ARRO-CITO: (UMCC 2017.055) Phase Ib/II Single-Arm Multi-Center Study of IONIS-AR-2.5Rx, a Next Generation Androgen Receptor Antisense Oligonucleotide, in Combination With Enzalutamide in Metastatic Castration Resistant Prostate Cancer
Phase: PHASE1
Conditions: Prostate Cancer
Sponsor: University of Michigan Rogel Cancer Center

ID: UMCC 
2017.055 
     
 
 
 
 
 
 
 
 
 
 
ARRx in Combination With Enzalutamide in 
Metastatic Castration Resistant Prostate Cancer 
    NCT03300505 
 

Protocol UMCC 2017.055 
 
 
 
 
PROTOCOL UMCC 2017.055 
 
ARRO-CITO: (UMCC 2017.055) Phase Ib/II Single-Arm Multi-Center Study of IONIS-AR-2.5Rx, a Next 
Generation Androgen Receptor Antisense Oligonucleotide, in combination with Enzalutamide in 
Metastatic Castration Resistant Prostate Cancer 
 
 
 
 
Sponsor Investigator: 
Ajjai Alva, MD 
Internal Medicine - Hematology/Oncology 
University of Michigan 
7316 Cancer Center 
1500 E. Medical Center Drive 
Ann Arbor, MI 48109 
Phone: (734) 936-0091 
Fax: 
(734) 615-2719 
Email: ajjai@umich.edu 
 
 
Biostatistician: 
Emily Bellile, MS  
Statistician Lead 
Cancer Data Sciences Shared 
Resource-Biostatistics  
M2531 SPH II, University of Michigan 
1415 Washington Heights 
Ann Arbor MI 48109-2029 
Phone: 734-936-1984  
Email: lighte@umich.edu 
 
Coordinating Center: 
University of Michigan 
 
Study Drug: 
IONIS-AR-2.5Rx or specifically ISIS 560131; formerly 
known as AZD5312) 
 
 
Initial version: 
May 4, 2017 
Amended: 
May 16,2017 
September 1, 2017 
November 8, 2017 
November 29, 2017 
August 20, 2018 
October 22, 2019 
March 11,2020 
April 7, 2020  
August 26, 2020 
February 4, 2021 
 
 
(COVID-19 Addendum) NOTE: The study was amended to address protocol-required items that the COVID-19 
pandemic may temporarily affect.  The potential changes are listed in Section 18.0 (COVID-19 Addendum). 
 
 
 

Protocol UMCC 2017.055 
 
 
 
TABLE OF CONTENTS 
ABBREVIATIONS................................................................................................. 1 
STUDY SYNOPSIS ............................................................................................... 3 
1.0 
BACKGROUND AND RATIONALE ...................................................... 10 
1.1 
Disease Background .......................................................................................... 10 
1.2 
Treatment Background ....................................................................................... 10 
1.3 
Study Agent(s) Background and Associated Known Toxicities ......................... 11 
1.4 
Other Agents ...................................................................................................... 12 
1.5 
Rationale ............................................................................................................ 18 
1.6 
Correlative Studies ............................................................................................. 18 
2.0 
STUDY OBJECTIVES/ENDPOINTS ..................................................... 18 
2.1 
Primary Objective ............................................................................................... 18 
2.2 
Secondary Objectives ........................................................................................ 18 
2.3 
Exploratory/Correlative Objectives ..................................................................... 19 
2.4 
Primary Endpoint ................................................................................................ 19 
2.5 
Secondary Endpoints ......................................................................................... 19 
2.6 
Exploratory/Correlative Endpoints ...................................................................... 19 
3.0 
PATIENT ELIGIBILITY .......................................................................... 19 
3.1 
Inclusion Criteria ................................................................................................. 20 
3.2 
Exclusion Criteria ............................................................................................... 21 
4.0 
SUBJECT SCREENING AND REGISTRATION PROCEDURES ......... 22 
5.0 
TREATMENT PLAN .................................................................................. 23 
5.1 
Treatment Dosage and Administration............................................................... 23 
5.2 
Toxicities and Dosing Delays/Dose Modifications ............................................. 25 
5.3 
Concomitant Medications/Treatments ................................................................ 29 

Protocol UMCC 2017.055 
 
5.4 
Other Modalities or Procedures ......................................................................... 30 
5.5 
Duration of Therapy ........................................................................................... 30 
5.6 
Off Treatment Criteria ......................................................................................... 30 
5.7 
Duration of Follow-Up ........................................................................................ 31 
5.8 
Off Study Criteria ................................................................................................ 31 
5.9 
Patient Replacement .......................................................................................... 31 
6.0 
STUDY PROCEDURES ........................................................................ 32 
Time and Events Table ................................................................................................ 32 
7.0 
MEASUREMENT OF EFFECT .............................................................. 34 
7.1 
Antitumor Effect- Solid Tumors .......................................................................... 34 
7.2 
Response Criteria for RECIST 1.1 subjects with measurable disease .............. 36 
7.3 
Safety/Tolerability ............................................................................................... 38 
8.0 
ADVERSE EVENTS .............................................................................. 39 
8.1 
Experimental Therapy ........................................................................................ 39 
8.2 
Adverse Event Reporting Requirements ............................................................ 39 
8.3 
Definitions ........................................................................................................... 40 
8.4 
Adverse Event Characteristics ........................................................................... 41 
8.5 
Serious Adverse Event Reporting Guidelines .................................................... 41 
8.6 
Routine Reporting .............................................................................................. 42 
8.7 
Reporting of Unanticipated Problems ................................................................ 42 
8.8 
Unblinding Procedures ....................................................................................... 43 
8.9 
Stopping Rules ................................................................................................... 43 
9.0 
DRUG INFORMATION .......................................................................... 43 
9.1 
IONIS-AR-2.5Rx (or specifically ISIS 560131; formerly known as AZD5312) ..... 43 
9.2 
Enzalutamide ...................................................................................................... 48 
10.0 
CORRELATIVES/SPECIAL STUDIES .................................................. 49 

Protocol UMCC 2017.055 
 
10.1 
Sample Collection Guidelines (Refer to Lab Manual) .................................... 50 
11.0 
STATISTICAL CONSIDERATIONS ...................................................... 50 
11.1 
Study Design .................................................................................................. 51 
11.2 
Endpoints ....................................................................................................... 51 
11.3 
Sample Size and Accrual ............................................................................... 52 
11.4 
Analysis Datasets ........................................................................................... 53 
11.5 
Assessment of Safety ..................................................................................... 53 
11.6 
Data Analysis Plans ....................................................................................... 54 
12.0 
DATA MANAGEMENT .......................................................................... 55 
13.0 
DATA AND SAFETY MONITORING ..................................................... 55 
14.0 
QUALITY ASSURANCE AND AUDITS ................................................ 56 
15.0 
CLINICAL MONITORING PROCEDURES ............................................ 56 
16.0 
REFERENCES ...................................................................................... 58 
17.0 
APPENDICES ....................................................................................... 60 
18.0 
COVID-19 ADDENDUM ................................................................................ 69 

Protocol UMCC 2017.055 
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ABBREVIATIONS 
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ALC 
Absolute Lymphocyte Count 
AR 
Androgen Receptor 
ISIS 560131/IONIS- 
AR-2.5Rx 
Next Generation (Gen 2.5) Androgen Receptor Antisense 
Oligonucleotide 
ASO 
Antisense Oligonucleotide 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CMP 
Comprehensive Metabolic Panel 
CR 
Complete Response 
CRPC 
Castrate Resistant Prostate Cancer 
CT 
Computed Tomography 
CTC 
Circulating Tumor Cells 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTSU 
Clinical Trials Support Unit 
DLT 
Dose Limiting Toxicity 
DSMC 
Data and Safety Monitoring Committee 
H&P 
History & Physical Exam 
HRPP 
Human Research Protections Program 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV (or iv) 
Intravenously 
mCRPC 
Metastatic Castrate Resistant Prostate Cancer 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
ORR 
Overall Response Rate 
OS 
Overall Survival 
O-CTSU 
Oncology-Clinical Trials Support Unit 
PBMCs 
Peripheral Blood Mononuclear Cells 
PD 
Progressive Disease 
PDL1 
Programmed Death Ligand 1 
PFS 
Progression Free Survival 
PI 
Principal Investigator 
p.o. 
per os/by mouth/orally 
PR 
Partial Response 
PRC 
Protocol Review Committee 
RPFS 
Radiographic Progression Free Survival 

Protocol UMCC 2017.055 
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SAE 
Serious Adverse Event 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SPGT 
Serum Glutamic Pyruvic Transaminase 
UaP 
Unanticipated Problem 
WBC 
White Blood Cells 

Protocol UMCC 2017.055 
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STUDY SCHEMA 
 
 
 
 
 
 
 
STUDY SYNOPSIS 
 
Title 
ARRO-CITO: Phase Ib/II Single-Arm Multi-Center Study of IONIS-AR- 
2.5Rx, an Androgen Receptor Antisense Oligonucleotide in combination 
with Enzalutamide in Metastatic Castration Resistant Prostate Cancer. 
Phase 
Phase Ib/II 
Methodology 
Open label, Single Arm, 
Phase Ib/II: IONIS-AR-2.5Rx (AR ASO) therapy + enzalutamide 
Study Duration 
• 
Subject accrual over 24 months 
• 
Anticipated median duration of protocol therapy of 12 months 
• 
Follow-up of 24months 
Study Center(s) 
Two-centers (University of Michigan, Karmanos Cancer Center) 

Protocol UMCC 2017.055 
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Objectives/Endpoints 
Primary Objectives 
1. Phase Ib: To determine the maximum tolerated dose (MTD) of 
IONIS-AR-2.5Rx in combination with enzalutamide. 
2. Phase II: To estimate the anti-tumor efficacy of IONIS-AR-2.5Rx in 
combination with enzalutamide as measured by PSA response 
rate.   
Secondary Objectives 
1. To estimate secondary measures of efficacy of IONIS-AR-2.5Rx in 
combination with enzalutamide in CRPC subjects including 
radiographic progression-free survival (rPFS) by PCWG3- 
modified RECIST 1.1, PSA progression free survival. 30% PSA 
reduction proportion, Duration of Therapy (DOT), Duration of PSA 
Response (DOR), and OS. 
2. To determine the safety and toxicity of IONIS-AR-2.5Rx, in 
patients with metastatic castration resistant prostate cancer. 
Exploratory/Correlative Objectives 
1. To determine the inhibition of androgen receptor driven signaling 
by IONIS-AR-2.5Rx in tumor tissues. 
2. To identify molecular (including genomic, metabolic, and/or 
proteomic) biomarkers in blood and tissues that may be indicative 
of clinical response/resistance, safety, pharmacodynamic activity 
of IONIS-AR-2.5Rx in combination with enzalutamide. 
3. To evaluate changes in health-related quality of life assessment 
from baseline using FACT-P and EuroQoL-5D. 
4. To explore pharmacokinetic (PK) characteristics of IONIS-AR- 
2.5Rx in combination with enzalutamide. 

Protocol UMCC 2017.055 
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Primary Endpoint 
1. Dose-limiting toxicity (DLT) and MTD during the first cycle of 
IONIS-AR-2.5Rx (in combination with enzalutamide) 
2. PSA decline of 50% or greater from baseline using PCWG3 
criteria at any time after the start of combination therapy 
Secondary Endpoints 
1. Efficacy: Radiographic progression-free survival time (rPFS) by 
PCWG3-modifed RECIST 1.1, PSA progression-free survival 
time, PSA reductions by 30% and 50% from baseline, duration of 
therapy (DOT), duration of PSA Response (DOR), and overall 
survival time 
2. Safety and toxicity: Adverse events as assessed by CTCAE 
criteria 5.0 and classified by body system, grade and attribution. 
Other toxicity endpoints include intrapatient dose delays and 
dose reductions. 
Exploratory/Correlative Endpoints 
1. Androgen receptor driven signaling measures in tumor tissues 
2. Measures of genomic metabolomics and proteomic biomarkers in 
blood and tissues 
3. FACT-P and EuroQoL-5D scores with comparisons to baseline 
scores 
4. Pharmacokinetic (PK) characteristics 
Number of Subjects 
35 evaluable subjects 

Protocol UMCC 2017.055 
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Key Inclusion Criteria 
1. Histologically confirmed prostate adenocarcinoma cancer, either 
pure or mixed. NO small cell/neuroendocrine differentiation is 
allowed in any quantity. 
2. Castrate levels of serum testosterone (≤50 ng/dL). Patients must 
continue androgen deprivation therapy with an LHRH analogue 
or antagonist if they have not undergone bilateral orchiectomy. 
3. Patients must have metastatic disease, either measurable OR 
non-measurable per RECIST 1.1. 
4. Progressive disease despite ongoing treatment with Androgen 
Deprivation Therapy (ADT) based on ANY ONE of the following: 
• 
Progression on axial imaging per treating investigator. 
• 
PSA evidence for progressive prostate cancer consisting 
of a PSA level of at least 1 ng/ml which has risen on at 
least 2 successive occasions, at least one week apart. If 
the confirmatory PSA (#3) value is less (i.e., #3b) than 
the screening PSA (#2) value, then an additional test for 
rising PSA (#4) will be required to document progression 
for the purposes of eligibility. 
• 
Radionuclide bone scan: At least two new foci consistent 
with metastatic lesions. 
5. Patients treated with first generation anti-androgen (e.g. 
bicalutamide, nilutamide, flutamide) as part of most recent 
systemic therapy must have at least 4 weeks elapsed from 
treatment discontinuation to start of protocol therapy with 
evidence of disease progression per criterion #4 following 
discontinuation of prior anti-androgen. 
6. Minimum PSA at entry of 1 ng/mL is required. 

Protocol UMCC 2017.055 
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Key Inclusion Criteria 
7. ECOG Performance Status 0, 1 or 2. 
8. Ability to understand and voluntarily agree to participate by 
providing written informed consent for the trial. 
9. Be ≥18 years of age on the day of signing informed consent. 
10. Demonstrate adequate organ function as defined below: 
Hematological: 
• 
ANC 
≥1,500/uL 
• 
Platelets ≥100,000/uL 
• 
Hemoglobin ≥9 g/dL or ≥5.6 mmol/L with or without a red 
blood cell transfusion. 
Renal: 
• 
Serum creatinine ≤1.5X ULN OR calculated creatinine 
clearance ≥30 mL/min for subjects with creatinine levels 
>1.5X institutional ULN (GFR can also be used in place 
of creatinine or CrCl). 
Hepatic: 
• 
Serum total bilirubin ≤1.5X ULN OR Direct bilirubin ≤ULN 
for subjects with total bilirubin levels >1.5 ULN. 
• 
AST (SGOT) and ALT (SGPT) ≤2.5X ULN OR ≤5X ULN 
for subjects with active liver metastases. 
• 
Alkaline Phosphatase If >2.5X ULN, then liver fraction 
should be ≤2.5X ULN 
Coagulation: 
• 
INR PT or aPTT or PTT ≤1.5X ULN (can vary if subject is 
receiving anticoagulant therapy, as long as PT or PTT 
remains within therapeutic range of the anticoagulant’s 
intended use). 
11. Subjects must agree to use an adequate method of contraception 
as outlined in Section 8.1.1, starting with the time of informed 
consent through 120 days after the last dose of trial therapy. 
Exclusion Criteria 
1. Prior chemotherapy and/or enzalutamide for metastatic 
castration-resistant prostate cancer. Prior abiraterone is allowed 
but not required. Chemotherapy administered in the castration- 
sensitive setting is allowed. 
2. Is currently participating and receiving study therapy or has 
participated in a study of an investigational agent and received 
study therapy or used an investigation device within 4 weeks of 
enrollment. 
3. Has not recovered (i.e., AE ≤Grade 1 or at baseline) from AEs 
due to a previously administered agent. Subjects with ≤Grade 2 
neuropathy or ≤Grade 2 alopecia are an exception to this criterion 
and are allowed if relevant toxicity is stabilized. 
4. If subjects received major surgery they must have recovered 
adequately from the toxicity and/or complications from the 
intervention prior to starting trial therapy. 
 
 

Protocol UMCC 2017.055 
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Exclusion Criteria 
5. Has a known additional malignancy that is progressing or 
requires active treatment. Exceptions include basal cell 
carcinoma of the skin and squamous cell carcinoma of the skin. 
6. Has a known history of active tuberculosis (TB) (Bacillus 
tuberculosis). 
7. Has known psychiatric or substance abuse disorders that would 
interfere with cooperation with the requirements of the trial. At the 
time of signing informed consent is a known regular user 
(including "recreational use") of any illicit drug(s) or had a recent 
history (within the last year) of drug or alcohol abuse. 
8. Has a known history of human immunodeficiency virus (HIV) (HIV 
1/2 antibodies). 
9. Has known history of active hepatitis B (e.g. HBsAg reactive) or 
hepatitis C (e.g., HCV RNA [qualitative] is detected). 
10. Has received a live virus vaccine within 30 days of planned start 
of trial therapy. 
11. Has known active CNS metastases and/or carcinomatous 
meningitis. Subjects with previously treated brain metastases 
may participate provided they have stable brain metastases 
(stability is normally defined as a period of 1 to 3 months in which 
there is no evidence of new or enlarging CNS metastases). 
12. Has symptomatic ascites or pleural effusion; a subject who is 
clinically stable following treatment for these conditions is eligible. 
13. Has had a prior allogeneic stem cell or bone marrow transplant. 
14. Has known contraindication to aspirin (81 mg). 
Study Product(s), Dose, 
Route, Regimen 
IONIS-AR-2.5Rx Androgen Receptor Antisense Oligonucleotide (AR 
ASO) at starting dose of 900 mg IV + enzalutamide 160 mg PO Qday in 
Phase Ib. 
IONIS-AR-2.5Rx (at MTD from Phase Ib) + enzalutamide in Phase II. 
Duration of Administration 
Until imaging/radiographic progression per PCWG3 criteria and/or until 
lack of clinical benefit as judged by the treating investigator. 
Clinical progression as judged by the treating investigator or 
unacceptable toxicity or withdrawal of informed consent or deterioration 
in general medical condition that is excessive per treating investigator 
would result in stopping therapy. 
Reference Therapy 
None 
 
 

Protocol UMCC 2017.055 
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Statistical Methodology 
This is a single dose-finding one-arm phase Ib/II trial to (i) estimate the 
MTD from among three dose levels of IONIS-AR-2.5Rx in combination 
with a fixed dose of enzalutamide, as described below, and (ii) obtain 
preliminary estimate of efficacy at this estimated MTD, as measured by 
PSA response rate. The MTD is defined as the highest dose of IONIS- 
AR-2.5Rx inducing a rate of DLT closest to but not larger than 35%, and 
we will assess the evidence that the PSA response rate at this dose level 
exceeds 5%. The planned enrollment is 35 evaluable patients. Success 
for the trial is defined as finding a dose level that is likely to be both 
tolerable and effective. 
Study Design 
Dose Assignment The first patient will be enrolled to dose level 3 of 
IONIS-AR-2.5Rx, in combination with a fixed dose of enzalutamide. 
Subsequent dose assignments to dose levels 3, 2, or 1 will be based 
upon the statistical-model-based TITE-CRM design. This trial will seek to 
estimate the MTD, the true value of which is defined as the dose level 
with probability of DLT closest to but not exceeding 35%. 
Final Efficacy Analysis After all 35 evaluable patients are enrolled and 
the PSA response endpoint is recorded for all patients, we will fit the 
Bayesian isotonic regression model on all patients’ data. If the probability 
that the PSA response rate at the final estimated dose exceeds 5% is at 
least 0.95, the trial will have successfully completed its primary objective. 
Interim Analysis/Criteria for Stopping Study Continuous monitoring of 
safety is built into the TITE-CRM model, and the trial will stop at any 
point in which all dose levels have a model-estimated probability of DLT 
exceeding 37.5%. 
Subject accrual is expected to be 15-18 patients per year per site for a 
total period of up to 24 months. We assume an anticipated median 
duration of protocol therapy of 12 months and a follow-up of 24 months. 

Protocol UMCC 2017.055 
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1.0 
BACKGROUND AND RATIONALE 
 
1.1 
Disease Background 
 
Prostate cancer is the second leading cause of cancer deaths in men. According to American 
Cancer Society1 estimates in 2014, as many as 233,000 American men will be diagnosed with 
prostate cancer, and nearly 29,480 will die of the disease. 
 
These clinical states involve the complex interplay of a network of signaling molecules that 
collectively promote net cell proliferation relative to cell death. The course of prostate cancer from 
diagnosis to death is best categorized as a series of clinical states. 
 
Figure 1. Clinical states of prostate cancer 
 
 
Treatment options for patients with castrate resistant prostate cancer (CRPC) are limited, and 
until recently only docetaxel was shown to improve survival. In the last several years, five new 
agents: abiraterone acetate, cabazitaxel, enzalutamide, radium-223 and sipuleucel-T, have been 
approved for use in this clinical state2-8. However, the optimal sequencing of these agents is 
unknown. Moreover, all patients with CRPC are treated with an identical paradigm, and there is 
currently no means of identifying which patient population would benefit from a particular agent. 
 
In recent studies of enzalutamide, a potent Androgen Receptor signaling inhibitor in combination 
with anti-PD1 blocking antibody immunotherapy9 (NCT02312557 and Merck’s ongoing and 
recently amended study Keynote-199, cohorts 4 and 5/UMCC 2016.055/NCT02787005), the 
hypothesis based on intriguing data (though early and limited dataset) is that sustained Androgen 
receptor signaling inhibition is needed to render prostate cancer tissue responsive to 
immunotherapy. This is in line with other recent preclinical data that inhibition of intracellular 
signaling pathways such as CDK4/610 and wnt11 could render tumor cells more responsive to 
immunotherapy. 
 
1.2 
Treatment Background 
 
Extensive work has been performed to increase the understanding of the major mechanism 
driving resistance to castration. Preclinical and clinical studies have demonstrated that alterations 
in the AR, specifically up-regulation, are central to the progression to CRPC12. Several novel 
agents targeting the androgen receptor have been in development. 

Protocol UMCC 2017.055 
Page 11 of 69 
 
 
 
 
 
 
 
Enzalutamide inhibits androgen receptor (AR) signaling in three distinct ways: it inhibits 1) 
testosterone binding to ARs; 2) nuclear translocation of ARs; and 3) DNA binding and activation 
by ARs. Based on the AFFIRM trial, enzalutamide was approved by the FDA in 2012, and by the 
EMA in 2013, for the treatment of men with mCRPC who have progressed on or after first-line 
docetaxel chemotherapy7. Currently, the NCCN guidelines recommend enzalutamide in this 
setting as well as for men with mCRPC who are not candidates for docetaxel. Recently, Beer and 
colleagues (PREVAIL phase III trial) have shown that enzalutamide significantly reduced the risk 
for radiographic progression, delayed initiation of chemotherapy and improved overall survival 
(OS) in men with CRPC that have not received prior chemotherapy2. In September 2014, the U.S. 
Food and Drug Administration (FDA) expanded the use of enzalutamide to include men with 
CRPC who have not received prior chemotherapy. Thus, enzalutamide has become a standard of 
care as systemic therapy for men with mCRPC, and since there is no need for concurrent 
administration of systemic steroids, it is expected to be the predominant agent to be used in the 
pre-chemotherapy setting. However, enzalutamide as well as abiraterone acetate are associated 
eventual development of resistance and re-activation of the AR. 
 
1.3 
Study Agent(s) Background and Associated Known Toxicities 
Therapeutic nucleic acid- based approaches, including antisense oligonucleotides (ASOs), offer 
the potential to develop drugs to targets that have proven to be intractable to alternative drug 
modalities13. With the ASO approach inhibitors can be rationally designed solely based on gene 
sequence information, thereby enabling the development of inhibitors to a wide range of target 
classes, including those regarded as undruggable. There have been several successes in the 
development of systemically administered ASOs in non-oncological settings,14 15 and the US 
Food and Drug Administration has now approved the first systemically administered ASO drug 
(Kynamro). Continued efforts to improve upon the stability and potency of ASOs has resulted in 
the discovery of a next generation class of ASOs that employ 2’-4’ constrained ethyl (cEt) 
residues,16,17. These next generation cEt ASOs, Generation 2.5, exhibit enhanced in vitro and in 
vivo potency compared to earlier ASO chemistries, and recently a cEt ASO (AZD4785) targeting 
the oncogene KRAS has demonstrated robust activity in preclinical models of cancer18 and 
another cEt ASO (AZD9150) targeting the previously undruggable target, the transcription factor 
STAT3, has shown single agent activity in highly treatment refractory cancer patients I phase I 
studies19. 
 
IONIS-AR-2.5Rx (specifically ISIS 560131, formerly known as AZD5312) is a novel Generation 2.5 
(constrained ethyl bicyclic nucleic acid) phosphorothioate antisense oligonucleotide (ASO) 
designed to target full length, splice variant and mutated forms of the androgen receptor, 
specifically resulting in suppression of human AR expression. 

Protocol UMCC 2017.055 
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IONIS-AR-2.5Rx has been shown in pre-clinical trials to cause dose-dependent down-regulation 
of full-length AR mRNA and protein, inhibits AR-dependent gene expression and induces 
apoptosis in prostate cancer cell lines20. IONIS-AR-2.5Rx was also shown to downregulate the 
splice variant AR-v7 and was also shown to inhibit proliferation of 22Rv1 cells, a human prostate 
carcinoma xenograft-derived epithelial cell line expressing PSA. Of note, this ASO was shown to 
have differential activity from enzalutamide in preclinical data, as enzalutamide does not inhibit 
22Rv1 cell proliferation. 
 
A first-time-in-patients (FTIP) phase I dose escalation, safety and pharmacokinetic study (Phase I 
Open Label Dose Escalation Study to Investigate the Safety & Pharmacokinetics of IONIS-AR- 
2.5Rx in Patients With Androgen Receptor Tumors NCT02144051/D5860C00001) was conducted 
in mCRPC patients who had previously failed standard of care treatment options including 
enzalutamide, abiraterone, and chemotherapy.21 Patients were treated on a 28-day cycle in 4 
cohorts (drug doses 150, 300, 600 and 900 mg). IONIS-AR-2.5Rx was given on days 1, 4, 8, 11, 
15 and 22 of cycle 1, and on days 1, 8, 15 and 22 of each subsequent 28-day cycle. 
 
Pharmacodynamic response was assessed at each cycle by PSA and circulating tumor cells 
(CTCs) and IHC and gene expression in a limited number of tissue biopsies. A maximum 
tolerated dose (MTD) of 900 mg once daily was established after treatment of 29 patients across 
the 4 cohorts. Dose-limiting toxicity was an increase in liver function tests at 900 mg (1 of 13 pts). 
Adverse events reported in preliminary data included fatigue, diarrhea, nausea, vomiting, dry 
skin, headache, insomnia, loss of appetite, mouth pain, muscle pain, pruritus, increased 
ALT/AST, elevated ALP and GGT, taste alteration, thrombocytopenia, gastrointestinal cramping, 
constipation, and weight loss. 
 
Of note, after the cut-off date for review of emerging safety data, several AE incidents of venous 
thromboembolism (pulmonary embolism and deep venous thrombosis) were reported. At the time 
of reporting, 15 patients had been treated on the D5860C00001 study, and 4 episodes of grade 3 
pulmonary embolism and 3 episodes of non-serious deep venous thrombosis were reported. We 
have noted this clinical finding and with recent unpublished work from the Palapattu lab at the 
University of Michigan showing platelet aggregation with other anti-sense oligonucleotides, built in 
a low dose aspirin of 81 mg daily into the protocol. We will continue to monitor this aspect closely 
in our proposed trial. 
 
 
1.4 
Other Agents 
Enzalutamide (standard of care as monotherapy) 
 
Enzalutamide is an androgen receptor antagonist which acts by competitively inhibiting (1) 
testosterone binding to androgen receptors, (2) nuclear translocation of androgen receptors, and 
(3) DNA binding and activation by androgen receptors. Enzalutamide was approved by the FDA 
in 2012 for the treatment of med with mCRPC who have progressed on or after first-line 
docetaxel chemotherapy. In September 2014, the FDA expanded the use of enzalutamide to 
include men with CRPC that have not received prior chemotherapy. 
 
Clinical Trial Experience 
Because clinical trials are conducted under widely varying conditions, adverse reaction rates 
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials 
of another drug and may not reflect the rates observed in practice. 
 
Three randomized clinical trials enrolled patients with metastatic prostate cancer that has 
progressed on androgen deprivation therapy (GnRH therapy or bilateral orchiectomy), a disease 
setting that is also defined as metastatic CRPC. Two trials were placebo-controlled (Studies 1 
and 2), and one trial was bicalutamide-controlled (Study 3). In Studies 1 and 2, patients 
received enzalutamide 160 mg or placebo orally once daily. In Study 3, patients received 

Protocol UMCC 2017.055 
Page 13 of 69 
 
 
 
 
enzalutamide 160 mg or bicalutamide 50 mg orally once daily. All patients continued androgen 
deprivation therapy. 
 
Patients were allowed, but not required, to take glucocorticoids. 
 
The most common adverse reactions (≥ 10%) that occurred more commonly (≥ 2% over 
placebo) in the enzalutamide- treated patients from the two randomized placebo-controlled 
clinical trials were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, 
diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, 
musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo. 
 
Study 1: Enzalutamide versus Placebo in Metastatic CRPC Following Chemotherapy 
In this study of patients with metastatic CRPC who had previously received docetaxel, the median 
duration of treatment was 8.3 months with enzalutamide and 3.0 months with placebo. During 
the trial, 48% of patients on the enzalutamide arm and 46% of patients on the placebo arm 
received glucocorticoids. 
 
Grade 3 and higher adverse reactions were reported among 47% of enzalutamide-treated 
patients and 53% of placebo- treated patients. Discontinuations due to adverse events were 
reported for 16% of enzalutamide-treated patients and 18% of placebo-treated patients. The 
most common adverse reaction leading to treatment discontinuation was seizure, which 
occurred in 0.9% of the enzalutamide-treated patients compared to none (0%) of the placebo- 
treated patients. 
 
Table 1 shows adverse reactions reported in Study 1 that occurred at a ≥ 2% higher frequency in 
the enzalutamide arm compared to the placebo arm. 

Protocol UMCC 2017.055 
Page 14 of 69 
 
 
 
 
Table 1. Adverse Reactions in Study 1 
Enzalutamide N = 
800 
Placebo N = 399 
Grade 1-4a 
(%) 
Grade 3-4 
(%) 
Grade 1-4 
(%) 
Grade 3-4 
(%) 
General Disorders 
Asthenic Conditionsb 
50.6 
9.0 
44.4 
9.3 
Peripheral Edema 
15.4 
1.0 
13.3 
0.8 
Musculoskeletal And Connective Tissue Disorders 
Back Pain 
26.4 
5.3 
24.3 
4.0 
Arthralgia 
20.5 
2.5 
17.3 
1.8 
Musculoskeletal Pain 
15.0 
1.3 
11.5 
0.3 
Muscular Weakness 
9.8 
1.5 
6.8 
1.8 
Musculoskeletal Stiffness 
2.6 
0.3 
0.3 
0.0 
Gastrointestinal Disorders 
Diarrhea 
21.8 
1.1 
17.5 
0.3 
Vascular Disorders 
Hot Flush 
20.3 
0.0 
10.3 
0.0 
Hypertension 
6.4 
2.1 
2.8 
1.3 
Nervous System Disorders 
Headache 
12.1 
0.9 
5.5 
0.0 
Dizzinessc 
9.5 
0.5 
7.5 
0.5 
Spinal Cord Compression and 
Cauda Equina Syndrome 
7.4 
6.6 
4.5 
3.8 
Paresthesia 
6.6 
0.0 
4.5 
0.0 
Mental Impairment Disordersd 
4.3 
0.3 
1.8 
0.0 
Hypoesthesia 
4.0 
0.3 
1.8 
0.0 
Infections And Infestations 
Upper Respiratory Tract 
Infectione 
10.9 
0.0 
6.5 
0.3 
Lower Respiratory Tract And 
Lung Infectionf 
8.5 
2.4 
4.8 
1.3 
Psychiatric Disorders 
Insomnia 
8.8 
0.0 
6.0 
0.5 
Anxiety 
6.5 
0.3 
4.0 
0.0 
Renal And Urinary Disorders 
Hematuria 
6.9 
1.8 
4.5 
1.0 
Pollakiuria 
4.8 
0.0 
2.5 
0.0 
Injury, Poisoning And Procedural Complications 
Fall 
4.6 
0.3 
1.3 
0.0 
Non-pathologic Fractures 
4.0 
1.4 
0.8 
0.3 
Skin And Subcutaneous Tissue Disorders 
Pruritus 
3.8 
0.0 
1.3 
0.0 
Dry Skin 
3.5 
0.0 
1.3 
0.0 

Protocol UMCC 2017.055 
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Enzalutamide N = 
800 
Placebo N = 399 
Grade 1-4a 
(%) 
Grade 3-4 
(%) 
Grade 1-4 
(%) 
Grade 3-4 
(%) 
Respiratory Disorders 
Epistaxis 
3.3 
0.1 
1.3 
0.3 
a CTCAE v5.0 
b Includes asthenia and fatigue. 
c Includes dizziness and vertigo. 
d Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. 
e Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and 
laryngitis. 
f Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection. 
 
Study 2: Enzalutamide versus Placebo in Chemotherapy-naïve Metastatic CRPC 
Study 2 enrolled 1717 patients with metastatic CRPC who had not received prior cytotoxic 
chemotherapy, of whom 1715 received at least one dose of study drug. The median duration of 
treatment was 17.5 months with enzalutamide and 4.6 months with placebo. Grade 3-4 adverse 
reactions were reported in 44% of enzalutamide-treated patients and 37% of placebo-treated 
patients. Discontinuations due to adverse events were reported for 6% of enzalutamide-treated 
patients and 6% of placebo-treated patients. The most common adverse reaction leading to 
treatment discontinuation was fatigue/asthenia, which occurred in 1% of patients on each 
treatment arm. Table 2 includes adverse reactions reported in Study 2 that occurred at a ≥ 2% 
higher frequency in the enzalutamide arm compared to the placebo arm. 
 
Table 2. Adverse Reactions in Study 2 
Enzalutamide N = 
871 
Placebo N = 844 
Grade 1-4a 
(%) 
Grade 3-4 
(%) 
Grade 1-4 
(%) 
Grade 3-4 
(%) 
General Disorders 
Asthenic Conditionsb 
46.9 
3.4 
33.0 
2.8 
Peripheral Edema 
11.5 
0.2 
8.2 
0.4 
Musculoskeletal And Connective Tissue Disorders 
Back Pain 
28.6 
2.5 
22.4 
3.0 
Arthralgia 
21.4 
1.6 
16.1 
1.1 
Gastrointestinal Disorders 
Constipation 
23.2 
0.7 
17.3 
0.4 
Diarrhea 
16.8 
0.3 
14.3 
0.4 
Vascular Disorders 
Hot Flush 
18.0 
0.1 
7.8 
0.0 
Hypertension 
14.2 
7.2 
4.1 
2.3 
Nervous System Disorders 
Dizzinessc 
11.3 
0.3 
7.1 
0.0 
Headache 
11.0 
0.2 
7.0 
0.4 
Dysgeusia 
7.6 
0.1 
3.7 
0.0 
Mental Impairment 
Disordersd 
5.7 
0.0 
1.3 
0.1 
Restless Legs Syndrome 
2.1 
0.1 
0.4 
0.0 
Respiratory Disorders 

Protocol UMCC 2017.055 
Page 16 of 69 
 
 
 
 
Dyspneae 
11.0 
0.6 
8.5 
0.6 
Infections And Infestations 
Upper Respiratory Tract 
Infectionf 
16.4 
0.0 
10.5 
0.0 
Lower Respiratory Tract And 
Lung Infectiong 
7.9 
1.5 
4.7 
1.1 
Psychiatric Disorders 
Insomnia 
8.2 
0.1 
5.7 
0.0 
Renal And Urinary Disorders 
Hematuria 
8.8 
1.3 
5.8 
1.3 
Injury, Poisoning And Procedural Complications 
Fall 
12.7 
1.6 
5.3 
0.7 
Non-Pathological Fracture 
8.8 
2.1 
3.0 
1.1 
Metabolism and Nutrition Disorders 
Decreased Appetite 
18.9 
0.3 
16.4 
0.7 
Investigations 
Weight Decreased 
12.4 
0.8 
8.5 
0.2 
Reproductive System and Breast disorders 
Gynecomastia 
3.4 
0.0 
1.4 
0.0 
a CTCAE v5.0 
b Includes asthenia and fatigue. 
c Includes dizziness and vertigo. 
d Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. 
e Includes dyspnea, exertional dyspnea, and dyspnea at rest. 
f Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and 
laryngitis. 
g Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection. 
 
Study 3: enzalutamide versus Bicalutamide in Chemotherapy-naïve Metastatic CRPC 
Study 3 enrolled 375 patients with metastatic CRPC who had not received prior cytotoxic 
chemotherapy, of whom 372 received at least one dose of study drug. The median duration of 
treatment was 11.6 months with enzalutamide and 5.8 months with bicalutamide. 
Discontinuations with an adverse event as the primary reason were reported for 7.6% of 
enzalutamide-treated patients and 6.3% of bicalutamide-treated patients. The most common 
adverse reactions leading to treatment discontinuation were back pain and pathological fracture, 
which occurred in 3.8% of enzalutamide-treated patients for each event and in 2.1% and 1.6% 
of bicalutamide-treated patients, respectively. Table 3 shows overall and common adverse 
reactions (≥ 10%) in enzalutamide-treated patients. 

Protocol UMCC 2017.055 
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Table 3. Adverse Reactions in Study 3 
Enzalutamide 
(N=183) 
Bicalutamide (N=189) 
Grade 1-4 a 
(%) 
Grade 3-4 
(%) 
Grade 1-4 a 
(%) 
Grade 3-4 
(%) 
Overall 
94.0 
38.8 
94.2 
37.6 
General Disorders 
Asthenic Conditionsb 
31.7 
1.6 
22.8 
1.1 
Musculoskeletal And Connective Tissue Disorders 
Back Pain 
19.1 
2.7 
18.0 
1.6 
Musculoskeletal Painc 
16.4 
1.1 
14.3 
0.5 
Vascular Disorders 
Hot Flush 
14.8 
0 
11.1 
0 
Hypertension 
14.2 
7.1 
7.4 
4.2 
Gastrointestinal Disorders 
Nausea 
14.2 
0 
17.5 
0 
Constipation 
12.6 
1.1 
13.2 
0.5 
Diarrhea 
11.5 
0 
9.0 
1.1 
Infections And Infestations 
Upper Respiratory Tract 
Infectiond 
12.0 
0 
6.3 
0.5 
Investigational 
Weight Loss 
10.9 
0.5 
7.9 
0.5 
a CTCAE v 5.0 
b Including asthenia and fatigue. 
c Including musculoskeletal pain and pain in extremity 
d Including nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and 
laryngitis 
 
Laboratory Abnormalities 
In the two randomized placebo-controlled clinical trials, Grade 1-4 neutropenia occurred in 15% 
of patients treated with enzalutamide (1% Grade 3-4) and in 6% of patients treated with 
placebo (0.5% Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was 6% of patients 
treated with enzalutamide (0.3% Grade 3-4) and 5% of patients treated with placebo (0.5% 
Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of patients treated with enzalutamide 
(0.2% Grade 3-4) and 16% of patients treated with placebo (0.2% Grade 3-4). Grade 1-4 
elevations in bilirubin occurred in 3% of patients treated with enzalutamide (0.1% Grade 3-4) 
and 2% of patients treated with placebo (no Grade 3-4). 
 
Infections 
In Study 1, 1% of patients treated with enzalutamide compared to 0.3% of patients treated with 
placebo died from infections or sepsis. In Study 2, 1 patient in each treatment group (0.1%) had 
an infection resulting in death. 
 
Falls and Fall-related Injuries 
In the two randomized placebo-controlled clinical trials, falls including fall-related injuries, 
occurred in 9% of patients treated with enzalutamide compared to 4% of patients treated with 
placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries 
were more severe in patients treated with enzalutamide and included non- pathologic fractures, 

Protocol UMCC 2017.055 
Page 18 of 69 
 
 
 
 
 
joint injuries, and hematomas. 
Hypertension 
In the two randomized placebo-controlled trials, hypertension was reported in 11% of patients 
receiving enzalutamide and 4% of patients receiving placebo. No patients experienced 
hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension 
led to study discontinuation in < 1% of patients in each arm. 
 
1.5 
Rationale 
Metastatic castration resistant prostate cancer (CRPC) is an area of urgent unmet clinical need, 
especially in the clinical state characterized by resistance to or progression on monotherapy with 
androgen signaling inhibitors (ASI) such as abiraterone acetate and/or enzalutamide. In the 
CRPC setting, androgen receptor (AR) signaling continues to remain active and drives cancer 
progression. More potent inhibitors of AR-driven signaling, especially those that circumvent 
mechanisms of castration resistance involving the AR (e.g. AR splice variants or AR mutations), 
could help prolong the duration of benefit from ASI such as enzalutamide by avoiding or delaying 
development of resistance. We therefore propose a Phase Ib/II Single-Arm Multi-Center Study of 
IONIS-AR-2.5Rx, the Androgen Receptor Antisense Oligonucleotide in combination with 
enzalutamide in Metastatic Castration Resistant Prostate Cancer. 
 
1.6 
Correlative Studies 
IONIS-AR-2.5Rx acts by targeting full length and all variants of AR mRNA by targeting them for 
degradation. AR mRNA levels and those of the AR mutant and variants are expected to be 
reduced upon treatment with IONIS-AR-2.5Rx. We seek to determine the inhibition of androgen 
receptor driven signaling by IONIS-AR-2.5Rx in tumor tissues. Secondly, we seek to identify other 
molecular (including genomic, metabolic, and/or proteomic) biomarkers in blood and tumor tissue 
potentially indicative of clinical response/resistance, safety, pharmacodynamic activity and/or the 
mechanism of action of IONIS-AR-2.5Rx in combination with enzalutamide. We will explore 
pharmacokinetic (PK) characteristics of IONIS-AR-2.5Rx. Finally, we will explore the quality of life 
impact of IONIS-AR-2.5Rx in combination with enzalutamide. 
 
 
2.0 
STUDY OBJECTIVES/ENDPOINTS 
 
2.1 
Primary Objective 
Phase Ib: To determine the maximum tolerated dose (MTD) of IONIS-AR-2.5Rx in combination 
with enzalutamide. 
 
Phase II: To estimate the anti-tumor efficacy of IONIS-AR-2.5Rx in combination with enzalutamide 
as measured by PSA response rate in patients with metastatic castration resistant prostate 
cancer. 
 
2.2 
Secondary Objectives 
 
2.2.1 
To estimate secondary measures efficacy of IONIS-AR-2.5Rx in combination with 
enzalutamide in CRPC subjects including radiographic progression-free survival (rPFS) 
by PCWG3-modified RECIST 1.1, 30% PSA reduction proportion, PSA progression-free 
survival, Duration of Therapy (DOT), Duration of Response (DOR), PFS and OS. 
 
2.2.2 
To determine the safety and toxicity of IONIS-AR-2.5Rx, the Androgen Receptor 
AntiSense Oligonucleotide (AR ASO) in patients with metastatic castration resistant 
prostate cancer. 

Protocol UMCC 2017.055 
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2.3 
Exploratory/Correlative Objectives 
 
2.3.1 
To determine the inhibition of androgen receptor driven signaling by IONIS-AR-2.5Rx in 
tumor tissues. 
 
2.3.2 
To identify molecular (including genomic, metabolic, and/or proteomic) biomarkers in 
blood and tissues that may be indicative of clinical response/resistance, safety, 
pharmacodynamic activity and/or the mechanism of action of IONIS-AR-2.5Rx in 
combination with enzalutamide. 
 
2.3.3 
To evaluate changes in health-related quality of life assessment from 
baseline using FACT-P and EuroQoL-5D. 
 
2.3.4 
To explore pharmacokinetic (PK) characteristics of IONIS-AR-2.5Rx in combination with 
enzalutamide. 
 
 
2.4 
Primary Endpoint 
 
2.4.1 
Dose-limiting toxicity (DLT) during the first cycle of IONIS-AR-2.5Rx (in combination with 
enzalutamide) 
 
2.4.2 
PSA decline of 50% or greater from baseline using PCWG3 criteria at any time after 
the start of combination therapy 
 
 
2.5 
Secondary Endpoints 
 
2.5.1 
Efficacy: Radiographic progression-free survival time (rPFS) by PCWG3-modifed 
RECIST 1.1, PSA reduction from baseline, PSA progression-free survival time, duration 
of therapy (DOT), duration of PSA Response (DOR), progression-free survival time and 
overall survival time 
 
2.5.2 
Safety and toxicity: Adverse events as assessed by CTCAE criteria 5.0 and classified by 
body system, grade and attribution. Other toxicity endpoints include intrapatient dose 
delays and dose reductions. 
 
2.6 
Exploratory/Correlative Endpoints 
 
2.6.1 
Androgen receptor driven signaling measures in tumor tissues 
 
2.6.2 
Measures of genomic metabolomics and proteomic biomarkers in blood and tissues 
 
2.6.3 
FACT-P and EuroQoL-5D scores with comparisons to baseline scores 
 
2.6.4 
Pharmacokinetic (PK) characteristics 
 
 
3.0 
PATIENT ELIGIBILITY 
Subjects must meet all of the inclusion and exclusion criteria to be enrolled to the study. Study 
treatment may not begin until a subject is enrolled. No eligibility waivers will be granted for this 
clinical trial. 

Protocol UMCC 2017.055 
Page 20 of 69 
 
 
 
 
 
3.1 
Inclusion Criteria 
 
3.1.1 
Ability to understand and voluntarily agree to participate by providing written informed 
consent for the trial. 
 
3.1.2 
Histologically confirmed prostate adenocarcinoma cancer, either pure or mixed. Small 
cell/neuroendocrine differentiation is not allowed. 
 
3.1.3 
Castrate levels of serum testosterone (≤ 50 ng/dL). Patients must continue androgen 
deprivation therapy with an LHRH analogue or antagonist if they have not undergone 
bilateral orchiectomy. 
 
3.1.4 
Patients must have metastatic disease; either non-measurable disease OR measurable 
disease per RECIST 1.1. 
 
3.1.5 
Progressive disease despite ongoing treatment with Androgen Deprivation Therapy (ADT) 
based on ANY one of the following: 
 
1) Progression on axial imaging per treating investigator 
 
2) PSA evidence for progressive prostate cancer consists of a PSA level of at least 1 
ng/ml which has risen on at least 2 successive occasions, at least one week apart. 
If the confirmatory PSA (#3) value is less (i.e., #3b) than the screening PSA (#2) 
value, then an additional test for rising PSA (#4) will be required to document 
progression for the purposes of eligibility. 
 
 
 
3) Radionuclide bone scan: At least two new foci consistent with metastatic 
lesions 
 
3.1.6 
Patients treated with first generation anti-androgen as most recent systemic therapy (e.g. 
bicalutamide, nilutamide) must have at least 4 weeks elapsed from treatment 
discontinuation to start of protocol therapy with evidence of disease progression per 
criterion 3.1.5 following discontinuation of prior anti-androgen. 
 
3.1.7 
Minimum PSA at entry of 1 ng/mL is required. 
 
3.1.8 
ECOG Performance Status 0,1 or 2 
 
3.1.9 
Be ≥18 years of age on the day of signing informed consent. 
 
3.1.10 Demonstrate adequate organ function as defined below: 

Protocol UMCC 2017.055 
Page 21 of 69 
 
 
 
 
 
 
System 
Laboratory Value 
Hematological 
ANC 
≥1,500/uL 
Platelets 
≥100,000/uL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L with or without a  red 
blood cell transfusion within 2 weeks of enrollment 
Renal 
Serum creatinine 
OR 
calculated 
creatinine 
clearance 
≤1.5X ULN 
OR ≥30 mL/min for subjects with creatinine levels 
>1.5X institutional ULN 
(GFR can also be used in place of 
creatinine or CrCl) 
Hepatic 
Serum total bilirubin 
≤1.5X ULN OR 
Direct bilirubin ≤ULN for subjects with total bilirubin 
levels >1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤2.5X ULN OR 
≤5X ULN for subjects with active liver metastases 
Alkaline Phosphatase 
If >2.5X ULN, then liver fraction should be ≤2.5X 
ULN 
Coagulation 
INR PT 
aPTT or PTT 
≤1.5X ULN 
This can vary if subject is receiving anticoagulant 
therapy, as long as PT or PTT remains within 
therapeutic range of the anticoagulant’s intended use 
 
 
3.1.11 Subjects must agree to use an adequate method of contraception as outlined in Section 
8.1.1. starting with the time of informed consent through 120 days after the last dose 
trial therapy. 
 
3.2 
Exclusion Criteria 
 
3.2.1 
Prior chemotherapy and/or enzalutamide for metastatic castration-resistant prostate 
cancer. Chemotherapy administered in the castration-sensitive setting is allowed provided 
last dose of chemotherapy was greater than 6 months prior to study entry. 
 
3.2.2 
Is currently participating and receiving study therapy or has participated in a study of an 
investigational agent and received study therapy or used an investigation device within 4 
weeks of enrollment. 
 
3.2.3 
Has not recovered (i.e., AE ≤Grade 1 or at baseline) from AEs due to a previously 
administered agent. Subjects with ≤Grade 2 neuropathy or ≤Grade 2 alopecia are an 
exception to this criterion and are allowed if relevant toxicity is stabilized. 
 
3.2.4 
If subjects received major surgery they must have recovered adequately from the toxicity 
and/or complications from the intervention prior to starting trial therapy. 
 
3.2.5 
Has a known additional malignancy that is progressing or requires active treatment. 
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the 
skin. 

Protocol UMCC 2017.055 
Page 22 of 69 
 
 
 
 
 
 
3.2.6 
Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. At the time of signing informed consent is a known 
regular user (including "recreational use") of any illicit drug(s) or had a recent history 
(within the last year) of drug or alcohol abuse. 
 
3.2.7 
Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies). 
 
3.2.8 
Has known active hepatitis B (e.g., HBsAg reactive) or hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
 
3.2.9 
Has received a live virus vaccine within 30 days of planned start of trial therapy. 
 
3.2.10 Has known active CNS metastases and/or carcinomatous meningitis. Subjects with 
previously treated brain metastases may participate provided they have stable brain 
metastases (stability is normally defined as a period of 1 to 3 months in which there is no 
evidence of new or enlarging CNS metastases). 
 
3.2.11 Has symptomatic ascites or pleural effusion; a subject who is clinically stable following 
treatment for these conditions is eligible. 
 
3.2.12 Has had a prior allogeneic stem cell or bone marrow transplant. 
 
3.2.13 Has known contraindication to aspirin (81 mg). 
 
 
4.0 
SUBJECT SCREENING AND REGISTRATION PROCEDURES 
Patient registration for this trial will be centrally managed by the Coordinating Center of the 
University of Michigan Rogel Cancer Center as described below: 
 
A potential study subject who has been screened for the trial and who has signed the Informed 
Consent document will be initially documented by the participating site on the Screening and 
Enrollment Log provided by the Coordinating Center. 
 
It is the responsibility of the local site investigator to determine patient eligibility prior to submitting 
patient registration request to the Coordinating Center. After patient eligibility has been 
determined, a copy of the completed Eligibility Worksheet together with all the pertinent de- 
identified source documents will be submitted by the requesting site to the Coordinating Center, 
by email to CTSU-Oncology-Multisite@med.umich.edu. 
 
The Multi-Site Coordinator, who acts as the registrar, will review the submitted documents and 
process the registration. Sites should inform the Multi-Site Coordinator of a potential registration 
by 5 p.m. on the day prior to registration. Same day registrations cannot be guaranteed. 
 
An email will be sent by the registrar to the requesting site registrar to confirm patient registration 
and to provide the study identification number that has been assigned to the patient. In addition, a 
copy of the completed Eligibility Worksheet signed and dated by the registrar, will be sent back to 
the requesting site registrar. 
 
Patients found to be ineligible for participation after being consented will be considered screen 
failures, and documented as such in the Screening and Enrollment Log. These patients will not 
have study identification number assigned to them, and will not receive study treatment. 

Protocol UMCC 2017.055 
Page 23 of 69 
 
 
 
 
 
5.0 
TREATMENT PLAN 
 
5.1 
Treatment Dosage and Administration 
Protocol treatment must start within 14 business days of enrollment to the study. 
 
5.1.1 
Overall Treatment Plan: 
 
Phase Ib/II: All registered subjects will be treated with IONIS-AR-2.5Rx (ASO) in combination 
with enzalutamide. IONIS-AR-2.5Rx will be given intravenously in 60-minute infusions on Days 
1, 4, 8, 11, 15 on cycle 1, then on days 1,8,15 in subsequent 21-day cycles. Enzalutamide will 
be taken daily in 21 day cycles starting Day 1 of cycle 1. Treatment will continue until clinical or 
radiologic progression or unacceptable toxicity. The infusion duration may be extended to 120 
minutes for individuals experiencing infusion reactions. 
 
 
• 
Baseline archival CRPC tumor tissue will be collected (mandatory) as well as tumor biopsies 
(optional) after 2 cycles of IONIS-AR-2.5Rx and, tumor biopsies (optional) at progression. 
 
Phase 
Agent 
Premedications; 
Precautions 
Starting 
Dose 
Route 
Schedule 
Phase Ib 
and II 
IONIS-AR-2.5Rx 
Per institutional 
standards for low 
emetogenic risk 
Assigned 
Dose 
Level (See 
table in 
5.1.2) 
IV 
infusion 
over 60 
minutes 
(+/-15 
minutes) 
*Days 
1,4, 8, 11 
and 15 of 
cycle #1. 
*Days 1, 
8, 15 of 
each 
subseque 
nt 21-day 
cycle 
Phase Ib 
Enzalutamide 
No premedications 
160 
mg Oral 
Day 1-21 
and II 
mandated but may 
Qday 
of each 
be used at 
21-day 
investigator 
cycle 
discretion/institution 
al standards 
 
Starting on Cycle 1 Day 1, all subjects should take ASA 81 mg PO Qday unless 
contraindicated. 
 
As noted in section 1.2, the primary study drug IONIS-AR-2.5Rx has been associated with an 
increased risk of venous thromboembolism (VTE) in early clinical data. Prostate cancer is not 
associated with a high baseline incidence of VTE, and therefore routine VTE prophylaxis is not 
required in this patient population based on current NCCN guidelines for cancer-associated VTE. 
Low-dose aspirin for VTE prophylaxis has been recommend in multiple myeloma patients based 
on these NCCN guidelines (https://www.nccn.org/professionals/physician_gls/f_guidelines.asp). 
The overall likelihood of increased risk of VTE events with use of IONIS-AR-2.5Rx in prostate 
cancer patients is unknown, but given the relatively increased rate of VTE events in the initial 
study population, VTE prophylaxis appears to be warranted in further clinical study populations. 

Protocol UMCC 2017.055 
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Patients in the current phase II trial will receive low dose aspirin (81 mg) daily while receiving 
study drug to mitigate the apparent increased risk of VTE. 
 
Clotting and bleeding functions including platelet counts will be closely monitored on this study 
including weekly CBCPD, PT/PTT/INR and reviewed continuously as well at the interim analysis 
time points. If so needed and indicated by the data, including at interim safety analysis and 
continually by the Data and Safety Monitoring Board, we would modify the above strategy 
towards either escalating the prophylactic anti-coagulation to enoxaparin 40 mg daily, for 
example, or removing the 81 mg daily dose of aspirin. 
 
5.1.2 
Upon enrollment, each patient will be assigned a dose level from the statistician to initiate 
treatment.  (See Section 11 for further details.) 
Assigned Dose level (TITE-CRM): 
 
Assigned Dose Level 
Enzalutamide Dose 
IONIS-AR-2.5Rx Dose 
3 
160 mg 
900 mg 
2 
160 mg 
750 mg 
1 
160 mg 
600 mg 
 
 
5.1.3 
Definition of Dose Limiting Toxicity (DLT): 
Excessive toxicity/dose limiting toxicity (DLT) will be defined as any Grade 3 or higher toxicity (as 
defined by CTCAE v5.0) that occurs during the DLT evaluation period (2 cycles plus labs prior to 
start of cycle 3). Toxicity that is clearly and directly related to the primary disease or to another 
etiology is excluded from this definition. The following will be DLTs: 
 
• 
Liver transaminase elevation Grade 2 lasting 14 calendar days or more OR 
Liver transaminase elevation Grade 3 or 4 
• 
Grade 3 or Grade 4 febrile neutropenia will be a DLT regardless of duration or 
reversibility 
• 
Grade 3 thrombocytopenia that IS associated with clinically significant bleeding that 
requires medical intervention 
 
 
The DLT Definition excludes the following conditions: 
 
• 
Grade 3 fatigue lasting ≤ 7 days 
• 
Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that is managed 
with or without systemic corticosteroid therapy and/or hormone replacement therapy and 
the subject is asymptomatic 
• 
Grade 3 infusion-related reaction (first occurrence and in the absence of steroid 
prophylaxis) that resolves within 6 hours with appropriate clinical management 
• 
Grade 3 or 4 lymphopenia 
• 
Grade 3 or 4 neutropenia that is not associated with fever or systemic infection that 
improves within 7 days 
• 
Grade 3 thrombocytopenia that is not associated with clinically significant bleeding that 
requires medical intervention, and improves by at least 1 grade within 3 days 
• 
Isolated Grade 3 electrolyte abnormalities that are not associated with clinical signs or 
symptoms OR are reversed with appropriate maximal medical intervention within 3 days 
• 
Grade 3 laboratory abnormalities that are responsive to oral supplementation OR deemed 
by the investigator to be clinically non-significant 
 
A withdrawal or death within the first 2 cycles (42 days) not related to treatment will not be 
considered a DLT. 
 
DLTs will be counted based on the number of subjects with DLT at a given dose level, not the 
absolute number of DLTs. No single subject can trigger more than one DLT event. 

Protocol UMCC 2017.055 
Page 25 of 69 
 
 
 
5.2 
Toxicities and Dosing Delays/Dose Modifications 
Any patient who receives treatment on this protocol will be evaluable for toxicity. Each patient will 
be assessed for the development of toxicity according to the Time and Events Table (Section 
6.4). Toxicity will be assessed according to the NCI Common Terminology Criteria for Adverse 
Events (CTCAE), version 5.0. Dose adjustments should be made according to the system 
showing the greatest degree of toxicity. 
 
5.2.1 
IONIS-AR-2.5Rx 
 
IONIS-AR-2.5 Rx Dose Modification Levels 
 
Dose reduction levels 
Assigned Dose Level = 1 
Assigned Dose Level = 2 Assigned Dose Level = 3 
Starting Dose 
600 mg 
750 mg 
900 mg 
-1 
450 mg 
600 mg 
750 mg 
-2 
300 mg 
450 mg 
600 mg 
-3 
150 mg 
300 mg 
450 mg 
 
Hematological Toxicities 
 
Hematological Toxicity Dose Reductions for IONIS-AR-2.5Rx (AR ASO) 
ANC1 
Platelets 
Action 
≥ 1,500/µL or 
≥100,000/µL 
None. 
1000-1499/µL or 
75,000-99,000/µL 
-1st Occurrence: Hold current dose until ANC ≥ 
1,500/µL and platelets ≥ 100,000/µL. Do not 
replace missed doses. Restart IONIS-AR-2.5Rx at 
the next lower dose level as available. 
-2nd Occurrence: Hold current dose until ANC ≥ 
1,500/µL and platelets ≥ 100,000/µL. Do not 
replace missed doses. Restart IONIS-AR-2.5Rx at 
the next lower dose level as available. 
-3rd Occurrence: Hold current dose until ANC ≥ 
1,500/µL and platelets ≥ 100,000/µL. Do not 
replace missed doses. Restart IONIS-AR-2.5Rx at 
the next lower dose level as available. 
-4th Occurrence: Discontinue protocol therapy. 
500-999/µL or 
50,000-74,000/µL 
-1st Occurrence: Hold current dose until ANC ≥ 
1,500/µL and platelets ≥ 100,000/µL. Do not 
replace missed doses. Restart IONIS-AR-2.5Rx at 
the next lower dose level as available. 
-2nd Occurrence: Hold current dose until ANC ≥ 
1,500/µL and platelets ≥ 100,000/µL. Do not 
replace missed doses. Restart IONIS-AR-2.5Rx at 
the next lower dose level as available. 
-3rd Occurrence: Hold current dose until ANC ≥ 
1,500/µL and platelets ≥ 100,000/µL. Do not 
replace missed doses. Restart IONIS-AR-2.5Rx at 
the next lower dose level as available. 
-4th Occurrence: Discontinue protocol therapy. 

Protocol UMCC 2017.055 
Page 26 of 69 
 
 
 
 
 
<500/µL or 
<50,000/µL 
-1st Occurrence: Hold current dose until ANC ≥ 
1,500/µL and platelets ≥ 100,000/µL. Restart 
IONIS-AR-2.5Rx at the next lower dose level as 
available. 
-2nd Occurrence: Hold current dose until ANC ≥ 
1,500/µL and platelets ≥ 100,000/µL. Do not 
replace missed doses. Restart IONIS-AR-2.5Rx at 
the next lower dose level as available. 
-3rd Occurrence: Discontinue protocol therapy. 
1Note: G-CSF (Filgrastim) may be added for low ANC on day of treatment BEFORE a dose reduction 
is instituted at treating physician’s discretions. Neulasta® is NOT allowed. 
 
Dose Modifications for Hepatic Toxicity 
Patients who develop abnormal liver function tests as defined below, for any reason while on 
study, will have treatment held and/or reduced according to the following schedules: 
 
HEPATOTOXICITY (BILIRUBIN, SGPT/ALT, SGOT/AST) 
TOTAL BILIRUBIN without ALT/AST increase above baseline value 
Grade 1 (> ULN – 1.5 x ULN) 
Maintain IONIS-AR-2.5Rx level with LFTs monitored bi-weekly. 
 
 
Grade 2 (> 1.5 – 3.0 x 
ULN) 
Interrupt dosing of IONIS-AR-2.5Rx. If resolved to ≤ grade 1 in ≤ 28 days, 
then reduce by 1 dose level and resume IONIS-AR-2.5Rx therapy. If 
toxicity recurs after three dose reductions OR does NOT resolve to ≤ 
grade 1 in ≤ 28 days, discontinue IONIS-AR-2.5Rx therapy. 
Grade 3 (> 3.0 – 10.0 x 
ULN) 
Interrupt dosing of IONIS-AR-2.5Rx. If resolved to ≤ grade 1 in ≤ 28 days, 
lower by 1 dose level of IONIS-AR-2.5Rx. If toxicity does NOT resolve to 
≤ grade 1 in ≤ 28 days or toxicity recurs, discontinue IONIS-AR-2.5Rx 
Grade 4 (> 10.0 x ULN) 
Discontinue IONIS-AR-2.5Rx. 
Confounding factors and/or alternative causes for increase of total bilirubin should be excluded before 
dose interruption/reduction. They include but are not limited to: evidence of obstruction, such as elevated 
ALP and GGT typical of gall bladder or bile duct disease, hyperbilirubinemia due to the indirect component 
only (i.e. direct bilirubin component ≤ 1 x ULN) due to hemolysis or Gilbert Syndrome, pharmacologic 
treatment, viral hepatitis, alcoholic or autoimmune hepatitis, other hepatotoxic drugs. 
For patients with Gilbert Syndrome, these dose modifications apply to changes in direct bilirubin only.
Bilirubin will be fractionated if elevated. 
 
AST or ALT 
AST or ALT without bilirubin elevation > 2 x ULN 
Same grade as baseline or increase from baseline grade 
0 to grade 1 
No dose adjustment required with LFTs 
monitored weekly if same grade as baseline or 
bi-weekly in case of increase from baseline 
grade 0 to 1. 

Protocol UMCC 2017.055 
Page 27 of 69 
 
 
 
 
 
Increase from baseline to grade 2 (> 3.0– 5.0 x ULN) 
OR 
from baseline grade 2 to grade 3 (> 5.0 – 
20.0 x ULN) 
Interrupt dosing of IONIS-AR-2.5Rx. If resolved to 
≤ grade 1 in ≤ 28 days, then reduce by one dose
level and resume IONIS-AR-2.5Rx therapy. 
If toxicity recurs, then reduce by 1 dose level and 
resume IONIS-AR-2.5Rx. 
If toxicity recurs after three dose reductions OR
does NOT resolve to ≤ grade 1 in ≤ 28  days,
discontinue IONIS-AR-2.5Rx therapy. 
Increase from baseline grade 0 or 1 to grade 3 (> 5.0– 
20.0 x ULN) 
Interrupt dosing of IONIS-AR-2.5Rx until resolved
to ≤ baseline value, then lower 1 dose level of
IONIS-AR-2.5Rx. 
If toxicity recurs, discontinue IONIS-AR-2.5Rx. 
If toxicity does NOT resolve to ≤ baseline value in 
≤ 28 days, discontinue IONIS-AR-2.5Rx therapy. 
Grade 4 (> 20.0 x ULN) 
Discontinue IONIS-AR-2.5Rx. 
 
AST or ALT and concurrent Bilirubin elevation 
AST or ALT ≥ grade 2 (> 3 x ULN) in patients with normal 
values at baseline and total bilirubin > 2 x ULN 
OR 
AST or ALT ≥ grade 3 (> 5 x ULN) in patients with grade 
1 or 2 at baseline, and total bilirubin > 2 x ULN 
Discontinue IONIS-AR-2.5Rx. 
Confounding factors and/or alternative causes for increased transaminases should be excluded before 
dose interruption/reduction. They include but are not limited to: concomitant medications, herbal 
preparations or dietary supplements, infection, hepato-biliary disorder or obstruction, new or progressive 
liver metastasis, and alcohol intake. 
 
Additional follow-up for hepatic toxicities 
Hepatic toxicity monitoring includes the following LFTs: albumin, ALT, AST, total bilirubin 
(fractionated if total bilirubin > 2 x ULN), alkaline phosphatase, and GGT. For patients with Gilbert 
Syndrome: total and direct bilirubin must be monitored, intensified monitoring applies to changes 
in direct bilirubin only. 
 
Close observation is recommended in case of AST, ALT, and/or bilirubin increase requiring dose 
interruption, which involves: 
 Repeating liver enzyme and serum bilirubin tests two or three times weekly. Frequency 
of re- testing can decrease to once a week or less if abnormalities stabilize or return to 
normal values. 
 Obtaining a more detailed history of current symptoms. 
 Obtaining a more detailed history of prior and/or concurrent diseases. 
 Obtaining a history of concomitant drug use (including non-prescription medications, 
herbal and dietary supplements), alcohol use, recreational drug use, and special diets. 
 Ruling out acute viral hepatitis types A, B, C, D, and E; hepatotropic virus infections (CMV, 
EBV or HSV); autoimmune or alcoholic hepatitis; NASH; hypoxic/ischemic hepatopathy; 
and biliary tract disease. 

Protocol UMCC 2017.055 
Page 28 of 69 
 
 
 
 
 
 Obtaining a history of exposure to environmental chemical agents. 
 Obtaining additional tests to evaluate liver function, as appropriate (e.g., INR, direct 
bilirubin). 
 Considering gastroenterology or hepatology consultations. 
 Assessing cardiovascular dysfunction or impaired liver oxygenation, including 
hypotension or right heart failure as possible etiologies for liver dysfunction. 
 
Hypersensitivity infusion reaction. 
Patients will be monitored for signs and symptoms of infusion-related reactions including rigors, 
chills. wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For severe (Grade 3) 
or life-threatening (Grade 4) infusion-related reactions, stop infusion of IONIS-AR-2.5Rx. Signs and 
symptoms usually develop during or shortly after drug infusion and generally resolve completely 
within 24 hours of completion of infusion. 
 
Dose Modifications for other Non-Hematologic Toxicity 
• 
For treatment regimen-related toxicities > grade 3 (excluding the hematologic, liver 
toxicities outlined above, as well as grade 3 nausea/vomiting/diarrhea/fatigue lasting less 
than 48 hours with optimal medical management, any grade alopecia, or non-clinically 
significant laboratory abnormalities that resolve within 48 hours with optimal medical 
management), IONIS-AR-2.5Rx should be withheld until resolution to < grade 1 (or to 
baseline if baseline was greater than grade 1). Treatment may be restarted at next lower 
dose level if the toxicity improves to grade 1 or lower within 14 days of onset of adverse 
event. If toxicity recurs at grade 3 or higher, patients will be required to discontinue IONIS- 
AR-2.5Rx therapy. 
 
• 
 IONIS-AR-2.5Rx treatment days should be skipped for grade 2 related toxicities and 
restarted at the original dose level once recovered to grade ≤ 1. If the same toxicity recurs 
at grade 2, interrupt IONIS-AR-2.5Rx until recovery to grade ≤ 1, then restart IONIS-AR-
2.5Rx at the next lower dose level. Discontinue IONIS-AR-2.5Rx therapy IF toxicity recurs 
after three dose reductions or does not improve to grade 1 or lower within 28 days of onset 
of adverse event. 
 
• 
 IONIS-AR-2.5Rx should be discontinued for Grade 4 non-hematologic toxicities that are 
possibly related to the study treatment, unless otherwise specified in the protocol 
(excluding: grade 4 nausea/vomiting/diarrhea/fatigue lasting less than 48 hours with 
optimal medical management, any grade alopecia, or non-clinically significant laboratory 
abnormalities that resolve within 48 hours with optimal medical management). 
 
5.2.2 
Enzalutamide 
 
Enzalutamide Dose Modification Levels 
 
Dose reduction levels 
enzalutamide 
(starting dose) 
160 mg/day 
-1 
120 mg/day 
-2 
80 mg/day 
 
Hepatic Toxicity 
 
 
For ≥ Grade 2 ALT or AST or Bilirubin (see Investigations in CTCAE v. 5.0), treatment days 
should be skipped for grade 2 related toxicities and restarted at the original dose level once 
recovered to grade ≤ 1. If the same toxicity recurs at ≥ grade 2, interrupt enzalutamide. Restart 
enzalutamide at one dose level reduction when ALT, AST, and bilirubin recover to Grade 1. 
Discontinue enzalutamide therapy IF toxicity recurs after two dose reductions or does not 
improve to grade 1 or lower within 28 days of onset of adverse event. 

Protocol UMCC 2017.055 
Page 29 of 69 
 
 
 
For hepatic failure (see Hepatobiliary Disorders in CTCAE v. 5.0), discontinue enzalutamide.  
 
Neurologic toxicity 
Discontinue enzalutamide for any seizure. 
 
Reversible posterior leukoencephalopathy syndrome (RPLS) 
For signs and symptoms suggestive of reversible posterior leukoencephalopathy syndrome 
(RPLS) such as confusion, headache, seizures, and cortical blindness, hold enzalutamide for up 
to 4 weeks. Suspected RPLS should be investigated with MRI. If diagnosis of RPLS is confirmed, 
enzalutamide should be permanently discontinued. If RPLS is ruled out via MRI and signs and 
symptoms attributed to another cause, enzalutamide should resume. 
 
Hypersensitivity 
Discontinue enzalutamide. 
 
Ischemic Heart Disease 
Optimize management of cardiovascular risk factors. Discontinue enzalutamide for Grade 3-4 
events. 
 
Falls and Fractures 
Falls and fractures occurred in 10% and 8% of patients receiving enzalutamide, respectively. 
Evaluate patients for fracture and fall risk, and treat patients with bone-targeting agents according 
to established guidelines. 
 
Other Non-Hematologic Grade 3 or 4 Toxicity 
For patients who experience a Grade 3 or greater toxicity attributed to enzalutamide, 
enzalutamide should be held for one week or until symptoms improve to ≤ Grade 2. Patients 
may be re-started on enzalutamide at the same or one dose level reduction. If treatment is 
held for more than 4 weeks, discontinue protocol therapy. 
 
5.3 
Concomitant Medications/Treatments 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial. If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may be 
required. The investigator should discuss any questions regarding this with the Study PI. The 
final decision on any supportive therapy or vaccination rests with the investigator and/or the 
subject's primary physician. However, the decision to continue the subject on trial therapy or 
vaccination schedule requires the mutual agreement of the investigator, the Sponsor and the 
subject. 
Use of bisphosphonates/RANKL inhibitors are standard in CRPC and are allowed on the study. 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment of this trial: 
• 
Antineoplastic systemic chemotherapy or biological therapy except for ongoing 
androgen deprivation therapy (e.g. with LHRH agonist/antagonist) 
• 
Immunotherapy 
• 
Chemotherapy not specified in this protocol 
• 
Investigational agents 
• 
5 α-reductase inhibitors (e.g., finasteride, dutasteride). 
• 
Any herbal product known to decrease PSA levels (eg. Saw Palmetto and PC-SPES) 
• 
Neulasta® 
• 
Radiation therapy 
o 
Local intervention is discouraged unless medically unavoidable. Radiation 
therapy to a symptomatic solitary lesion/area may be considered on a 

Protocol UMCC 2017.055 
Page 30 of 69 
 
 
 
 
 
case-by-case basis after consultation with the Principal Investigator 
(except during screening). Subjects receiving local intervention (e.g., 
palliative radiation) are allowed to continue to receive study treatment at 
the investigator’s discretion. Subjects who receive local intervention may 
be considered not evaluable (and may be assigned a conservative 
censoring or progression date). 
• 
Live vaccines within 30 days prior to the first dose of treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited   
to, the following: measles, mumps, rubella, varicella/zoster, yellow fever, 
intranasal influenza, rabies, BCG (tuberculosis vaccine), and typhoid vaccine. 
• 
Systemic glucocorticoids or other immunosuppressive drugs for any purpose other 
than to modulate symptoms from a drug-related AE of immunologic  etiology (refer 
to Section 5.2 – Dose Modification). The use of physiologic doses of corticosteroids 
may be approved after consultation with the Study PI. 
o Use of prophylactic corticosteroids to avoid allergic and other adverse 
reactions (e.g., to IV contrast dye or transfusions) is permitted. 
o Use of intermittent inhaled steroids or local  injection  of  corticosteroids is 
permitted upon consultation with the Principal Investigator. 
o Physiologic doses of prednisone ≤10 mg (or equivalent) per day. 
• 
Avoid strong CYP2C8 inhibitors CYP3A4 inducers as they can increase the 
plasma exposure to enzalutamide. If co-administration is necessary, reduce the 
dose of enzalutamide. 
• 
Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic 
index as enzalutamide may decrease the plasma exposure of these drugs. 
• 
The exclusion criteria describe other medications prohibited in this trial. 
5.4 
Other Modalities or Procedures 
No other modalities or procedures will be used in this protocol 
 
5.5 
Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue until any one 
or more of the following criteria apply: 
• 
Disease progression 
• 
Inter-current illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Patient voluntarily withdraws from treatment 
• 
General or specific changes in the patient’s condition that render the patient unacceptable for 
further treatment in the judgment of the treating investigator OR 
• 
Investigator determination that the patient is no longer benefitting from protocol therapy. 
If treatment is stopped due to one or more of the criteria above, both enzalutamide and IONIS- 
AR-2.5Rx ASO will be discontinued. 
 
5.6 
Off Treatment Criteria 
Patients will be removed from protocol specified therapy when any of the respective criteria listed 
in Section 5.5 apply. 
 
Document in the source the reason for ending protocol therapy and the date the patient was 
removed from treatment. 

Protocol UMCC 2017.055 
Page 31 of 69 
 
 
 
 
 
All patients who discontinue treatment should comply with protocol specific follow-up procedures. 
The only exception to this requirement is when a subject withdraws consent for all study 
procedures or loses the ability to consent freely. 
 
5.7 
Duration of Follow-Up 
Patients will be followed for up to 24 months after removal from treatment or until death, 
whichever occurs first. Patients removed from treatment for unacceptable adverse events will be 
followed until resolution or stabilization of the adverse events. 
 
5.8 
Off Study Criteria 
Patients can be taken off study at any time at their own request, or they may be withdrawn at the 
discretion of the investigator for safety, behavioral or administrative reasons. The reason(s) for 
discontinuation from study will be documented and may include: 
 
5.8.1 
Patient withdraws consent (termination of treatment and follow-up); 
 
5.8.2 
Loss of ability to freely provide consent through imprisonment or involuntary incarceration 
for treatment; 
 
5.8.3 
Patient is unable to comply with protocol requirements; 
 
5.8.4 
Treating physician determines continuation on the study would not be in the patient’s best 
interest; 
 
5.8.5 
Development of second malignancy (except for basal cell carcinoma or squamous cell 
carcinoma of the skin) that requires treatment, which would interfere with this study; 
 
5.8.6 
Lost to Follow-up. If a research subject cannot be located to document survival after a 
period of 2 years, the subject may be considered “lost to follow-up.” All attempts to 
contact the subject during the two years must be documented; 
 
5.8.7 
Termination of the study by the University of Michigan; 
 
5.8.8 
Patient completes protocol treatment and follow-up criteria. 
 
5.9 
Patient Replacement 
Patients who do not receive any dose of the study drug IONIS-AR-2.5Rx will be replaced. 

Protocol UMCC 2017.055 
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6.0 
STUDY PROCEDURES 
Time and Events Table 
All assessments have a window of ± 3 business days except for imaging/tumor measurements where a 
window of ± 7 business days will apply or unless otherwise specified. 
 
Cycle length = 21 days 
 
Trial period 
Screening 
Treatment 
Safety Follow- 
up/EOT 
Follow-up 
Visits 
Treatment Cycle/Title 
Screening 
Visit 
Cycle 1 
Cycle 2+ 
(every 21 
days) 
(+/-3 business 
days) 
30 days from 
last dose of 
IONIS-AR-
2.5Rx (+/- 7 
business 
days) 
Every 12 
weeks (+/-7 
business 
days) For up 
to 24 months 
Scheduling Window 
(Days) 
-28 to -1 
D 
1 
D 
4 
D 
8 
D 
11 
D 
15 
D 
1 
D 
8 
D 
15 
Administrative 
Procedures: 
Informed Consent 
X 
Review Eligibility Criteria 
X 
Demographics and 
Medical History 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Survival Status 
X6 
Clinical Assessments: 
Review Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height5, Weight 
X 
X 
X 
X 
ECOG Performance 
Status 
X 
X 
X 
X 
Laboratory 
Assessments: 
PT/INR and PTT/aPTT 
X 
X 
X 
X 
X 
X 
X 
CBC with differential, 
platelets 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Comprehensive 
Metabolic Panel1, D- 
dimer 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PSA 
X 
X 
X 
X 
X 
Testosterone 
X 
X 
X 
TSH, free T3, free T4 (If 
Clinically Indicated: FSH, 
LH, ACTH) 
X 
X 
Treatment: 
IONIS-AR-2.5Rx4 
X 
X 
X 
X 
X 
X 
X 
X 
Enzalutamide 
PO daily in 21-day cycles 

Protocol UMCC 2017.055 
Page 33 of 69 
 
 
 
Trial period 
Screening 
Treatment 
Safety Follow- 
up/EOT 
Follow-up 
Visits 
Treatment Cycle/Title 
Screening 
Visit 
Cycle 1 
Cycle 2+ 
(every 21 
days) 
(+/-3 business 
days) 
30 days from 
last dose of 
IONIS-AR-
2.5Rx (+/- 7 
business 
days) 
Every 12 
weeks (+/-7 
business 
days) For up 
to 24 months 
Scheduling Window 
(Days) 
-28 to -1 
D 
1 
D 
4 
D 
8 
D 
11 
D 
15 
D 
1 
D 
8 
D 
15 
Imaging Tumor 
Assessments2 
CT chest/CXR 
X 
X 
X 
MRI Abdomen/Pelvis or 
CT Abdomen/Pelvis 
X 
X 
X 
Bone Scan 
X 
X 
X 
QoL questionnaires3 
X 
X 
X 
Correlatives 
Whole blood for banking 
 
X 
pre-
dose 
Tumor Tissue Archival 
CRPC 
X 
Tumor Tissue Biopsy7 
X 
X 
X 
PK Plasma IONIS-AR- 
2.5Rx concentration (pre-
dose)8,10 
X 
X 
X 
X 
X 
X 
X 
X 
PK Plasma IONIS-AR- 
2.5Rx concentration (end 
of infusion)8,9,10 
X 
X 
X 
X 
X 
X 
X 
X 
 
1. Comprehensive metabolic panel (CMP) to include: albumin, alkaline phosphatase, ALT/SGPT, 
AST/SGOT, BUN, creatinine, electrolytes (sodium, potassium, calcium, chloride, 
bicarbonate), glucose, and total bilirubin; LDH, D-dimer. 
 
2. Imaging Assessments: Every 12 weeks or as clinically indicated. 
 
3. QoL questionnaires: FACT-P and EuroQoL-5D.  
 
4. Starting Cycle 1 Day 1, all subjects should take ASA 81 mg PO q day unless contraindicated. 
 
5. Height only at baseline. 
 
6. Survival status every 6 months. 
 
7. Tumor Tissue Biopsy at Screening is required only if Archival Tissue is not available. Tissue biopsy collection at 
post cycle 2 and Safety Follow-up/EOT is optional if subject consents; +/- 7working days. 
 
8. Plasma PK samples may also be used for profiling of drug binding proteins, bioanalytical method 
development and/or validation purposes, stability assessments, metabolite assessments, 
immunogenicity assessments or to assess other actions of IONIS-AR-2.5Rx with plasma 
constituents. 
 
9. Collected within 2 minutes before infusion is stopped 
 
10. Collected Cycle 1 Days 1, 4, 8, 11 and 15 and Cycle 2 Day 1, 8 and 15 only. 

Protocol UMCC 2017.055 
Page 34 of 69 
 
 
 
 
7.0 
MEASUREMENT OF EFFECT 
 
7.1 
Antitumor Effect- Solid Tumors 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee [JNCI 
92(3):205-216, 2000]. Changes in only the largest diameter (unidimensional measurement) of the 
tumor lesions are used in the RECIST v1.1 criteria. 
 
7.1.1 
Definitions 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their first 
treatment with IONIS-AR-2.5Rx. 
 
Evaluable for PSA response. Only those patients who have received at least 1 dose of 
IONIS-AR-2.5Rx, and have at least 2 PSA measures at least 1 week apart after initiating 
treatment will be considered evaluable for PSA response. (Note: Patients who exhibit 
objective disease progression prior to the end of cycle 2 will also be considered 
evaluable and will be classified as PSA non-response). 
 
Evaluable for objective response. Only those patients who have measurable disease 
present at baseline, have received at least 1 dose of IONIS-AR-2.5Rx, and have had 
their disease re-evaluated will be considered evaluable for objective response. These 
patients will have their response classified according to the definitions stated below. 
(Note: Patients who exhibit objective disease progression prior to the end of cycle 4 will 
also be considered evaluable). 
 
7.1.2 
Disease Parameters 
Measurable disease. Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter in the plane of measurement is to 
be recorded) with a minimum size of: 
 
• 
10mm by CT scan (irrespective of scanner type) for studies with a slice thickness 
of <5mm or twice the slice thickness or MRI 
• 
10mm caliper measurement by clinical exam (lesions which cannot be 
accurately measured with calipers should be recorded as 
non-measurable) 
• 
20mm by chest X-ray (if clearly defined and surrounded by aerated lung) 
 
All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Note: Tumor lesions that are situated in a previously irradiated area are not considered 
measurable. 
 
Non-measurable disease. All other lesions (or sites of disease), including small lesions 
(longest diameter <20 mm with conventional techniques or <10 mm using CT scan), are 
considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, 
abdominal masses (not followed by CT or MRI), and cystic lesions are all non- 
measurable. 
 

Protocol UMCC 2017.055 
Page 35 of 69 
 
 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total should be identified as target lesions and recorded and measured at 
baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organ, but in addition should be those 
that lend themselves to reproducible repeated measurements. 
 
Lymph nodes merit special mention since they are normal anatomical structures which 
may be visible by imaging even if not involved by tumor. Pathological nodes which are 
defined as measurable and may be identified as target lesions must meet the criterion of 
a short axis of ≥15mm by CT scan. Only the short axis of these nodes will contribute to 
the baseline sum. The short axis of the node is the diameter normally used by 
radiologists to judge if a node is involved by solid tumor. Nodal size is normally reported 
as two dimensions in the plane in which the image is obtained (for CT scan this is almost 
always the axial plane; for MRI the plane of acquisition may be axial, sagittal or coronal). 
The smaller of these measures is the short axis. For example, an abdominal node which 
is reported as being 20mm x 30mm has a short axis of 20mm and qualifies as a 
malignant, measurable node. In this example, 20mm should be recorded as the node 
measurement. All other pathological nodes (those with short axis ≥10mm but <15 mm) 
should be considered non-target lesions. Nodes that have a short axis <10mm are 
considered nonpathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters. If lymph 
nodes are to be included in the sum, then as noted above, only the short axis is added 
into the sum. The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
 
Non-target lesions. All other lesions (or sites of disease) including pathological lymph 
nodes should be identified as non-target lesions and should also be recorded at baseline. 
Measurements are not required and these lesions should be followed as ‘present’, 
‘absent’, or in rare cases ‘unequivocal progression’ (more details to follow). In addition, it 
is possible to record multiple non-target lesions involving the same organ as a single item 
on the case record form (e.g. ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver 
metastases’). 
 
7.1.3 
Guidelines for Evaluation of Measurable Disease 
All measurements should be recorded in metric notation, using calipers if clinically 
assessed. All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. Imaging 
based evaluation should always be done rather than clinical examination unless the 
lesion(s) being followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial and >10mm diameter as assessed using calipers (e.g. skin nodules). For the 
case of skin lesions, documentation by color photography including a ruler to estimate the 
size of the lesion is suggested. As noted above, when lesions can be evaluated by both 
clinical exam and imaging, imaging evaluation should be undertaken since it is more 
objective and may also be reviewed at the end of the study. 
 
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions on chest X-ray may be considered measurable if they are 
clearly defined and surrounded by aerated lung. 
 
CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has defined measurability of lesions on 
CT scan based on the assumption that CT slice thickness is 5mm or less. When CT 

Protocol UMCC 2017.055 
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scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion 
should be twice the slice thickness. MRI is also acceptable in certain situations (e.g. for 
body scans). 
 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement. Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, 
it cannot be guaranteed that the same technique and measurements will be taken from 
one assessment to the next. If new lesions are identified by ultrasound in the course of 
the study, confirmation by CT or MRI is advised. If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. However, they can be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence 
following complete response or surgical resection is an endpoint. 
 
Tumor markers: Tumor markers alone cannot be used to assess objective tumor 
response. If markers are initially above the upper normal limit, however, they must 
normalize for a patient to be considered in complete response. Because tumor markers 
are disease specific, instructions for their measurement should be incorporated into 
protocols on a disease specific basis. Specific guidelines for PSA response (in recurrent 
prostate cancer), have been published 
 
Cytology, Histology: These techniques can be used to differentiate between PR and CR 
in rare cases if required by protocol (for example, residual lesions in tumor types such as 
germ cell tumors, where known residual benign tumors can remain). When effusions are 
known to be a potential adverse effect of treatment (e.g. with certain taxane compounds 
or angiogenesis inhibitors), the cytological confirmation of the neoplastic origin of any 
effusion that appears or worsens during treatment can be considered if the measurable 
tumor has met criteria for response or stable disease in order to differentiate between 
response (or stable disease) and progressive disease. 
 
7.2 
Response Criteria for RECIST 1.1 subjects with measurable disease 
 
7.2.1.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions, determined by two 
separate observations conducted not less than 4 weeks apart. There can be no 
appearance of new lesions. 
Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) 
of target lesions, taking as reference the baseline sum LD. There can be no appearance 
of new lesions. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, 
taking as reference the smallest sum LD recorded since the treatment started, or the 
appearance of one or more new lesions. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum LD since the treatment started. 
 
7.2.1.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker level. 

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Incomplete Response/Stable Disease (SD): Persistence of one or more non-target 
lesion(s) and/or maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. 
 
7.2.1.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started). The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
Target 
Lesions 
Non- 
Target 
Lesions 
New Lesions 
Overall 
Response 
Best 
Response for 
this Category 
Also 
Requires: 
CR 
CR 
No 
CR 
>4 wks. 
confirmation 
CR 
Non- 
CR/SD 
No 
PR 
>4 wks. 
confirmation 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
documented at 
least once >4 
wks. from 
baseline 
PD 
Any 
Yes or No 
PD 
no prior SD, 
PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression. 
Note: 
 Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of 
disease progression at that time should be reported as 
“symptomatic deterioration”. Every effort should be made to 
document the objective progression even after discontinuation of 
treatment. 
 
Note: If subjects respond to treatment and are able to have their disease resected, the 
patient’s response will be assessed prior to the surgery. 
 
 
7.2.2 
PSA Response 
 
Per PCWG3 criteria, PSA response rate will be defined as the proportion of subjects who have a PSA 
response defined by a 50% decline or more in PSA (ng/ml) from baseline measured twice at least 3 
weeks apart. Based on the PCWG3 criteria, a favorable effect on PSA may be delayed for ≥ 12 weeks. 
PSA will be monitored every cycle, but treatment will be planned to continue through early rises for 12 
weeks unless other evidence of progression, such as radiographic progression.  Therefore, early rises in 
PSA before 12 weeks will not be considered progression when determining PSA response.   
 
7.2.3 
PSA Progression by PCWG3 criteria 
 
PSA evidence for progressive prostate cancer consists of a PSA level of at least 1 ng/ml which has risen 

Protocol UMCC 2017.055 
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on at least 2 successive occasions, at least one week apart. If the third PSA (#3) value is less (i.e., #3b) 
than the screening PSA (#2) value, then an additional test for rising PSA (#4) will be required to document 
progression by PSA. All PSA progression as above will require confirmation of equal or higher PSA value 
at least 4 weeks later (from the #3a or #4 value as applicable).  Based on the PCWG3 criteria, a 
favorable effect on PSA may be delayed for ≥ 12 weeks. PSA will be monitored every cycle, but 
treatment will be planned to continue through early rises for 12 weeks unless other evidence of 
progression, such as radiographic progression. Therefore, early rises in PSA before 12 weeks will 
not be considered progression when determining PSA progression by PCWG3 criteria without 
evidence of other progression. 
 
 
 
7.2.4 
Bone Scan 
On bone scan, radiographic progression will be defined by PCWG3 criteria as ≥ 2 new 
bone lesions (Appendix B). However, for the first reassessment scan only, patients should 
remain on study and have a confirmatory scan performed 12 weeks later. If this 
confirmatory scan shows 2 or more additional new lesions, this defines progression. The 
date of progression is the date of the first reassessment bone scan. If the confirmatory 
scan does not show any additional new lesions, patient remains on study. If progression is 
observed on subsequent bone scans, a confirmatory scan is not required; the date of this 
bone scan is the date of progression (Appendix B). 
 
7.2.5 
Duration of Response 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for response (whether PSA response and/or RECIST 1.1 
response when applicable) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that recurrent disease is objectively documented. 
 
Duration of stable disease: Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started. 
 
7.2.6 
Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of treatment 
to time of progression whether PSA progression by PCWG3 criteria (see section 7.2.3 
above) and/or RECIST 1.1 criteria as applicable. 
 
 
 
7.3 
Safety/Tolerability 
 
Analyses will be performed for all patients having received at least one dose of study drug. The 
study will use the CTCAE version 5.0 for reporting of non-hematologic adverse events. 

Protocol UMCC 2017.055 
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8.0 
ADVERSE EVENTS 
 
8.1 
Experimental Therapy 
 
For the most recent safety update, please refer to the current Investigator’s Brochure or 
Study Agent Prescribing Information. 
 
8.1.1 
Special Warnings and Precautions for Use 
Contraception: 
Subjects receiving IONIS-AR-2.5Rx are advised to use two acceptable (to treating 
investigator) methods of birth control (one of which must include a condom as a barrier 
method of contraception) starting at the time of informed consent and continuing 
throughout the course of treatment and for at least 120 days after last dose of trial 
therapy. 
 
8.2 
Adverse Event Reporting Requirements 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial and is done to 
ensure the safety of subjects enrolled in the studies as well as those who will enroll in future 
studies using similar agents. Data on adverse events will be collected from the time of the initial 
study treatment administration or intervention through 30 days after the last dose of study 
treatment or study intervention. Any serious adverse event that occurs more than 30 days after 
the last study treatment or intervention and is considered related to the study treatment or 
intervention must also be reported. Serious Adverse Events (SAEs) will continue to be followed 
until: 
 
• 
Resolution or the symptoms or signs that constitute the serious adverse event return 
to baseline; 
• 
There is satisfactory explanation other than the study treatment or intervention for the 
changes observed; or 
• 
Death. 
 
The investigator is responsible for the detection, documentation, grading and assignment of 
attribution of events meeting the criteria and definition of an AE or SAE. The definitions 
 of AEs and SAEs are given below. It is the responsibility of the principal investigator to 
ensure that all staff involved in the trial is familiar with the content of this section. 
 
Any medical condition or laboratory abnormality with an onset date before initial study treatment 
administration or intervention is considered to be pre-existing in nature. Any known pre-existing 
conditions that are ongoing at time of study entry should be considered medical history. 
 
All events meeting the criteria and definition of an AE or SAE, as defined in Section 8.3, occurring 
from the initial study treatment administration or intervention through 30 days following the last 
dose of the study treatment or study intervention must be recorded as an adverse event in the 
patient’s source documents and on the CRF regardless of frequency, severity (grade) or 
assessed relationship to the study treatment or intervention. 
 
In addition to new events, any increase in the frequency or severity (i.e., toxicity grade) of a pre- 
existing condition that occurs after the patient begins study treatment or intervention is also 
considered an adverse event. 
 
 
 

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8.3 
Definitions 
 
8.3.1 Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient receiving study 
treatment and which does not necessarily have a causal relationship with this treatment. 
An AE can be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of an experimental 
intervention, whether or not related to the intervention. 
• 
Diagnostic and therapeutic non-invasive and invasive (i.e., surgical) procedures will 
not be reported as adverse events. However, the medical condition for which the 
procedure was performed must be reported if it meets the definition of an adverse 
event unless it is a pre-existing (prior to protocol treatment) condition.  
 
 
• 
Abnormal laboratory values or test results constitute adverse events if they induce 
clinical signs or symptoms or require therapy. They are to be captured under the 
signs, symptoms or diagnoses associated with them. 
 
8.3.2 Serious Adverse Event 
An adverse event is considered “serious” if, in the view of the sponsor investigator, it 
results in any of the following outcomes: 
 
o 
Death 
If death results from (progression of) the disease, the disease should be reported as 
event (SAE) itself. 
 
o 
A life-threatening adverse event 
An adverse event is considered ‘life-threatening’ if, in the view of either the 
investigator [or sponsor], its occurrence places the patient or subject at immediate 
risk of death. It does not include an adverse event that, had it occurred in a more 
severe form, might have caused death. 
 
o 
Inpatient hospitalization or prolongation of existing hospitalization for > 24 hours. 
 
o 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
 
o 
A congenital anomaly/birth defect 
o 
Important medical event 
Any event that may not result in death, be life-threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition of “Serious Adverse Event”. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home; convulsions that do not result in 
inpatient hospitalization or the development of drug dependency or drug abuse. 
 
Previously planned (prior to signing the informed consent form) surgeries should not 
be reported as SAEs unless the underlying medical condition has worsened during 
the course of the study. Preplanned hospitalizations or procedures for 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. However, if the preexisting condition worsened during the course of the study, 
it should be reported as an SAE. 

Protocol UMCC 2017.055 
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o 
Procedure in case of Pregnancy 
If during the conduct of the clinical trial, a male subject impregnates his partner, the 
subject should report the pregnancy to the investigator. The investigator should 
report the pregnancy to the Coordinating Center as an SAE within 24 hours of 
awareness of the event. The expected date of delivery or expected date of the end of 
the pregnancy, last menstruation, estimated fertility date, pregnancy result and 
neonatal data etc., should be included in this information. 
 
The investigator should report the outcome of the pregnancy (independent of 
outcome, e.g., full term delivery, pre-term delivery, spontaneous abortion, induced 
abortion, stillbirth, death of newborn, congenital anomaly [including anomaly in a 
miscarried fetus, etc.) in accordance with the same reporting procedure as for SAEs. 
The date of outcome of the pregnancy, gestational age, date of birth and neonatal 
data etc., should be included in this information. 
 
8.3.3 Expected Adverse Events 
An adverse event (AE) is considered “expected” if: 
 
• 
For approved and marketed drugs or devices, those adverse events are 
described in the approved Package Insert (Label). 
• 
For investigational new drugs or devices, those adverse events are described in 
the FDA Investigator’s Brochure. 
• 
In clinical research studies, information on expected adverse events is also 
summarized in the protocol and in the consent document. See section 9.1 for the 
list of expected adverse events related to the drug under study. 
 
8.3.4 Unexpected Adverse Event 
An adverse event (AE) is considered “unexpected” if it is not described in the Package 
Insert, Investigator’s Brochure, in the protocol, or in the informed consent document. 
 
8.4 
Adverse Event Characteristics 
 
8.4.1 CTCAE Term 
(AE description) and grade: The descriptions and grading scales found in the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for 
AE reporting. All appropriate treatment areas should have access to a copy of the 
CTCAE version 5.0. A copy of the CTCAE version 5.0 can be down loaded from the 
CTEP web site. (http://ctep.cancer.gov) 
 
8.4.2 Attribution of the AE 
The investigator or co-investigator is responsible for assignment of attribution. 
Definite – The AE is clearly related to the study [treatment/intervention]. 
Probable – The AE is likely related to the study [treatment/intervention]. 
Possible – The AE may be related to the study [treatment/intervention]. 
Unlikely – The AE is doubtfully related to the study [treatment/intervention]. 
Unrelated – The AE is clearly NOT related to the study [treatment/intervention]. 
 
8.5 
Serious Adverse Event Reporting Guidelines 
 
All serious adverse events (SAEs) and unanticipated problems (UPs), regardless of causality to 
study drug, will be reported to the Principal Investigator and also to the Coordinating Center. All 
SAEs and UPs must be reported to the Coordinating Center within 24 hours of first awareness of 
the event. Events should be reported using the Coordinating Center SAE form as available in the 
study database. A copy of the Coordinating Center SAE form should be sent to the Coordinating 
Center via fax at 734-232-0744 or via email to CTSU-Oncology-Multisite@med.umich.edu within 
24 hours of the site’s knowledge of the event. 

Protocol UMCC 2017.055 
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Principal Investigator Contact Information for SAE reporting: 
Ajjai Alva, MD 
Internal Medicine - Hematology/Oncology 
University of Michigan 
7316 Cancer Center 
1500 E. Medical Center Drive 
Ann Arbor, MI 48109 
Phone: (734) 936-0091 
Fax: 
(734) 615-2719 
Email: ajjai@umich.edu 
 
 
Follow-up information must also be reported within 24 hours of receipt of the information by the 
investigator. 
 
All SAEs and UPs will be reported to the local IRBs per current local institutional standards. 
 
The Coordinating Center will disseminate information regarding SAEs and UPs to the 
participating sites within 5 days of review of the information by the Coordinating Center’s Principal 
Investigator (or designee in the event of extended absence) only in the case that the event(s) is 
believed to be related (i.e., possibly, probably, or definitely) to the study drug. The Coordinating 
Center will be responsible for reporting of events to the FDA and supporters, as appropriate 
(outlined below). 
 
The University of Michigan acting as the Coordinating Center will be responsible for reporting to 
Ionis Pharmaceuticals by facsimile any Serious Adverse Event that occur during the SAE 
reporting period. The coordinating center will report the SAE within 24 hours of first awareness of 
the event (immediately if the event is fatal or life-threatening). 
 
8.5.1 
SERIOUS ADVERSE EVENT REPORTING TO THE FDA 
It is the responsibility of the IND Sponsor to submit an IND for clinical trials conducted 
with investigational agents and to ensure that FDA and all participating investigators are 
promptly informed of significant new AEs or risks with respect to the investigational 
agent. 
In this trial, serious unexpected adverse events believed to be definitely, probably 
or possibly related to the study treatment will be reported to the Food and Drug 
Administration via the MedWatch 3500A. The Coordinating Center, will coordinate 
with the IND Sponsor and/or designee for the reporting of any and all IND safety 
reports to the FDA as per the requirements outlined in 21 CFR 312.32. 
 
8.6 
Routine Reporting 
All other adverse events such as those that are expected, or are unlikely or definitely not related 
to the study participation are to be reported annually as part of regular data submission. 
 
8.7 
Reporting of Unanticipated Problems 
There are types of incidents, experiences and outcomes that occur during the conduct of human 
subjects research that represent unanticipated problems but are not considered adverse events. 
For example, some unanticipated problems involve social or economic harm instead of the 
physical or psychological harm associated with adverse events. In other cases, unanticipated 
problems place subjects or others at increased risk of harm, but no harm occurs. 
 
Upon becoming aware of any incident, experience, or outcome (not related to an adverse event) 
that may represent an unanticipated problem, the investigator should assess whether the 
incident, experience, or outcome represents an unanticipated problem. The incident, experience 
or outcomes is considered unanticipated if it meets all of the following criteria: 
 
1. Unexpected (in terms of nature, severity, or frequency); 

Protocol UMCC 2017.055 
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2. Related or possibly related to participation in the research; and 
3. Suggests that the research places subjects or others at a greater risk of harm 
than was previously known or recognized. 
 
If the investigator determines that the incident, experience, or outcome represents an 
unanticipated problem, the investigator must report it to the local IRB as per local 
guidelines. 
 
8.8 
Unblinding Procedures 
Not applicable 
 
8.9 
Stopping Rules 
See section 11.1 Safety Monitoring and Stopping Rule. The DSMC will have oversight on the 
safety and data integrity of the study on an ongoing basis. 
 
 
9.0 
DRUG INFORMATION 
 
9.1 
IONIS-AR-2.5Rx (or specifically ISIS 560131; formerly known as AZD5312) 
IONIS-AR-2.5Rx is an ASO targeting a region of the AR that results in selective and 
specific inhibition of full length, mutated, and splice-variant AR proteins. 
 
IONIS-AR-2.5Rx was designed with the purpose of specifically suppressing human AR 
expression, thereby providing potential therapeutic benefit to the patients who became 
unresponsive to traditional anti-hormonal therapies. Preclinical studies indicate that IONIS-AR- 
2.5Rx suppresses several other AR-regulated genes, suggesting a potential for this agent to be 
used as a cancer therapy where aberrant AR-signaling drives the disease progression. 
 
Nomenclature 
Laboratory Code: IONIS-AR-2.5Rx pentadecasodium 
 
General properties 
IONIS-AR-2.5Rx is an amorphous powder and a pentadecasodium salt. IONIS-AR-2.5Rx 
pentadecasodium is freely soluble in water and has solubility >250 mg/mL at 25°C. 
 
Presentation 
The drug product is presented as a sterile solution for injection/infusion filled into 2 mL clear 
glass vials. Each vial contains an extractable volume of at least 1.2 mL of a 167 mg/mL 
solution of IONIS-AR-2.5Rx (as the free acid) giving a maximum dose per vial of 200 mg. The 
product can be administered by direct injection, or by dilution into 0.9% sodium chloride for 
infusion. The formulation should be prepared and administered according to the handling 
instructions provided. The vials are intended for single use only. 
 
Composition 
The composition of IONIS-AR-2.5Rx solution for injection/infusion is IONIS-AR-2.5Rx, water for 
injection (Ph Eur or USP), pH adjusted as needed with either sodium hydroxide or hydrochloric 
acid to pH 8. 
 
 
Storage conditions 
The product should be stored in the pack provided and used as detailed in the handling 
instructions. Store refrigerated at 2-8°C protected from light. 
 
Intravenous Dose Preparation 
1. Obtain required materials: 
• 250 mL Normal Saline I.V. Bag 
• Study Drug Vials 

Protocol UMCC 2017.055 
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• Filter Needles 19G or 18G, 5 micron (Becton Dickinson Part # 305200 or 305201 or 
equivalent) 
 
• Regular 18-22 Gauge Needles 
 
2. Volume of drug to yield the intended dose of 900 mg for AR 
 
3. Warm vial(s) to room temperature for approximately 15 minutes and record the patient 
number on each vial before dose preparation. 
 
4. Use a filter needle 19G or 18G, 5 micron (Becton Dickinson Part # 305200 or 305201 or 
equivalent) to withdraw study drug from vials. 
 
5. Remove the used filter needle, replacing it with a regular 18-22-gauge needle. 
 
6. Transfer the study drug to the 250 mL Normal Saline I.V. bag. Vials are for single-use only. 
 
7. Label the I.V. bag per your institution’s procedures. Include a label with the statement “Caution: 
New Drug – Limited by Federal (or United States) law to investigational use”. Record on the label 
the total volume contained in the I.V. bag. Be sure to include in the total volume, the overfill 
(assume 25 mL 
unless otherwise known) and the volume of study drug that was added. 
 
8. Start infusion within 2 hours of preparation if kept at room temperature or within 24 hours if 
refrigerated at 2-8°C. 
 
Availability 
• 
Provided by Ionis Pharmaceutical 
 
• 
Under no circumstance will the study medication IONIS-AR-2.5Rx be used other than as 
directed by the protocol. 
 
Drug Accountability 
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the inventory and disposition of the investigational drug IONIS-AR-2.5Rx. The drug 
accountability records will capture drug receipt, drug dispensing, drug return and final disposition. 
 
Clinical Experience with IONIS-AR-2.5Rx: 
The first-time-in-patients (FTIP) study, D5860C00001: A Phase I, open-label, multicenter dose- 
escalation study to investigate the safety and pharmacokinetics of IONIS-AR-2.5Rx in patients 
with advanced solid tumors where the androgen receptor pathway is a potential factor was 
conducted. Patients are administered IONIS-AR-2.5Rx IV on Days 1, 4, 8, 11, 15, and 22 of Cycle 
1 and Days 1, 8, 15, and 22 of each subsequent 28-day cycle in an accelerated 3+3 dose 
escalation. Preliminary PK and safety data are presented in the following sections. 
 
Pharmacokinetics and drug metabolism in humans 
Study D5860C00001: The pharmacokinetics of the dose levels of 150, 300, 600, and 900 mg 
were assessed in 4 cohorts. Intravenous infusion doses of IONIS-AR-2.5Rx were administered 
over 1 hour in Cycle 1 on Days 1, 4, 8, and 11 (±2 days). Blood samples were obtained over a 
24-hour period on Day 1 and prior to dosing on Days 4, 8, and 11. Patients also received weekly 
treatments on Days 15 and 22 to complete Cycle 1. During subsequent cycles, patients received 
once weekly treatments on Days 1, 8, 15, and 22 (±2 days). In Cycle 2, blood samples were 
obtained over a 24-hour period on Day 22 to characterize the PK profile on that day. 
 
Additional samples were taken prior to the first dose during Cycles 3 and 4, during which doses 
were administered on Days 1, 8, 15, and 22 (±2 days). 
 
 
 

Protocol UMCC 2017.055 
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Cohort 1 (150 mg) 
During Cohort 1, PK data was collected for 3 patients on Cycle 1 Day 1 and for 2 patients on 
Cycle 2 Day 22. The Cycle 1 Day 1 Cmax values averaged 32.4 μg/mL, Tmax occurred at the 
end of the infusion sampling time (1 hour). 
 
The results of the Cycle 2 Day 22 PK parameter analysis were very similar to Cycle 1 Day 1 
results; Cmax values averaged 26.1 μg/mL, Tmax occurred at the end-of-infusion sampling time 
(1 hour). 
 
Cohort 2 (300 mg) 
During Cohort 2, one of the 3 patients had blood samples taken after the end of infusion rather 
than at the beginning, both on Cycle 1 Day 1 and on Cycle 2 Day 22, so the peak 
concentrations were not determined for that patient, but rather for the 2 other patients in the 
cohort. The Cycle 1 Day 1 Cmax values averaged 49.0 μg/mL, Tmax occurred at the end-of- 
infusion sampling time (1 hour). 
 
For Cycle 2 Day 22, Cmax values averaged 42.5 μg/mL, Tmax occurred at the end-of-infusion 
sampling time (1 hour). 
 
Cohort 3 (600 mg) 
During Cohort 3, one of the 3 patients had blood samples taken after the end of infusion rather 
than at the beginning, both on Cycle 1 Day 1 and on Cycle 2 Day 22, so the peak 
concentrations were not determined for that patient, but rather for the 2 other patients in the 
cohort. The Cycle 1 Day 1 Cmax values averaged 61.3 μg/mL, Tmax occurred at the end-of- 
infusion sampling time (1 hour). 
 
For Cycle 2 Day 22, Cmax values averaged 58.3 μg/mL, Tmax occurred at the end-of-infusion 
sampling time (1 hour). 
 
Cohort 4 (900 mg) 
During Cohort 4, PK data was collected for 5 patients on Cycle 1 Day 1 and for 2 patients on 
Cycle 2 Day 22. The Cycle 1, Day 1 Cmax values averaged 102 μg/mL, Tmax occurred at the 
end-of-infusion sampling time (1 hour). 
 
For Cycle 2 Day 22, Cmax values averaged 72.5 μg/mL, Tmax occurred at the end-of-
infusion sampling time (1 hour). 
 
Urinary excretion 
Twenty-four-hour urinary collections were made in 2 intervals (0 to 8 and 8 to 24 hours) on Cycle 
1 Day 1 and Cycle 2 Day 22. The results of the analysis showed: 
-Cohort 1 (150 mg) - the amount of unchanged drug excreted in the urine ranged from 1.04 to 
9.96 mg, accounting for 0.694% to 6.94% of the administered dose. 
-Cohort 2 (300 mg) - the amount of unchanged drug excreted in the urine ranged from 14.4 to 
30.2 mg, accounting for 4.79% to 10.1% of the administered dose. 
-Cohort 3 (600 mg), the amount of unchanged drug excreted in the urine ranged from 17.3 to 84.6 
mg, accounting for 2.87% to 14.1% of the administered dose. 
-Cohort 4 (900 mg), the amount of unchanged drug excreted in the urine ranged from 121 to 245 
mg, accounting for 13.5% to 27.2% of the administered dose. 
 
Overall, 0.694% to 27.2% of IONIS-AR-2.5Rx was excreted unchanged in the urine. There was a 
trend toward increasing percentage excreted with increase in dose. 
 
Safety and efficacy 
 
Hepatic Function test abnormalities: Review of laboratory data has identified a trend for increases 
in ALT/AST and ALP in the 600 mg and 900 mg dose cohorts, however, which was most 
apparent at 900 mg. Elevations tend to develop slowly and have been mostly Grade 1. One 

Protocol UMCC 2017.055 
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patient was noted to have Grade 2 ALT and Grade 1 AST elevations at Cycle 2 Day 8 leading to 
a hold of study treatment. The patient returned 1 week later and ALT and AST had returned to 
normal range, and the patient restarted study medication with no new issues identified at this 
time. Adverse events reported in preliminary, unaudited safety information include fatigue, 
diarrhea, nausea, vomiting, dry skin, headache, insomnia, loss of appetite, mouth pain, muscle 
pain, pruritus, increased ALT/ AST, elevated ALP and GGT, taste alteration, thrombocytopenia, 
gastrointestinal cramping, constipation, and weight loss. Most AEs were Grade 1 and 2. One 
patient in Cohort 2 (300 mg) experienced an immediate Grade 3 infusion reaction at the Cycle 5 
Day 15 dose (hypotension and flushing), which resolved on treatment with steroids. The patient 
received prophylactic pre-medication following standard local procedures prior to the Cycle 5 Day 
22 dose, but still experienced another infusion reaction (arthralgia, chills). The patient has been 
discontinued due to disease progression. No serious AEs that were considered to be related to 
the study drug by an Investigator have been reported up to the cut-off date, and no fatal events 
have been reported. 
 
Venous thromboembolism: After the data cut-off date for inclusion in the above review of 
emerging safety data, a number of AE reports of venous thromboembolism (pulmonary embolism, 
and deep vein thrombosis) were received for patients in study D5860C00001. By 18 August 2015 
there were a total of 4 events of Grade 3 pulmonary embolism in 4 patients reported to 
AstraZeneca for patients in study D5860C00001. At that date, 29 patients had been treated with 
IONIS-AR-2.5Rx in that study. Of the 4 patients, 3 were symptomatic (and were incidental findings 
on routine CT restaging), and 1 patient presented with shortness of breath. All patients continued 
on study after diagnosis and treatment. Initially 2 of these events were assessed as unrelated to 
IONIS-AR-2.5Rx by the site investigators, but considering the cluster of pulmonary embolism 
events, AstraZeneca reassessed these events as possibly related to study therapy. In addition, 3 
other events of non-serious deep venous thrombosis were reported, and constitute similar 
thromboembolic phenomena. 
 
Marketing experiences: 
IONIS-AR-2.5Rx 2 is an investigational drug and is not available as a marketed product in any 
region. 
 
Emerging safety profile: 
This section is the Reference Safety Information for IONIS-AR-2.5Rx and presents those events 
that are to be regarded as expected for safety reporting purposes: 
Venous thromboembolism (pulmonary embolism and deep vein thrombosis) – Occurs at a 
Council for International Organizations of Medical Sciences (CIOMS) III frequency of very 
common (>10%). The majority of pulmonary embolism reports were incidental. 
 
SUMMARY OF DATA AND GUIDANCE FOR THE INVESTIGATORS: 
Contraindications 
IONIS-AR-2.5Rx is an investigational drug and should only be used in accordance with the 
relevant clinical protocol. Patients must fulfil the Inclusion Criteria and not violate any of the 
Exclusion Criteria specified within the relevant protocol. 
 
Warnings and precautions 
Pregnancy 
Reproductive and developmental toxicity studies and juvenile toxicity studies have not been 
conducted with IONIS-AR-2.5Rx to date, and it is unknown whether the drug is excreted in human 
milk. Therefore, men taking IONIS-AR-2.5Rx and their female partners of childbearing potential 
should agree to use adequate contraception for the duration of study participation, and for 120 
days following last study treatment. 
 
Male subjects should be fully informed of the lack of reproductive toxicity testing. The clinical 
protocol gives details on the requirements to report pregnancy and its outcome. 

Protocol UMCC 2017.055 
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Interaction potential 
No interaction studies have been conducted with IONIS-AR-2.5Rx to date. 
 
Phosphorothioate oligonucleotides are not substrates for the classic CYP metabolic pathways 
and are thus unlikely to interact with other drugs that modulate or are modulated by CYP, and the 
same would again be expected for IONIS-AR-2.5Rx, though not yet evaluated. 
 
Overdose 
IONIS-AR-2.5Rx must only be used in accordance with the relevant clinical protocol. An overdose 
is defined is a dose of IONIS-AR-2.5Rx 2 administered to a patient that is greater than the protocol 
defined dose for the patient. Symptomatic and non-symptomatic overdose must be documented 
in accordance with the protocol. 
 
There is currently no specific treatment in the event of an overdose with IONIS-AR-2.5Rx and 
possible symptoms of overdose have not been established. In the event of overdose, the 
patient should be observed and appropriate symptomatic treatment given. 
 
IONIS-AR-2.5Rx toxicity observed in preclinical studies 
The anticipated AE profile and potential risks seen with IONIS-AR-2.5Rx22in mice and monkeys, 
include accumulation of compound as basophilic granules in multiple tissues, complement 
activation and prolongation of activated partial thromboplastin time (aPTT) in monkeys and pro- 
inflammatory effects in mice are consistent with expected effects of ASOs (Burel et al 2013).22 
 
Evidence of effects on AR signaling, including tissue weight and histopathological changes, are in 
line with expected pharmacodynamics. 
 
Safety considerations for phosphorothioate oligonucleotides. 
More than twenty 2′-MOE-modified phosphorothioate ASOs, a chemical class similar to 
IONIS-AR-2.5Rx, have been administered to human subjects, including ASOs that are under 
evaluation for the treatment of cancer. Clinical safety results of such 2′-MOE-modified ASOs can 
provide guidance to the potential attributes of IONIS-AR-2.5Rx. Some profile differences exist 
between class members and extrapolations from one ASO to another should be made 
cautiously23,24. 
 
Potential class-related effects are informed by prior clinical experience with IV-administered 2nd 
generation ASOs and include transient constitutional symptoms associated with early doses and 
transient prolongation of aPTT24. Also, due to prior preclinical findings for one or more members 
of the drug class, the following additional areas are monitored in the clinical trials of ASOs: renal 
effects, liver effects, complement activation, and proinflammatory effects23,24. 
 
Constitutional symptoms 
Transient fever, chills, body aches, nausea, and other constitutional symptoms have been 
experienced following the first few administrations of some ASOs24. In general, these symptoms 
appear within hours of ASO administration, are mild in intensity, and resolve spontaneously 
overnight. The occurrence and intensity of these symptoms generally diminishes over the course 
of repeated administrations. The proportion of patients that experience infusion-associated 
constitutional symptoms and the symptom spectrum is dose dependent. 
 
At doses in the range of 200 to 400 mg, mild body aches, and general discomfort are the most 
frequent complaints. However, at higher doses, fever and chills become more prominent 
complaints. The relationship between dose and constitutional symptoms is variable between 
ASOs. 
 
Constitutional symptoms associated with dose administration should be monitored through 
adverse event recording, and should be managed as required. 

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Prolongation of aPTT 
Prolongation of aPTT associated with ASO administration has been shown to be the result of low- 
affinity oligonucleotide binding to the tenase complex (Factor IXa-Factor VIIIa phospholipid) and 
the effect is proportional to concentration of oligonucleotide in plasma 
(Cmax)24,25. In monkeys, there were acute, transient increases in aPTT at 12 mg/kg IONIS-AR- 
2.5Rx and above. There was no evidence of associated hemorrhage or bleeding. Changes in 
activity of the intrinsic clotting pathway reverse when ASO is cleared from plasma. Coagulation 
effects should be monitored by adverse event recording. 
 
Renal effects 
The kidney is the organ of greatest ASO distribution. The dose-dependent presence of 
basophilic granules in proximal tubular epithelial cells is a common finding for animals 
treated with ASOs23. They arise from the accumulation of ASOs in 
endosomal vesicles and as such are an indication of ASO uptake and compartmentalization. 
 
No toxicological effects have been associated with the presence of basophilic granules. 
Renal effects should be monitored through adverse event recording, clinical chemistry 
evaluations, and urinalysis. 
 
Liver effects 
The liver is the organ having the second highest distribution of ASOs. In humans and 
monkeys, elevations of transaminases or other signs of hepatotoxicity are not a class-effect of 
phosphorothioate oligonucleotides. Two to three-fold increases in transaminases are routinely 
observed in mice and other rodents; however, the elevations are secondary to the 
proinflammatory effects of ASOs in this most sensitive species (manifested by inflammatory cell 
infiltrates in multiple organs including the liver). In some cases, liver enzyme elevations have 
occurred after administration of oligonucleotides in humans. 
 
Liver effects should be monitored through adverse event recording and clinical chemistry 
parameters. 
 
Complement activation 
Complement pathway activation has been observed in monkeys treated with high doses of 
phosphorothioate oligonucleotides. The effect arises from the interaction of oligonucleotides with 
Factor H, an inhibitor of complement activation, and occurs when oligonucleotide levels in plasma 
exceed threshold concentrations (approximately >100 μg/mL for most ASOs after IV 
administration)23,26. Monkeys are known to be more sensitive to complement activation than 
humans27. 
 
Proinflammatory effects 
Pro-inflammation is a well described non-specific class effect of ASOs28,29. In preclinical 
toxicology studies, particularly in studies conducted in rodents, proinflammatory effects are often 
observed for the phosphorothioate oligonucleotide chemical class. In general, rodents appear to 
be more sensitive to ASO-mediated pro-inflammatory effects than primates23. 
 
Pro-inflammatory effects should be monitored by adverse event recording. 
 
9.2 
Enzalutamide 
Other names for the drug: XTANDI® 
 
Description: 
Enzalutamide is a white crystalline non-hygroscopic solid. Enzalutamide is provided as a liquid- 
filled soft gelatin capsule for oral administration. Each capsule contains 40 mg of enzalutamide 
as a solution in caprylocaproyl polyoxylglycerides. 
 
Classification: type of agent: androgen receptor inhibitor 

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Mode of action: 
Enzalutamide is an androgen receptor inhibitor that acts on different steps in the androgen 
receptor signaling pathway. Enzalutamide has been shown to competitively inhibit androgen 
binding to androgen receptors and inhibit androgen receptor nuclear translocation and interaction 
with DNA. 
 
Pharmacokinetics: 
Absorption: rapid with time to peak concentration in 1 hour (range 0.5-3 hours). A high-fat 
meal did not alter the AUC to enzalutamide or N-desmethyl enzalutamide. 
Distribution: 110 L; protein binding of parent drug is 97-98% to primarily albumin; protein 
binding of active metabolite is 95% to plasma proteins 
Metabolism: Hepatic via CYP2C8 (formation of active metabolite N-desmethyl enzalutamide) 
and CYP3A4 
Excretion: Primarily eliminated by hepatic metabolism. Following single oral administration of 
14C-enzalutamide 160 mg, 85% of the radioactivity is recovered by 77 days post dose: Urine 
(71%), feces (14%) primarily as inactive metabolite 
T1/2: Enzalutamide: 5.8 days (range 2.8-10.2 days); N-desmethyl enzalutamide: 7.8-8.6 days. 
 
Side effects: 
The most common adverse reactions (≥ 10%) are asthenia/fatigue, back pain, decreased 
appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral 
edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and 
dizziness/vertigo. 
 
Drug Interactions: Please refer to the package insert for enzalutamide. 
 
Storage and stability: Store enzalutamide at 20º to 25ºC (68º to 77ºF) in a dry place and keep the 
container tightly closed. Excursions permitted to 15º to 30ºC (59º to 86º F). 
 
Administration: 
Enzalutamide is administered orally once daily with or without food for 21 day cycles. Patients 
should be instructed to swallow capsules whole, and not to open or crush the capsules. Subjects 
will be asked to keep a pill diary noting the date they take enzalutamide. They will be asked to 
bring their pill diary on day one of each cycle and all used and unused medication bottles and 
remaining pills in the bottle(s) will be counted to document compliance. This information should 
be recorded on the patient’s pill diary and/or in the patient data file. 
 
Availability: Commercially available 
 
Drug Accountability: 
The investigator, or a responsible party designated by the investigator, must maintain a record of 
the disposition of enzalutamide. The drug accountability records should capture drug dispensing, 
drug return and final disposition. 
 
 
10.0 
CORRELATIVES/SPECIAL STUDIES 
The goal of the planned laboratory correlative studies is to ascertain if ISIS 560131 effectively 
inhibits AR signaling in the tissues, confirm its mechanism of action as postulated, profile the 
tumor cell intracellular pathways and understand mechanisms of resistance. 
 
• 
Submission of tissue samples for correlative studies is mandatory at baseline 
(archival/fresh biopsy). 

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• 
Submission of tissue samples for correlative studies is optional at 2 cycles post therapy 
and at progression. 
 
• 
Whole blood samples collected at C1D1 pre-dose will be banked for possible future 
analysis including to identify potential molecular biomarkers that may be indicative of 
clinical response/resistance. Refer to Lab Manual. 
 
• 
Blood samples will be collected pre and post dose of IONIS-AR-2.5Rx for 
pharmacokinetic analysis for the first two cycles only. Plasma PK samples may also be 
used for profiling of drug binding proteins, bioanalytical method development and/or 
validation purposes, stability assessments, metabolite assessments, immunogenicity 
assessments or to assess other actions of IONIS-AR-2.5Rx with plasma constituents. 
Refer to Lab Manual. 
10.1 
Sample Collection Guidelines (Refer to Lab Manual) 
Tumor Tissue 
Tumor tissue should be processed and shipped to the Michigan Center for Translational 
Pathology (below). From each patient, tissue specimens will be collected at time points indicated 
in the Study Calendar. Generally, tissue specimens will be collected from: 
 
a. A metastatic site of disease (via biopsy) or adequate metastatic tissue from prior biopsy 
or resection. 
 
b. Archived prostatectomy or biopsy specimen from the primary prostate tumor (if available, 
via retrieval of previously archived specimens). 
 
Archived Prostate Cancer Samples: 
Occasionally, castration resistant prostate cancer tissue may have been obtained previously for 
the subject and archived. This tissue may be utilized for baseline tissue purposes. 
 
• 
If resection specimens are available (preferred): The block with the highest volume of 
representative tumor histology from the index focus OR 16 unstained, unbaked sections 
(4-5 microns in thickness) on glass slides (charged or uncharged) should be shipped at 
room temperature to the University of Michigan. 
 
• 
If biopsy specimens are available: Three blocks with the highest volume of representative 
tumor histology OR 15 unstained, unbaked sections (4-5 microns in thickness) on glass 
slides (charged or uncharged) from up to three blocks should be shipped at room 
temperature to the University of Michigan. If unstained sections are sent, they should be 
labeled with the block number/letter. If less than three blocks have cancer, then all blocks 
with cancer OR as many unstained sections as can be cut from blocks with cancer 
without exhaustion should be sent. 
 
 
Whole blood and PK Plasma IONIS-AR-2.5Rx Samples: 
Whole blood and PK plasma samples should be processed and shipped according to the Lab 
Manual. 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
This is a single dose-finding one-arm, phase Ib/II trial to (i) estimate the MTD from among three 
dose levels of IONIS-AR-2.5Rx in combination with a fixed dose of enzalutamide, as described 
below, and (ii) obtain preliminary estimate of efficacy at this estimated MTD, as measured by PSA 
response rate. The MTD is defined as the highest dose of IONIS-AR-2.5Rx inducing a rate of DLT 
closest to but not larger than 35%, and we will assess the evidence that the PSA response rate at 

Protocol UMCC 2017.055 
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this dose level exceeds 5%. The planned enrollment is 35 evaluable patients. Success for the trial 
is defined as finding a dose level that is likely to be both tolerable and effective. 
 
There are two novel elements relative to standard Phase Ib/II designs. First, statistical-model- 
based between-patient dose modifications of IONIS-AR-2.5Rx accounting for cumulative toxicity 
outcomes will be implemented during the entire trial. Second, instead of using only patients at the 
MTD to determine the PSA response rate, a monotonic model of PSA response using all 
response evaluable patients will be used to estimate the PSA response rate at the MTD. The 
only formal statistical mechanism for stopping the trial early is due to exceeding toxicity (safety) 
thresholds. 
 
11.1 
Study Design 
 
Dose Assignment in Phase 1b: The first patient will be enrolled to dose level 3 of IONIS-AR- 
2.5Rx, in combination with a fixed dose of enzalutamide. Subsequent dose assignments to dose 
levels 1, 2 or 3 will be based upon the statistical-model-based TITE-CRM design. This trial will 
seek to estimate the MTD, the true value of which is defined as the dose level with probability of 
DLT closest to but not exceeding 35%. 
 
Final Efficacy Analysis After all 35 evaluable patients are enrolled and the PSA response 
endpoint is recorded for all patients, we will fit the Bayesian isotonic regression model on all 
patients’ data. If the probability that the PSA response rate at the final estimated dose exceeds 
5% is at least 0.95, the trial will have successfully completed its primary objective. 
 
Interim Analysis/Criteria for Stopping Study Continuous monitoring of safety is built into the 
TITE-CRM model, and the trial will stop at any point in which all dose levels have a model- 
estimated probability of DLT exceeding 37.5%. 
 
11.2 
Endpoints 
 
11.2.1 
Primary Endpoints 
 
The primary endpoints are (i) dose-limiting toxicity (DLT) during the first cycle of IONIS- 
AR-2.5Rx (in combination with enzalutamide) and (ii) PSA response (PSA decline of 50% 
or greater from baseline) at any time after the start of combination therapy. 
 
11.2.2 
Definition of Secondary Endpoints 
 
The secondary endpoints of efficacy are radiographic progression-free survival time 
(rPFS) by PCWG3-modified RECIST 1.1, 30% PSA reduction from baseline, PSA 
progression-free survival time, duration of therapy (DOT), duration of PSA Response 
(DOR), progression-free survival time and overall survival time. 
 
The secondary endpoints for safety and toxicity are adverse events as assessed by 
CTCAE criteria 5.0 and classified by body system, grade, and attribution. Other toxicity 
endpoints include intrapatient dose delays and dose reductions. 
 
11.2.3 
Exploratory/Correlative Endpoints 
Androgen receptor driven signaling measures in tumor tissues, measures of genomic, 
metabolomics, and proteomic biomarkers in blood and tissues, FACT-P and EuroQoL-5D 
scores with comparisons to baseline scores, and pharmacokinetic (PK) characteristics 
will be the exploratory and correlative endpoints. 

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11.3 
Sample Size and Accrual 
We will enroll a total of up to 35 toxicity evaluable patients, depending on if the trial stops early for 
safety (toxicity). Justification for this design and sample size is based upon 250 simulated trials for 
each of 28 true data-generating scenarios (seven sets of dose-DLT probabilities crossed with four 
sets of dose-efficacy probabilities). 
 
The results of the simulation study are given in Tables 1A-1C. The true probabilities of DLT for 
the three dose levels of IONIS-AR-2.5Rx are given in the rows. The true probabilities of PSA 
response for the three dose levels of IONIS-AR-2.5Rx are given in the columns. 
 
Table 1A gives the probability of making the correct MTD determination. The true MTD is always 
defined as the dose level closest to but not exceeding 35% by more than 2.5% in the simulations. 
From Table 1A, we can see that this probability is high (>0.85) when the true MTD is dose level 3 
or >67% when all dose levels are unsafe and lower when the true DLT probabilities are closer to 
each other or when dose level 1 is close to being too toxic. 
 
Table 1B give the simulation-based probabilities of declaring success, i.e. finding a dose level 
that statistically appears to be both safe and sufficiently efficacious. These probabilities 
approximately represent the ‘type I error’ and ‘power’ of our design. These probabilities are low 
(<0.45) in the left-hand columns (non-efficacious scenarios) and/or bottom rows (unsafe 
scenarios). Conversely, they are high (>0.70) in the top-right cells (efficacious, safe scenarios). 
 
Finally, Table 1C gives the 25th and 75th percentiles for total enrollment. Because the trial will 
only stop for safety (and not futility), expected enrollment decreases only in the unsafe scenarios. 
The trial will generally stop after 9 - 35 patients when no dose levels are safe. 
 
Table 1A: Simulation-based probability of correctly identifying the true MTD (highlighted in bold 
in the left column), regardless of efficacy. The correct determination in the last row is to stop for 
toxicity, because no dose levels have true rate of DLT less than 35%. 
 
True PSA Response Probabilities (when DLT is observed) 
True DLT 
probabilities 
{3%,8%,10%} 
{5%,13%,20%} 
{5%,10%,25%} 
{20%,28%,35%} 
{8%,13%,25%} 
0.97 
0.97 
0.97 
0.97 
{10%,20%,30%} 
0.86 
0.87 
0.82 
0.84 
{14%,21%,35%} 
0.72 
0.72 
0.73 
0.72 
{20%,27%,40%} 
0.46 
0.45 
0.43 
0.45 
{25%,33%,45%} 
0.48 
0.46 
0.46 
0.46 
{30%,45%,55%} 
0.46 
0.45 
0.42 
0.40 
{40%,50%,70%} 
0.67 
0.66 
0.66 
0.71 
 
Table 1B: Simulation-based probability of ‘declaring success’, i.e. finding any dose level that is 
estimated to be safe AND efficacious. 
True PSA Response Probabilities (when DLT is observed) 
True DLT probabilities 
{3%,8%,10%} 
{5%,13%,20%} 
{5%,10%,25%} 
{20%,28%,35%} 
{8%,13%,25%} 
0.47 
0.92 
0.94 
0.99 
{10%,20%,30%} 
0.35 
0.84 
0.84 
0.97 
{14%,21%,35%} 
0.37 
0.74 
0.73 
0.92 
{20%,27%,40%} 
0.17 
0.54 
0.48 
0.86 
{25%,33%,45%} 
0.14 
0.37 
0.32 
0.69 
{30%,45%,55%} 
0.04 
0.07 
0.05 
0.46 
{40%,50%,70%} 
0.008 
0.04 
0.01 
0.15 
 
Table 1C: Simulation-based interquartile range of number of patients enrolled over all simulated 
trials. 

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True PSA Response Probabilities (when DLT is observed) 
True DLT 
probabilities 
{10%,12%,15%} 
{12%,16%,23%} 
{16%,26%,30%} 
{10%,13%,33%} 
{8%,13%,25%} 
(35, 35) 
(35, 35) 
(35, 35) 
(35, 35) 
{10%,17%,30%} 
(35, 35) 
(35, 35) 
(35, 35) 
(35, 35) 
{14%,21%,35%} 
(35, 35) 
(35, 35) 
(35, 35) 
(35, 35) 
{20%,27%,42%} 
(35, 35) 
(35, 35) 
(35, 35) 
(35, 35) 
{25%,38%,46%} 
(35, 35) 
(35, 35) 
(35, 35) 
(35, 35) 
{33%,46%,60%} 
(22, 35) 
(23, 35) 
(28, 35) 
(25, 35) 
{38%,50%,70%} 
(10, 35) 
(9, 35) 
(9, 35) 
(10, 35) 
 
 
11.4 
Analysis Datasets 
All subjects who enroll and receive at least one dose of each treatment in the combination 
therapy will be used for updating the TITE-CRM model. Patients who withdraw prior to completing 
their DLT window and without the occurrence of DLT will have their likelihood contribution 
downweighted as described in the first paragraph of Section 11.6.1 and will be replaced. 
 
All subjects who have completed one or more cycles of treatment or who are removed from 
protocol due to progression or toxicity will be evaluable in the efficacy analyses. 
 
 
Population 
Definition 
Enrolled 
This will comprise all subjects who meet the eligibility criteria 
and are registered onto the study. 
Evaluable 
This will comprise all subjects who receive at least one cycle 
of treatment or who are removed from protocol due to 
progression or toxicity. 
Intention-to-treat (ITT) 
This will comprise all subjects who meet the eligibility criteria 
and are registered onto the study irrespective of their 
compliance to the planned course of treatment. (See ITT 
principle below*). 
Per Protocol Set (Valid 
Cases, Efficacy Sample, 
Evaluable Subjects 
Sample) 
This will comprise all subjects who completed at least one 
cycle of protocol therapy and have a post-baseline PSA 
drawn. 
Safety 
This will comprise all subjects who receive any protocol 
treatment. 
Treated 
This will comprise all subjects who have been exposed to the 
planned course of treatment to any extent. 
 
 
11.5 
Assessment of Safety 
All subjects who enroll and receive at least one dose of the combination therapy (one dose each 
of IONIS-AR-2.5Rx and Enzalutamide) will be eligible for DLT assessment. Formal assessment of 
safety is built into the dose-escalation design. No dose level having a model-estimated probability 
of DLT exceeding 35% plus a 2.5% margin will ever be assigned, and patient enrollment will stop 
entirely if dose level 1 ever has a model-estimated probability of DLT exceeding 37.5% after the 
first 6 patients. 

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11.6 
Data Analysis Plans 
 
11.6.1 Primary Objective Analyses 
Dose Assignment with toxicity assessment The first patient will be assigned to dose 
level 3. For each patient after the first, we will estimate the one-parameter power model, 
Pr (Tox|dose j) = (dj)^exp{b}, where {d1,d2,d3}={0.10, 0.20, 0.30} is the pre-specified 
skeleton (the anticipated probabilities of DLT at each dose level) and the parameter b is 
to be estimated, using its posterior mean from a Bayesian analysis. We will place a 
Normal (0, 0.62) prior on b. Each patient will be assigned to dose level j, j=1,2,3, such that 
the model estimated probability of DLT at that dose level, (dj)^exp{b}, is closest to 0.35 
but not exceeding 0.375. Any patients who are free of DLT but have only finished t days 
of their first cycle, t < 42, will have their likelihood contribution down-weighted by a factor 
(t2/422). At any point after the first 6 patients, if the model-estimated rate of DLT at dose 
level 1 exceeds 0.375, the trial will stop for toxicity. 
 
Efficacy Analysis The efficacy analysis will occur in the PSA response evaluable dataset 
after the patients have their PSA Response endpoint recorded. Let {m1, m2, m3} denote 
the true, unknown probability that a patient exhibits PSA response at the three dose levels 
of IONIS-AR-2.5Rx (with fixed dose of enzalutamide), respectively. We will use weakly 
informative, independent Beta prior distributions: m1~Beta (0.1, 1.9), m2~Beta (0.3,1.7), 
and m3~Beta (0.5,1.5), or the information equivalent of 2 historical patients’ worth of data 
at each dose level, with historical response rates of 0.05, 0.15, and 0.25, respectively. The 
posterior distributions will also be Beta: add the number of PSA responders at each dose 
level to the first shape parameter (0.1, 0.3, or 0.5), and add the number of PSA non-
responders at each dose level to the second shape parameter (1.9, 1.7, or 1.5). So, for 
example, if 4 patients received dose level 1, and one of these patients exhibited a PSA 
response, then posterior Beta distribution for m1 would be Beta (0.1+1, 1.9+3) = Beta 
(1.1,4.9). We will then independently sample a large number, e.g., 200,000, of draws from 
each of these posterior Beta distributions. In order to preserve the isotonic assumption 
that the potential for response is not decreasing with dose level, we will only keep 
posterior samples satisfying m1 <= m2 <= m3. To estimate the Bayesian probability that the 
response rate at the MTD exceeds 5%, we will calculate the proportion of isotonic draws 
at the mi exceeding 0.05, where dose level i is the estimated MTD. We will calculate the 
Bayesian probability that the probability of PSA response at the final estimated MTD 
exceeds 5%. If the proportion of posterior draws at the estimated MTD exceeding 0.05, 
subject to the isotonic constraint, is at least 0.95, the trial will have successfully completed 
its primary objective. 
 
11.6.2 Secondary Objective Analyses 
 
The time-to-event secondary endpoints of efficacy including rPFS, time to PSA 
progression, PSA progression-free survival time, DOT, DOR, PFS and OS will be 
analyzed using Kaplan-meier methods. Percentiles of each will be reported with 
associated 95% confidence intervals and a Kaplan-meier plot. The proportion of patients 
who are able to reach a 30% or greater PSA reduction from baseline will be reported with 
the associated 95% binomial confidence interval. Each of the above will be reported 
overall and by dose level during cycle 1. 
 
Safety and toxicity will be described by dose level. Adverse events as assessed by 
CTCAE criteria 5.0 and classified by body system, grade, and attribution will be reported 

Protocol UMCC 2017.055 
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using counts and proportions. Intrapatient dose delays and reductions will be described 
for each starting dose level. 
 
11.6.3 Exploratory/Correlative Analyses 
Inhibition of androgen receptor driven signaling in tumor tissues by IONIS-AR-2.5Rx will 
be reported using descriptive statistics. 
 
To identify molecular (including genomic, metabolic, and/or proteomic) biomarkers in 
blood and tissues that may be indicative of clinical response/resistance, safety, 
pharmacodynamic activity and/or the mechanism of action of IONIS-AR-2.5Rx, each 
biomarker will be described in the overall treated population and compared between PSA 
response/non-response outcome. If a biomarker is found to be interesting, Kaplan-Meier 
methods may be used to explore the relationship with secondary endpoints of rPFS and 
PSA-PFS. 
 
Changes in health-related quality of life assessment from baseline using FACT-P and 
EuroQoL-5D will be described using descriptive statistics. 
 
Pharmacokinetic (PK) characteristics of IONIS-AR-2.5Rx will be described using 
summary descriptive statistics and figures. 
 
 
12.0 
DATA MANAGEMENT 
All information will be recorded locally and entered into Case Report Forms (CRFs) on the web-based 
electronic data capture (EDC) system of the University of Michigan. Online access will be provided to 
each site by the Coordinating Center. 
 
CRFs will be reviewed and source verified by the MSC during annual monitoring visits and prior to and 
between visits. Discrepant, unusual and incomplete data will be queried by the MSC. The investigator or 
study coordinator will be responsible for providing resolutions to the data queries, as appropriate. The 
investigator must ensure that all data queries are dealt with promptly. 
 
The data submission schedule is as follows: 
• 
At the time of registration 
o 
Subject entry into EDC 
 
Subject Status 
 
Demographics 
• 
During study participation 
 
All data should be entered online within 10 business days of data acquisition. [Information on dose 
limiting toxicity events must be entered within one business day.] Information on Serious Adverse Events 
must be entered within the reporting timeframe specified in Section 8 of the protocol. 
 
13.0 
DATA AND SAFETY MONITORING 
This study will be monitored in accordance with the NCI approved University of Michigan Rogel Cancer 
Center Data and Safety Monitoring Plan, with oversight by the Rogel Cancer Center Data and Safety 
Monitoring Committee (DSMC).\ 
 
The Sponsor-Investigator (S-I)/Study Principal Investigator will provide ongoing monitoring of data and patient safety in 
this trial and conduct regular data review with participating sites. : 
 
The Sponsor-Investigator (S-I)/Study Principal Investigator and/or the Project Manager/Delegate will review data and 
patient safety issues with participating sites per a defined monthly meeting cadence. Depending on the protocol activity, 
the meeting cadence may be more frequent. This data review meeting may be achieved via a teleconference or another 
similar mechanism to discuss matters related to: 
 

Protocol UMCC 2017.055 
Page 56 of 69 
 
 
o 
Enrollment rate relative to expectations, characteristics of participants 
o 
Safety of study participants (Serious Adverse Event & Adverse Event reporting) 
o 
Adherence to protocol (protocol deviations) 
o 
Completeness, validity and integrity of study data 
o 
Retention of study participants 
 
Participating sites are required to ensure all pertinent data for the review period are available in 
the database at the time of the discussion. 
 
Participating sites unable to participate in the data review meeting are required to provide written 
confirmation that their site has reviewed the relevant data and patient safety issues for the review 
period and their site’s data are in alignment with the data reported in the database. Written 
confirmation is to be provided to the Project Manager/Delegate within the timeline requested to 
retain compliance with monitoring timelines. 
 
Documentation of the teleconference or alternate mechanism utilized to review items above is to 
be retained in the Trial Master File.  
 
The Project Manager/Delegate is responsible for collating the data from all participating sites and 
completing the Protocol Specific Data and Safety Monitoring Report (DSMR) form to document 
the data review meeting discussion.  
 
The DSMR will be signed by the Sponsor-Investigator (S-I)/Study Principal Investigator or 
designated Co-Investigator and submitted to the DSMC on a monthly basis for independent 
review. 
 
14.0 
QUALITY ASSURANCE AND AUDITS 
The Data and Safety Monitoring Committee can request a ‘for cause’ quality assurance audit of the trial if 
the committee identifies a need for a more rigorous evaluation of study-related issues. 
 
A regulatory authority (e.g., FDA) may also wish to conduct an inspection of the study, during its conduct 
or even after its completion. If an inspection has been requested by a regulatory authority, investigator 
must immediately inform the Coordinating Center that such a request has been made. 
 
15.0 
CLINICAL MONITORING PROCEDURES 
 
Clinical studies coordinated by The University of Michigan Rogel Cancer Center must be conducted in 
accordance with the ethical principles that are consistent with Good Clinical Practices (GCP) and in 
compliance with other applicable regulatory requirements. Adverse event lists, guidelines, and 
instructions for AE reporting can be found in Section 8.0 (Adverse Events: List and Reporting 
Requirements). 
 
This study will be monitored by a representative of the Coordinating Center of the University of Michigan 
Rogel Cancer Center. Monitoring visits will be made during the conduct of the study and at study close- 
out. 
 
Prior to subject recruitment, a participating site will undergo site initiation meeting to be conducted by the 
Coordinating Center. This will be done as an actual site visit; teleconference, videoconference, or web- 
based meeting after the site has been given access to the study database and assembled a study 
reference binder. The site’s principal investigator and his study staff should make every effort in attending 
the site initiation meeting. Study related questions or issues identified during the site initiation meeting will 
be followed-up by the appropriate Coordinating Center personnel until they have been answered and 
resolved. 
 
Monitoring of this study will include both ‘Centralized Monitoring’, the review of source documents at the 
Coordinating Center, and ‘On-site Monitoring’, an actual site visit. The first ‘Centralized’ visit should occur 
after the first subject enrolled completes the first treatment cycle. The study site will send the de-identified 
source documents to the Coordinating Center for monitoring. ‘Centralized’ monitoring may be requested 

Pr ot o c ol U M C C 2 0 1 7. 0 5 5 
P a g e 5 7 of 6 9 
 
 
b y t h e C o or di n ati n g C e nt er if a n a m e n d m e nt r e q uir e s c h a n g e s t o t h e pr ot o c ol pr o c e d ur e s. T h e sit e will 
s e n d i n p erti n e nt d e-i d e ntifi e d s o ur c e d o c u m e nt s, a s d efi n e d b y t h e C o or di n ati n g C e nt er f or m o nit ori n g. 
 
T h e fir st a n n u al ‘ O n- sit e’ m o nit ori n g vi sit s h o ul d o c c ur aft er t h e fir st fi v e st u d y p arti ci p a nt s ar e e nr oll e d or 
t w el v e m o nt h s aft er a st u d y o p e n s, w hi c h e v er o c c ur s fir st. T h e a n n u al vi sit m a y b e c o n d u ct e d a s a 
‘ C e ntr ali z e d’ vi sit if l e s s t h a n t hr e e s u bj e ct s h a v e e nroll e d at t h e st u d y sit e. T h e t y p e of vi sit i s at t h e 
di s cr eti o n of t h e C o or di n ati n g C e nt er. At a mi ni m u m, a r o uti n e m o nit ori n g vi sit will b e d o n e at l e a st o n c e a 
y e ar, or o n c e d uri n g t h e c o ur s e of t h e st u d y if t h e st u d y d ur ati o n i s l e s s t h a n 1 2 m o nt h s. T h e p ur p o s e of 
t h e s e vi sit s i s t o v erif y: 
 
  
A d h er e n c e t o t h e pr ot o c ol 
  
C o m pl et e n e s s a n d a c c ur a c y of st u d y d at a a n d s a m pl e s c oll e ct e d 
  
Pr o p er st or a g e, di s p e n si n g a n d i n v e nt or y of st u d y m e di c ati o n 
 C o m pli a n c e
 
wit h
 
r e g ul ati o n s
 
 
D uri n g a m o nit ori n g vi sit t o a sit e, a c c e s s t o r el e v a nt h o s pit al a n d cli ni c al r e c or d s m u st b e gi v e n b y t h e 
sit e i n v e sti g at or t o t h e C o or di n ati n g C e nt er r e pr e s e nt ati v e c o n d u cti n g t h e m o nit ori n g vi sit t o v erif y 
c o n si st e n c y of d at a c oll e ct e d o n t h e C R F s wit h t h e ori g i n al s o ur c e d at a. W hil e m o st p ati e nt c a s e s will b e 
s el e ct e d fr o m p ati e nt s a c cr u e d si n c e t h e pr e vi o u s m o nit o ri n g vi sit, a n y p ati e nt c a s e h a s t h e p ot e nti al f or 
r e vi e w. At l e a st o n e or m or e u n a n n o u n c e d c a s e s will b e r e vi e w e d, if t h e t ot al a c cr u al s w arr a nt s el e cti o n of 
u n a n n o u n c e d c a s e s. 
 
T h e C o or di n ati n g C e nt er e x p e ct s t h e r e l e v a nt i n v e sti g ati o n al st aff t o b e a v ail a bl e t o f a cilit at e t h e c o n d u ct 
of t h e vi sit, t h at s o ur c e d o c u m e nt s ar e a v ail a bl e at t h e ti m e of t h e vi sit, a n d t h at a s uit a bl e e n vir o n m e nt 
will b e pr o vi d e d f or r e vi e w of st u d y -r el at e d d o c u m e nt s. A n y i s s u e s i d e ntifi e d d uri n g t h e s e vi sit s will b e 
c o m m u ni c at e d t o t h e sit e a n d ar e e x p e ct e d t o b e r e s ol v e d b y t h e sit e i n a ti m el y m a n n er. F or r e vi e w of 
st u d y-r el at e d d o c u m e nt s at t h e C o or di n a ti n g C e nt er, t h e sit e will b e r e q uir e d t o s hi p or f a x d o c u m e nt s t o 
b e r e vi e w e d. 
 
P arti ci p ati n g sit e will al s o u n d er g o a sit e cl o s e- o ut u p o n c o m pl eti o n, t er mi n ati o n or c a n c ell ati o n of a st u d y 
t o e n s ur e f ulfill m e nt of st u d y o bli g ati o n s d uri n g t h e c o n d uct of t h e st u d y, a n d t h at t h e sit e I n v e sti g at or i s 
a w ar e of hi s/ h er o n g oi n g r e s p o n si biliti e s. I n g e n er al, a sit e cl o s e- o ut i s c o n d u ct e d d uri n g a sit e vi sit; 
h o w e v er, sit e cl o s e- o ut c a n o c c ur wit h o ut a sit e vi sit. 

Protocol UMCC 2017.055 
Page 58 of 69 
 
 
 
 
16.0 
REFERENCES 
1. 
American Cancer Society: Prostate Cancer Statistics, 2014 
2. 
Beer TM, Armstrong AJ, Rathkopf DE, et al: Enzalutamide in metastatic prostate cancer 
before chemotherapy. N Engl J Med 371:424-33, 2014 
3. 
de Bono JS, Logothetis CJ, Molina A, et al: Abiraterone and increased survival in 
metastatic prostate cancer. N Engl J Med 364:1995-2005, 2011 
4. 
de Bono JS, Oudard S, Ozguroglu M, et al: Prednisone plus cabazitaxel or mitoxantrone 
for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a 
randomised open-label trial. Lancet 376:1147-54, 2010 
5. 
Kantoff PW, Higano CS, Shore ND, et al: Sipuleucel-T immunotherapy for castration- 
resistant prostate cancer. N Engl J Med 363:411-22, 2010 
6. 
Parker C, Nilsson S, Heinrich D, et al: Alpha emitter radium-223 and survival in 
metastatic prostate cancer. N Engl J Med 369:213-23, 2013 
7. 
Ryan CJ, Smith MR, de Bono JS, et al: Abiraterone in metastatic prostate cancer without 
previous chemotherapy. N Engl J Med 368:138-48, 2013 
8. 
Scher HI, Fizazi K, Saad F, et al: Increased survival with enzalutamide in prostate cancer 
after chemotherapy. N Engl J Med 367:1187-97, 2012 
9. 
Graff JN, Alumkal JJ, Drake CG, et al: Early evidence of anti-PD-1 activity in 
enzalutamide-resistant prostate cancer. Oncotarget 7:52810-52817, 2016 
10. 
Goel S, DeCristo MJ, Watt AC, et al: CDK4/6 inhibition triggers anti-tumour immunity. 
Nature, 2017 
11. 
Spranger S, Bao R, Gajewski TF: Melanoma-intrinsic beta-catenin signalling prevents 
anti-tumour immunity. Nature 523:231-5, 2015 
12. 
Therasse P, Arbuck SG, Eisenhauer EA, et al: New Guidelines to Evaluate the Response 
to Treatment in Solid Tumors. J Natl Cancer Inst 92:205-216, 2000 
13. 
Zellweger T, Miyake H, Cooper S, et al: Antitumor activity of antisense clusterin 
oligonucleotides is improved in vitro and in vivo by incorporation of 2'-O-(2- 
methoxy)ethyl chemistry. J Pharmacol Exp Ther 298:934-40, 2001 
14. 
Kole R, Krainer AR, Altman S: RNA therapeutics: beyond RNA interference and 
antisense oligonucleotides. Nat Rev Drug Discov 11:125-40, 2012 
15. 
Raal FJ, Santos RD, Blom DJ, et al: Mipomersen, an apolipoprotein B synthesis inhibitor, 
for lowering of LDL cholesterol concentrations in patients with homozygous familial 
hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet 
375:998-1006, 2010 
16. 
Buller HR, Bethune C, Bhanot S, et al: Factor XI antisense oligonucleotide for prevention 
of venous thrombosis. N Engl J Med 372:232-40, 2015 
17. 
Murray S, Ittig D, Koller E, et al: TricycloDNA-modified oligo-2'-deoxyribonucleotides 
reduce scavenger receptor B1 mRNA in hepatic and extra-hepatic tissues--a comparative 

Protocol UMCC 2017.055 
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study of oligonucleotide length, design and chemistry. Nucleic Acids Res 40:6135-43, 
2012 
18. 
Ross SJ, Revenko AS, Hanson LL, et al: Targeting KRAS-dependent tumors with 
AZD4785, a high-affinity therapeutic antisense oligonucleotide inhibitor of KRAS. Sci 
Transl Med 9, 2017 
19. 
Hong D, Kurzrock R, Kim Y, et al: AZD9150, a next-generation antisense 
oligonucleotide inhibitor of STAT3 with early evidence of clinical activity in lymphoma 
and lung cancer. Sci Transl Med 7:314ra185, 2015 
20. 
Seth PP, Siwkowski A, Allerson CR, et al: Short antisense oligonucleotides with novel 
2'-4' conformationaly restricted nucleoside analogues show improved potency without 
increased toxicity in animals. J Med Chem 52:10-3, 2009 
21. 
Chowdhury S, Burris H, Patel M, et al: A phase I dose escalation, safety and 
pharmacokinetic (PK) study of AZD5312 (IONIS-ARRx), a first-in-class Generation 2.5 
antisense oligonucleotide targeting the androgen receptor (AR). Eur J Cancer. December 
2016 Volume 69, Supplement 1, Page S145, 2016 
22. 
Burel SA, Han SR, Lee HS, et al: Preclinical evaluation of the toxicological effects of a 
novel constrained ethyl modified antisense compound targeting signal transducer and 
activator of transcription 3 in mice and cynomolgus monkeys. Nucleic Acid Ther 23:213- 
27, 2013 
23. 
Henry S, Kim TW, Kramer-Strickland K, et al: Toxicologic properies of 2- 
Omethoxyethyl chimeric antisense inhibitors in animals and man (ed 2nd), CRC Press, 
2008 pp. 327-364 
24. 
Kwoh T: An overview of the clinical safety experience of first- and second-generation 
asntisense oligonucleotides (ed 2nd), CRC Press, 2008 pp. 365-399 
25. 
Sheehan JP, Lan HC: Phosphorothioate oligonucleotides inhibit the intrinsic tenase 
complex. Blood 92:1617-25, 1998 
26. 
Levin A, SP H, DK M, et al: Toxicity of antisense oligonucleotides,, 2001 pp. 201-267 
27. 
Henry SP, Beattie G, Yeh G, et al: Complement activation is responsible for acute 
toxicities in rhesus monkeys treated with a phosphorothioate oligodeoxynucleotide. Int 
Immunopharmacol 2:1657-66, 2002 
28. 
Jason TL, Koropatnick J, Berg RW: Toxicology of antisense therapeutics. Toxicol Appl 
Pharmacol 201:66-83, 2004 
29. 
Henry S, Stecker K, Brooks D, et al: Chemically modified oligonucleotides exhibit 
decreased immune stimulation in mice. J Pharmacol Exp Ther 292:468-79, 2000 

Protocol UMCC 2017.055 
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17.0 APPENDICES 
 
APPENDIX A 

Protocol UMCC 2017.055 
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Appendix B 
 
Assessment of Progression on Bone Scan 
 
 
 
 
 

Protocol UMCC 2017.055 
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APPENDIX C 
 
 
 
 
 
Health Questionnaire 
English version for the USA 
USA (English) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group 
Check the ONE box that best describes your health TODAY. 

Protocol UMCC 2017.055 
Page 63 of 69 
 
 
 
 
 
MOBILITY 
I have no problems walking 
 
I have slight problems walking 
 
I have moderate problems walking 
 
I have severe problems walking 
 
I am unable to walk 
 
SELF-CARE 
I have no problems washing or dressing myself 
 
I have slight problems washing or dressing myself 
 
I have moderate problems washing or dressing myself 
 
I have severe problems washing or dressing myself 
 
I am unable to wash or dress myself 
 
USUAL ACTIVITIES (e.g. work, study, housework, family or leisure activities) 
I have no problems doing my usual activities 
 
I have slight problems doing my usual activities 
 
I have moderate problems doing my usual activities 
 
I have severe problems doing my usual activities 
 
I am unable to do my usual activities 
 
PAIN / DISCOMFORT 
I have no pain or discomfort 
 
I have slight pain or discomfort 
 
I have moderate pain or discomfort 
 
I have severe pain or discomfort 
 
I have extreme pain or discomfort 
 
ANXIETY / DEPRESSION 
I am not anxious or depressed 
 
I am slightly anxious or depressed 
 
I am moderately anxious or depressed 
 
I am severely anxious or depressed 
 
I am extremely anxious or depressed 
 

Protocol UMCC 2017.055 
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We would like to know how good or bad your health is TODAY. 
This scale is numbered from 0 to 100. 
100 means the best health you can imagine. 
0 means the worst health you can imagine. 
Mark an X on the scale to indicate how your health is TODAY. 
Now, please write the number you marked on the scale in the box below. 
 
 
 
 
 
 
 
 
 
 
YOUR HEALTH TODAY = 

Protocol UMCC 2017.055 
Page 65 of 69 
 
 
 
 
APPENDIX D 
FACT-P 
 
Below is a list of statements that other people with your illness have said are important. Please circle or 
mark one number per line to indicate your response as it applies to the past 7 days. 
 
PHYSICAL WELL-BEING 
Not 
at all 
A little 
bit 
Some 
what 
Quite 
a bit 
Very 
much 
GP1 
I have a lack of energy ......................................................... 0 
1 
2 
3 
4 
GP2 
I have nausea ........................................................................ 0 
1 
2 
3 
4 
GP3 
Because of my physical condition, I have trouble 
meeting the needs of my family .......................................... 0 
1 
2 
3 
4 
GP4 
I have pain ............................................................................. 0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of treatment ......................... 0 
1 
2 
3 
4 
GP6 
I feel ill .................................................................................... 0 
1 
2 
3 
4 
GP7 
I am forced to spend time in bed ......................................... 0 
1 
2 
3 
4 
 
 
SOCIAL/FAMILY WELL-BEING 
Not 
at all 
A little 
bit 
Some 
what 
Quite 
a bit 
Very 
much 
GS1 
I feel close to my friends .................................................... 0 
1 
2 
3 
4 
GS2 
I get emotional support from my family .............................. 0 
1 
2 
3 
4 
GS3 
I get support from my friends ............................................. 0 
1 
2 
3 
4 
GS4 
GS5 
My family has accepted my illness ...................................... 0 
I am satisfied with family communication about my  
illness ...................................................................................... 0 
1 
1 
2 
2 
3 
3 
4 
4 
GS6 
I feel close to my partner (or the person who is my main 
support) ................................................................................... 0 
1 
2 
3 
4 
Q1 
Regardless of your current level of sexual activity, please 
answer the following question. If you prefer not to answer it, 
please mark this box and go to the next section. 
GS7 
I am satisfied with my sex life .............................................. 0 
1 
2 
3 
4 
 
 
EMOTIONAL WELL-BEING 
Not 
at all 
A little 
bit 
Some 
what 
Quite 
a bit 
Very 
much 
GE1 
I feel sad ................................................................................ 0 
1 
2 
3 
4 
GE2 
I am satisfied with how I am coping with my illness ........ 0 
1 
2 
3 
4 
GE3 
I am losing hope in the fight against my illness ............... 0 
1 
2 
3 
4 
GE4 
I feel nervous ......................................................................... 0 
1 
2 
3 
4 
GE5 
I worry about dying ............................................................... 0 
1 
2 
3 
4 
GE6 
I worry that my condition will get worse ............................. 0 
1 
2 
3 
4 
 
 
FUNCTIONAL WELL-BEING 
Not 
at all 
A little 
bit 
Some 
what 
Quite 
a bit 
Very 
much 
GF1 
I am able to work (include work at home) ......................... 0 
1 
2 
3 
4 
GF2 
My work (include work at home) is fulfilling ..................... 0 
1 
2 
3 
4 
GF3 
I am able to enjoy life .......................................................... 0 
1 
2 
3 
4 
GF4 
I have accepted my illness ................................................. 0 
1 
2 
3 
4 
GF5 
I am sleeping well ................................................................ 0 
1 
2 
3 
4 
GF6 
I am enjoying the things I usually do for fun .................... 0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life right now ............ 0 
1 
2 
3 
4 

Protocol UMCC 2017.055 
Page 66 of 69 
 
 
 
 
English (Universal) 
19 November 2007 
Copyright 1987, 1997 
Page 1 of 2 
 
 
Please circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
 
ADDITIONAL CONCERNS 
Not 
at all 
A little 
bit 
Some 
what 
Quite 
a bit 
Very 
much 
C2 
I am losing weight ................................................................ 0 
1 
2 
3 
4 
C6 
I have a good appetite ........................................................ 0 
1 
2 
3 
4 
P1 
I have aches and pains that bother me. ............................. 0 
1 
2 
3 
4 
P2 
I have certain parts of my body where I experience pain..0 
1 
2 
3 
4 
P3 
My pain keeps me from doing things I want to do ............. 0 
1 
2 
3 
4 
P4 
I am satisfied with my present comfort level ..................... 0 
1 
2 
3 
4 
P5 
I am able to feel like a man ................................................... 0 
1 
2 
3 
4 
P6 
I have trouble moving my bowels ....................................... 0 
1 
2 
3 
4 
P7 
I have difficulty urinating ...................................................... 0 
1 
2 
3 
4 
BL2 
I urinate more frequently than usual .................................... 0 
1 
2 
3 
4 
P8 
My problems with urinating limit my activities ................... 0 
1 
2 
3 
4 
BL5 
I am able to have and maintain an erection ......................... 0 
1 
2 
3 
4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
English (Universal) 
19 November 2007 
Copyright 1987, 1997 
Page 2 of 2 
 

Protocol UMCC 2017.055 
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APPENDIX E         Statistical Appendix to track Amendment changes to the Design and Prior Simulation Results 
 
After 2 patients were treated at Dose 3 and found to have toxicity that the study team felt should require dose 
modification, an amendment to the trial to modified the DLT definition to include Grade 2 liver transaminase toxicity and 
expanded the DLT window of toxicity from 1 cycle to include 2 cycles plus labs prior to initiation of cycle 3.  These 
changes required re-estimation of the trial characteristics.  Below are the trial characteristics with a toxicity window of 1 
cycle (21 days).  The current statistical section in 11.7 includes trial characteristics based upon sumulations with a toxicity 
window of 2 cycles plus labs prior to initiation of cycle 3 (42 days). 
 
Sample Size and Accrual 
We will enroll a total of up to 35 toxicity evaluable patients, depending on if the trial stops early for 
safety (toxicity). Justification for this design and sample size is based upon 250 simulated trials for 
each of 28 true data-generating scenarios (seven sets of dose-DLT probabilities crossed with four 
sets of dose-efficacy probabilities). 
 
The results of the simulation study are given in Tables 1A-1C. The true probabilities of DLT for 
the three dose levels of IONIS-AR-2.5Rx are given in the rows. The true probabilities of PSA 
response for the three dose levels of IONIS-AR-2.5Rx are given in the columns. 
 
Table 1A gives the probability of making the correct MTD determination. The true MTD is always 
defined as the dose level closest to but not exceeding 35% by more than 2.5% in the simulations. 
From Table 1A, we can see that this probability is high (>0.85) when the true MTD is dose level 3 
or >67% when all dose levels are unsafe and lower when the true DLT probabilities are closer to 
each other or when dose level 1 is close to being too toxic. 
 
Table 1B give the simulation-based probabilities of declaring success, i.e. finding a dose level 
that statistically appears to be both safe and sufficiently efficacious. These probabilities 
approximately represent the ‘type I error’ and ‘power’ of our design. These probabilities are low 
(<0.45) in the left-hand columns (non-efficacious scenarios) and/or bottom rows (unsafe 
scenarios). Conversely, they are high (>0.70) in the top-right cells (efficacious, safe scenarios). 
 
Finally, Table 1C gives the 25th and 75th percentiles for total enrollment. Because the trial will 
only stop for safety (and not futility), expected enrollment decreases only in the unsafe scenarios. 
The trial will generally stop after 9 - 35 patients when no dose levels are safe. 
 
Table 1A: Simulation-based probability of correctly identifying the true MTD (highlighted in bold 
in the left column), regardless of efficacy. The correct determination in the last row is to stop for 
toxicity, because no dose levels have true rate of DLT less than 35%. 
 
True PSA Response Probabilities (when DLT is observed) 
True DLT 
probabilities 
{3%,8%,10%} 
{5%,13%,20%} 
{5%,10%,25%} 
{20%,28%,35%} 
{8%,13%,25%} 
0.98 
0.98 
0.99 
0.96 
{10%,20%,30%} 
0.88 
0.85 
0.87 
0.85 
{14%,21%,35%} 
0.70 
0.70 
0.70 
0.70 
{20%,27%,40%} 
0.42 
0.45 
0.41 
0.46 
{25%,33%,45%} 
0.46 
0.46 
0.44 
0.44 
{30%,45%,55%} 
0.45 
0.47 
0.42 
0.40 
{40%,50%,70%} 
0.67 
0.70 
0.66 
0.68 
 
Table 1B: Simulation-based probability of ‘declaring success’, i.e. finding any dose level that is 
estimated to be safe AND efficacious. 
True PSA Response Probabilities (when DLT is observed) 
True DLT probabilities 
{3%,8%,10%} 
{5%,13%,20%} 
{5%,10%,25%} 
{20%,28%,35%} 
{8%,13%,25%} 
0.42 
0.90 
0.99 
0.996 
{10%,20%,30%} 
0.38 
0.85 
0.87 
0.98 
{14%,21%,35%} 
0.31 
0.72 
0.71 
0.96 

Protocol UMCC 2017.055 
Page 68 of 69 
 
 
{20%,27%,40%} 
0.24 
0.59 
0.51 
0.88 
{25%,33%,45%} 
0.16 
0.34 
0.31 
0.71 
{30%,45%,55%} 
0.03 
0.10 
0.08 
0.42 
{40%,50%,70%} 
0.004 
0.02 
0.01 
0.16 
 
Table 1C: Simulation-based interquartile range of number of patients enrolled over all simulated 
trials. 
True PSA Response Probabilities (when DLT is observed) 
True DLT 
probabilities 
{10%,12%,15%} 
{12%,16%,23%} 
{16%,26%,30%} 
{10%,13%,33%} 
{8%,13%,25%} 
(35, 35) 
(35, 35) 
(35, 35) 
(35, 35) 
{10%,17%,30%} 
(35, 35) 
(35, 35) 
(35, 35) 
(35, 35) 
{14%,21%,35%} 
(35, 35) 
(35, 35) 
(35, 35) 
(35, 35) 
{20%,27%,42%} 
(35, 35) 
(35, 35) 
(35, 35) 
(35, 35) 
{25%,38%,46%} 
(35, 35) 
(35, 35) 
(35, 35) 
(35, 35) 
{33%,46%,60%} 
(33, 35) 
(35, 35) 
(34, 35) 
(18, 35) 
{38%,50%,70%} 
(9, 35) 
(10, 35) 
(10, 35) 
(9, 35) 
 
 
 

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18.0 COVID-19 Addendum 
18.1 
Purpose 
The purpose of this addendum is to address protocol-required items that the COVID-19 pandemic 
may temporarily affect. 
 
18.2 
Study Visit Schedules/Schedule of Events 
During the COVID-19 pandemic, and in accordance with regulatory requirements, temporary visit or 
follow-up visit adjustments may be made at the site level specific to the scenario (e.g., In the event 
of virtual visits per clinician/subject discretion). For instances where protocol-specified assessments 
cannot be made and/or data are unable to be collected, the study team is expected to document the 
specific reason(s) (e.g., identifying the specific limitation imposed by COVID-19 leading to the 
inability to perform the protocol-specified assessment), and report as appropriate. For reporting to 
Coordinating Center, this should be documented using the Protocol Deviation form.  
 
Safety Follow-up/EOT visits 
Adjustments to the imaging and bone scan window (30 days from last dose of IONIS-AR-2.5RX (+/- 
7 business days) are permitted by the Sponsor-Investigator if on schedule visit not possible due to 
COVID-19. 
 
Follow-Up Visits 
Adjustments to the imaging window (every 12 weeks (+/- 7 business days) are permitted by the 
Sponsor-Investigator if on schedule visit not possible due to COVID-19. 
 
Virtual Clinic Visits 
In the event of virtual clinic visits”, Vitals will likely not be collected; If subject has items such as 
blood pressure cuff, thermometer, weight scale, etc. at home, clinical staff may request the subject 
to use such apparatuses and record values in source documents – noting that home equipment was 
used for the reading. 
 
18.3 
Fresh Tumor Biopsy 
During the COVID-19 pandemic, the Post-Cycle 2 and EOT biopsy may be temporarily unable to be 
processed at the receiving lab due to COVID-19 outages. The recommendation is to not collect if 
the lab is still unavailable at the time of the next scheduled time point (please consult with the 
Coordinating Center). If not collecting, this should be documented using the Protocol Deviation 
form, specifically addressing impact from COVID-19. If the sample is obtained (patient consented to 
biopsy), please store specimen at -80°C until notification to deliver to the receiving lab is received. 
 
18.4  
Blood draws 
During the COVID-19 pandemic, the Cycle 2+ PK Draws for D1, D8 and D15 may be temporarily 
unable to be processed at the receiving lab due to COVID-19 outages. The recommendation is to 
not collect if the lab is still unavailable at the time of the next scheduled time point (please consult 
with the Coordinating Center). If not collecting, this should be documented using the Protocol 
Deviation form, specifically addressing impact from COVID-19.