant progression of disease. 
• No decline in ECOG PS. 
• No requirements for intensified management, including increased analgesia, radiation, or 
other palliative care. 
Any participant deemed clinically unstable should be discontinued from study treatment at site-
assessed first radiologic evidence of PD, and is not required to have repeat tumor imaging for 
confirmation of PD by iRECIST. 
If the Investigator decides to continue treatment, the participant may continue to receive study 
treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm PD by 
iRECIST, per Investigator assessment. Images should continue to be sent in to the central 
imaging vendor for potential retrospective Blinded Independent Central Review (BICR).  


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If repeat imaging does not confirm PD per iRECIST, as assessed by the Investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the regular 
imaging schedule. If PD is confirmed, participants will be discontinued from study treatment. 
If a participant has confirmed radiographic progression (iCPD) as defined in Appendix 12.3, 
study treatment should be discontinued; however, if the participant is achieving a clinically 
meaningful benefit, an exception to continue study treatment may be considered following 
consultation with the Sponsor. In this case, if study treatment is continued, tumor imaging 
should continue to be performed following the intervals as outlined in Table 5 and submitted to 
the central imaging vendor.  
A description of the adaptations and iRECIST process is provided in Appendix 12.3, with 
additional details in the iRECIST publication (Seymour et al, 2017). A summary of imaging and 
treatment requirements after first radiologic evidence of progression is provided in Table 4 and 
illustrated as a flowchart in Figure 2. 


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Table 4: 
Imaging and Treatment after First Radiologic Evidence of  
Progressive Disease 
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
First radiologic 
evidence of PD by 
RECIST 1.1  
Repeat imaging at 
4 to 8 weeks to 
confirm PD. 
May continue study 
treatment at the 
Investigator’s 
discretion while 
awaiting 
confirmatory tumor 
imaging by site by 
iRECIST. 
Repeat imaging at 
4 to 8 weeks to 
confirm PD per 
Investigator’s 
discretion only. 
Discontinue treatment 
Repeat tumor 
imaging confirms 
PD (iCPD) by 
iRECIST per 
Investigator 
assessment 
No additional 
imaging required. 
Discontinue treatment 
(exception is possible 
upon consultation 
with Sponsor). 
No additional 
imaging required. 
Not applicable 
Repeat tumor 
imaging shows 
iUPD by iRECIST 
per Investigator 
assessment 
Repeat imaging at 
4 to 8 weeks to 
confirm PD. May 
occur at next 
regularly 
scheduled 
imaging visit. 
Continue study 
treatment at the 
Investigator’s 
discretion. 
Repeat imaging at 
4 to 8 weeks to 
confirm PD per 
Investigator’s 
discretion only. 
Discontinue treatment 
Repeat tumor 
imaging shows 
iSD, iPR, or iCR 
by iRECIST per 
Investigator 
assessment. 
Continue 
regularly 
scheduled 
imaging 
assessments. 
Continue study 
treatment at the 
Investigator’s 
discretion. 
Continue 
regularly 
scheduled 
imaging 
assessments. 
May restart study 
treatment if condition 
has improved and/or 
clinically stable per 
Investigator’s 
discretion. Next tumor 
imaging should occur 
according to the regular 
imaging schedule. 
iCPD=iRECIST confirmed progressive disease; iCR=iRECIST complete response; iRECIST=modified Response Evaluation 
Criteria in Solid Tumors 1.1 for immune-based therapeutics; iSD=iRECIST stable disease; iUPD=iRECIST unconfirmed 
progressive disease; PD=progressive disease; RECIST 1.1=Response Evaluation Criteria in Solid Tumors 1.1. 
Note:  If progression has been centrally verified, further management is by the site, based on iRECIST. Any further imaging 
should still be submitted to the central imaging vendor, but no rapid review will occur. 


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Figure 2: 
Imaging and Treatment after First Radiologic Evidence of  
Progressive Disease  
 
 
6.3. 
Post-Treatment Follow-up and Mortality Assessments 
Upon discontinuation of study drugs, all participants will enter the Clinical/Safety Follow-up 
period once the decision is made to discontinue the participant from treatment (eg, at EOT). The 
EOT visit will be the most recent on-treatment visit (with all available safety and response data) 
and will be considered the start of the Week 1 Clinical/Safety Follow-up visit. Participants who 
discontinue the treatment phase will enter the Clinical/Safety Follow-up period. Participants 
must be followed for at least 100 days (representing approximately 5 half-lives for DKN-01) 
after the last dose of study drug. Follow-up visits should occur at Days 30, 60, and 
100 (±10 days) after the last dose of study drug or should coincide with the date of 
discontinuation (±10 days) if date of discontinuation is greater than 30 days after the last dose of 
study drug to monitor for AEs. All patients will be required to complete 3 Clinical/Safety 
Follow-up visits regardless of whether they start new anti-cancer therapy, except those patients 
who withdraw consent for study participation. 
After completion of the Clinical/Safety Follow-up period, all participants will then enter the 
Survival/Long-term Follow-up period. During this period, clinic visits or telephone contact 
every 3 months will be performed to assess survival status. The duration of the Survival/Long-
term Follow-up period will be approximately 2 years following the first dose of study drug, and 
a minimum of 12 months following the last dose of study drug. After completion of the Safety 
Follow-up period, participants who discontinue study with ongoing SD, PR, or CR at the EOT 
visit will enter the Response Follow-up period. These periods will occur simultaneously with 
the Survival Follow-up period for mentioned participants. These participants will continue to 
have tumor radiological and clinical tumor assessments every 3 months (every 12 weeks) during 


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the Response Follow-up period or until disease progression or withdrawal of study or initiation 
of a new systemic anti-cancer therapy. Radiological tumor assessments for participants who 
have ongoing clinical benefit may continue to be collected after participants complete the 
survival phase of the study. 
6.4. 
Pharmacodynamics 
Blood sample collection for pharmacodynamic studies will be mandatory and will be collected 
at the Screening visit and at Days 1 and 15 of each cycle and at the EOT visit. Mandatory pre-
treatment, on-treatment, and progression tumor samples will also be utilized for 
pharmacodynamic analysis.  
6.5. 
Immunogenicity 
6.5.1. 
Immunogenicity in Blood 
Blood samples will be drawn for assessment of DKN-01 anti-drug antibodies (ADA) as per the 
Schedule of Events. Immunogenicity blood samples will be assayed for ADA using a validated 
assay. The testing process will follow a tiered approach of screening, confirmation, and titer 
determination. Details regarding the collection, processing, storage, and shipping of the blood 
samples will be provided in the Laboratory Manual to maintain sample integrity. Any deviations 
from the processing steps (eg, sample collection and processing steps, interim storage or 
shipping conditions), including any actions taken, must be documented and reported to the 
Sponsor. On a case by case basis, the Sponsor may make a determination as to whether sample 
integrity has been compromised. Any deviation from the specified sample handling procedure 
resulted in compromised sample integrity, will be considered a protocol deviation. 
6.5.2. 
Tumor Biopsy Samples 
6.5.2.1. 
Tumor biopsy for DKK1 Testing 
Retrospective correlation of anti-tumor activity with tumoral DKK1 expression is a key 
secondary endpoint of this study. Submission of a tumor sample (archival or fresh) is 
recommended but not required. Tumor samples will be tested for DKK1 expression but neither 
the sample submission nor the results of said testing are required for protocol eligibility.  
Archival tumor tissue can be from a biopsy/surgery performed within 5 years prior to study 
enrollment. Provision of a formalin-fixed paraffin–embedded (FFPE) tumor tissue block, or of 
at least 15 unstained slides (if the block cannot be submitted due to documented 
local/institutional regulations) can be submitted.  
Patients in Dose Expansion Cohort 1B can have their  fresh biopsy from a locally recurrent or 
metastatic tumor site amenable to biopsy that is not the only RECIST v1.1 target lesion. Patients 
in Dose escalation Cohort 1A and 2A and Dose expansion Cohort 2B can have their fresh 
biopsy from any locally recurrent or metastatic tumor site amenable to biopsy regardless of 
whether this site is the only RECIST v1.1 target lesion. A core biopsy, using a minimum 18-
gauge needle should be performed, in order to maximize the quality and value of obtained 
tissue. A minimum of 3 separate cores are requested for each biopsy procedure. Tumor tissue 
from soft tissue or effusion cytologic sampling (fine needle aspiration provided as an FFPE cell 
pellet material) can be submitted, however, we recommend an FFPE tumor tissue block to 
maximize the chance of identifying DKK1 positive cells. If a block cannot be provided due to 


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documented local/institutional regulations, at least 15 unstained slides are required. Bone biopsy 
material is acceptable provided that a gentle decalcification protocol was used. Bone core 
biopsy or bone fine needle aspiration provided as an FFPE cell pellet material (preferred) can be 
submitted.  
6.5.2.2. 
Tumor Biopsy for Exploratory Studies 
Archival tumor tissue samples and tissue from biopsies of the primary and/or metastatic lesions 
will be used to analyze candidate DNA, RNA, or protein markers, or a relevant signature of 
markers, for their ability to identify those patients who are most likely to benefit from treatment.  
On-treatment tumor biopsies are encouraged and tumor tissue is requested for those patients 
who undergo a biopsy or tumor resection as part of routine clinical care at any time during the 
treatment period. For patients on the combination arm, this biopsy can be obtained from C2D15 
through C3D1 or C3D15 through C4D1 at the discretion of the treating investigator and after 
consideration of the risk of neutropenia related to docetaxel. Patients on monotherapy arms can 
have their biopsy at any point in C2 or C3 at the discretion of the treating investigator. Every 
effort should be made to perform a tumor biopsy at the time of iRECIST or PCWG3 confirmed 
disease progression if a patient discontinues study treatment due to disease progression, except 
in instances where the procedure poses an unacceptable risk to patients in the clinical research 
setting. A 14-day window from the EOT visit is permitted. Candidate markers of interest 
include, but may not be limited to: 
• Abundance and enrichment of infiltrating CD8+ T cells, CD4+ T cells, granulocytic and 
monocyte myeloid-derived suppressor cells, NK cells, Regulatory T cells, and 
Monocyte-derived cells as determined by flow cytometry from peripheral blood and 
immunohistochemistry (IHC)/immunofixation of FFPE. 
• Inhibitory ligand and co-receptor expression on tumor and infiltrating immune cells 
measured by IHC. 
• Expression of genes associated with active antitumor immunity. 
• Frequency and diversity of different TCR sequences. 
• Expression of genes associated with activated Wnt signaling 
• Expression of genes associated with basal-type prostate cancer 
• Neutrophil/lymphocyte ratio 


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7. 
ADVERSE EVENTS 
7.1. 
Definitions, Documentation, and Reporting 
7.1.1. 
Adverse Event Definition 
An AE is any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. An adverse event (also referred to as an adverse 
experience) can be any unfavorable and unintended sign (eg, an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a drug, without any judgment about 
causality. An adverse event can arise from any use of the drug (eg, off-label use, use in 
combination with another drug) and from any route of administration, formulation, or dose, 
including an overdose. 
The Investigator is required to provide appropriate information concerning any findings that 
suggest significant hazards, contraindications, side effects, or precautions pertinent to the safety 
of the drug under investigation. 
In addition to collecting the AE verbatim and the NCI CTCAE severity grade, AE verbatim text 
will also be mapped by the Sponsor or designee to corresponding terminology within the 
Medical Dictionary for Regulatory Activities (MedDRA). 
Cases of pregnancy that occur during paternal exposures to study drug should be reported. Data 
on fetal outcome are collected for regulatory reporting and drug safety evaluation. 
7.1.2. 
Serious Adverse Event Definition 
An AE is considered to be serious if, in the view of either the Investigator or the Sponsor, it 
results in any of the following outcomes: 
• Death. 
• Life-threatening. Life-threatening means that the patient was at immediate risk of death 
from the reaction as it occurred, ie, it does not include a reaction which hypothetically 
might have caused death had it occurred in a more severe form. 
• In-patient hospitalization or prolongation of existing hospitalization. Hospitalization 
admissions and/or surgical operations scheduled to occur during the study period, but 
planned prior to study entry are not considered AEs if the illness or disease existed 
before the patient was enrolled in the study, provided that it did not deteriorate in an 
unexpected manner during the study (eg, surgery performed earlier than planned). 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• Congenital anomaly/birth defect. 
• Important medical event. An important medical event is an event that may not result in 
death, be life-threatening, or require hospitalization but may be considered an SAE 
when, based upon appropriate medical judgment, it may jeopardize the patient or patient 
and may require medical or surgical intervention to prevent one of the outcomes listed in 
the definitions for SAEs. Examples of such medical events include allergic 


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bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in in-patient hospitalization, or the 
development of drug dependency or drug abuse. 
Planned surgeries should not be reported as SAEs unless the underlying medical condition has 
worsened during the course of the study. 
Planned hospitalizations or elective procedures for underlying preexisting conditions that are 
already recorded in the patient’s medical history at the time of study enrollment should not be 
considered SAEs. Hospitalization or prolongation of hospitalization without a precipitating 
clinical AE (for example, for the administration of study therapy or other protocol-required 
procedure) should not be considered SAEs. 
7.1.2.1. 
Reporting of Pregnancy to the Sponsor 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
Investigators or their designees to report any pregnancy (spontaneously reported to them) that 
occurs during the study.  
Pregnancies that occur after the consent form is signed but before treatment allocation must be 
reported by the Investigator if they cause the patient to be excluded from the study, or are the 
result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.  
Pregnancies that occur from the time of treatment allocation through 6 months following 
cessation of study treatment, or 30 days following cessation of treatment if the patient initiates 
new anticancer therapy, whichever is earlier, must be reported by the Investigator. All reported 
pregnancies must be followed to the completion/termination of the pregnancy. Pregnancy 
outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, 
fetal death, intrauterine death, miscarriage, and stillbirth must be reported as serious events 
(Important Medical Events). If the pregnancy continues to term, the outcome (health of infant) 
must also be reported. 
Such events must be reported within 24 hours to the Sponsor (see Section 7.2). 
7.2. 
Procedures for Recording and Reporting AEs and SAEs 
Each patient must be carefully monitored for the development of any AEs. This information 
should be obtained in the form of non-leading questions (eg, “How are you feeling?”) and from 
signs and symptoms detected during each examination, observations of study personnel, patient 
diaries, and spontaneous reports from patients. 
All AEs (serious and non-serious) spontaneously reported by the patient and/or in response to 
an open question from study personnel or revealed by observation, physical examination or 
other diagnostic procedures will be recorded on the appropriate page of the eCRF. Any 
clinically relevant deterioration in laboratory assessments or other clinical findings is 
considered an AE and must be recorded on the appropriate pages of the eCRF. When possible, 
signs and symptoms indicating a common underlying pathology should be noted as one 
comprehensive event. 


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Study site personnel must alert the Sponsor or its designee, the PI and Data Safety Monitoring 
Committee (DSMC) if meeting the requirements for expedited reporting of any SAE within 24 
hours of Investigator awareness of the event via a Sponsor-approved method. Alerts issued via 
telephone are to be immediately followed with official notification on study-specific SAE 
forms. The AEs which are serious and unexpected, and assessed as at least possibly related to 
study drug (possibly or related) will be reported to the regulatory authority by the Sponsor, or 
it’s designee in accordance with 21 CFR § 312.32. Patients will be monitored for AEs and 
concomitant medications starting 14 days prior to C1D1 to 30 days after the last dose of DKN-
01. Only SAEs that develop from C1D1 and onwards need to be reported..  
All SAEs that occur during the course of the study (starting C1D1) must be reported by the 
Investigator within 24 hours from the point in time when the Investigator becomes aware of the 
SAE (Contact information will be provided by the Sponsor or its designee). 
Within 24 hours of the event, the Serious Adverse Event Form must be emailed to 
NYUPCCsafetyreports@nyulangone.org whether full information regarding the event is known 
or not. Additional follow-up by the Investigator will be required if complete information is not 
known. De-identified source documentation of all examinations, diagnostic procedures, etc. 
which were completed with respect to the event should be included with the SAE form. Care 
should be taken to ensure that the patient’s identity is protected and the patient’s identifiers (as 
assigned at the time of study enrollment) are properly mentioned on any copy of source 
document provided to the Sponsor. For laboratory results, include the laboratory normal ranges.  
All SAEs must be reported whether or not considered causally related to the study drug. SAE 
forms will be completed and the information collected will include patient number, a narrative 
description of the event and an assessment by the Investigator as to the intensity of the event 
and relatedness to study drug. Follow-up information on the SAE may be requested by the 
Sponsor or designee. 
Certain SAEs require expedited reporting to regulatory authorities and Institutional Review 
Boards (IRB). If there are serious, unexpected adverse drug experiences associated with the use 
of the study drug, the Sponsor or designee will notify the appropriate regulatory agency(ies) and 
all participating Investigators on an expedited basis. It is the responsibility of the Investigator to 
promptly notify the IRB/IEC of all unexpected serious adverse drug experiences associated with 
the use of the study drug. 
For both serious and non-serious AEs, the Investigator must determine both the intensity of the 
event and the relationship of the event to study drug administration. 
Intensity of all AEs, including clinically significant treatment-emergent laboratory 
abnormalities and potential systemic reactions, will be graded according to the NCI CTCAE, 
version 5.0 (available at: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_
Reference_8.5x11.pdf). For AEs without matching terminology within the NCI CTCAE, 
version 5, criteria, the Investigator will be responsible for selecting the appropriate system 
organ class and assessing severity grade based on the intensity of the event. Note that both 
CTCAE term (actual or coded) and severity grade must be selected by study site personnel and 
collected in the eCRF. This collection is in addition to verbatim text used to describe the AE.  


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The CTCAE grade refers to the severity of the AE and ranges from Grade 1 (mild AE), Grade 2 
(moderate AE), Grade 3 (severe AE) and Grade 4 (life-threatening or disabling AE) to Grade 5 
(death related to AE). 
AEs not listed by the CTCAE will be graded as follows: 
• Mild: discomfort noticed but no disruption of normal daily activity. 
• Moderate: discomfort sufficient to reduce or affect daily activity. 
• Severe: inability to work or perform normal daily activity. 
• Life threatening:  represents an immediate threat to life. 
• Death 
Relationship to study drug administration will be determined by the Investigator according to the 
following criteria. 
• Not Related: No relationship can be established between the event and the 
administration of study drug. The event is related to other etiologies, such as 
concomitant medications or patient’s clinical state. 
• Possible:  A reaction that follows a plausible temporal sequence from administration of 
the study drug and follows a pattern to the suspected study drug. The event recurs on re-
challenge. The event is not commonly associated with drug exposure but is also 
uncommon in the patient population. The reaction might have been produced by the 
patient’s clinical state or other modes of therapy administered to the patient. 
• Related:  A reaction that is known to be strongly associated with drug exposure. A 
temporal relationship can be established between the administration of study drug and 
the event. The reaction cannot be reasonably explained by the known characteristics of 
the patient’s clinical state or other modes of therapy administered to the patient. 
For the purpose of safety analyses, all AEs that are classified as having a possible or related 
relationship to study drug will be considered treatment-related events. 
SAEs occurring after a patient has received the study drug will be collected for 30 days after the 
last dose of study drug, regardless of the Investigator’s opinion of causation. Thereafter, SAEs 
are not required to be reported unless the Investigator feels the events were related to either the 
study drug or a protocol procedure. 
PD will be documented in the eCRF intended to capture tumor response and PD, and will be 
analyzed accordingly. Signs and symptoms related to PD should be reported in the appropriate 
eCRF as either an AE or SAE. Verbatim terms such as “disease progression” or “progressive 
disease” etc. should not be reported as AEs or SAEs unless the Investigator considers the 
progression to be atypical, accelerated or caused by the study drug. Similarly, for deaths 
occurring as a result of PD during the study or until 30 days after the last dose of study drug is 
administered, the sign or symptom with an outcome of death should be reported on the AE and 
SAE pages: the verbatim term of “death” should not be used on the AE or SAE forms as the 
event. Additional information pertaining to the death should be reported on the eCRF intended 
to capture death information. 


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7.3. 
Monitoring of Adverse Events and Period of Observation 
AEs and SAEs will be recorded starting at the time of patient consent up to and including 100 
days after administration of the last dose of DKN-01. In the event that the patient starts a new 
treatment after discontinuation of DKN-01 and within the 100-day clinical/safety follow-up 
period, only treatment-related AEs will need to be followed. All AEs should be monitored until 
they are resolved or are clearly determined to be due to a patient’s stable or chronic condition or 
intercurrent illness(es).  
Any SAE that occurs at any time after end of treatment procedures are performed, which the 
Investigator considers to be related to study drug, must be reported to the Sponsor or designee. 
If a patient’s dosage is reduced or treatment is discontinued as a result of an AE, study site 
personnel must clearly report to the Sponsor or its designee via eCRF the circumstances and 
data leading to any such dosage reduction or discontinuation of treatment. 
All AEs should be monitored until they are resolved or are clearly determined to be due to a 
patient’s stable or chronic condition or intercurrent illness(es). 
Patients will be evaluated for AEs at each visit. Each patient will be instructed to call his or her 
physician to report any AEs between visits. Study site personnel will record the occurrence and 
nature of each patient’s preexisting conditions, including clinically significant signs and 
symptoms of the disease under treatment in the study.  
After the ICF is signed, site personnel will record any change in the condition(s) and the 
occurrence and nature of any AEs. All AEs related to protocol procedures will be reported to the 
Sponsor or designee. Any clinically significant findings from ECGs, laboratory, or vital sign 
measurements that result in a diagnosis should be reported to the Sponsor or its designee. 
Investigators will be instructed to report to the Sponsor or its designee their assessment of the 
potential relatedness of each AE to protocol procedure, study drug, and/or drug delivery system 
via designated data transmission methods.  
7.1. 
Reporting Procedures – Notifying the FDA 
The Sponsor is required to report certain study events in an expedited fashion to the FDA. These written 
notifications of adverse events are referred to as Investigational New Drug Application 
(IND)/Investigational Device Exemption (IDE) safety reports.  
The following describes the IND safety reporting requirements by timeline for reporting and associated 
type of event: 
• Within 7 calendar days (via telephone or facsimile report) 
Any study event that is: 
- associated with the use of the study drug 
- unexpected,  
- fatal or life-threatening 


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• Within 15 calendar days (via written report) 
Any study event that is: 
- associated with the use of the study drug, 
- unexpected, and 
- serious, but not fatal or life-threatening 
or 
- a previous adverse event that was not initially deemed reportable but is later found to fit the 
criteria for reporting (reporting within 15 calendar days from when event was deemed 
reportable). 
• Any finding from tests in laboratory animals that:  
- suggest a significant risk for human patients including reports of mutagenicity, 
teratogenicity, or carcinogenicity. 
7.2. 
Reporting Procedures – Participating Investigators  
For multi-center clinical studies, in addition to reporting certain unanticipated problems and 
adverse events noted above to the FDA, it is the responsibility of the study Sponsor to report 
those same adverse events or findings to participating investigators.  
The Investigator shall maintain a copy of the Medical Events Form on file at the study site. All 
report forms must be signed and dated by the PI. If the PI is not available at the time of the 
initial report, then the form can be submitted by a Sub-Investigator. This form should be 
reviewed by the PI, whom sign/date initial report upon return. 
Report to: 
Email:  NYUPCCsafetyreports@nyulangone.org 
Telephone: (212) 273-2748 
AND 
David R. Wise, MD, PhD 
160 E. 34th Street, Suite 1009 
New York, NY 10016 
Phone: 212-731-6366 
Email:  David.Wise@nyulangone.org 
Events of Clinical Interest (any medical event that is deemed significant via PI’s expertise, but 
does not apply to SAE categories) will be reported within 2-5 days, or as per study Sponsor 
specifications. 
7.1. 
Safety Oversight 
It is the responsibility of the PI to oversee the safety of the study at his/her site. This safety 
monitoring will include careful assessment and appropriate reporting of adverse events as noted 
above, as well as the construction and implementation of a site data and safety-monitoring plan. 


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Medical monitoring will include a regular assessment of the number and type of serious adverse 
events. 
Safety oversight will be under the direction of a DSMB composed of individuals with the 
appropriate expertise. The DSMB will meet at least semiannually to assess safety and efficacy 
data on each arm of the study. The DSMB will operate under the rules of an approved charter 
that will be written and reviewed at the organizational meeting of the DSMB. At this time, each 
data element that the DSMB needs to assess will be clearly defined. The DSMB will provide its 
input to the New York University (NYU) Clinical Trials Office (CTO). 
All Internal SAEs reported by the CTO, occurring to patients on clinical studies that are not 
monitored by any other institution or agency, are reported via email to the 
NYUPCCsafetyreports@nyulangone.org and reviewed within 24 hours by the DSMC. Based on 
the review, one of three determinations will be made: 
• SAE report is considered to be adequate 
• Queries for clarification to PI regarding treatment attribution and/or resolution of 
SAE or completeness of other information. The committee may request a cumulative 
review of all SAEs on the study to date. 
• Request for full DSMC committee review of protocol at the next scheduled meeting. 
The DSMC Coordinator will record the committee’s decision and incorporate it into the study 
summary for the next protocol review. 
7.2. 
Data and Safety Monitoring Plan (DSMP) 
This Investigator-initiated study will be monitored by the DSMC of the NYU Perlmutter Cancer 
Center (PCC). The DSMC operates based on the NCI approved Charter. It is an existing and 
multidisciplinary committee (consisting of clinical investigators/oncologists, biostatisticians, 
nurses, and research administration staff knowledgeable of research methodology and design 
and in proper conduct of clinical studies) that is responsible for monitoring safety, conduct and 
compliance in accordance with protocol data monitoring plans for clinical studies conducted in 
the NYULH Perlmutter Cancer Center that are not monitored by another institution or agency. 
The DSMC reports to the Director of the NYULH PCC. 
Per the NYU PCC Institutional Data Safety and Monitoring Plan, this phase Ib/ II study will be 
monitored by DSMC at least quarterly, (from the date the first patient is enrolled), subsequent 
cohort activation, and at the completion of the study prior to study closure. This review includes 
accrual data, patient demographics, and AEs. Accrual to the next dose level cohort or expansion 
cohort will be held until real-time review of the toxicity from the prior cohort has occurred to 
assure no defined DLTs have occurred prior to proceeding to the next level or expanding the 
current cohort. PIs are required to attend the review of their studies. Additional reviews can be 
scheduled based on SAE reports, Investigator-identified issues, external information, etc. The 
DSMC will review safety data every 3 months. 


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NYU CTO oversight responsibilities:  
• Review all adverse events requiring expedited reporting as defined in the protocol 
• Provide study accrual progress, safety information and data summary reports to the 
Sponsor-Investigator (David Wise, MD PhD) and NYU PCC DSMC. 
Documentation of DSMC reviews will be provided to the Sponsor-Investigator. Issues of 
immediate concern by the DSMC will be brought to the attention of the Sponsor-Investigator 
and other regulatory bodies as appropriate. The Sponsor-Investigator will address the DSMC’s 
concerns. 
Other external sites will be monitored and informed of other AEs by the DSMC within 7 days 
of toxicities and within 3 business days of SAE. Scheduled conference calls will be conducted 
after 3 patients are enrolled. Additional conference calls will be scheduled as indicated based on 
the recommendations from the DSMC and the PI of the study. 
7.3. 
Study Monitoring Plan 
This study will be monitored according to the monitoring plan detailed below. The Investigator 
will allocate adequate time for such monitoring activities. The Investigator will also ensure that 
the monitor or other compliance or quality assurance reviewer is given access to all the above 
noted study-related documents and study related facilities (e.g. pharmacy, diagnostic laboratory, 
etc.), and has adequate space to conduct the monitoring visit. At each visit, the monitor will 
review various aspects of the study including, but not limited to: compliance with the protocol 
and study manual and with the principles of GCP; completion of case report forms; source data 
verification; study drug accountability and storage; facilities and staff.  
During scheduled monitoring visits, the Investigator and the investigational site staff must be 
available in order to discuss the progress of the study, make necessary corrections to case report 
form entries, respond to data clarification requests and respond to any other study-related 
inquiries of the monitor. Any queries identified through this review will be managed within the 
systems established for query resolution and tracking. Inquiries related to study conduct, which 
require further information or action will be discussed within the study team for appropriate and 
documented escalation plans. It is expected that response to data clarification requests and other 
study-related inquiries will occur throughout the course of the study through regular 
communication with the NYU CTO monitoring study team and review/entry of data into the 
electronic study database.  
7.3.1. 
Subsite Monitoring 
Monitoring visits are done remotely unless otherwise specified, via remote electronic medical 
record access. If not possible, secure email exchange will be utilized. The quality assurance 
specialist will confirm an upcoming monitoring visit with a Subsite Investigator and staff. If 
remote EMR access is not available, then the Subsite Coordinator will ensure that all source 
documents for patients are de-identified and labeled only with the patient ID number(s), and 
emails all requested documents to the quality assurance specialist by the specified visit date. All 
documents are reviewed and a monitoring report is submitted within 5 business days from the 
date of the visit. Any outstanding documents will be listed in the report as a high-priority 


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request for the next monitoring visit. It is expected that response to data clarification requests 
and other study-related inquiries will occur throughout the course of the study through regular 
communication with the site monitor, the Sponsor or representatives, and review/entry of data 
into the electronic study database. Continued non-compliance and failure to submit 
documentation will result in the suspension of patient enrollment at the site, until the documents 
have been received. 
At any time during the course of the study, representatives of the FDA and/or local regulatory 
agencies may review the conduct or results of the study at the investigational site. The 
Investigator must promptly inform NYU CTO of any audit requests by health authorities, and 
NYU CTO will provide Sponsor-Investigator and Leap Therapeutics with the results of any 
such audits and with copies of any regulatory documents related to such audits.  
In accordance with the Health Insurance Portability and Accountability Act (HIPAA) and 
associated privacy regulations, a patient’s authorization to use personal identifiable health 
information may be required from each patient before commencement of research activities. 
This authorization document must clearly specify what parties will have access to a patient’s 
personal health information, for what purpose and for what duration.  
At the NYULH Perlmutter Cancer Center, all Investigator-initiated protocols are subject to a 
standardized data and safety monitoring, which includes scientific peer review, IRB review and 
DSMC review as well as internal auditing.  
The review of AEs and study conduct for this study occurs at several levels: 
1. PI: AEs are evaluated monthly by the PI in conjunction with the research nurses, data 
manager, and research team.  
2. DSMC, quarterly. 
3. IRB: An annual report to the IRB is submitted by the study PI for continuation of the 
protocol. It includes a summary of all AEs, total enrollment with demographics, protocol 
violations, and current status of patients as well as available research data. 
4. In addition, the quality assurance unit will monitor this study every 4-6 weeks, this 
includes real-time review of all eCRFs to ensure completeness and to verify adherence 
to the protocol; the completeness, accuracy and consistency of the data; and adherence 
to ICH GCP guidelines. Additionally, a first patient audit is to be conducted within four 
weeks of enrollment. 
7.4. 
Data Quality Oversight Activities 
Remote validation of electronic data capture (EDC) system data will be completed on a 
continual basis throughout the life cycle of the study. Automated edit check listings will be used 
to generate queries in the EDC system and transmitted to the site to address in a timely fashion. 
Corrections will be made by the study site personnel.  
The study site may also be subject to quality assurance audit by Leap Therapeutics or its 
designee as well as inspection by appropriate regulatory agencies.  


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7.5. 
Onsite Monitoring 
There will be at least one routine visit per site per year for sites that have accrued. Additional 
for cause visits may occur as necessary. Selected source documents will be reviewed for 
verification of agreement with data entered into the EDC system. It is important for the 
Investigator and their relevant personnel to be available for a sufficient amount of time during 
the monitoring visits or audit, if applicable. The Investigator and institution guarantee access to 
source documents by NYU CTO or its designee.  
7.6. 
Compliance with Study Registration and Results Posting 
Requirements 
Under the terms of the Food and Drug Administration Modernization Act and the Food and 
Drug Administration Amendments Act, the Sponsor-Investigator of the study is solely 
responsible for determining whether the study and its results are subject to the requirements for 
submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. The Sponsor-
Investigator has delegated responsibility to NYU CTO for registering the study and posting the 
results on clinicaltrials.gov. Information posted will allow patients to identify potentially 
appropriate studies for their disease conditions and pursue participation by calling a central 
contact number for further information on appropriate study locations and study site contact 
information.  


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8. 
STATISTICAL CONSIDERATIONS 
8.1. 
Sample Size Determination 
A standard 3 + 3 design will be used for the dose escalation cohorts with up to 6 patients tested 
per dose level for a total of up to 12 patients per cohort.  
Simon’s two-stage design (Simon, 1989) will be used to evaluate Dose Expansion Cohorts 1B. 
The null hypothesis that the true response rate is 0.2 will be tested against a one-sided 
alternative. In the first stage, 18 patients will be accrued. If there are 4 or fewer responses in 
these 18 patients, the study will be terminated. Otherwise, an additional 15 patients will be 
accrued for a total of 33. The null hypothesis will be rejected if 11 or more responses are 
observed in 33 patients. This design yields a Type I error rate of 0.05 and a power of 0.8 when 
the true response rate is 0.4. 
Simon's two-stage design (Simon, 1989) will be used to evaluate Dose Expansion Cohorts 
2B. The null hypothesis that the true response rate is 0.05 will be tested against a one-sided 
alternative. In the first stage, 13 patients will be accrued. If there are 0 responses in these 13 
patients, the study will be stopped. Otherwise, 14 additional patients will be accrued for a total 
of 27. The null hypothesis will be rejected if 4 or more responses are observed in 27 patients. 
This design yields a type I error rate of 0.05 and a power of 0.8 when the true response rate 
is 0.2. 
 
8.2. 
Randomization 
No randomization will take place as part of this study. 
8.3. 
Populations for Analysis 
The following populations will be used for analysis:  
• Evaluable analysis set (EAS): All evaluable patients, i.e., patients who received any 
amount of DKN-01 and have at least one evaluable post-baseline tumor response 
assessment or who discontinued treatment due to death, toxicity, or clinical progression. 
All primary analyses of ORR, PFS, OS, DoR, PSA response rate, and time to response, 
OS will use the EAS. This set will also support analysis of tumor-related endpoints, and 
exploratory endpoints.  
• Safety population: All enrolled patients who receive any amount of study treatment 
(DKN-01 or docetaxel). All safety analyses will be based on this population.  
• A per-protocol (PP) subset may also be used for secondary analysis of select efficacy 
endpoints and will be based on study drug exposure (compliance and/or time on study 
drug) and major protocol deviations. The criteria for inclusion in the PP subset will be 
finalized and documented. The PP set will be defined and finalized separately for each 
group.  
• PK analysis set: The PK analysis set includes all patients in the safety analysis set who 
have at least one PK assessment.  


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• Pharmacodynamic/Biomarker analysis set: The biomarker analysis set includes all 
patients in the safety analysis set who have at least one screening biomarker assessment. 
Analysis sets will be defined separately for blood-based and tumor tissue-based 
biomarkers. 
8.4. 
Procedures for Handling Missing, Unused and Spurious Data 
The procedures for handling missing, unused, or spurious data, along with the detailed method 
for analysis of each variable, transformations, and exploratory analyses will be presented in the 
statistical Analysis Plan (SAP). 
8.5. 
Interim Analyses 
Independent interim efficacy analysis will be carried out for Cohorts 1B in the dose expansion 
phase. If there are 4 or fewer responses in the first 18 patients accrued, the study will be 
terminated. Enrollment to the study to Cohorts 1B will be on hold during the interim efficacy 
analysis. Enrollment to the study on Cohort 2A and 2B will continue during the interim 
analysis. 
An interim analysis will be carried out after 13 patients are be accrued in Cohort 2B. If there are 
0 responses in these 13 patients, the study will be stopped. Enrollment to Cohort 2B will be on 
hold during the interim efficacy analysis. Enrollment to Cohort 1B will continue during this 
interim analysis. 
8.6. 
Statistical Methods 
A 3 + 3 strategy will be employed for the dose escalation phase. A Simon’s 2-stage design will 
be used for dose expansion Cohorts 1B and 2B.  
8.6.1. 
General Methods 
Descriptive statistics (N, mean, standard deviation, median, minimum, and maximum) will be 
presented for continuous variables. Frequency distributions (counts and associated percentages) 
will be presented for categorical variables. Median, 25th and 75th percentiles and standard error 
will be presented for time-to-event data. 
This study is descriptive in nature; no formal comparisons between groups will be performed. 
All CIs will be 95%, unless stated otherwise. 
Individual patient data listings will be provided to support summary tables.  
The effects of noncompliance, treatment discontinuations, premature study withdrawals, 
subsequent therapies, and covariates will be assessed to determine the impact on the general 
applicability of results from this study. 
8.6.2. 
Disposition of Patients 
All patient discontinuations will be documented, and the extent of each patient’s participation in 
the study will be reported. If known, a reason for their discontinuation will be given. The 
following information will be summarized: 
• Number enrolled 
• Number receiving treatment 


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• Number and percentage who completed the protocol 
• Number and percentage of patients who discontinued treatment 
• Reason for discontinuation 
8.6.3. 
Baseline Characteristics 
Patient characteristics will include a summary/listing of the following: 
• Patient demographics 
• Baseline disease characteristics 
• Prior disease-related therapies 
• Concomitant medications 
Other patient characteristics will be summarized as deemed appropriate. 
8.6.4. 
Efficacy Analysis 
8.6.4.1. 
Primary Efficacy Endpoint and Analysis 
The primary endpoint for Dose Expansion Cohort 1B is OR rate. OR is defined as the 
proportion of patients with a best overall soft tissue response of CR or PR per iRECIST from 
the first dose of study treatment until disease progression or death due to any cause. Soft tissue 
responses will be confirmed by a follow-up radiographic assessment at least 4 weeks later with 
a repeated CT or MRI with no evidence of confirmed bone disease progression per PCWG3 
criteria by Investigator. The radiographic assessment of soft tissue disease will use iRECIST, 
and bone disease will be evaluated per PCWG3. 
A secondary endpoint for Dose Expansion Cohort 2B is composite OR rate defined as the 
number of patients with a reduction of PSA by ≥50% relative to baseline or conversion of CTC 
from unfavorable ≥5 to 4 or fewer CTC per 7.5 mL or iRECIST soft tissue response. 
8.6.4.2. 
Secondary Efficacy Endpoints and Analysis 
Secondary efficacy variables in the study include: 
• TTR is defined as the time from the first dose of study treatment to the first objective 
evidence of soft tissue response with no evidence of confirmed bone disease progression 
on bone scan per PCWG3. Soft tissue response is defined as a BOR of CR or PR as 
assessed by Investigator using iRECIST. The response must be confirmed at least 
4 weeks later with a repeated CT/MRI. 
• DR is defined for patients with confirmed objective response (CR or PR) as the time 
from the first objective evidence of soft tissue response (subsequently confirmed) as 
assessed by Investigator iRECIST and no evidence of confirmed bone disease 
progression by PCWG3 to the first time of objective evidence of radiographic 
progression or death due to any cause, whichever occurs first. Radiographic progression 
is defined as soft tissue progression as assessed by Investigator using iRECIST or bone 
disease progression as assessed by Investigator using PCWG3.  


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• PFS is defined as the time from the first dose of study treatment to documentation of 
radiographic progression in soft tissue as assessed by Investigator using iRECIST (see 
Appendix 12.3), in bone as assessed by Investigator using PCWG3 (see Appendix 12.7), 
or death, whichever occurs first.  
• PSA response is defined as the proportion of patients with confirmed PSA decline ≥50% 
compared to baseline. PSA response will be calculated as a decline from baseline PSA 
(ng/mL) to the maximal PSA response with a threshold of 50%. A PSA response must 
be confirmed by a second consecutive value at least 3 weeks later. The proportion of 
patients with confirmed PSA decline ≥50% compared with baseline will be calculated 
along with the 90% and 95% CIs. Percentage change in PSA from baseline to 12 weeks 
post-treatment and maximal decline in PSA after treatment initiation will also be 
calculated and displayed as a waterfall plot as per PCWG3 guidelines. 
• Time to PSA progression for patients with metastatic CRPC is defined as the time from 
the first dose to the date that a ≥25% increase in PSA with an absolute increase of 
≥2 µg/L (2 ng/mL) above the nadir (or baseline for patients with no PSA decline) is 
documented, confirmed by a second consecutive PSA value obtained ≥3 weeks 
(21 days) later. Details associated with censoring will be presented in the SAP. 
• OS is defined as the time from the first dose of study treatment to the date of death. 
Patients without an event (death) will be censored at the date of last contact. 
• TTR will be summarized using simple descriptive statistics (eg, median and range). DR, 
PFS, time to PSA progression and OS will be analyzed using Kaplan Meier methods and 
descriptive statistics. Point estimates will be presented with their 90% and 95% CIs. 
• 
CTC conversion from unfavorable (5 or greater CTC/7.5 mL) to favorable (4 or fewer 
CTC/7.5 mL). 
• 
CTC ≥1 per 7.5 mL at baseline and 0 CTC per 7.5 mL at 13 weeks (CTC0) will be calculated. 
8.6.5. 
Safety Analysis 
All analysis of safety and toxicity will be conducted in the safety population. 
AE terms and severity grades will be assigned by the Investigator using the NCI CTCAE, 
version 5.0. Safety parameters will be listed and summarized using standard descriptive 
statistics. 
Analyses will be conducted to characterize the safety and tolerability of DKN-01. 
Safety analyses will include presentations of the following: 
• DLTs 
• TEAEs, including severity and possible relationship to study drug 
• Dose adjustments 
• Laboratory values 
• Vital signs 
• ECOG performance status 


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• Physical examinations 
• ECG readings 
• Infusion-related reactions 
• Concomitant medication 
8.6.5.1. 
Study Drug Exposure 
Descriptive statistics of the amount of each drug, the number of infusions administered, and 
compliance will be tabulated, along with information on missed doses, dosing delays, and dose 
reductions. 
8.6.5.2. 
Adverse Events 
AEs will be coded using the current MedDRA dictionary. 
Analyses of AEs will be performed for those events that are considered treatment-emergent, 
where a TEAE is defined as any AE with onset or (worsening of a pre-existing condition) after 
the first dose of study drug through 100 days following the last dose of study drug. AEs with 
partial dates will be assessed using the available date information to determine if treatment-
emergent; AEs with completely missing dates will be assumed to be treatment-emergent. 
TEAEs, TEAEs leading to study drug discontinuation, TEAEs leading to dose 
reduction/interruption, TEAEs related to study drug, SAEs, TEAEs leading to study drug 
discontinuation, and TEAEs with an outcome of death will be summarized by system organ 
class, and preferred term. A summary of TEAEs of CTCAE Grade 3 or higher, will also be 
provided. The number and percent of patients with infusion-related reactions and immune-
reactions will be summarized, overall and by visit. 
No formal hypothesis-testing analysis of TEAE incidence rates will be performed. All TEAEs 
occurring on-study will be listed in patient data listings. By-patient listings also will be provided 
for the following:  patient deaths, SAEs, TEAEs leading to study drug discontinuation, and 
TEAEs with intensity ≥Grade 3. 
8.6.5.3. 
Clinical Laboratory Data 
Clinical laboratory values will be summarized in SI units (Système Internationale d'Unités; 
International System of Units). 
The actual value and change from baseline to each on-study evaluation will be summarized for 
each clinical laboratory parameter, including hematology and clinical chemistry. Summaries 
will be presented. In the event of multiple evaluations for the same parameter at the same visit, 
the last non-missing value per study day/time will be used. 
Shift tables that present changes from baseline to worst on-study values relative to NCI CTCAE 
classification ranges and incidence of treatment-emergent Grade 3 / 4 clinical laboratory 
abnormalities will be presented.  
All laboratory data will be provided in data listings. A subset listing will be presented for all 
clinically significant abnormal laboratory values. 


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8.6.5.4. 
Other Safety Parameters 
Safety will be evaluated by assessment of adverse events, physical examination, ECOG PS, 
vital signs, ECG, clinical and laboratory values. 
8.6.6. 
Analysis of Exploratory Endpoints 
• Flow cytometry-based intratumoral and peripheral immunoprofiling will be carried out 
in the immune monitoring core facility at Perlmutter cancer center at NYU Langone and 
will be used to compare the effect of the DKN-01 as monotherapy and in combination 
with docetaxel on the abundance and activation of the immune cell repertoire enriched in 
the tumor.  
• PK levels of DKN-01 as monotherapy and in combination with docetaxel.  
• Concordance analysis of plasma DKK1 and tumoral DKK1 
• Pre-treatment, on-treatment, and time-of-progression assessment of peripheral and 
intratumoral immune cell abundance and activation  
• Viability of pre-treatment patient-derived 3D organotypic cultures incubated with DKN-
01 and docetaxel 
• Immune cell abundance and activation of pre-treatment patient-derived 3D organotypic 
cultures incubated with DKN-01 and docetaxel. 
• Overall response stratified by “PSA-high” (concordant radiographic and PSA 
progression) and “PSA-low” (radiographic evidence in the absence of PSA progression) 
prostate cancer status. 
8.6.7. 
Procedures for Reporting Deviations to the Original Statistical Analysis Plan 
All deviations from the original SAP will be provided in the final clinical study report. 


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9. 
ADMINISTRATIVE REQUIREMENTS 
9.1. 
Good Clinical Practice 
The study will be conducted in accordance with ICH GCP and the appropriate regulatory 
requirement(s). The Investigator will be thoroughly familiar with the appropriate use of the 
study drug as described in the protocol and Investigator’s Brochure. Essential clinical 
documents will be maintained to demonstrate the validity of the study and the integrity of the 
data collected. Master files should be established at the beginning of the study, maintained for 
the duration of the study and retained according to the appropriate regulations. 
9.2. 
Ethical Considerations 
The study will be conducted in accordance with ethical principles founded in the Declaration of 
Helsinki (see Appendix 12.6). The IRB will review all appropriate study documentation in order 
to safeguard the rights, safety, and well-being of the patients. The study will only be conducted 
at sites where IRB approval has been obtained. The protocol, Investigator’s Brochure, informed 
consent, advertisements (if applicable), written information given to the patients (including 
diary cards), safety updates, annual progress reports, and any revisions to these documents will 
be provided to the IRB by the Investigator. 
9.3. 
Patient Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from either 
the patient or his/her guardian or legal representative prior to study participation. The method of 
obtaining and documenting the informed consent and the contents of the consent will comply 
with ICH-GCP and all applicable regulatory requirement(s). 
9.3.1. 
Consent Procedures and Documentation 
The consenting process and documentation will follow Standard Operating Procedures 
(Obtaining Informed Consent for Clinical Trials) of the NYULH PCC CTO. 
9.3.1.1. 
Informed Consent 
A participating Investigator who has completed requisite training for human patient research 
and has been instructed by the PI about the potential participant; also must address any 
questions/concerns prior to obtaining written informed consent for participation and HIPAA 
authorization can also obtain consent. 
Patients will be given adequate time to read the consent form. They will be given time to ask 
questions about the study in private exam rooms. Questions will be answered by a participating 
physician, or qualified research study team member all of whom have completed requisite 
training for human patient research. Investigators will review the informed consent form with 
patients and address any questions or concerns prior to obtaining written informed consent for 
participation. Investigators will stress that participation in the study is completely voluntary and 
will not affect the care patients receive or result in any loss of benefits to which patients are 
otherwise entitled. 
The Investigator will explain to each potential participant the nature of the study, its purpose, 
the procedures involved, the expected duration, the potential risks and benefits involved, 


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potential compensation and or costs incurred by the patient and any discomfort this study may 
entail. This informed consent should be given by means of standard written statement, written in 
non-technical language. All patients will be required to sign a written informed consent prior to 
being registered on this study. No patient can enter the study before his/her informed consent 
has been obtained. Every effort will be made to answer questions raised by patients and their 
families or advocates regarding the protocol and alternative therapies prior to asking a patient to 
sign the consent form. 
The informed consent form is considered to be part of the protocol, and must be submitted by 
the Investigator with it for IRB approval. 
For non-English speaking patients, institutional translation services will be utilized. All 
procedures for consenting non-English speaking patients will be in accordance with NYU 
Langone Health PCC CTO guidelines and policies.  
For patients who cannot read. A witness, not related to the research study will be present. The 
consent will be read to the patient. The patient will also be allowed to ask any questions s/he 
may have. The Investigator will ask the patient questions to ensure s/he understands the study. 
If the Investigator determines the patient understands the study, the patient will mark an X 
where his/her name would go and the witness will sign the consent form.  
9.3.1.2. 
Documentation of Consent 
The PI or IRB approved sub-investigator will be responsible for documentation in the medical 
record that consent has been obtained from all participants. A signed copy of the consent form 
will be given to each participant. Original consent forms will be stored in the patient’s medical 
chart. 
9.3.2. 
Registration Procedures 
Each patient must sign and date an informed consent form before undergoing any study specific 
procedure unless a procedure is being performed as part of the patient’s standard of care. 
Enrollment in the study requires that all inclusion and exclusion criteria have been met. 
Enrollment occurs upon confirmation of registration from the NYULH PCC Clinical Trials 
Office. The following materials must be submitted to the CTO for patient registration: 
1. Complete signed and dated informed consent form 
2. Complete signed and dated eligibility checklist 
3. All supporting documentation verifying each eligibility criterion has been met 
Registration will occur within 48 hours of research coordinator receipt of all of the above 
documents. A written confirmation of enrollment including a unique study identification 
number assigned by the research coordinator will be disbursed to the study team upon 
registration. 
Once eligibility is verified, a unique patient study number will be issued within 24 hours of 
receiving all required registration material. The patient will not be identified by name. This is 
the point, at which, the patient is considered accrued on study.  


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9.3.3. 
Multi-Site Surveillance 
As the lead investigator in a multi-site study, the PI is responsible for organizing and conducting 
monthly teleconferences with all participating sites. The PI will also be responsible for 
including data from all of the participating sites within the overall study’s quarterly Data and 
Safety Monitoring report to the DSMC to include minutes from monthly PI teleconferences. 
Each participating site will be responsible for submitting the results and recommendations from 
the DSMC’s quarterly reviews to their IRB of record at the time of continuing review. 
Additionally, the NYU Langone Health PPC CTO, Quality Assurance Unit will provide a 
remote interim monitoring visit, beginning within the first 6-8 weeks of the first patient 
enrollment and every 6-8 weeks thereafter to ensure completeness, accuracy and consistency of 
the data. 
9.3.4. 
Patient Registrations at Additional Sites 
Enrollment at addition sites can begin once each site’s IRB has approved this protocol, a copy 
of each site’s IRB approval, collaborative institutional training initiative (CITI) training 
certificates, Medical Licenses and signed curricula vitae are provided to NYU Langone Health 
PCC CTO. Once, all required documents are provided to NYU Clinical Trials Office an 
activation notification will be sent to the PI and research coordinator of that site. Central 
registration for this study will take place at NYU Langone Health PCC Quality Assurance Unit 
(PCC-QAU@nyulangone.org). 
Each patient must sign and date an informed consent form before undergoing any study specific 
procedures unless a procedure is being performed as part of the patient’s standard of care. Once 
a patient has signed consent, each site must notify the NYU Langone Health PCC Quality 
Assurance Unit and forward a copy of the signed consent to NYU Langone Health PCC CTO 
within 24 hours. 
Enrollment in the study requires that all inclusion and exclusion criteria have been met. 
Enrollment occurs upon confirmation of registration from the NYU Langone Health PCC CTO. 
The following materials must be submitted to the Quality Assurance Unit at NYU Langone 
Health via email (PCC-QAU@nyulangone.org): 
1. Complete signed and dated informed consent form 
2. Complete signed and dated informed consent checklist 
3. Complete signed and dated eligibility checklist 
4. All supporting documentation verifying each criterion has been met. 
Registration will occur once the Senior Research Nurse for Quality Assurance conducts a 
central review of the submitted materials. Once eligibility is verified, a unique patient study 
number will be issued within 48 hours of receiving all required registration material. This 
number is unique to the participant and must be written on all data and correspondence for the 
participant. The NYU Langone Health PCC CTO will return a signed eligibility confirmation 
worksheet email with the patient’s unique study number. 
The patient will not be identified by name. This is the point, at which, the patient is considered 
accrued on study. Protocol treatment should begin within designated timeframe; issues that 


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would cause treatment delays should be discussed with the overall PI, Dr. Wise. All screen 
failures/ineligible patients, as well as patient’s who withdraw consent prior to initiation of 
protocol therapy must be submitted to the CTO in a manner analogous to the procedures noted 
above. Applicable source documentation will be required within the corresponding submissions. 
Patients must not start any protocol procedures prior to registration; each participating 
institution will order the study agent directly from the supplier.  
Each site is responsible for reporting all unexpected problems involving risks to participants or others to 
NYU Langone PCC Clinical Trials Office and to their IRB as per site institutional policy. Please email 
all SAEs to NYUPCCsafetyreports@nyulangone.org, Dr. Wise, and the NYU Langone Health CTO 
regulatory specialist.  
9.4. 
Patient Confidentiality 
In order to maintain patient privacy, all eCRFs, study drug accountability records, study reports 
and communications will identify the patient by initials and the assigned patient number. The 
Investigator will grant monitor(s) and auditor(s) from the Sponsor or its designee and regulatory 
authority(ies) access to the patient’s original medical records for verification of data gathered on 
the eCRFs and to audit the data collection process. The patient’s confidentiality will be 
maintained and will not be made publicly available to the extent permitted by the applicable 
laws and regulations. 
9.5. 
Protocol Compliance 
The Investigator will conduct the study in compliance with the protocol provided by the 
Sponsor, and given approval/favorable opinion by the IRB and the appropriate regulatory 
authority(ies). Modifications to the protocol should not be made without agreement of both the 
Investigator and the Sponsor. Changes to the protocol will require written IRB 
approval/favorable opinion prior to implementation, except when the modification is needed to 
eliminate an immediate hazard(s) to patients. The IRB may provide, if applicable regulatory 
authority(ies) permit, expedited review and approval/favorable opinion for minor change(s) in 
ongoing studies that have the approval /favorable opinion of the IRB. The Sponsor will submit 
all protocol modifications to the regulatory authority(ies) in accordance with the governing 
regulations.  
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
patients, the Investigator will contact the Sponsor, if circumstances permit, to discuss the 
planned course of action. Any departures from the protocol must be fully documented in the 
eCRF and source documentation.  
9.6. 
Direct Access to Source Data 
The NYU CTO will serve as the Clinical Research Organization for this study. TrialMaster, an 
electronic database capture system will be created to record the data for this study. Research 
coordinators will input clinical study data into the database. This database is password protected 
and only the PI, assigned study team members, and CTO personnel will have access to the 
database. DataCore, a core resource of the institution, will provide the primary data collection 
instrument for the study. All data requested in the system must be reported. All missing data 


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must be explained. The quality assurance specialists will monitor this study every 4-6 weeks for 
data entry accuracy. All data will be collected and entered into the EDC system by study site 
personnel from participating institutions.  
Monitoring and auditing procedures developed by the Sponsor or designee will be followed, in 
order to comply with GCP guidelines. 
The study will be monitored by the Sponsor or its designee. Monitoring will be done by 
personal visits from a representative of the Sponsor (site monitor) and will include on-site 
review of the eCRFs for completeness and clarity, cross-checking with source documents, and 
clarification of administrative matters will be performed. The review of medical records will be 
performed in a manner to ensure that patient confidentiality is maintained. 
The site monitor will ensure that the investigation is conducted according to protocol design and 
regulatory requirements by frequent communications (letter, telephone, and fax). 
All unused study drug and other study materials are to be returned to the Sponsor after the 
clinical phase of the study has been completed or, if authorized, disposed of at the study site and 
documented (see Section 5.7). 
Regulatory authorities, the IEC/IRB, and/or the clinical quality assurance group of the Sponsor 
or designee may request access to all source documents, eCRFs, and other study documentation 
for on-site audit or inspection. Direct access to these documents must be guaranteed by the 
Investigator, who must provide support at all times for these activities. 
9.7. 
Case Report Form Completion 
The Sponsor or its designee will provide the study sites with an eCRF that will be completed for 
each study patient. 
It is the Investigator’s responsibility to ensure the accuracy, completeness, and timeliness of the 
data reported in the patient’s eCRF. Source documentation supporting the eCRF data should 
indicate the patient’s participation in the study and should document the dates and details of 
study procedures, adverse events, and patient status. 
The Investigator, or designated representative, should complete the eCRF pages as soon as 
possible after information is collected, preferably on the same day that a study patient is seen 
for an examination, treatment, or any other study procedure. Any outstanding entries must be 
completed immediately after the final examination. An explanation should be given for all 
missing data. 
The Investigator must sign and date the Investigator’s Statement at the end of the eCRF to 
endorse the recorded data. 
9.8. 
Record Retention 
The Investigator will maintain all study records according to ICH-GCP and applicable 
regulatory requirement(s). If the Investigator withdraws from the responsibility of keeping the 
study records, custody must be transferred to a person willing to accept the responsibility. The 
Sponsor must be notified in writing if a custodial change occurs. 


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9.9. 
Liability and Insurance 
The Sponsor has subscribed to an insurance policy covering, in its terms and provisions, its 
legal liability for injuries caused to participating persons and arising out of this research 
performed strictly in accordance with the scientific protocol as well as with applicable law and 
professional standards. 
9.10. 
Publication of Study Findings and Use of Information 
All information regarding DKN-01 supplied by the Sponsor to the Investigator is privileged and 
confidential information. The Investigator agrees to use this information to accomplish the 
study and will not use it for other purposes without consent from the Sponsor. The Investigator 
is obligated to provide the Sponsor with complete data obtained during the study. The 
information obtained from the clinical study will be used towards the development of DKN-01 
and may be disclosed to regulatory authority(ies), other Investigators, corporate partners, or 
consultants as required. 
It is anticipated that the results of this study will be presented at scientific meetings and/or 
published in a peer reviewed scientific or medical journal. A Publications Committee, 
comprised of investigators participating in the study and representatives from the Sponsor, as 
appropriate, will be formed to oversee the publication of the study results, which will reflect the 
experience of all participating study centers. Subsequently, individual investigators may publish 
results from the study in compliance with their agreement with the Sponsor. A pre-publication 
manuscript is to be provided to the Sponsor at least 30 days prior to the submission of the 
manuscript to a publisher. Similarly, the Sponsor will provide any company-prepared 
manuscript to the investigators for review at least 30 days prior to submission to a publisher. 
9.11. 
Research Use of Stored Human Samples, Specimens, or Data 
• Intended Use: Samples and data collected under this protocol will be stored indefinitely 
for future cancer research. No germline genetic testing will be performed. 
• Storage: Access to stored samples will be limited using password-protected computers. 
Only investigators will have access to the samples and data. 
- Disposition at the completion of the study: All stored samples will be archived 
through the NYU Center for Biospecimen Research and Development for indefinite 
storage. Study participants who request destruction of samples will be notified of 
compliance with such request and all supporting details will be maintained for 
tracking. 
9.12. 
Future Use of Stored Specimens 
Data collected for this study will be analyzed and stored at the NYU CTO Coordinating Center. 
After the study is completed, the de-identified, archived data will be transmitted to and stored at 
the Perlmutter Cancer Center under the supervision of David Wise for use by other researchers 
including those outside of the study. Permission to transmit data to the Perlmutter Cancer 
Center will be included in the informed consent. 
With the participant’s approval and as approved by local IRBs, de-identified biological samples 
will be stored indefinitely at the NYU Center for Biospecimen Research and Development 


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(CBRD) with the same goal as the sharing of data. The storage of these samples for future 
research will be optional for participants.  For participants who consent to the storage of their 
samples for future research, these samples could be used for research into the causes of cancer, 
its complications and other conditions for which individuals with cancer are at increased risk, 
and to improve treatment. The data repository will also be provided with a code-link that will 
allow linking the biological specimens with the phenotypic data from each participant, 
maintaining the masking of the identity of the participant. 
During the conduct of the study, an individual participant can choose to withdraw consent to 
have biological specimens stored for future research. However, withdrawal of consent with 
regard to bio-sample storage will not be possible after the study is completed. 
When the study is completed, access to study data and/or samples will be provided through the 
Perlmutter Cancer Center. 
9.13. 
Conflict of Interest Policy 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this study will be 
disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be 
required to have such conflicts managed in a way that is appropriate to their participation in the 
study. The study leadership in conjunction with the relevant NIH Institute or Center has 
established policies and procedures for all study group members to disclose all conflicts of 
interest and will establish a mechanism for the management of all reported dualities of interest.  
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the 
conflict reviewed by the NYU Langone Conflict of Interest Management Unit with a 
Committee-sanctioned conflict management plan that has been reviewed and approved by the 
Sponsor prior to participation in this study. All NYULH investigators will follow the applicable 
conflict of interest policies. 
 


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12. 
APPENDICES 
 
12.1. 
Schedule of Assessments 
The schedule of study assessments is presented in Table 5. 
Table 5 
Schedule of Assessments 
Activity 
Screening 
All Cycles 
EOT (± 
14 days)  
Clinical/ Safety 
Follow-up 
Long-term 
Follow-up 
-28 days of 
C1D1 
-14 days of 
C1D1 
Day 1 (+/- 3 
days for Cycle 
≥2) 
Day 15 (+/-3 
days) 
Study team procedures 
  
  
  
  
  
 
 
1Informed Consent 
X 
 
 
2Diagnosis and Staging 
X 
 
 
 
 
 
 
3Medical History and Height 
X 
 
 
4Physical Examination 
X 
X 
X 
X 
X 
 
5Vitals signs and ECOG PS 
X 
X 
X 
X 
X 
 
                                                     
1 
Consent. Must be obtained prior to undergoing any study-specific procedure and maybe obtained >28 days prior to enrollment. .  
2 
Diagnosis and staging to include pathology report and TNM staging. 
3 
Medical history. Includes oncology history, information on prior regimens (duration of administration, best overall response [BOR] observed, and recurrence date), surgery, 
and radiation therapy. Includes history of medically significant diseases or injuries (active or resolved) and concomitant illnesses that are not considered to be the disease under 
study. 
4 
A complete physical examination will be required during Screening. Abbreviated physical exams are allowed starting C1D1 and at the subsequent designated time points. 
5 
Vital signs. Record blood pressure, pulse, heart rate, and temperature; weight will be measured Day1 of each cycle. On days when both docetaxel and DKN-01 are infused, 
one set of vital signs is to be recorded pre-dose. Repeat vital signs, between completion of DKN-01 and administration of docetaxel, are not required. 


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Activity 
Screening 
All Cycles 
EOT (± 
14 days)  
Clinical/ Safety 
Follow-up 
Long-term 
Follow-up 
-28 days of 
C1D1 
-14 days of 
C1D1 
Day 1 (+/- 3 
days for Cycle 
≥2) 
Day 15 (+/-3 
days) 
AE and concomitant medications 
X 
X 
X 
X6 
 
Review of inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
 
Laboratory and Safety 
Assessments 
 
 
 
 
 
 
Electrocardiogram 
X 
 
 
7Chemistries 
 
X 
X 
X 
X 
X 
 
8Hematology 
X 
X 
X 
X 
X 
 
9Serum PSA, CgA, CEA 
 
X 
X 
 
X 
X 
X 
Coagulation Studies (PT, PTT, 
and INR) 
X 
 
 
 
 
 
 
Serum 25-hydroxyvitamin D 
X 
 
 
 
 
 
 
Serum Testosterone 
 
X 
 
 
 
 
 
                                                     
6 
Follow-up visits should occur at Days 30, 60, and 100 (±10 days) after the last dose of study drug or should coincide with the date of discontinuation (±10 days) if date of 
discontinuation is greater than 30 days after the last dose of study drug to monitor for AEs. If the patient starts a new treatment than only pre-existing treatment-related AEs 
that started prior the subject enrolling on the new treatment will need to be followed. 
7 
Chemistries includes a basic metabolic panel (sodium, potassium, chloride, bicarbonate, calcium, creatinine, blood urea nitrogen, and glucose [random]), liver function tests 
(AST, ALT, total bilirubin, alkaline phosphatase, total protein, and albumin), direct bilirubin, lactate dehydrogenase (LDH), creatine kinase (CK), uric acid, cholesterol, 
phosphorus, and carbon dioxide. 
8  
Hematology includes hemoglobin, hematocrit, erythrocyte count (RBC), mean cell volume (MCV), mean cell hemoglobin concentration (MVHC), platelets, leukocytes 
(WBC) and differential [absolute counts of] neutrophils (segmented and banded), lymphocytes, monocytes, eosinophils, and basophils, Neutrophil/lymphocyte ratio (a 
calculated ratio). 
9        (PSA, CgA, and CEA) testing will continue every 3 months (every 12 weeks) until progressive disease (PD), withdrawal from the study, or initiation of new treatment. 


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Activity 
Screening 
All Cycles 
EOT (± 
14 days)  
Clinical/ Safety 
Follow-up 
Long-term 
Follow-up 
-28 days of 
C1D1 
-14 days of 
C1D1 
Day 1 (+/- 3 
days for Cycle 
≥2) 
Day 15 (+/-3 
days) 
10Hepatitis B and C Virus Tests 
X 
 
 
 
 
 
 
11Serious adverse event and 
adverse event review
 
 
X 
X 
X 
X 
X 
 
Disease Assessments 
 
 
 
 
 
 
 
12Bone Scan and CT Chest, 
Abdomen, Pelvis 
X 
 
 
 
X 
 
X
13 
Specimen Collection 
 
 
 
 
 
 
 
14Pre-Treatment Tumor 
Specimen 
X 
 
 
 
 
 
 
15On-Treatment Tumor Biopsy 
 
 
X 
 
 
 
 
                                                     
10 
Includes HBV surface antigen and anti-HCV antibody tests. If anti-HCV antibody test is positive, HCV RNA test must be performed. 
11 
Patients continuing to experience toxicity following discontinuation of investigational products will continue to be followed at least every 4 weeks until resolution or 
determination, in the clinical judgment of the Investigator, that no further improvement is expected. Only SAEs that begin at C1D1 need to be reported. 
12 
Every 9 weeks (±7 days) after C1D1 for the first 27 weeks. Every 12 weeks thereafter until progression of disease. Tumor assessment should be performed at the time of 
treatment discontinuation if the reason was other than radiologically confirmed disease progression and it has been ≥8 weeks since the last assessment (see Section 6.2). 
13 
Participants who discontinue study with ongoing SD, PR, or CR at the EOT visit will enter the Response Follow-up period. These participants will continue to have tumor 
radiological and clinical tumor assessments every 12 weeks during the Response Follow-up period or until disease progression, withdrawal of study, or initiation of new 
treatment. Radiological tumor assessments for participants who have ongoing clinical benefit may continue to be collected after participants complete the survival phase of the 
study (see Section 6.3 for further detail). 
14 
In all instances, if a block cannot be provided due to documented local/institutional regulations, at least 15 unstained slides are acceptable.  
15 
An on-treatment tumor biopsy is encouraged. For patients on the combination arm, this biopsy can be obtained from C2D15 through C3D1 or C3D15 through C4D1 at the 
discretion of the treating investigator and after consideration of the risk of neutropenia related to docetaxel. Patients on monotherapy arms can have their biopsy at any point 
in C2 or C3 at the discretion of the treating investigator. Tumor tissue is requested for those patients who undergo a biopsy or tumor resection as part of routine clinical care at 
any time during the treatment period. In all instances, if a block cannot be provided due to documented local/institutional regulations, at least 15 unstained slides are required. 


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Activity 
Screening 
All Cycles 
EOT (± 
14 days)  
Clinical/ Safety 
Follow-up 
Long-term 
Follow-up 
-28 days of 
C1D1 
-14 days of 
C1D1 
Day 1 (+/- 3 
days for Cycle 
≥2) 
Day 15 (+/-3 
days) 
Tumor Biopsy at Progression 
 
 
 
 
X 
 
 
16Blood for DKN-01 PK/ADA 
 
 
X 
 
 
 
 
17Whole blood for Immune 
Biomarkers and ctDNA  
 
X 
X 
X 
X 
 
 
18Whole blood for DKK1 testing  
X 
 
X 
 
X 
 
 
19Whole Blood for CTC 
enumeration 
 
 
X 
 
 
 
 
Treatment Exposure 
 
 
 
 
 
 
 
20Docetaxel administration 
 
 
X 
 
 
 
 
21DKN-01 administration 
 
 
X 
X 
 
 
 
                                                     
16 
Collect blood (serum) pre-dose on Day 1, and then within 1 hour post-infusion at the end of infusion on Day 1. For each pre-dose sample collect enough for ADA analysis as 
well; ADA should only be collected pre-dose. 
17 
Required pre-dose whole blood will be collected for immunoprofiling and ctDNA analysis at the prescribed time points (required). Serial blood samples will be collected to 
support biomarker research (required). Serum and plasma will be collected from a whole blood sample and peripheral blood mononuclear cells will be isolated.  
18 
Required pre-dose whole blood for DKK1 testing will be obtained in the Screening period, however DKK1 level will not affect eligibility. 
19 
Blood for CTC enumeration should be collected at Cycle 1 Day 1 and at Week 13 (C5D1 for Cohorts 1A/1B and C4D1 for Cohorts 2A/2B).  Blood should be collected at the 
indicated time points in CellSave tubes (10ml) for analysis with the CellSearch assay. 
20 
In Dose Escalation Cohort 1A and expansion Cohort 1B (combination docetaxel + DKN-01 cohorts), cycle length = 21 days. Treatment windows of +/- 3 days are allowable 
for day 1 and day 15 starting with cycle 2, however at least 7 days must elapse between Day 15 and the Day 1 treatment of the subsequent cycle. 
21 
In dose escalation Cohort 2A and expansion Cohort 2B (DKN-01 monotherapy cohorts), the cycle length = 28 days. Treatment windows of +/- 3 days are allowable for day 1 
and day 15 starting with cycle 2, however at least 7 days must elapse between Day 15 and the Day 1 treatment of the subsequent cycle. 


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12.2. Response Evaluation Criteria in Solid Tumors (RECIST) Quick Reference Guide 
Response and progression will be evaluated in this study using the international criteria 
proposed in:  Eisenhauer EA, Therasse P, Bogaerts J, et al. 2009. New response evaluation 
criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 45:228-247. 
Eligibility 
Only patients with measurable disease at baseline should be included in protocols where ORR is 
the primary endpoint. Measurable disease is defined as the presence of at least one measurable 
lesion. 
Methods of Assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. 
• CT is the best currently available and reproducible method to measure lesions selected 
for response assessment. MRI is also acceptable in certain situations (eg, for body scans 
but not for lung). 
• Lesions on a chest X-ray may be considered measurable lesions if they are clearly 
defined and surrounded by aerated lung. However, CT is preferable. 
• Clinical lesions will only be considered measurable when they are superficial and 
≥10 mm in diameter as assessed using calipers. For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, 
is recommended. 
• Ultrasound should not be used to measure tumor lesions. 
• Tumor markers alone cannot be used to assess response. If markers are initially above 
the upper normal limit, they must normalize for a patient to be considered in complete 
response. 
• Cytology and histology can be used in rare cases (eg, for evaluation of residual masses 
to differentiate between Partial Response [PR] and Complete Response [CR] or 
evaluation of new or enlarging effusions to differentiate between Progressive Disease 
[PD] and Response/Stable Disease [SD]).  
Use of endoscopy and laparoscopy is not advised. However, they can be used to confirm 
complete pathological response. 
Baseline Disease Assessment 
All baseline evaluations should be performed as closely as possible to the beginning of treatment 
and never more than 4 weeks before the beginning of the treatment. 
Measurable Lesions - Must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size of: 


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• 10 mm by CT scan (CT scan slice thickness no greater than 5 mm; when CT scans have 
slice thickness >5 mm, the minimum size should be twice the slice thickness). 
• 10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non- measurable). 
• 20 mm by chest X-ray 
• Malignant lymph nodes 
- 
To be considered pathologically enlarged and measurable, a lymph node must be ≥15 
mm in short axis when assessed by CT scan (CT scan slice thickness is recommended 
to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be 
measured and followed. 
- 
Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue 
components that can be evaluated by cross-sectional imaging techniques such as CT 
or MRI can be considered measurable if the soft tissue component meets the definition 
of measurability described above. 
- 
‘Cystic lesions’ thought to represent cystic metastases can be considered measurable 
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. 
Non-Measurable Lesions - Non-measurable lesions are all other lesions, including small 
lesions (longest diameter <10 mm or pathological lymph nodes with 10 to <15 mm short axis), 
as well as truly non-measurable lesions. Lesions considered truly non-measurable include: 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques. 
Blastic bone lesions are non-measurable. 
Lesions with prior local treatment, such as those situated in a previously irradiated area or in 
an area subjected to other loco-regional therapy, are usually not considered measurable unless 
there has been demonstrated progression in the lesion. Study protocols should detail the 
conditions under which such lesions would be considered measurable. 
Target Lesions 
- 
All measurable lesions up to a maximum of two lesions per organ and five 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) and be representative of all involved organs, as well as their suitability for 
reproducible repeated measurements. 
- 
All measurements should be recorded in metric notation using calipers if clinically 
assessed. 


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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, which will be used as 
reference to further characterize any objective tumor regression in the measurable dimension of 
the disease. If lymph nodes are to be included in the sum, only the short axis will contribute. 
Non-Target Lesions 
All lesions (or sites of disease) not identified as target lesions, including pathological lymph 
nodes and all non-measurable lesions, should be identified as non-target lesions and be recorded 
at baseline. Measurements of these lesions are not required and they should be followed as 
‘present’, ‘absent’ or in rare cases, ‘unequivocal progression’. 
Response Criteria 
Evaluation of Target Lesions 
Complete Response (CR) 
Disappearance of all target lesions. Any pathological lymph nodes (whether 
target or non-target) must have reduction in short axis to <10 mm.  
Partial Response (PR) 
At least a 30% decrease in the sum of the diameters of target lesions, taking as 
reference the baseline sum of diameters. 
Progressive Disease (PD) 
At least a 20% increase in the sum of the LD of target lesions, taking as reference 
the smallest sum on study (this may include the baseline sum). The sum must 
also demonstrate an absolute increase of at least 5 mm. 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD. 
Special Notes on the Assessment of Target Lesions 
• Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded even if the nodes regress to below 10 mm on study. When lymph 
nodes are included as target lesions, the ‘sum’ of lesions may not be zero even if 
complete response criteria are met since a normal lymph node is defined as having a 
short axis of <10 mm. 
• Target lesions that become ‘too small to measure’. While on study, all lesions (nodal and 
non-nodal) recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small. However, sometimes lesions or lymph 
nodes become so faint on a CT scan that the radiologist may not feel comfortable 
assigning an exact measure and may report them as being ‘too small to measure’, in 
which case a default value of 5 mm should be assigned. 
• Lesions that split or coalesce on treatment. When non-nodal lesions ‘fragment’, the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum. Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the ‘coalesced lesion’. 


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Evaluation of Non-Target Lesions 
Complete Response 
(CR) 
• 
Disappearance of all non-target lesions and normalization of tumor marker 
levels. 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) or/and maintenance of 
tumor marker level above the normal limits 
Progressive Disease 
(PD) 
• 
Unequivocal progression of existing non-target lesions. 
• 
When patient has measurable disease. To achieve ‘unequivocal progression’ 
on the basis of the non-target disease, there must be an overall level of 
substantial worsening in non-target disease such that, even in 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 
• 
When patient has only non-measurable disease. There is no measurable 
disease assessment to factor into the interpretation of an increase in non-
measurable disease burden. Because worsening in non-target disease cannot 
be easily quantified, a useful test that can be applied is to consider if the 
increase in overall disease burden based on change in non-measurable 
disease is comparable in magnitude to the increase that would be required 
to declare PD for measurable disease. Examples include an increase in a 
pleural effusion from ‘trace’ to ‘large’ or an increase in lymphangitic 
disease from localized to widespread progression status. 
New Lesions 
The appearance of new malignant lesions denotes disease progression: 
• The finding of a new lesion should be unequivocal (ie, not attributable to differences in 
scanning technique, change in imaging modality or findings thought to represent 
something other than tumor, especially when the patient’s baseline lesions show partial 
or complete response). 
• If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans 
confirm there is definitely a new lesion, then progression should be declared using the 
date of the initial scan. 
• A lesion identified on a follow-up study in an anatomical location that was not scanned 
at baseline is considered a new lesion and disease progression. 
It is sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT in 
assessment of progression (particularly possible ‘new’ disease). New lesions on the basis of FDG-
PET imaging can be identified according to the following algorithm: 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is PD based on a new 
lesion. 


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No FDG-PET at baseline and a positive FDG-PET at follow-up: 
• If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by 
CT, this is PD. 
• If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan). 
• If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT 
that is not progressing on the basis of the anatomic images, this is not PD. 
Time Point Response 
A summary of the overall response status calculation at each time point for patients who have 
measurable disease at baseline is presented in Table 1 below. 
Table 1 
Time Point Response: Patients with Target (+/–non-target) Disease 
Target lesions 
Non-Target lesions 
New Lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
NE 
No 
PR 
PR 
Non-PD/or not all evaluated 
No 
SD 
SD 
Non-PD/or not all evaluated 
Yes or No 
PD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; PR – partial response; SD – stable disease; PD = progressive disease; NE – inevaluable 
When patients have non-measurable (therefore non-target) disease only, Table 2 is to be used. 


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Table 2 
Time Point Response: Patients with Non-target Disease 
Non-Target lesions 
New Lesions 
Overall response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD1 
Not all evaluated 
No 
NE 
PD 
Yes or No 
PD 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR = complete response; PR – partial response; SD – stable disease; PD = progressive disease; NE – inevaluable.  
1 Non-CR / non-PD is preferred over ‘Stable Disease’ for non-target disease since SD is increasingly used as an endpoint for 
assessment of efficacy in some trials. To assign this category when no lesions can be measured is not advised. 
Confirmation 
In non-randomized trials where response is the primary endpoint, confirmation of PR and CR is 
required to ensure responses identified are not the result of measurement error. This will also 
permit appropriate interpretation of results in the context of historical data where response has 
traditionally required confirmation in such trials.  
However, in all other circumstances, (ie, in randomized Phase 2 or 3 trials or studies where 
stable disease or progression are the primary endpoints), confirmation of response is not 
required since it will not add value to the interpretation of trial results. However, elimination of 
the requirement for response confirmation may increase the importance of central review to 
protect against bias, in particular in studies, which are not blinded.  
In the case of SD, measurements must have met the SD criteria at least once after study entry at a 
minimum interval (in general not less than 6–8 weeks) that is defined in the study protocol. 
Missing Assessments and Inevaluable Designation 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable (NE) at that time point. 
If only a subset of lesion measurements are made at an assessment, usually the case is also 
considered NE at that time point, unless a convincing argument can be made that the 
contribution of the individual missing lesion(s) would not change the assigned time point 
response. This would most likely happen in the case of PD. 
Criteria for Continuing Treatment after Evidence of Progressive Disease by RECIST 1.1 
Radiologic tumor flare, which is not defined in RECIST 1.1, has been observed in patients 
undergoing treatment (Hales et al., 2010). Thus, patients who have evidence of clinical benefit 
but with PD as defined by RECIST 1.1 may be considered for continued study treatment at the 
Investigator’s discretion (after discussion with the Medical Monitor) if they meet the following 
criteria: 


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• Tumor shrinkage (at least 30% decrease in diameter from baseline) of one or more 
evaluable lesions 
Improvement in one or more symptoms or signs attributable to the underlying cancer as 
assessed by the Investigator. 
 


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12.3. 
Description of iRECIST Process for Assessment of Disease 
Progression 
Assessment at Screening and Prior to RECIST 1.1 Progression 
Until radiographic disease progression based on RECIST 1.1, there is no distinct iRECIST 
assessment. 
Assessment and Decision at RECIST 1.1 Progression 
For participants who show evidence of radiological PD by RECIST 1.1 as determined by the 
Investigator; the Investigator will decide whether to continue a participant on study treatment 
until repeat imaging is obtained (using iRECIST for participant management (see Table 4 and 
Figure 2). This decision by the Investigator should be based on the participant’s overall clinical 
condition. 
Clinical stability is defined as the following:  
• Absence of symptoms and signs indicating clinically significant progression of disease 
• No decline in ECOG performance status  
• No requirements for intensified management, including increased analgesia, radiation, or 
other palliative care 
Any participant deemed clinically unstable should be discontinued from study treatment at site-
assessed first radiologic evidence of PD, and is not required to have repeat tumor imaging for 
confirmation of PD by iRECIST. 
If the Investigator decides to continue treatment, the participant may continue to receive study 
treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm PD by 
iRECIST, per Investigator assessment. Images should continue to be sent in to the central 
imaging vendor for potential retrospective BICR as necessary. 
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including: 
• Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% and 
≥5 mm from nadir 
- 
Note: the iRECIST publication uses the terminology “sum of measurements”, but 
“sum of diameters” will be used in this protocol, consistent with the original 
RECIST 1.1 terminology. 
• Unequivocal progression of non-target lesion(s) identified at baseline 
• Development of new lesion(s) 
iRECIST defines new response categories, including iUPD (unconfirmed progressive disease) 
and iCPD (confirmed PD). For purposes of iRECIST assessment, the first visit showing 
progression according to RECIST 1.1 will be assigned a visit (overall) response of iUPD, 
regardless of which factors caused the progression. 


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At this visit, target and non-target lesions identified at baseline by RECIST 1.1 will be assessed 
as usual. 
New lesions will be classified as measurable or non-measurable, using the same size thresholds 
and rules as for baseline lesion assessment in RECIST 1.1. From measurable new lesions, up to 
5 lesions total (up to 2 per organ), may be selected as New Lesions – Target. The sum of 
diameters of these lesions will be calculated, and kept distinct from the sum of diameters for 
target lesions at baseline. All other new lesions will be followed qualitatively as New Lesions – 
Non-target. 
Assessment at the Confirmatory Imaging 
On the confirmatory imaging, the participant will be classified as progression confirmed (with 
an overall response of iCPD), or as showing persistent unconfirmed progression (with an overall 
response of iUPD), or as showing disease stability or response (iSD/iPR/iCR). 
Confirmation of Progression 
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs: 
• Any of the factors that were the basis for the initial iUPD show worsening 
- 
For target lesions, worsening is a further increase in the sum of diameters of ≥5 mm, 
compared to any prior iUPD time point 
- 
For non-target lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD time point; this does not have to meet the “unequivocal” 
standard of RECIST 1.1 
- 
For new lesions, worsening is any of these: 
 An increase in the new lesion sum of diameters by ≥5 mm from a prior iUPD 
time point  
 Visible growth of new non-target lesions  
 The appearance of additional new lesions 
• Any new factor appears that would have triggered PD by RECIST 1.1 
Persistent iUPD 
Progression is considered not confirmed, and the overall response remains iUPD, if: 
• None of the progression-confirming factors identified above occurs AND 
• The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1) 
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging on 
which iUPD is seen. This may correspond to the next visit in the original visit schedule. The 
assessment of the subsequent confirmation imaging proceeds in an identical manner, with 
possible outcomes of iCPD, iUPD, and iSD/iPR/iCR. 


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Resolution of iUPD 
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if: 
• None of the progression-confirming factors identified above occurs, AND 
• The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold.  
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve. 
In this case, the initial iUPD is considered to be pseudo-progression, and the level of suspicion 
for progression is “reset”. This means that the next visit that shows radiographic progression, 
whenever it occurs, is again classified as iUPD by iRECIST, and the confirmation process is 
repeated before a response of iCPD can be assigned. 
Management Following the Confirmatory Imaging 
If repeat imaging does not confirm PD per iRECIST, as assessed by the Investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the regular 
imaging schedule. If PD is confirmed, participants will be discontinued from study treatment. 
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, but the 
participant is achieving a clinically meaningful benefit, an exception to continue study treatment 
may be considered following consultation with the Sponsor. In this case, if study treatment is 
continued, tumor imaging should continue to be performed following the intervals as outlined in 
Section 2 and submitted to the central imaging vendor. 
Detection of Progression at Visits after Pseudo-progression Resolves 
After resolution of pseudo-progression (ie, achievement of iSD/iPR/iCR), iUPD is indicated by 
any of the following events: 
• Target lesions 
- 
Sum of diameters reaches the PD threshold (≥20% and ≥5 mm increase from nadir) 
either for the first time, or after resolution of previous pseudo-progression. The nadir 
is always the smallest sum of diameters seen during the entire trial, either before or 
after an instance of pseudo-progression. 
• Non-target lesions 
- 
If non-target lesions have never shown unequivocal progression, their doing so for 
the first time results in iUPD. 
- 
If non-target lesions have shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth of 
non-target lesions, taken as a whole. 
• New lesions 
- 
New lesions appear for the first time 


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- 
Additional new lesions appear 
- 
Previously identified new target lesions show an increase of ≥5 mm in the new lesion 
sum of diameters, from the nadir value of that sum 
- 
Previously identified non-target lesions show any significant growth 
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated. 
Progression must be confirmed before iCPD can occur. 
The decision process is identical to the iUPD confirmation process for the initial PD, with one 
exception:  if new lesions occurred at a prior instance of iUPD, and at the confirmatory imaging 
the burden of new lesions has increased from its smallest value (for new target lesions, the sum 
of diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve to iSD or iPR. It will 
remain iUPD until either a decrease in the new lesion burden allows resolution to iSD or iPR, or 
until a confirmatory factor causes iCPD. 
Additional details about iRECIST are provided in the iRECIST publication (Seymour et al, 
2017). 
 


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12.4. 
NCI-CTCAE v 5 Infusion-related Reactions 
Adverse 
Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Infusion-
related 
reaction 
Mild transient 
reaction; infusion 
interruption not 
indicated; 
intervention not 
indicated 
Therapy or infusion 
interruption indicated 
but responds promptly 
to symptomatic 
treatment (eg, 
antihistamines, 
NSAIDS, narcotics, 
I.V. fluids); 
prophylactic 
medications indicated 
for ≤ 24 hrs 
Prolonged (eg, not 
rapidly responsive to 
symptomatic 
medication and/or brief 
interruption of 
infusion); recurrence of 
symptoms following 
initial improvement; 
hospitalization 
indicated for clinical 
sequelae 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Definition: A disorder characterized by an adverse reaction to the infusion of pharmacological or biological substances. 
Allergic 
reaction 
Systemic 
intervention not 
indicated 
Oral intervention 
indicated 
 
Bronchospasm; 
hospitalization 
indicated for clinical 
sequelae. Intravenous 
intervention indicated 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Definition: A disorder characterized by an adverse local or general response from exposure to an allergen. 
Anaphylaxis 
- 
- 
Symptomatic 
bronchospasm, with or 
without urticaria; 
parenteral intervention 
indicated; allergy-
related 
edema/angioedema; 
hypotension 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Definition: A disorder characterized by an acute inflammatory reaction resulting from the release of histamine and histamine-
like substances from mast cells, causing a hypersensitivity immune response. Clinically, it presents with breathing difficulty, 
dizziness, hypotension, cyanosis, and loss of consciousness and may lead to death. 
Cytokine 
release 
syndrome 
Fever with or 
without 
constitutional 
symptoms 
Hypotension 
responding to fluids; 
hypoxia responding to 
<40% Oxygen 
Hypotension managed 
with one pressor; 
hypoxia requiring 
>40% O2 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Definition: A disorder characterized by fever, tachypnea, headache, tachycardia, hypotension, rash, and/or hypoxia caused by 
the release of cytokines.  
 
 


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12.5. 
Management of DKN-01 Infusion-related Reactions 
Grade  
Management 
Grade 1 
• 
Slow the infusion rate by 50%. 
• 
Monitor the patient for worsening of condition. 
• 
For subsequent infusions, premedicate with diphenhydramine hydrochloride 50 mg IV (or 
equivalent); additional premedication may be administered at the Investigator’s discretion. 
Grade 2 
• 
Stop the infusion. 
• 
Administer diphenhydramine hydrochloride 50 mg IV (or equivalent), acetaminophen 
650 mg orally for fever, and oxygen.  
• 
Resume the infusion at 50% of the prior rate once the infusion reaction has resolved or 
decreased to Grade 1. 
• 
Monitor for worsening of condition. 
• 
For subsequent infusions, premedicate with diphenhydramine hydrochloride 50 mg IV (or 
equivalent); additional premedication may be administered at the Investigator’s discretion. 
• 
For a second Grade 1 or 2 infusion reaction, administer dexamethasone 10 mg IV 
(or equivalent); then, for subsequent infusions, premedicate with diphenhydramine 
hydrochloride 50 mg IV (or equivalent), acetaminophen 650 mg orally, and dexamethasone 
10 mg IV (or equivalent). 
Grade 3 
• 
Stop the infusion and disconnect the infusion tubing from the patient. 
• 
Administer diphenhydramine hydrochloride 50 mg IV (or equivalent), dexamethasone 10 mg 
IV (or equivalent), bronchodilators for bronchospasm, and other medications/treatment as 
medically indicated. 
• 
Patients who have a Grade 3 infusion reaction with premedication will not receive further 
DKN-01 treatment, but will continue to be followed on the protocol. 
Grade 4 
• 
Stop the infusion and disconnect the infusion tubing from the patient. 
• 
Administer diphenhydramine hydrochloride 50 mg IV (or equivalent), dexamethasone 10 mg 
IV (or equivalent), and other medications/treatment as medically indicated. 
• 
Give epinephrine or bronchodilators as indicated. 
• 
Hospital admission for observation may be indicated. 
• 
Patients who have a Grade 4 infusion reaction with or without premedication will not receive 
further DKN-01 treatment, but will continue to be followed on the protocol. 
 
 


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12.6. Declaration of Helsinki 
World Medical Association Declaration of Helsinki: 
Recommendations Guiding Medical Doctors in Biomedical Research Involving Human Subjects 
Adopted by the 18th World Medical Association (WMA) General Assembly, Helsinki, Finland, 
June 1964 and amended by the 29th WMA General Assembly, Tokyo, Japan, October 1975, 35th 
WMA General Assembly, Venice, Italy, October 1983, and the 41st WMA General Assembly, 
Hong Kong, September 1989, the 48th WMA General Assembly, Somerset West, Republic of 
South Africa, October 1996; 52nd WMA General Assembly, Edinburgh, Scotland, October 2000; 
53rd WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 added); 
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added); and 
59th WMA General Assembly, Seoul, October 2008. 
A. 
INTRODUCTION  
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including 
research 
on 
identifiable 
human 
material 
and 
data.  
The Declaration is intended to be read as a whole and each of its constituent paragraphs 
should not be applied without consideration of all other relevant paragraphs.  
2. Although the Declaration is addressed primarily to physicians, the WMA encourages other 
participants in medical research involving human subjects to adopt these principles.  
3. It is the duty of the physician to promote and safeguard the health of patients, including 
those who are involved in medical research. The physician's knowledge and conscience 
are dedicated to the fulfilment of this duty.  
4. The Declaration of Geneva of the WMA binds the physician with the words, "The health 
of my patient will be my first consideration," and the International Code of Medical Ethics 
declares that, "A physician shall act in the patient's best interest when providing medical 
care."  
5. Medical progress is based on research that ultimately must include studies involving 
human subjects. Populations that are underrepresented in medical research should be 
provided appropriate access to participation in research.  
6. In medical research involving human subjects, the well-being of the individual research 
subject must take precedence over all other interests.  
7. The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and 
therapeutic interventions (methods, procedures and treatments). Even the best current 
interventions must be evaluated continually through research for their safety, 
effectiveness, efficiency, accessibility and quality.  
8. In medical practice and in medical research, most interventions involve risks and burdens.  
9. Medical research is subject to ethical standards that promote respect for all human subjects 
and protect their health and rights. Some research populations are particularly vulnerable 


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and need special protection. These include those who cannot give or refuse consent for 
themselves and those who may be vulnerable to coercion or undue influence.  
10. Physicians should consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable 
international norms and standards. No national or international ethical, legal or regulatory 
requirement should reduce or eliminate any of the protections for research subjects set 
forth in this Declaration.  
B. 
BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH  
11. It is the duty of physicians who participate in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal 
information of research subjects.  
12. Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant 
sources of information, and adequate laboratory and, as appropriate, animal 
experimentation. The welfare of animals used for research must be respected.  
13. Appropriate caution must be exercised in the conduct of medical research that may harm 
the environment.  
14. The design and performance of each research study involving human subjects must be 
clearly described in a research protocol. The protocol should contain a statement of the 
ethical considerations involved and should indicate how the principles in this Declaration 
have been addressed. The protocol should include information regarding funding, 
Sponsors, institutional affiliations, other potential conflicts of interest, incentives for 
subjects and provisions for treating and/or compensating subjects who are harmed as a 
consequence of participation in the research study. The protocol should describe 
arrangements for post-study access by study subjects to interventions identified as 
beneficial in the study or access to other appropriate care or benefits.  
15. The research protocol must be submitted for consideration, comment, guidance and 
approval to a research ethics committee before the study begins. This committee must be 
independent of the researcher, the Sponsor and any other undue influence. It must take 
into consideration the laws and regulations of the country or countries in which the 
research is to be performed as well as applicable international norms and standards but 
these must not be allowed to reduce or eliminate any of the protections for research 
subjects set forth in this Declaration. The committee must have the right to monitor 
ongoing studies. The researcher must provide monitoring information to the committee, 
especially information about any serious adverse events. No change to the protocol may 
be made without consideration and approval by the committee.  
16. Medical research involving human subjects must be conducted only by individuals with 
the appropriate scientific training and qualifications. Research on patients or healthy 
volunteers requires the supervision of a competent and appropriately qualified physician 
or other health care professional. The responsibility for the protection of research subjects 


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must always rest with the physician or other health care professional and never the 
research subjects, even though they have given consent.  
17. Medical research involving a disadvantaged or vulnerable population or community is 
only justified if the research is responsive to the health needs and priorities of this 
population or community and if there is a reasonable likelihood that this population or 
community stands to benefit from the results of the research.  
18. Every medical research study involving human subjects must be preceded by careful 
assessment of predictable risks and burdens to the individuals and communities involved 
in the research in comparison with foreseeable benefits to them and to other individuals 
or communities affected by the condition under investigation.  
19. Every clinical trial must be registered in a publicly accessible database before recruitment 
of the first subject.  
20. Physicians may not participate in a research study involving human subjects unless they 
are confident that the risks involved have been adequately assessed and can be 
satisfactorily managed. Physicians must immediately stop a study when the risks are found 
to outweigh the potential benefits or when there is conclusive proof of positive and 
beneficial results.  
21. Medical research involving human subjects may only be conducted if the importance of 
the objective outweighs the inherent risks and burdens to the research subjects.  
22. Participation by competent individuals as subjects in medical research must be voluntary. 
Although it may be appropriate to consult family members or community leaders, no 
competent individual may be enrolled in a research study unless he or she freely agrees.  
23. Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information and to minimize the impact of the study on 
their physical, mental and social integrity.  
24. In medical research involving competent human subjects, each potential subject must be 
adequately informed of the aims, methods, sources of funding, any possible conflicts of 
interest, institutional affiliations of the researcher, the anticipated benefits and potential 
risks of the study and the discomfort it may entail, and any other relevant aspects of the 
study. The potential subject must be informed of the right to refuse to participate in the 
study or to withdraw consent to participate at any time without reprisal. Special attention 
should be given to the specific information needs of individual potential subjects as well 
as to the methods used to deliver the information. After ensuring that the potential subject 
has understood the information, the physician or another appropriately qualified individual 
must then seek the potential subject's freely-given informed consent, preferably in writing. 
If the consent cannot be expressed in writing, the non-written consent must be formally 
documented and witnessed.  
25. For medical research using identifiable human material or data, physicians must normally 
seek consent for the collection, analysis, storage and/or reuse. There may be situations 
where consent would be impossible or impractical to obtain for such research or would 


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pose a threat to the validity of the research. In such situations the research may be done 
only after consideration and approval of a research ethics committee.  
26. When seeking informed consent for participation in a research study the physician should 
be particularly cautious if the potential subject is in a dependent relationship with the 
physician or may consent under duress. In such situations, the informed consent should be 
sought by an appropriately qualified individual who is completely independent of this 
relationship.  
27. For a potential research subject who is incompetent, the physician must seek informed 
consent from the legally authorized representative. These individuals must not be included 
in a research study that has no likelihood of benefit for them unless it is intended to 
promote the health of the population represented by the potential subject, the research 
cannot instead be performed with competent persons, and the research entails only 
minimal risk and minimal burden.  
28. When a potential research subject who is deemed incompetent is able to give assent to 
decisions about participation in research, the physician must seek that assent in addition 
to the consent of the legally authorized representative. The potential subject's dissent 
should be respected.  
29. Research involving subjects who are physically or mentally incapable of giving consent, 
for example, unconscious patients, may be done only if the physical or mental condition 
that prevents giving informed consent is a necessary characteristic of the research 
population. In such circumstances the physician should seek informed consent from the 
legally authorized representative. If no such representative is available and if the research 
cannot be delayed, the study may proceed without informed consent provided that the 
specific reasons for involving subjects with a condition that renders them unable to give 
informed consent have been stated in the research protocol and the study has been 
approved by a research ethics committee. Consent to remain in the research should be 
obtained as soon as possible from the subject or a legally authorized representative.  
30. Authors, editors and publishers all have ethical obligations with regard to the publication 
of the results of research. Authors have a duty to make publicly available the results of 
their research on human subjects and are accountable for the completeness and accuracy 
of their reports. They should adhere to accepted guidelines for ethical reporting. Negative 
and inconclusive as well as positive results should be published or otherwise made 
publicly available. Sources of funding, institutional affiliations and conflicts of interest 
should be declared in the publication. Reports of research not in accordance with the 
principles of this Declaration should not be accepted for publication.  


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C 
ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE  
31. The physician may combine medical research with medical care only to the extent that the 
research is justified by its potential preventive, diagnostic or therapeutic value and if the 
physician has good reason to believe that participation in the research study will not 
adversely affect the health of the patients who serve as research subjects.  
32. The benefits, risks, burdens and effectiveness of a new intervention must be tested against 
those of the best current proven intervention, except in the following circumstances:  
• The use of placebo, or no treatment, is acceptable in studies where no current proven 
intervention exists; or  
• Where for compelling and scientifically sound methodological reasons the use of 
placebo is necessary to determine the efficacy or safety of an intervention and the 
patients who receive placebo or no treatment will not be subject to any risk of serious 
or irreversible harm. Extreme care must be taken to avoid abuse of this option.  
33. At the conclusion of the study, patients entered into the study are entitled to be informed 
about the outcome of the study and to share any benefits that result from it, for example, 
access to interventions identified as beneficial in the study or to other appropriate care or 
benefits.  
34. The physician must fully inform the patient which aspects of the care are related to the 
research. The refusal of a patient to participate in a study or the patient's decision to 
withdraw from the study must never interfere with the patient-physician relationship.  
35. In the treatment of a patient, where proven interventions do not exist or have been 
ineffective, the physician, after seeking expert advice, with informed consent from the 
patient or a legally authorized representative, may use an unproven intervention if in the 
physician's judgement it offers hope of saving life, re-establishing health or alleviating 
suffering. Where possible, this intervention should be made the object of research, 
designed to evaluate its safety and efficacy. In all cases, new information should be 
recorded and, where appropriate, made publicly available.  


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12.7. 
PCWG3 Criteria for Disease Assessment 
PCWG3 endorses RECIST v1.1 for soft tissue response assessment (see RECIST v1.1 appendix). 
PCWG3 criteria will be used to document evidence of disease progression in bone lesions as 
described by Scher, et al. 2016. 
Imaging of Baseline Bone Disease: 
The use of bone scan as the standard for bone imaging is retained in PCWG3, with the presence 
or absence of metastasis recorded first. A quantitative measure of disease burden, such as lesion 
number, the bone scan index, or lesion area, is also suggested, recognizing that these measures 
require further analytical and prospective clinical validation. Changes in lesions considered 
metastatic on bone scintigraphy should be followed and assessed serially using a bone scan 
assessment form. Areas/lesions on bone scintigraphy that are suggestive can be assessed further 
with CT or MRI and followed separately, but such supplemental imaging should not be used to 
establish indicator lesions for the purposes of a trial. Different modalities for imaging bone 
metastases can provide different information for the same patient. However, because of the lack 
of standards for reporting disease presence or changes after treatment, positron emission 
tomography imaging with sodium fluoride, fluorodeoxyglucose, choline, or prostate-specific 
membrane antigen, bone marrow MRI (body MRI), and other modalities that are in use to image 
bone, should be approached as new biomarkers subject to independent validation.  
Criteria for progression in bone at study entry  
• Two new lesions observed on 99mTc-methylene diphosphonate radionuclide bone 
scintigraphy 
• Confirm ambiguous results by other imaging modalities (eg, CT or MRI) however only 
positivity on the bone scan defines metastatic disease to bone 
Documentation of baseline bone disease 
• Presence or absence of metastasis recorded first 
• A quantitative measure of disease burden, such as lesional number, the bone scan index, 
or lesion area, is required 
• Changes in lesions considered metastatic on bone scintigraphy should be followed and 
assessed serially using a bone scan assessment form. Areas/lesions on bone scintigraphy 
that are suggestive can be assessed further with CT or MRI and followed separately, but 
such supplemental imaging should not be used to establish indicator lesions for the 
purposes of a trial. 
Following for bone progression during the study 
• Exclude pseudoprogression in the absence of symptoms or other signs of progression  
At least two new lesions on first post-treatment scan, with at least two additional lesions on the 
next scan (2+2 rule) 


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• 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 scan when the first two new lesions 
were documented 
• For scans after the first post-treatment scan, at least two new lesions relative to the first 
posttreatment scan confirmed on a subsequent scan  
• Date of progression is the date of the scan that first documents the second lesion  
• Changes in intensity of uptake alone do not constitute either progression or regression