A Phase I Study to Evaluate Safety, Tolerability, PK, Pharmacodynamics, and Preliminary Anti-Tumor Activity of AC176 in Patients With Metastatic Castration Resistant Prostate Cancer Who Have Progressed on at Least Two Prior Systemic Therapies
Phase: PHASE1
Conditions: Metastatic Castration Resistant Prostate Cancer
Sponsor: Accutar Biotechnology Inc

                        
 
CONFIDENTIAL 
This document is confidential and is the property of Sarah Cannon Development Innovations, LLC.  No 
part of this document may be transmitted, reproduced, published, or used by other persons without prior 
written authorization from Sarah Cannon Development Innovations, LLC. 
Page 1 of 121 
GU 207 
A Phase I, Open-label, Multi-center, Clinical Study to Evaluate Safety, 
Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Anti-
Tumor Activity of AC176 in Patients with Metastatic Castration Resistant 
Prostate Cancer (mCRPC) Who Have Progressed on at Least Two Prior 
Systemic Therapies 
DEVELOPMENT INNOVATIONS STUDY 
NUMBER: 
GU 207 
SPONSOR STUDY NUMBER: 
AC176-001 
IND NUMBER: 
158793 
STUDY DRUG: 
AC176 
SPONSOR: 
Accutar Biotechnology, Inc. 
8 Clarke Drive, Suite 4 
Cranbury, NJ 08512 
929-262-0884 
CONTRACT RESEARCH ORGANIZATION: 
Sarah Cannon Development Innovations, LLC 
1100 Dr. Martin L. King Jr. Blvd. 
Suite 800 
Nashville, TN 37203 
615-329-7274 
STUDY CHAIR: 
Benjamin Garmezy, MD  
Assistant Director, Genitourinary Cancer Research 
Program  
250 25th Ave North, Suite 200 
Nashville, TN 37203 USA 
1-877-MY-1-SCRI 
MEDICAL MONITOR: 
Biebele Iyagba, MD  
Medical Monitor 
Sarah Cannon Development Innovations, LLC 
1100 Dr. Martin L. King Jr. Blvd. 
Suite 800 
Nashville, TN 37203 
615-329-7274 
DATE FINAL: 
10 July 2023 
 
VERSION NUMBER: 
4 

                        
 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 2 of 121 
Clinical Study Statement of Compliance 
GU 207 
A Phase I, Open-label, Multi-center, Clinical Study to Evaluate Safety, 
Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Anti-
Tumor Activity of AC176 in Patients with Metastatic Castration Resistant 
Prostate Cancer (mCRPC) Who Have Progressed on at Least Two Prior 
Systemic Therapies 
 
This clinical study shall be conducted in compliance with the protocol, as referenced herein, and 
all applicable local, national, and international regulatory requirements to include, but not be 
limited to: 
• 
International Council for Harmonisation (ICH) Guidelines on Good Clinical Practice 
(GCP) 
• 
Ethical principles that have their origins in the Declaration of Helsinki 
• 
Food and Drug Administration (FDA) Code of Federal Regulation (CFR): 
o 
Title 21CFR Part 50 & 45 CFR Part 46, Protection of Human Subjects 
o 
Title 21CFR Part 54, Financial Disclosure by Clinical Investigators 
o 
Title 21CFR Part 56, Institutional Review Boards (IRBs) 
o 
Title 21CFR Part 312, Investigational New Drug (IND) Application 
o 
Title 45CFR Parts 160, 162, and 164, Health Insurance Portability and 
Accountability Act (HIPAA)  
As the Study Chair and/or Principal Investigator, I understand that my signature on the 
protocol constitutes my agreement and understanding of my responsibilities to conduct the 
clinical study in accordance to the protocol and applicable regulations.  Furthermore, it 
constitutes my understanding and agreement that any changes initiated by myself, without 
prior agreement in writing from the Sponsor, shall be defined as a deviation from the protocol, 
and shall be formally documented as such. 
 
As the Contract Research Organization (CRO) Representative, I understand that my signature 
constitutes agreement and understanding of acceptance of the defined and contracted sponsor 
responsibilities as defined by the protocol, applicable Clinical Trial Agreements (CTA), and/or 
business contracts.  Additionally, my signature constitutes my understanding and agreement 
that any changes to the protocol, CTA, or contracts shall be implemented with the Sponsor’s 
review and approval prior to implementation. 
 
As the Sponsor Representative, I understand that my signature constitutes agreement and 
understanding of acceptance of the defined and contracted Sponsor responsibilities to the CRO 
and the Principal Investigator as defined by the protocol, applicable clinical trial agreements 
(CTA), and/or business contracts, but does not in any capacity relieve me of my responsibilities 
as the Sponsor.  Additionally, my signature constitutes my understanding and agreement that 
any changes to the protocol, CTA, or contracts shall be implemented timely with my review and 
approval prior to implementation. 

                        
 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 3 of 121 
Clinical Study Approval Page 
GU 207 
A Phase I, Open-label, Multi-center, Clinical Study to Evaluate Safety, 
Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Anti-
Tumor Activity of AC176 in Patients with Metastatic Castration Resistant 
Prostate Cancer (mCRPC) Who Have Progressed on at Least Two Prior 
Systemic Therapies 
DEVELOPMENT INNOVATIONS 
STUDY NUMBER: 
GU 207 
SPONSOR STUDY NUMBER: 
AC176-001 
IND NUMBER: 
158793 
STUDY DRUG: 
AC176 
DATE FINAL: 
10 July 2023 
 
 
__________________________ 
__________________________         ______________ 
Study Chair 
Assistant Director, Genitourinary Cancer 
Research   
Sarah Cannon Research Institute 
Study Chair Signature 
 
Date 
 
 
__________________________ 
__________________________         ______________ 
Sponsor Representative 
VP of Clinical Development 
Accutar Biotechnology, Inc. 
Sponsor Representative Signature 
Date 
 
 
__________________________ 
__________________________         ______________ 
VP, Development Innovations  
Sarah Cannon Development Innovations, 
LLC 
 
Development Innovations Representative 
Signature 
Date 
Benjamin Garmezy, MD 
Su Young Kim, MD, PhD 
Marcy Vallone 

                        
 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 4 of 121 
 
Clinical Study Principal Investigator Signature Form 
GU 207 
A Phase I, Open-label, Multi-center, Clinical Study to Evaluate Safety, 
Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Anti-
Tumor Activity of AC176 in Patients with Metastatic Castration Resistant 
Prostate Cancer (mCRPC) Who Have Progressed on at Least Two Prior 
Systemic Therapies 
DEVELOPMENT INNOVATIONS STUDY 
NUMBER: 
GU 207 
SPONSOR STUDY NUMBER: 
AC176-001 
IND NUMBER: 
158793 
STUDY DRUG: 
AC176 
DATE FINAL: 
10 July 2023 
 
By signing this protocol acceptance page, I confirm I have read, understand, and agree to conduct the 
study in accordance with the current protocol. 
 
 
 
___________________________ 
_______________________________     _______ 
Principal Investigator Name 
<<Insert Site Name and ID info as 
applicable>> 
<<Insert Site Location>> 
Principal Investigator Signature 
 
Date 
 
Please retain a copy of this page for your study files and return the original signed and dated 
form to: 
 
Sarah Cannon Development Innovations, LLC 
1100 Dr. Martin L. King Jr. Blvd., Suite 800 
Attention:  GU 207 Study Team 
Nashville, TN 37203 

                        
 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 5 of 121 
GU 207 CONTACT INFORMATION 
Sponsor Contact Address and Phone#: 
Accutar Biotechnology, Inc. 
8 Clarke Drive, Suite 4 
Cranbury, NJ 08512 
929-262-0884 
Development Innovations Contact 
Address and Phone#: 
Sarah Cannon Development Innovations, LLC 
1100 Dr. Martin L. King Jr. Blvd. 
Suite 800 
Nashville, TN 37203 USA 
615-329-7274 
 
Study Chair: 
Benjamin Garmezy, MD  
Assistant Director, Genitourinary Cancer 
Research  
250 25th Ave North, Suite 200 
Nashville, TN 37203 USA 
1-877-MY-1-SCRI 
Medical Monitor: 
Biebele Iyagba, MD  
Medical Monitor 
Sarah Cannon Development Innovations, LLC 
1100 Dr. Martin L. King Jr. Blvd. 
Suite 800 
Nashville, TN 37203 
615-329-7274 
Safety Department Fax #: 
Safety Department Email: 
1-866-807-4325 
CANN.SAE@SCRI-Innovations.com 
Regulatory Department Phone #: 
Regulatory Department Email: 
1-877-MY-1-SCRI /1-615-524-4518 
SCRIRegulatory@SCRI-Innovations.com 
Development Innovations Enrollment 
Fax #: 
Development Innovations Enrollment 
Email: 
866-346-1062 or 615-524-4012 
CANN.SCRIInnovationsEnr@scri-
innovations.com 

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 6 of 121 
GU 207 PROTOCOL SYNOPSIS 
Title of Study: 
A Phase I, Open-label, Multi-center, Clinical Study to Evaluate Safety, Tolerability, 
Pharmacokinetics, Pharmacodynamics, and Preliminary Anti-Tumor Activity of AC176 in Patients with Metastatic 
Castration Resistant Prostate Cancer (mCRPC) Who Have Progressed on at Least Two Prior Systemic Therapies 
Development Innovations Study Number:  GU 207 
Sponsor: 
 Accutar Biotechnology, Inc. 
Phase of Study:  
I 
Number of Patients: 
 Up to 130 patients are planned to be enrolled in this study. 
Objectives:  
Endpoint/Variable: 
Primary Objective: 
 
Evaluate the safety and tolerability of AC176 
Dose-limiting toxicities  
Adverse events (AEs)/Serious adverse events (SAEs) 
Vital signs 
Clinical chemistry/hematology parameters 
Electrocardiograms (ECGs) 
Secondary Objectives: 
Endpoint/Variable: 
Characterize the pharmacokinetics (PK) profile of a 
single dose and after multiple doses of AC176 
PK parameters  
Evaluate the preliminary anti-tumor activity of AC176 
on prostate specific antigen (PSA) response rate 
PSA confirmed response is defined as the proportion of 
participants with a reduction in the level of PSA of 
≥50% from baseline to the lowest post-baseline PSA 
results, measured twice, at least 3 weeks apart, by the 
Prostate Cancer Working Group 3 criteria (PCWG3, 
Scher et al. 2016) 
Evaluate the preliminary anti-tumor activity of AC176 
on objective response rate (ORR) for patients with 
measurable disease 
ORR based on PCWG3-modified Response Evaluation 
Criteria in Solid Tumors (RECIST) v1.1 (Eisenhauer et 
al. 2009) 
Evaluate the preliminary anti-tumor activity of AC176 
on duration of response (DoR)  
DoR is defined as the time from the date of first 
documented response until date of documented 
progression or death in the absence of disease 
progression  
Evaluate the preliminary anti-tumor activity of AC176 
on time-to-progression (TTP) 
TTP based on PCWG3-modified RECIST v1.1 and/or 
PCWG3 PSA criteria (≥25% increase and ≥2 ng/mL 
increase above the nadir or baseline value for patients 
who had a PSA decrease on treatment, which is 
confirmed by a second value 3 or more weeks later.  
For patients without a decrease on treatment, PSA 
progression is defined as ≥25% increase and an 
absolute increase of ≥2 ng/mL after 12 weeks.)   
Evaluate the effect of AC176 on radiographic 
progression-free survival (rPFS) 
Radiographic disease progression based on PCWG3-
modified RECIST v1.1 criteria.  rPFS is defined as the 
time from the first study drug administration to first 
objective evidence of radiographic disease progression 
assessed by the study Investigator, or death, whichever 
occurs first.  

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 7 of 121 
Objectives:  
Endpoint/Variable: 
Evaluate the effect of AC176 on progression-free 
survival (PFS) 
PFS based on PCWG3-modified RECIST v1.1 and/or 
PCWG3 PSA criteria.  PFS is defined as the time from 
first study drug administration until objective disease 
progression (based on bone or CT/MRI scans), or PSA, 
or death, whichever occurs first. 
Exploratory Objectives: 
Endpoint/Variable: 
Evaluate the relationship between androgen receptor 
(AR) degradation on tumor tissue and administration 
of AC176 
Change of AR expression in tumors from baseline to 
post-treatment, if tumor tissue is available from paired 
biopsies 
Evaluate the relationship between AR degradation in 
circulating tumor cells (CTCs) and administration of 
AC176, if available 
Change of AR expression in CTCs from baseline to 
post-treatment 
Evaluate the relationship of CTC numbers (baseline 
and post-treatment) and anti-tumor activity of AC176, 
if available 
Baseline CTC numbers or changes of CTC numbers 
post-treatment.  Correlation to anti-tumor activity (PSA 
response rate, ORR, rPFS, PFS, DoR and TTP) 
Evaluate the relationship of nuclear ARv7 expression 
(baseline and post-treatment) and anti-tumor activity of 
AC176 
Baseline ARv7 nuclear expression and changes of 
ARv7 nuclear expression post-treatment in CTCs.  
Correlation to anti-tumor activity (PSA response rate, 
ORR, rPFS, PFS, DoR and TTP) 
Evaluate the relationship between baseline AR 
genomic profiles and anti-tumor activity of AC176 
AR genomic profiles by circulating tumor DNA 
(ctDNA).  Correlation to anti-tumor activity (PSA 
response rate, ORR, rPFS, PFS, DoR and TTP) 
 
Study Design:  This is a Phase I, first-in-human, open-label, multi-center dose-escalation (Part A) study followed by 
an Expansion cohort (Part B) of AC176 given as a single agent.  During Part A Dose-Escalation, successive cohorts 
of patients will be treated with increasing doses of AC176 to evaluate safety and tolerability.  
In Part A Dose-Escalation, AC176 will be given orally (PO).  The starting dose will be 30 mg and will follow a 3+3 
design (see study schema below).  If suggested by emerging safety or PK findings, or as appropriate based on other 
data from previous cohorts, and approved by the Safety Review Committee (SRC), an alternative dosing level 
and/or dosing schedule may be considered, which could include twice daily (BID) or intermittent dosing.  
Alternative dosing schedules may be tested concurrently, provided the total dose is not greater than that of the dose 
level being evaluated.   
Prostate cancers with androgen receptor (AR) mutations are more dependent on the AR pathway for their growth.  
Degradation of AR makes these cancers more susceptible to cell death.  Thus, AR-mutated cancers may respond to 
AR degradation at lower doses than their wildtype counterparts.  As more data emerges from Part A, and the tested 
cohorts are cleared and deemed safe, patients with known AR point mutations may be eligible to enroll in Backfill 
cohorts.  The backfill patients will be enrolled to further characterise the objectives for the study.  The total number 
of patients enrolled in the Backfill cohort will not total more than 12 patients when combined with the number of 
patients already enrolled in the same cohort.  Toxicity for the patients enrolled in a Backfill cohort will be managed 
according to the Dose Modification Section 6.  Up to approximately 70 patients are expected to be enrolled in Part A 
dose-escalation, plus the backfill patients. 
The recommended dose for the Expansion cohort will be determined in the Part A Dose-Escalation part of the study.  
Up to two cohorts may be explored in Part B with approximately 30 patients each.  One cohort will be for patients 
with AR point mutations.  The other cohort will be for patients without AR point mutations.  The Sponsor and SRC 
will determine the dose and schedule(s) for the Expansion cohorts based on tolerability and emerging data.   

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 8 of 121 
Patients enrolled in Backfill (Part A) and Expansion cohorts (Part B) will be pre-screened for AR mutation status, 
unless patients can provide documentation that they have the AR point mutation.  All patients will retrospectively 
undergo central laboratory testing for AR mutation confirmation at Cycle 1 Day 1 per the Schedule of Activities 
(SOA). 
The Dose-Escalation phase will identify a maximum tolerated dose (MTD), if possible, with safety and tolerability 
data.  The Expansion cohorts of the study will support the selection of a dose for future clinical studies (i.e., 
recommended Phase 2 dose [RP2D]). 
Study Schema 
 
Study Drugs, Doses, and Modes of Administration: 
 
AC176 will be given as PO dosing.  Patients will be instructed to take 1 dose of AC176, immediately after a meal. 
Main Inclusion Criteria: 
Patients must meet the following criteria in order to be included in the research study: 
1. Written informed consent, according to local guidelines, signed and dated by the patient or by a legal 
guardian prior to the performance of any study-specific procedures, sampling, or analyses. 
2. Males who are at least 18 years-of-age at the time of signature of the informed consent form.  
3. Patients with histological, pathological, or cytological confirmed diagnosis of advanced or metastatic 
castration resistant adenocarcinoma of the prostate excluding neuroendocrine differentiation or small cell 
features who have had disease progression per PCWG3 guidance following standard treatment, including 
approved taxane-based chemotherapy, or who are not amenable (intolerability, patient choice) to standard 
therapies, or for whom no therapy of proven efficacy exists.   
4. Progressive disease per PCWG3 guidance documented by either: 
• 
Positive bone scan (at least 2 new lesions) or metastatic lesions on computed tomography 
(CT)/magnetic resonance imaging (MRI) (Appendix B) that can be followed for response.   
Or 
• 
If PSA criteria is the only indication of progression, then the PSA values with a starting value of ≥1.0 
ng/mL that have increased on at least 2 occasions obtained a minimum of 1 week apart. 

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 9 of 121 
5. Patients must have progressed on at least 2 prior approved systemic therapies (in any setting), with at least 
1 being abiraterone or enzalutamide, or apalutamide or darolutamide. 
6. Patients must have had surgical or ongoing medical castration.  Surgical castration is defined as bilateral 
orchiectomy.  Medical castration is defined as ongoing ADT with a gonadotropin releasing hormone 
(GnRH) analog or inhibitor, plus serum testosterone level <50 ng/dL (or <1.7 nmol/L). 
7. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 to 1 (Appendix A). 
8. Acceptable organ functions, as evidenced by the following laboratory data: 
• 
Renal function, as follows: 
o 
Creatinine clearance of ≥50 mL/min by the Cockcroft-Gault equation or equivalent 
• 
Liver function, as follows: 
o 
Total bilirubin ≤1.5 × ULN (unless the patient has Grade 1 bilirubin elevation due to 
Gilbert’s disease or a similar syndrome involving slow conjugation of bilirubin) 
o 
Aspartate aminotransferase ≤2.5 × ULN or ≤5 × ULN in the presence of liver metastases 
o 
Alanine aminotransferase ≤2.5 × ULN or ≤5 × ULN in the presence of liver metastases 
• 
International normalized ratio (INR) <2.  If the patient is receiving anticoagulated medication, 
then an INR range of 2.0 – 3.0 is allowed. 
• 
Acceptable hematologic function: 
o 
Hemoglobin ≥9 g/dL 
o 
Absolute neutrophil count ≥1,500 cells/mm3 
o 
Platelet count ≥100,000 cells/mm3 
9. Male patients with female partners of childbearing potential are required to use two forms of acceptable 
contraception (Appendix D), including one barrier method, during their participation in the study and for 90 
days following last dose.  Male patients must also refrain from donating sperm during their participation in 
the study and for 90 days following last dose. 
10. Life expectancy ≥3 months after the start of the treatment according to the Investigator’s judgment. 
Inclusion Criteria – Backfill Cohorts 
1. Patients may enroll to a Backfill cohort if they have documentation of the AR point mutations.  Patients 
who have not had AR mutation testing may have the testing performed after signing a pre-screening 
informed consent form (ICF) (see Section 7.2).  
Additionally, patients must meet the main inclusion criteria listed above to be enrolled. 
Inclusion Criteria – Part B Expansion Cohorts 
1. Patients are required for AR mutation testing after signing a pre-screening ICF (see Section 7.2), unless the 
patients have documentation of the AR point mutations.  
Additionally, patients must meet the main inclusion criteria listed above to be enrolled. 
Main Exclusion Criteria: 
Patients who meet any of the following criteria will be excluded from study entry: 
1. Treatment with any of the following: 
• 
More than 2 lines of chemotherapy in the CRPC setting. 
• 
Any systemic anti-cancer therapy chemotherapy or biologic from a previous treatment regimen or 
clinical study within 4 weeks prior to the first dose of study drug.  Any systemic small molecules 
from a previous treatment regimen or clinical study within 2 weeks or 5 half-lives (whichever is 
longer, not to exceed 4 weeks) prior to the first dose of study drug, except ADT for medical 
castration purpose.   

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 10 of 121 
• 
Any investigational agents from a previous clinical study within 4 weeks prior to the first dose of 
study treatment 
• 
Radiation therapy (including therapeutic radioisotopes) within 4 weeks prior to first dose of study 
drug.  Radiation for palliation within 2 weeks of study drug. Palliative radiation for the alleviation 
of pain due to bone metastasis will be allowed after the DLT evaluation period. 
2. With the exception of alopecia and ≤ Grade 2 peripheral neuropathy, any unresolved toxicities from prior 
therapy greater than the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI 
CTCAE) Grade 1 at the time of starting study treatment. Note: subjects with chronic Grade 2 toxicities that 
are asymptomatic or adequately managed with stable medication may be eligible with Sponsor approval.  
3. Major surgery (excluding placement of vascular access) within 4 weeks of first dose of study drug. 
4. Known symptomatic brain metastases requiring steroids (above physiologic replacement doses). 
5. Men who plan to father a child while in the study or within 90 days after the last administration of study 
treatment 
6. Any condition that impairs a patient’s ability to swallow whole pills.  Presence of active gastrointestinal 
disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or 
excretion of AC176 (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea Grade ≥2, 
malabsorption syndrome). 
7. Any of the following cardiac criteria experienced currently or within the last 6 months: 
• 
Any clinically important abnormalities (as assessed by the Investigator) in rhythm, conduction, or 
morphology of resting electrocardiograms (ECGs), e.g., complete left bundle branch block, third-
degree heart block 
• 
Congestive heart failure (New York Heart Association ≥ Grade 2 [Appendix E]) 
• 
Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart 
failure, acute hypokalemia, congenital long QT syndrome, family history of long QT syndrome or 
unexplained sudden death under 40 years-of-age, or any new concomitant medication known to 
prolong the QT interval 
8. Mean resting corrected QT interval (QTc) >470 msec. 
9. Left ventricular ejection fraction (LVEF) <50% or the lower limit of normal of the institutional standard.   
10. As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases, including 
uncontrolled hypertension, uncontrolled diabetes mellitus, active bleeding diatheses, or active infection.  
Screening for chronic conditions is not required. 
11. Human immunodeficiency virus (HIV)  infection with a current or a known history of acquired 
immunodeficiency syndrome (AIDS)-defining illness or HIV infection with a CD4+ T cell count <350 
cells/µL and an HIV viral load more than 400 copies/µL. 
12. Patients with active viral (any etiology) hepatitis are excluded.  However, patients with serologic evidence 
of chronic hepatitis B virus (HBV) infection (defined by a positive hepatitis B surface antigen test and a 
positive anti-hepatitis core antigen antibody test) who have a viral load below the limit quantification (HBV 
DNA titer <1000 cps/mL or 200 IU/mL), and are not currently on viral suppressive therapy may be eligible 
and should be discussed with the Medical Monitor.  Patients with a history of hepatitis C virus infection 
who have completed curative antiviral treatment and have a viral load below the limit of quantification may 
be eligible. 
13. Presence of other active, invasive cancers other than the one treated in this study within 3 years prior to 
screening, except appropriately treated basal cell carcinoma of the skin, or in situ carcinoma of uterine 
cervix, or other local tumors considered cured by local treatment. 
14. Prior history of allergic reaction to the composition/excipients of AC176. 

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 11 of 121 
15. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the 
protocol and/or follow-up procedures outlined in the protocol. 
Statistical Methodology: 
The Phase I dose-escalation will enroll 3 patients at the 30 mg dose level following a standard 3+3 cohort design 
until the MTD, if possible, is determined in this population.  There are two parts to this study: Part A, dose-
escalation and Part B, Expansion cohorts.  Approximately 70 patients are expected to be enrolled in the Part A Dose-
Escalation cohorts including the Backfill patients, and up to 60 patients to Part B Expansion cohorts.  Up to 130 
patients overall may enter the study. 
Depending on the totality of emerging data from safety, tolerability, PK, biomarkers, and preliminary anti-tumor 
activity, the recommended dose for the Expansion cohort will be determined in Part A, Dose-Escalation.  Two 
prostate cancer patient cohorts may be explored in Part B Expansion cohort.  The cohorts may encompass 30 
patients with AR point mutations and 30 patients without AR point mutations.  Guided by tolerability and emerging 
data, the Sponsor and SRC will determine the dose and schedule(s) for the expansion cohorts.   
Safety Analysis 
Safety will be assessed through the analysis of the reported incidence of treatment-emergent adverse events (AEs).  
Treatment-emergent AEs are those with an onset on or after the initiation of therapy and will be graded according to 
NCI CTCAE Version 5.0. 
The AEs will be coded using the current version of Medical Dictionary for Regulatory Activities (MedDRA) and 
summarized using system organ class and preferred term by dose level for all patients in the Safety Analysis Set.  In 
addition, summaries of serious AEs (SAEs), AEs leading to dose modification (dose hold, reduction, and 
discontinuation), AEs by maximum NCI CTCAE grade, and AEs related to study treatment will also be presented by 
dose level. 
Other safety endpoints, including laboratory results, vital signs, ECG, and ECOG findings, will be summarized for 
all patients in the Safety Analysis Set. 
Efficacy Analysis 
All efficacy analyses will be performed using the efficacy evaluable set. 
Measurement of PSA levels, bone scans and CT/MRI scans will be performed for all patients at screening, during 
the study according to the SOA, and at follow-up visits before a subsequent anti-cancer therapy or death. 
• 
PSA response rate, PSA confirmed response is defined as the proportion of participants with a 
reduction in the PSA level of ≥50% from baseline to the lowest post-baseline PSA results, 
measured twice, at least 3 weeks apart by the PCWG3 criteria. 
• 
Objective Response Rate (ORR), defined as the proportion of patients with confirmed complete 
response (CR) or partial response (PR) (i.e., 2 CRs or PRs at least 4 weeks apart) according to the 
PCWG3-modified RECIST Version 1.1 criteria (see Appendix B). 
• 
Duration of Response (DoR), defined as the time from the date of first documented response (the 
first CR or PR which has been subsequently confirmed) until date of documented progression or 
death in the absence of disease progression. 
• 
Time-to-Progression (TTP) based on PCWG3-modified RECIST v1.1 and/or PCWG3 PSA 
criteria (≥25% increase and ≥2 ng/mL increase above the nadir or baseline value for patients who 
had a PSA decrease on treatment, which is confirmed by a second value 3 or more weeks later.  
For patients without a decrease on treatment, PSA progression is defined as ≥25% increase and an 
absolute increase of ≥2 ng/mL after 12 weeks), defined as the time from start of study treatment to 
disease progression. 
• 
Radiographic Progression-Free Survival (rPFS), based on PCWG3-modified RECIST v1.1 
criteria.  rPFS is defined as the time from the first study drug administration to first objective 

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 12 of 121 
evidence of radiographic disease progression assessed by the Study Investigator, or death, 
whichever occurs first.   
• 
Progression-free Survival (PFS), based on PCWG3-modified RECIST v1.1 and/or PCWG3 PSA 
criteria.  PFS is defined as the time from first study drug administration until objective disease 
progression (based on bone or CT/MRI scans), or PSA, or death, whichever occurs first.   

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 13 of 121 
Table 1 
SOA 1 (GU 207 Schedule of Assessments) - Pre-screening (Backfill and 
Expansion Cohort Patients only) and Screening (All Patients) 
Study Period 
Pre-screening 
(Backfill and 
Expansion 
Cohort only)* 
Screening 
(For All Patients) 
Time Relative to First Dose 
 
Up to 28 
Daysd 
Up to 14 
dayse 
Pre-screening 
 
 
 
Pre-screening ICF for AR mutation testing (if no existing 
results are available)a  
X 
 
 
Allocation of pre-screening subject ID 
X 
 
 
Blood sampling for biomarkers (ctDNA)b 
X 
 
 
 
 
 
 
Screening 
 
 
 
Written ICF for main studyc 
 
X 
 
Allocation of new subject ID for the main study 
 
X 
 
Inclusion / exclusion criteria 
 
X 
 
Medical history and demographics 
 
X 
 
Testosterone blood sample 
 
X 
 
Physical examination, height, and weight 
 
 
X 
Vital signs 
 
 
X 
ECOG performance status 
 
 
X 
Safety laboratory (hematology, [including PT/PTT/(INR or 
aPTT)], biochemistry, urinalysis) 
 
 
X 
Concomitant medications 
 
X 
 
AEs 
 
X 
 
12-lead electrocardiograms (triplicate)h 
 
 
X 
Echocardiogrami 
 
X 
 
Serology infection testingf 
 
X 
 
Thyroid stimulating hormone (TSH) and free T4g 
 
 
X 
(Optional) Tumor biopsyj 
 
X 
 
PSAk 
 
X 
 
Tumor assessment CT/MRI and bone scansl,m 
 
X 
 
SOA 1 Footnotes: 
* 
Pre-screening for AR mutation status is required in the Backfill and Expansion cohorts.  If patients provide historic ctDNA 
testing results of a positive AR point mutation, then pre-screening ctDNA testing for AR mutation status by ctDNA testing 
is not needed.  All patients will retrospectively undergo central laboratory testing for AR mutation confirmation at Cycle 1 
Day 1 per the treatment SOA (see Section 7.2).  
a 
A separate pre-screening informed consent form (ICF) must be signed by the patient prior to the collection of any pre-
screening data or procedures. 
b 
A blood sample for ctDNA testing for AR mutation status is required at pre-screening for patients enrolling in Backfill and 
Expansion cohorts without AR point mutation documentation.   
c 
Written ICF for the main study must be obtained prior to initiation of study treatment and before undertaking any screening 
procedures. 
d 
During the Screening visit, review of inclusion criteria, informed consent, and medical history, concomitant therapy, and 
demographics, adverse events, and echocardiogram (ECHO) should take place within 28 days of start of study treatment.  
Tumor assessments (scans), and the PSA, and testosterone sample should be performed/collected ≤28 days prior to first dose 
of study drug administration. 
e 
The following screening parameters should be done ≤14 days prior to first dose of study drug administration: physical 
examination (including height and weight), Eastern Cooperative Oncology Group (ECOG) performance status, triplicate 
electrocardiograms (ECGs),vital signs, hematology (including absolute lymphocyte count, absolute neutrophil count, red 

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 14 of 121 
blood cell count, reticulocytes, hemoglobin, hematocrit, platelet counts, prothrombin time/partial thromboplastin time (or 
aPTT [activated/PTT])/ international normalized ratio [PT/PTT/INR]), biochemistry (sodium, potassium, phosphate, 
chloride, creatinine, total calcium, venous bicarbonate [HCO3], albumin, total protein, aspartate aminotransferase [AST], 
alanine aminotransferase [ALT], alkaline phosphatase [ALP], total bilirubin, lactate dehydrogenase, glucose, creatine kinase 
[CK-if CK is elevated, and if it is clinically significant at the PI’s discretion), then CK-MB, troponin I, and myoglobin 
should be reactively tested, with further follow-up as clinically warranted], urea nitrogen, and uric acid), and urinalysis.  
Vital signs (blood pressure, body temperature, pulse rate, and respiration rate) are checked at every visit prior to blood work 
and administration of treatment at the discretion of the Investigator.  Safety laboratory assessments including hematology, 
biochemistry, coagulation and urinalysis will be performed locally.  If some examinations cannot be completed at the study 
site, corresponding examinations should be used in replacement (e.g., CO2 vs HCO3), and this does not need to be reported 
as a protocol deviation. 
f 
Serology infection testing (Hepatitis B Virus Surface Antigen (HBsAg), Anti-HBc, Hepatitis B DNA, Hepatitis C Virus 
antibody, Hepatitis C RNA, Human Immunodeficiency Virus 1 [HIV-1], Human Immunodeficiency Virus 2 [HIV-2]) is 
required at screening. 
g 
Thyroid stimulating hormone [TSH] (and free T4 samples if available), will be taken at baseline and as clinically indicated 
thereafter. 
h 
Triplicate 12-lead ECGs will be done at screening (≤14 days prior to first dose).  ECGs should be assessed before other 
procedures and after the patient has rested for at least 3 minutes.  Each recording should be separated by at least 30 seconds. 
i 
An ECHO will be performed within 28 days of treatment and as clinically indicated thereafter.   
j 
Fresh tumor biopsies at baseline and on treatment are optional.  If patient agrees to Screening biopsy and on-treatment 
biopsies, the first biopsy will be taken ≤28 days prior to first dose of study drug treatment.  Another biopsy will be collected 
on Cycle 2 Day 1 (+ 5 days) (see Section 7.8.1). 
k 
Prostate-specific antigen (PSA) blood samples will be taken ≤4 weeks prior to initiation of treatment. 
l 
CT/MRI scans of the chest, abdomen and pelvis should be taken ≤4 weeks prior to initiation of treatment.   
m 
Bone scans - technetium only - ≤4 weeks prior to initiation of treatment. Bone lesions should be evaluated using PCWG3 
criteria and not RECIST v1.1.  
 

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 15 of 121 
Table 2 
SOA 2 (GU 207 Schedule of Assessments) - Part A [Dose-Escalation & Backfill] and Part B [Expansion 
Cohorts]) Once Daily(QD) dosing and Twice Daily (BID) dosing 
 
AC176 Monotherapy Treatment Period 
(1 Cycle =28 days)a 
 
EOTp 
30-Day 
Safety 
FUq 
FU for 
PDr 
 
Cycle 
C1 
C2 
C3+ 
 
 
 
Treatment day 
1a 
8 
15 (±2) 
1 (±2) 
1 (±2) 
 
±5 days 
±5 days 
Written ICF for main study 
See Table 1 for pre-screening/screening proceduresa 
Physical examination and weightb 
X 
 
X 
X 
X 
X 
X 
 
Vital signsc 
X 
 
X 
X 
X 
X 
X 
 
Safety laboratory (hematology, [including 
PT/PTT/(INR or aPTT)], immature platelet function, 
biochemistry, urinalysis)c,d 
X 
 
X 
X 
X 
X 
X 
 
CBC onlyd 
 
X 
 
 
 
 
 
 
Concomitant therapy 
X 
 
Adverse events (AEs)/Serious adverse events (SAEs) 
X 
 
ECOG performance statusc 
X 
 
X 
X 
X 
X 
X 
 
12-lead electrocardiograms (triplicate)e,f 
X 
 
X 
X 
Xe 
Xe 
 
 
Pharmacokineticsg,h 
X 
 
X 
Xg,h 
Xg,h 
C4 & C6 
only 
 
 
 
(Optional) Tumor biopsyi 
 
 
 
X (+ 5 
days) 
 
 
 
 
Blood sampling for biomarkers (ctDNA)j 
X (pre-
dose) 
 
 
X 
C5 & C8 
only 
X 
 
  
ARv7 blood samplek 
(CTC) 
X (pre-
dose) 
 
 
 
 
X 
 
 
AC176 dosingl 
Refer to footnote l 
 
 
 
Review patient dosing diaryl 
 
 
X 
X 
X 
X 
 
 
PSAm 
X (pre-
dose) 
 
 
X 
X 
X 
 
Xq 
Tumor assessment CT/MRI and bone scansn,o  
Every 2 cycles (8 weeks) ±5 days up to 24 weeks, 
then every 12 weeks ±5 days 
Xr,s 
 
X 
SOA 2 Footnotes  
a Pre-screening if applicable and screening procedures are described in Table 1.  Written ICF for the main study must be obtained before undertaking any study-related procedures 
and prior to the initiation of study treatment. 
Treatment cycles are 28 days (4 weeks).  Patients may continue treatment with AC176 as long as they are deriving clinical benefit according to the Investigator’s judgment. 

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 16 of 121 
b  Physical examinations including the measurements of height (screening only) and weight will be done at Cycle 1 Day 1, Cycle 1 Day 15, on Day 1 of each subsequent treatment 
cycle, at the end-of-treatment (EOT) visit, and at the 30-day safety follow-up (FU) visit.  ECOG performance status will be done at screening and at all subsequent visits. 
c The following parameters should be done as indicated: physical examination (including weight), Eastern Cooperative Oncology Group (ECOG) performance status, triplicate 
electrocardiograms (ECGs),vital signs, hematology (including absolute lymphocyte count, absolute neutrophil count, red blood cell count, reticulocytes, hemoglobin, hematocrit, 
platelet counts, prothrombin time/partial thromboplastin time (or aPTT [activated/PTT])/ international normalized ratio [PT/PTT/INR]), biochemistry (sodium, potassium, 
phosphate, chloride, creatinine, total calcium, venous bicarbonate [HCO3], albumin, total protein, aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline 
phosphatase [ALP], total bilirubin, lactate dehydrogenase, glucose, creatine kinase [CK-if CK is elevated, and if it is clinically significant at the PI’s discretion), then CK-MB, 
troponin I, and myoglobin should be reactively tested, with further follow-up as clinically warranted], urea nitrogen, and uric acid), and urinalysis.  Vital signs (blood pressure, 
body temperature, pulse rate, and respiration rate) are checked at every visit prior to blood work and administration of treatment at the discretion of the Investigator.  Safety 
laboratory assessments including hematology, biochemistry, coagulation and urinalysis will be performed locally.  On Cycle 1 Day 8, the CBC may be performed by local 
laboratory as long as it can be entered into the eCRF and is approved by the Investigator.  If some examinations cannot be completed at the study site, corresponding 
examinations should be used in replacement (e.g., CO2 vs HCO3), and this does not need to be reported as a protocol deviation. 
d Immature platelet fraction (IPF) testing will be evaluated when a patient experiences platelet count decrease, or anytime at the discretion of the physician and if the test can be 
run at the site.  CBC counts should be collected at the same time as the IPF collection.  
e Triplicate 12-lead ECGs will be done before treatment on Cycle 1 Day 1 and Cycle 1 Day 15; before treatment on Day 1 of each subsequent cycle, at the EOT, and at any other 
time the Investigator deems it necessary.  ECGs should be assessed before the patient takes the study drug that day, before other procedures, and after the patient has rested for at 
least 3 minutes.  Each recording should be separated by at least 30 seconds. 
f Additional triplicate ECGs will be performed on Cycle 1 Day 1 and Day 15 just before the 4-hour and 8-hour post-dose PK blood samples are collected.  Refer to Appendix G 
for additional ECG collections required during PK blood collections (Table 8 and Table 15). 
g Pharmacokinetic (PK) sampling will be collected on Cycle 1 Day 1 and 15 pre-dose and post-dose at: 1 and 2 hours (±5 minutes), 3 and 4 hours (±10 minutes), 6 (±20 minutes), 
8 and 10 hours (±1 hour), 12 hours (±1 hour, and if BID dosing must be prior to evening dose), and 24-hours post dose (±1 hour).  In addition to the pre-dose ECGs collected on 
Cycle 1 Day 1 and 15, triplicate ECGs will also be obtained on Cycle 1 Day 1 and 15 just before the 4-hour and 8-hour post-dose PK blood samples are collected.  On Cycle 2 
Day 1, Cycle 4 Day 1, and Cycle 6 Day 1, a pre-dose PK sample will be collected from all patients. Triplicate ECGs will be obtained before the pre-dose PK collection on Day 1 
of Cycle 4 and 8.  If the sample cannot be collected at the visit as scheduled, it should be collected at the next visit whenever possible.  Additional unscheduled PK samples may 
be drawn during the study if it is deemed clinically indicated for the patient and/or based on newly emerged data from clinical studies of AC176.  The visit days and sampling 
time points are outlined in Appendix G, Table 8 and Table 15.  The Expansion cohort will only collect a PK sample at C2D1. Meal consumption prior to PK collection will be 
collected.  The last meal consumed prior to dosing on the day of full 24 hour PK collections during Cycle 1 should be recorded. 
h Expansion Cohort (Part B) PKs sample collections are different from Part A cohort collections.  The Expansion cohort PKs are collected pre-dose on Cycle 2 Day 1, Cycle 4 
Day 1 and Cycle 6 Day 1. Additional unscheduled PK samples may be drawn during the study if it is deemed clinically indicated for the patient and/or based on newly emerged 
data from clinical studies of AC176.  The visit days and sampling time points are outlined in Appendix G, Table 8 and Table 15. 
i Fresh tumor biopsies at on treatment are optional.  If patient agrees to baseline biopsy and on-treatment biopsies, the first biopsy will be taken ≤28 days prior to first dose of 
study drug treatment.  Another biopsy will be collected on Cycle 2 Day 1 (+ 5 days) (see Section 7.8.1). 
j All patients in Backfill and Expansion Cohorts will retrospectively undergo central laboratory testing for AR mutation confirmation at C1D1.  Blood samples for ctDNA will be 
collected prior to dosing at predose Cycle 1 Day 1, and on Cycle 2 Day 1, Cycle 5 Day 1, and Cycle 8 Day 1, and at EOT as outlined in Section 7.8.2. 
k Blood samples for ARv7 testing will be collected prior to dosing at Cycle 1 Day 1 and at EOT as outlined in Section 7.8.2. 
l Dosing and schedule of AC176 will be determined by the Safety Review Committee and communicated separately as each new cohort opens for recruitment.  Patients will be 
instructed to take one dose of AC176 at the same time every day immediately after a meal. For QD dosing schedules, the patients will be asked to take AC176 in the morning 
immediately after a meal, and other concomitant medications in the evening; or at least 4 hours apart from taking AC176, if possible.  Study drug compliance will be assessed at 
each patient visit by review of the dosing diary. AC176 should be taken whole with liquid(s). For the BID dosing schedule, patients will be instructed to take 1 dose of AC176 
immediately after a meal in the morning and 1 dose of AC176 after a meal in the evening.  

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 17 of 121 
 
m Prostate-specific antigen (PSA) blood samples will be taken prior to initiation of treatment, prior to dosing Cycle 1 Day 1 (unless collected within the previous 72 hours), and at 
Day 1 of every cycle, and at the EOT visit if not taken in the previous 4 weeks, and at progression.  Additional PSA assessments after the 30-day safety follow-up visit will be 
performed as on treatment until PD or another withdrawal criterion is met 
n CT/MRI scans of the chest, abdomen and pelvis should be taken ≤4 weeks prior to initiation of treatment.  CT/MRI scans of the chest, abdomen, and pelvis should be taken 
every 2 cycles (8 weeks) ±5 days up to 24 weeks, then every 12 weeks ±5 days, and at the End of Study visit (if scans were not taken in the previous 8 weeks) and, if clinically 
indicated, imaging of any other known or suspected sites of disease (e.g., brain).  Lymph nodes should be evaluated using PCWG3 criteria and not RECIST v1.1.  . 
o Bone scans - technetium only - ≤4 weeks prior to initiation of treatment, every 2 cycles (8 weeks) ±5 days up to 24 weeks, then every 12 weeks ±5 days, and at the End of Study 
visit if scans were not taken in the previous 8 weeks.  Bone lesions should be evaluated using PCWG3 criteria and not RECIST v1.1.  
p An EOT visit should be performed for all patients who permanently discontinue study treatment.  If the decision to permanently discontinue treatment is made at a scheduled 
visit, the EOT visit should be performed instead of the scheduled visit (preferably within 7 days and no later than 14 days after the last treatment). 
q All patients will be followed during the off-treatment period until all treatment-related toxicity resolves, or for at least 30 days post-study drug discontinuation, or until the start 
of another anti-cancer treatment.  Any concomitant medications received up to 30 days after the last dose of study medication should be recorded. 
r Follow-up for PD visits for tumor assessment by imaging (CT scan/MRI/bone scan, if applicable) for patients who discontinue study treatment without having PD based on 
RECIST v1.1 (see Appendix B) should be performed as on treatment until PD or another withdrawal criterion is met (see Section 7.5.3).  At these visits, serious adverse events 
(SAEs) occurring during the study that are considered to be related to study treatment or procedures will be followed until resolution. 

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 18 of 121 
LIST OF ABBREVIATIONS 
Abbreviation 
or special term 
Explanation 
ADT 
Androgen deprivation therapy 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AR 
Androgen receptor 
AST 
Aspartate aminotransferase 
AUC0-24 
Area under the plasma concentration-time curve over the last 24 hours 
BID 
Twice daily 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CNS 
Central nervous system 
CR 
Complete response 
CRO 
Contract research organization 
CRPC 
Castration-resistant prostate cancer 
CT 
Computed tomography 
CTA 
Clinical trial agreement 
CTC 
Circulating tumor cells 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating tumor DNA 
CV 
Cardiovascular 
CYP 
Cytochrome P450 
DC50 
Half-maximal degradation concentration 
Development 
Innovations 
Sarah Cannon Development Innovations, LLC 
DLT 
Dose-limiting toxicity 
DoR 
Duration of response 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EFF 
Efficacy Evaluable Set 
EOT 
End-of-treatment (visit) 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
hERG 
Human ether-à-go-go 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s Brochure 

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 19 of 121 
Abbreviation 
or special term 
Explanation 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IPF 
Immature platelet fraction 
IRB 
Institutional Review Board 
ISF 
Investigator Study File 
IV 
Intravenous 
mCRPC 
Metastatic castration-resistant prostate carcinoma 
MRI 
Magnetic resonance imaging 
MTD 
Maximum-tolerated dose 
NCI  
National Cancer Institute  
ORR 
Objective response rate 
PCWG3 
Prostate Cancer Working Group 3 
PD 
Progressive disease 
PDx 
Pharmacodynamic 
PET 
Positron emission tomography 
PHI 
Protected health information 
PK 
Pharmacokinetic 
PO 
Orally / by mouth 
PR 
Partial response 
PSA 
Prostate specific antigen 
QD 
Once daily 
QT 
ECG interval measured from the onset of the QRS complex to the end of the 
T wave 
QTc 
QT interval corrected for heart rate 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended Phase 2 dose 
SAE 
Serious adverse event 
SAR 
Suspected adverse reaction 
SCRI 
Sarah Cannon Research Institute 
SD 
Stable disease 
SOA 
Schedule of assessments 
SRC 
Safety Review Committee 
SUSAR 
Suspected unexpected serious adverse reaction 
t1/2 
Half-life; drug concentration elimination by half 
TTP 
Time to progression 
ULN 
Upper limit of normal 
USPI 
U.S. Package Insert 
VCaP 
Vertebral metastatic growth of a prostate carcinoma 

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 20 of 121 
TABLE OF CONTENTS 
 
GU 207 PROTOCOL SYNOPSIS ...................................................................................... 6 
LIST OF ABBREVIATIONS .......................................................................................... 18 
1. 
INTRODUCTION ........................................................................................... 25 
1.1 
Background and Study Rationale ...................................................................... 25 
1.1.1 
AC176 ............................................................................................................. 25 
1.1.2 
Study Rationale................................................................................................ 27 
1.1.3 
Rationale for Starting Dose .............................................................................. 28 
1.2 
Potential Risks and Benefits of the Treatment Regimen ..................................... 28 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..................................................... 28 
3. 
STUDY PATIENT POPULATION AND DISCONTINUATION...................... 30 
3.1 
Inclusion Criteria ............................................................................................. 30 
3.2 
Exclusion Criteria ............................................................................................ 32 
3.3 
Discontinuation from Study Treatment ............................................................. 33 
3.4 
Study Completion ............................................................................................ 34 
4. 
STUDY REGISTRATION ............................................................................... 34 
5. 
STUDY DESIGN ............................................................................................ 35 
5.1 
Treatment Plan................................................................................................. 36 
5.1.1 
Dose-Escalation Procedure (Part A) .................................................................. 37 
5.1.2 
Backfill Cohorts............................................................................................... 37 
5.1.3 
Dose-Limiting Toxicity .................................................................................... 38 
5.1.4 
Maximum-Tolerated Dose................................................................................ 39 
5.1.5 
Intra-Patient Dose Adjustment .......................................................................... 39 
5.1.6 
Safety Review Committee ................................................................................ 40 
5.1.7 
Expansion Cohorts (Part B) .............................................................................. 40 
5.2 
Treatment Duration .......................................................................................... 40 
5.3 
Concomitant Medications ................................................................................. 40 
5.3.1 
Permitted Concomitant Medications ................................................................. 41 
5.3.2 
Prohibited Concomitant Medications ................................................................ 41 
6. 
DOSE MODIFICATIONS ............................................................................... 41 
6.1 
Dose Modifications Due to Hematologic Toxicity ............................................. 42 
6.2 
Dose Modifications Due to Non-Hematologic Toxicity ..................................... 43 
6.2.1 
Specific Recommendations for Liver Function Test Abnormalities .................... 44 
7. 
STUDY ASSESSMENTS AND EVALUATIONS............................................ 44 

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 21 of 121 
7.1 
Overview ......................................................................................................... 44 
7.2 
Pre-Screening AR Mutation Status for Backfill Patients and Expansion 
Cohorts............................................................................................................ 45 
7.3 
Screening......................................................................................................... 45 
7.4 
Assessments During Study Treatment ............................................................... 46 
7.4.1 
Response Assessments ..................................................................................... 47 
7.4.2 
PSA Progression .............................................................................................. 47 
7.4.3 
PSA Response ................................................................................................. 47 
7.5 
Follow-Up Periods and Study Completion ........................................................ 47 
7.5.1 
End-of-Treatment Visit .................................................................................... 47 
7.5.2 
Thirty-Day Safety Follow-up............................................................................ 48 
7.5.3 
Extended Follow-Up Period ............................................................................. 48 
7.6 
Early Patient Termination/Patient Withdrawal................................................... 48 
7.7 
Pharmacokinetic Assessments .......................................................................... 48 
7.8 
Biomarker Assessments ................................................................................... 49 
7.8.1 
Optional Fresh Biopsies ................................................................................... 49 
7.8.2 
Biomarker Blood Samples ................................................................................ 49 
8. 
DRUG FORMULATION, AVAILABILITY, ADMINISTRATION, AND 
TOXICITY INFORMATION........................................................................... 50 
8.1 
AC176 ............................................................................................................. 50 
8.1.1 
Labeling, Packaging, and Supply ...................................................................... 50 
8.1.2 
Preparation and Administration of AC176......................................................... 50 
8.1.3 
Precautions and Risks Associated with AC176.................................................. 50 
8.2 
Accountability for All Study Drugs................................................................... 51 
9. 
RESPONSE EVALUATIONS AND MEASUREMENTS ................................. 51 
10. 
STATISTICAL CONSIDERATIONS .............................................................. 51 
10.1 
Statistical Design ............................................................................................. 51 
10.2 
Sample Size Considerations.............................................................................. 51 
10.3 
Analysis Population ......................................................................................... 52 
10.4 
Data Analysis .................................................................................................. 52 
10.4.1 
Demographics and Baseline Characteristics ...................................................... 52 
10.4.2 
Efficacy Analysis ............................................................................................. 52 
10.4.3 
Safety Analysis ................................................................................................ 53 
10.4.4 
Pharmacokinetics ............................................................................................. 54 
10.5 
Analysis Time Points ....................................................................................... 54 
10.5.1 
Final Analysis .................................................................................................. 54 
10.5.2 
Interim Analysis............................................................................................... 54 
10.5.3 
Safety Review.................................................................................................. 54 

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 22 of 121 
11. 
SAFETY REPORTING AND ANALYSES ...................................................... 55 
11.1 
Definitions ....................................................................................................... 55 
11.1.1 
Adverse Events ................................................................................................ 55 
11.1.2 
Serious Adverse Event ..................................................................................... 55 
11.1.3 
Adverse Reaction ............................................................................................. 56 
11.1.4 
Suspected Adverse Reaction............................................................................. 56 
11.1.5 
Recording and Reporting of Adverse Events ..................................................... 56 
11.1.6 
Assessment of Adverse Events ......................................................................... 57 
11.2 
Serious Adverse Event Reporting by Investigators ............................................ 57 
11.3 
Recording of Adverse Events and Serious Adverse Events ................................ 58 
11.3.1 
Diagnosis versus Signs and Symptoms ............................................................. 58 
11.3.2 
Persistent or Recurrent Adverse Events............................................................. 58 
11.3.3 
Abnormal Laboratory Values ........................................................................... 58 
11.3.4 
Deaths ............................................................................................................. 59 
11.3.5 
Hospitalization, Prolonged Hospitalization, or Surgery ...................................... 59 
11.3.6 
Pre-Existing Medical Conditions ...................................................................... 59 
11.3.7 
New Cancers.................................................................................................... 60 
11.3.8 
Pregnancy, Abortion, Birth Defects/Congenital Anomalies................................ 60 
11.3.9 
AC176 Overdose ............................................................................................. 60 
11.4 
Sponsor Serious Adverse Event Reporting Requirements .................................. 60 
11.4.1 
Sponsor Assessment of Unexpected .................................................................. 60 
11.4.2 
Sponsor Reporting for Clinical Studies under an Investigational New Drug 
Application ...................................................................................................... 61 
12. 
QUALITY ASSURANCE AND QUALITY CONTROL .................................. 61 
12.1 
Monitoring....................................................................................................... 61 
12.2 
Audits and Inspections ..................................................................................... 61 
13. 
ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS............ 61 
13.1 
Institutional Review Board Approval ................................................................ 62 
13.2 
Regulatory Approval ........................................................................................ 62 
13.3 
Informed Consent ............................................................................................ 62 
13.3.1 
Confidentiality ................................................................................................. 63 
13.4 
Financial Information ....................................................................................... 64 
14. 
RESEARCH RETENTION AND DOCUMENTATION OF THE STUDY ........ 64 
14.1 
Amendments to the Protocol............................................................................. 64 
14.2 
Documentation Required to Initiate the Study ................................................... 65 
14.3 
Study Documentation and Storage .................................................................... 65 
14.4 
Data Collection ................................................................................................ 67 

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 23 of 121 
14.5 
Disclosure and Publication Policy..................................................................... 67 
15. 
REFERENCES ................................................................................................ 68 
16. 
APPENDICES ................................................................................................. 69 
 
LIST OF TABLES 
Table 1 
SOA 1 (GU 207 Schedule of Assessments) - Pre-screening (Backfill 
and Expansion Cohort Patients only) and Screening (All Patients) ........ 13 
Table 2 
SOA 2 (GU 207 Schedule of Assessments) - Part A [Dose-Escalation 
& Backfill] and Part B [Expansion Cohorts]) Once Daily(QD) dosing 
and Twice Daily (BID) dosing ............................................................. 15 
Table 3 
Study Objectives and Corresponding Endpoints ................................... 28 
Table 4 
Dose-Escalation (3+3) Design ............................................................. 37 
Table 5 
Dose Modifications Due to Hematologic Toxicities .............................. 42 
Table 6 
Dose Modifications due to Grade 3 or 4 Non-Hematologic Toxicities ... 43 
Table 7 
Overall radiological response – RECIST v1.1 and bone progression 
(PCWG3)............................................................................................ 76 
Table 8 
PK Sampling Timepoints Once Daily (QD Dosing) .............................. 86 
Table 9 
PK Sampling Timepoints ‒ Intermittent Dosing 7 days On / 7 days 
Off (28 days per cycle) ........................................................................ 88 
Table 10 
PK Sampling Timepoints – Intermittent Dosing 4 Days On / 3 Days 
Off (28 days per cycle) ........................................................................ 89 
Table 11 
PK Sampling Timepoints – Intermittent Dosing 5 Days On and 2 
Days Off  (28 days per cycle)............................................................... 91 
Table 12 
PK Sampling Timepoints – Intermittent Dosing 2 Weeks On / 2 
Weeks Off (28 days per cycle) ............................................................. 93 
Table 13 
PK Sampling Timepoints – Intermittent Dosing 2 Weeks On / 1 
Week Off (21 days per cycle) .............................................................. 95 
Table 14 
PK Sampling Timepoints – 3 Weeks On / 1 Week Off  (28 days per 
cycle).................................................................................................. 97 
Table 15 
PK Sampling Timepoints – Twice Daily (BID) Dosing (28 days per 
cycle).................................................................................................. 99 
Table 16 
SOA 3 (GU 207 Schedule of Assessments) – Intermittent Dosing:  
2 Weeks On / 1 Week Off, 21 Day Cycle ........................................... 102 

 
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Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
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Table 17 
SOA 4 (GU 207 Schedule of Assessments) - Intermittent Dosing:  3 
Weeks On and 1 Week Off, OR 2 Weeks On and 2 Weeks off, 28 
Day Cycle ......................................................................................... 105 
Table 18 
SOA 5 (GU 207 Schedule of Assessments) - Intermittent Dosing 
with 7, 5, or 4 Days on Followed by 7, 2, or 3 Days Off, 
Respectively, 28 Day Cycle ............................................................... 108 
 
LIST OF FIGURES 
Figure 1 
Study Schema ..................................................................................... 36 
 
LIST OF APPENDICES 
Appendix A: 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
Criteria ............................................................................................... 69 
Appendix B: 
Guidelines for Evaluation of Objective Tumor Response Using 
RECIST Version 1.1 (Response Evaluation Criteria in Solid Tumors) 
in Soft Tissue and PCWG3 (Prostate Cancer Working Group Criteria 
3) in Bone Lesions .............................................................................. 70 
Appendix C: 
Prostate Cancer Working Group 3 (PCWG) PSA Criteria ..................... 77 
Appendix D: 
Guidelines for Fertile Male Patients ..................................................... 79 
Appendix E: 
New York Heart Association Classification of Cardiac Disease ............ 80 
Appendix F: 
Hy’s Law ............................................................................................ 81 
Appendix G: 
PK Sampling Timepoint Schedules ...................................................... 85 
Appendix H: 
Schedule of Assessments for Intermittent Dosing ............................... 101 
Appendix I: 
Clinical Protocol Summary of Changes .............................................. 111 

 
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Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
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1. 
INTRODUCTION 
1.1 
Background and Study Rationale 
Prostate cancer affects one in every 8 men in the USA (American Cancer Society 2021) and is 
the second leading cause of cancer death in American males.  It is estimated that there will be 
248,530 men diagnosed, and 34,130 deaths in the USA in 2021.  Activation of the androgen 
receptor (AR) signalling axis is the main driver of prostate cancer growth and progression, which 
is achieved upon androgen’s binding to the AR, and in turn triggers a lineage-specific, oncogenic 
transcriptional program.  Therefore, for decades, targeting the AR signalling axis has been the 
mainstay of therapy for relapsed or metastatic prostate cancer patients.   
Androgen deprivation therapy (ADT), which lowers androgens produced by the testes, was 
developed as the standard of care for patients with locally advanced disease or metastatic 
disease.  ADT provides a high response rate of 80-90%, but unfortunately the majority of 
patients will progress to castration-resistant prostate cancer (CRPC) within 2-3 years (Harris et 
al. 2009).  
The development of first generation AR antagonists, such as bicalutamide, and more potent 
second generation AR antagonists, such as enzalutamide, as well as androgen synthesis 
inhibitors, such as abiraterone, have incrementally improved survival for metastatic castration-
resistant prostate cancer (mCRPC) patients by several months (Harris et al. 2009).  However, 
development of resistance over time remains unavoidable, and poses a major therapeutic 
challenge. 
Within diverse resistance mechanisms identified recently, persistent AR addiction through AR 
gene amplification, polyclonal and compound AR mutations, rearrangements, and novel exon 
deletions still play the major role (Tukachinsky et al. 2009; Annala et al. 2021).  Novel 
therapeutics targeting the AR signalling axis with deeper inhibition and broader activity against 
both wild-type AR and AR mutations are urgently needed. 
1.1.1 
AC176 
Accutar Biotechnology Inc, (Accutar) is developing AC176 as an orally bioavailable AR 
degrader for the treatment of mCRPC.  It is a chimeric, small molecule compound containing 
both ligands of human AR and cereblon (CRBN) E3 ligase and is able to induce robust AR 
ubiquitination and degradation by binding to AR and bringing it within close proximity of the 
CRBN E3 ligase.   
1.1.1.1 
Nonclinical Pharmacology 
The primary pharmacology program for AC176 included in vitro evaluation of the ability of 
AC176 to bind human AR, degrade wild-type AR and various AR mutants, inhibit AR-regulated 
transcription, and selectively inhibit growth of AR-positive prostate cancer cell lines and in vivo 
pharmacology studies in mice bearing AR-positive human prostate cancer cell xenografts.  The 
off-target binding potential of AC176 was evaluated against a panel of 44 critical safety targets.  
The safety pharmacology program included Good Laboratory Practice (GLP)-compliant in vitro 
human ether-à-go-go-related gene (hERG) assay, evaluation of the potential effect of AC176 on 
respiratory and central nervous system (CNS) function in rats, and an in vivo GLP-compliant 
study of the potential effect of AC176 on cardiovascular (CV) function in dogs.   

 
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Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 26 of 121 
AC176 was shown to potently bind to human AR and induce potent endogenous AR degradation 
with a sub-nanomolar half-maximal degradation concentration (DC50) in multiple AR-positive 
prostate cancer cell lines.  The AR degradation by AC176 is not limited to wild-type AR, but 
rather extends to all prevalent AR mutants identified in human patients.  This degradation 
occurred quickly and was dependent on the proteasome.  Functionally, AC176 stopped 
AR-regulated transcription in vitro and inhibited the growth of AR-positive cell lines.  AC176 is 
28- to 562-fold more potent than enzalutamide in PC3 engineered AR-responsive reporter cell 
lines bearing wild type AR or clinically-relevant AR mutants. 
In castrated mice bearing vertebral metastatic growth of a prostate carcinoma (VCaP) xenograft 
tumors, oral daily dosing of AC176 led to dose-dependent tumor growth inhibition/regression 
and concomitant tumor AR protein reduction of more than 90% at study termination.  In 
particular, 3 mg/kg oral daily dosing achieved more than 80% tumor growth inhibition.  In intact 
(non-castrated) mice bearing VCaP xenograft tumors, AC176 significantly inhibited or caused 
regression of tumor growth whereas enzalutamide, a standard of care medication, showed no 
efficacy.  Additionally, AC176 had a good safety profile in a battery of GLP-compliant safety 
pharmacology studies, including a hERG assay, a respiratory safety study in rats, a CNS safety 
study in rats, and a CV safety study in dogs. 
AC176 had low oral bioavailability in rats (17.0%) and in fed or fasted monkeys (21.5% to 
27.2%) and moderate to high oral bioavailability in mouse (95.4%) and in fed dogs (66.2 to 
93.5%).  In fasted dogs, the oral bioavailability was low (22%).  Oral absorption following a 
single dose was moderately quick with tmax observed between 2.6 to 9.7 hours following a single 
dose in all species.  The reported elimination t1/2 following a single oral administration ranged 
from 2.6 hours (in mice) to 29 hours (in dog).  In dogs, oral bioavailability of 2 or 3 mg/kg of 
AC176 was 3-fold greater under fed (66.2%) versus fasted (22.0%) conditions.  In vitro 
investigations indicated that AC176 is significantly more soluble in phosphate-buffered saline 
(PBS) at a low pH compared to PBS at a neutral pH.  In simulated intestinal fluid, the solubility 
of AC176 was 20-fold higher in the fed state compared to fasted state.  These data suggested that 
AC176 might have higher absorption in a fed state. 
Following repeat oral administration in the GLP-compliant toxicology studies in rats and dogs 
(dogs were dosed under fed conditions), AC176 exposure in terms of AUC0-24h generally did not 
significantly increase across the dose range of 30 to 120 mg/kg/day in rats and increased more 
than dose proportionally across the dose range of 3 to 10 mg/kg/day, and slightly less than dose 
proportionally from 10 to 30 mg/kg/day, in dogs.  There were no marked sex differences in 
exposure observed in rats or dogs; however, systemic exposure to AC176 and its enantiomer 
AC176-IM01 in rats was slightly lower in females compared to males on Day 1.  Systemic 
exposure to AC176 and its enantiomer, AC176-IM01, did not significantly change across a dose 
range of 30 to 120 mg/kg/day in rats.  No accumulation of AC176 was reported with repeated 
dosing in rats; however, in the 28-day toxicity study in dogs, there was evidence of accumulation 
of AC176 and AC176-IM01 at 10 and 30 mg/kg/day of AC176, with AUC0-24h accumulation 
ratios of 1.8 to 2.7 for AC176 and 4.0 to 7.2 for AC176-IM01, respectively.  The ratio of 
exposure (AUC0-24h) of the enantiomer AC176-IM01 to AC176 ranged from 0.088 to 0.130 in 
rats and 0.13 to 0.37 in dogs across the tested doses (rat 30, 60 and 120 mg/kg; dog 3, 10 and 
30 mg/kg) on Day 1 or Day 28. 

 
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Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
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AC176 was weakly metabolized by human CYP1A2 and CYP2D6 (t1/2 ≥148 min) in vitro when 
tested using recombinant human cytochrome P450 (CYP) enzymes.  There was very little to no 
metabolism observed when AC176 was incubated with human CYP2A6, CYP2B6, CYP2C8, 
CYP2C9, CYP2C19, CYP2E1, CYP3A4, or CYP3A5.  AC176 did not cause direct or time-
dependent inhibition of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or 
CYP3A.  AC176 did not significantly induce activity or mRNA expression of CYP2B6 or 
CYP3A4 in vitro.  However, 1 µM of AC176 weakly induced CYP1A2 in hepatocytes from 1 of 
3 donors in vitro.  The induction was not dose dependent as 3 µM of AC176 did not cause 
CYP1A2 induction.  Furthermore, the observed induction was less than 20% of the positive 
control used in the test.  Transporter studies suggested that AC176 was a potential substrate of p-
glycoprotein (P-gp) in vitro but did not show significant inhibition of P-gp-mediated digoxin 
transport, breast cancer resistance protein (BCRP)-mediated transport of pitavastatin, or 
OATP1B1- and OATP1B3-mediated transport of estradiol-17β-glucuronide.  Overall, the 
absorption, distribution, metabolism, and excretion (ADME) of AC176 appears sufficiently 
characterized to support continued clinical development of AC176 as a potential treatment for 
mCRPC. 
In the 28-day toxicity studies of AC176 in rats and dogs, consistent findings observed in both 
species included mild decreases in body weight gain and food consumption, and 
pharmacological effects on male reproductive tissues (decreased epididymides weights, 
glandular atrophy of seminal vesicles in rats and prostate in both species, and degeneration of 
testicular seminiferous tubules), the adrenal glands (cortical cell vacuolation in rats and 
hyperplasia of the adrenal cortex in dogs), and increases in total cholesterol.  These findings 
were similar to what has been reported in repeat dose toxicity studies with other AR antagonists 
approved for the treatment of prostate cancer, including enzalutamide, apalutamide, 
darolutamide, and bicalutamide, and these findings were reversible. 
Overall, the nonclinical testing program of AC176 supports further clinical investigations with 
the product as a treatment for mCRPC.  Refer to the Investigator Brochure (IB) for full 
summaries of preclinical evaluations. 
1.1.2 
Study Rationale 
Pharmacology investigations conducted by Accutar have shown that AC176 can potently bind to 
human AR and induce efficient degradation of both AR and all prevalent AR mutants tested thus 
far.  Subnanomolar DC50 was demonstrated in multiple AR-positive prostate cancer cell lines.  
This degradation occurred quickly and was dependent on the proteasome.   
Functionally, AC176 stopped AR-regulated transcription in vitro and selectively inhibited the 
growth of AR-dependent cell lines.  In castrated mice, AC176 was effective against castration-
resistant VCaP xenograft tumors.  In intact (non-castrated) mice, AC176 also significantly 
inhibited or caused regression of VCaP tumor growth, whereas enzalutamide, a standard of care 
medication, showed no efficacy.   
Overall, AC176 demonstrated robust AR degradation and anti-tumor efficacy in preclinical 
models and showed no significant safety pharmacology risks, supporting its continued 
investigation in the clinic. 

 
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Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 28 of 121 
1.1.2.1 
Rationale for Switching to AC176 Tablets 
The formulation for AC176, originally produced as 30 mg capsules, is produced as 30 mg 
tablets.  No modification to the clinical safety profile is expected with the dose being the same 
for the capsule vs tablet.  Because the size of the tablet is smaller than that of the capsule in the 
same dose strength, the switch to tablets will allow for less pill burden for the patient. 
1.1.3 
Rationale for Starting Dose 
There have been no human studies conducted with AC176 to date.  Thus, the justification of the 
starting dose in the Phase 1 clinical trial for AC176 was based on considerations of toxicology 
data from the 28-day GLP-compliant pivotal toxicology studies in rats and dogs using the same 
route of administration as intended in humans (oral).  A human safe starting dose of 116 mg/day 
was calculated based on 1/10th the severely toxic dose in 10% of animals (STD10) value in rats 
from 28-day GLP toxicity studies, and a human safe starting dose of 167 mg/day was calculated 
from 1/6th of the highest non-severely toxic dose (HNSTD) determined in the 28-day GLP 
toxicity studies in dogs.   
The proposed starting dose of AC176 in the IB is 30 mg/day, which provides an additional 3.9- 
and 5.6-fold safety margin compared to the recommended safe starting dose calculated from the 
rat and dog 28-day GLP toxicology studies.   
1.2 
Potential Risks and Benefits of the Treatment Regimen 
The pharmacokinetic (PK) and toxicology profile of AC176 has not identified any significant 
safety risks that would prevent further development of AC176 as a potential treatment for AR-
positive prostate cancer. 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
Table 3 
Study Objectives and Corresponding Endpoints 
Objectives: 
Endpoint/Variable: 
Primary Objective: 
Evaluate the safety and tolerability of AC176 
 
Dose-limiting toxicities (DLTs) 
Adverse events (AEs)/Serious adverse events 
(SAEs) 
Vital signs 
Clinical chemistry/hematology parameters 
Electrocardiograms (ECGs) 
Secondary Objectives: 
Endpoint/Variable: 
Characterize the pharmacokinetics (PK) profile of 
a single dose and after multiple doses of AC176 
PK parameters  
Evaluate the preliminary anti-tumor activity of 
AC176 on prostate-specific antigen (PSA) 
response rate 
PSA confirmed response is defined as the 
proportion of participants with a reduction in the 
level of PSA of ≥50% from baseline to the lowest 
post-baseline PSA results, measured twice, at least 
3 weeks apart, by the Prostate Cancer Working 
Group 3 criteria (PCWG3, Scher et al. 2016) 

 
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Final Protocol:  10 July 2023 Version 4.0  
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Objectives: 
Endpoint/Variable: 
Evaluate the preliminary anti-tumor activity of 
AC176 on objective response rate (ORR) for 
patients with measurable disease 
ORR based on PCWG3-modified Response 
Evaluation Criteria in Solid Tumors (RECIST) 
v1.1 (Eisenhauer et al. 2009) 
Evaluate the preliminary anti-tumor activity of 
AC176 on duration of response (DoR)  
Duration of Response (DoR) is defined as the time 
from the date of first documented response until 
date of documented progression or death in the 
absence of disease progression  
Evaluate the preliminary anti-tumor activity of 
AC176 on time-to-progression (TTP) 
TTP based on PCWG3-modified RECIST v1.1 
and/or PCWG3 PSA criteria (≥25% increase and 
≥2 ng/mL increase above the nadir or baseline 
value for patients who had a PSA decrease on 
treatment, which is confirmed by a second value 3 
or more weeks later.  For patients without a 
decrease on treatment, PSA progression is defined 
as ≥25% increase and an absolute increase of ≥2 
ng/mL after 12 weeks.) 
Evaluate the effect of AC176 on radiographic 
progression-free survival (rPFS) 
Radiographic disease progression based on 
PCWG3-modified RECIST v1.1 criteria.  rPFS is 
defined as the time from the first study drug 
administration to first objective evidence of 
radiographic disease progression assessed by the 
Study Investigator, or death, whichever occurs 
first.  
Evaluate the effect of AC176 on progression-free 
survival (PFS) 
PFS based on PCWG3-modified RECIST v1.1 
and/or PCWG3 PSA criteria.  PFS is defined as 
the time from first study drug administration until 
objective disease progression (based on bone or 
CT/MRI scans), or PSA, or death, whichever 
occurs first. 
Exploratory Objectives: 
Endpoint/Variable: 
Evaluate the relationship between AR degradation 
on tumor tissue and administration of AC176 
Change of AR expression in tumors from baseline 
to post-treatment, if tumor tissue is available from 
paired biopsies 
Evaluate the relationship between AR degradation 
in circulating tumor cells (CTCs) and 
administration of AC176, if available 
Change of AR expression in CTCs from baseline 
to post-treatment 
Evaluate the relationship of CTC numbers 
(baseline and post-treatment) and anti-tumor 
activity of AC176, if available 
Baseline CTC numbers or changes of CTC 
numbers post-treatment.  Correlation to anti-tumor 
activity (PSA response rate, ORR, rPFS, PFS, 
DoR and TTP) 

 
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Objectives: 
Endpoint/Variable: 
Evaluate the relationship of nuclear ARv7 
expression (baseline and post-treatment) and anti-
tumor activity of AC176 
Baseline ARv7 nuclear expression and changes of 
ARv7 nuclear expression post-treatment in CTCs.  
Correlation to anti-tumor activity (PSA response 
rate, ORR, rPFS, PFS, DoR and TTP) 
Evaluate the relationship between baseline AR 
genomic profiles and anti-tumor activity of 
AC176 
AR genomic profiles by circulating tumor DNA 
(ctDNA).  Correlation to anti-tumor activity (PSA 
response rate, ORR, rPFS, PFS, DoR and TTP) 
 
3. 
STUDY PATIENT POPULATION AND DISCONTINUATION 
3.1 
Inclusion Criteria 
Patients must meet the following criteria in order to be included in the research study: 
1. Written informed consent, according to local guidelines, signed and dated by the patient 
or by a legal guardian prior to the performance of any study-specific procedures, 
sampling, or analyses. 
2. Males who are at least 18 years-of-age at the time of signature of the informed consent 
form (ICF). 
3. Patients with histological, pathological, or cytological confirmed diagnosis of advanced 
or metastatic castration resistant adenocarcinoma of the prostate excluding 
neuroendocrine differentiation or small cell features who have had disease progression 
per Prostate Cancer Working Group 3 (PCWG3) (Scher et al. 2016) guidance following 
standard treatment, including approved taxane-based chemotherapy, or who are not 
amenable (intolerability, patient choice) to standard therapies, or for whom no therapy of 
proven efficacy exists.   
4. Progressive disease per PCWG3 guidance documented by either: 
• 
Positive bone scan (at least 2 new lesions) or metastatic lesions on computed 
tomography (CT)/magnetic resonance imaging (MRI) (Appendix B) that can be 
followed for response.   
Or 
• 
If PSA criteria is the only indication of progression, then the PSA values with a 
starting value of ≥1.0 ng/mL that have increased on at least 2 occasions obtained a 
minimum of 1 week apart. 

 
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5. Patients must have progressed on at least 2 prior approved systemic therapies (in any 
setting), with at least 1 being abiraterone, or enzalutamide, or apalutamide or 
darolutamide. 
6. Patients must have had surgical or ongoing medical castration.  Surgical castration is 
defined as bilateral orchiectomy.  Medical castration is defined as ongoing ADT with a 
gonadotropin releasing hormone (GnRH) analog or inhibitor, plus serum testosterone 
level <50 ng/dL (or <1.7 nmol/L). 
7. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 to 1 
(Appendix A). 
8. Acceptable organ functions, as evidenced by the following laboratory data: 
• 
Renal function, as follows: 
o 
Creatinine clearance of ≥50 mL/min by the Cockcroft-Gault equation or 
equivalent 
• 
Liver function, as follows: 
o 
Total bilirubin ≤1.5 × ULN (unless the patient has Grade 1 bilirubin 
elevation due to Gilbert’s disease or a similar syndrome involving slow 
conjugation of bilirubin) 
o 
Aspartate aminotransferase (AST) ≤2.5 × ULN or ≤5 × ULN in the 
presence of liver metastases 
o 
Alanine aminotransferase (ALT) ≤2.5 × ULN or ≤5 × ULN in the presence 
of liver metastases 
• 
International normalized ratio (INR) <2.  If the patient is receiving anticoagulated 
medication, then an INR range of 2.0 – 3.0 is allowed. 
• 
Acceptable hematologic function: 
o 
Hemoglobin ≥9 g/dL 
o 
Absolute neutrophil count (ANC) ≥1,500 cells/mm3 
o 
Platelet count ≥100,000 cells/mm3 
9. Male patients with female partners of childbearing potential are required to use two forms 
of acceptable contraception (Appendix D), including one barrier method, during their 
participation in the study and for 90 days following last dose.  Male patients must also 
refrain from donating sperm during their participation in the study and for 90 days 
following last dose. 
10. Life expectancy ≥3 months after the start of the treatment according to the Investigator’s 
judgment. 
Inclusion Criteria –Backfill Cohorts 
1. Patients may enroll to a Backfill cohort if they have documentation of the AR point 
mutation.  Patients who have not had AR mutation testing may have the testing 
performed after signing a pre-screening informed consent form (ICF [see Section 7.2]). 
Additionally, patients must meet the main inclusion criteria listed above to be enrolled. 
Inclusion Criteria – Part B Expansion Cohorts 
1. Patients are required for AR mutation testing after signing a pre-screening ICF (see 
Section 7.2 ), unless the patients have documentation of the AR point mutation.  

 
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Final Protocol:  10 July 2023 Version 4.0  
Page 32 of 121 
Additionally, patients must meet the main inclusion criteria listed above to be enrolled. 
3.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
1. Treatment with any of the following: 
• 
More than 2 lines of chemotherapy in the CRPC setting. 
• 
Any systemic anti-cancer therapy, chemotherapy or biologic from a previous 
treatment regimen or clinical study within 4 weeks prior to the first dose of study 
drug.  Any systemic small molecules from a previous treatment regimen or clinical 
study within 2 weeks or 5 half-lives (whichever is longer, not to exceed 4 weeks) 
prior to the first dose of study drug, except ADT for medical castration purpose.   
• 
Any investigational agents from a previous clinical study within 4 weeks prior to the 
first dose of study treatment. 
• 
Radiation therapy (including therapeutic radioisotopes) within 4 weeks prior to first 
dose of study drug.  Radiation for palliation within 2 weeks of study drug. Palliative 
radiation for the alleviation of pain due to bone metastasis will be allowed after the 
DLT evaluation period. 
2. With the exception of alopecia and ≤ Grade 2 peripheral neuropathy, any unresolved 
toxicities from prior therapy greater than the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) Grade 1 at the time of starting 
study treatment. Note: subjects with chronic Grade 2 toxicities that are asymptomatic or 
adequately managed with stable medication may be eligible with Sponsor approval.  
3. Major surgery (excluding placement of vascular access) within 4 weeks of first dose of 
study drug. 
4. Known symptomatic brain metastases requiring steroids (above physiologic replacement 
doses). 
5. Men who plan to father a child while in the study or within 90 days after the last 
administration of study treatment. 
6. Any condition that impairs a patient’s ability to swallow whole pills.  Presence of active 
gastrointestinal disease or other condition that will interfere significantly with the 
absorption, distribution, metabolism, or excretion of AC176 (e.g., ulcerative disease, 
uncontrolled nausea, vomiting, diarrhea Grade ≥2, malabsorption syndrome) 
7. Any of the following cardiac criteria experienced currently or within the last 6 months: 
• 
Any clinically important abnormalities (as assessed by the Investigator) in rhythm, 
conduction, or morphology of resting electrocardiograms (ECGs), e.g., complete left 
bundle branch block, third-degree heart block 
• 
Congestive heart failure (New York Heart Association ≥ Grade 2 [Appendix E]) 
• 
Any factors that increase the risk of QTc prolongation or risk of arrhythmic events 
such as heart failure, hypokalemia, congenital long QT syndrome, family history of 
long QT syndrome or unexplained sudden death under 40 years-of-age, or any new 
concomitant medication known to prolong the QT interval 

 
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8. Mean resting corrected QT interval (QTc) >470 msec. 
9. Left ventricular ejection fraction (LVEF) <50% or the lower limit of normal of the 
institutional standard. 
10. As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases, 
including uncontrolled hypertension, uncontrolled diabetes mellitus, active bleeding 
diatheses, or active infection.  Screening for chronic conditions is not required. 
11. Human immunodeficiency virus (HIV) infection with a current or a known history of 
acquired immunodeficiency syndrome (AIDS)-defining illness or HIV infection with a 
CD4+ T cell count <350 cells/µL and an HIV viral load more than 400 copies/µL. 
12. Patients with active viral (any etiology) hepatitis are excluded.  However, patients with 
serologic evidence of chronic hepatitis B virus (HBV) infection (defined by a positive 
hepatitis B surface antigen test and a positive anti-hepatitis core antigen antibody test) 
who have a viral load below the limit quantification (HBV DNA titer <1000 cps/mL or 
200 IU/mL), and are not currently on viral suppressive therapy may be eligible and 
should be discussed with the Medical Monitor.  Patients with a history of hepatitis C 
virus (HCV) infection who have completed curative antiviral treatment and have a viral 
load below the limit of quantification may be eligible. 
13. Presence of other active, invasive cancers other than the one treated in this study within 3 
years prior to screening, except appropriately treated basal cell carcinoma of the skin, or 
in situ carcinoma of uterine cervix, or other local tumors considered cured by local 
treatment. 
14. Prior history of allergic reaction to the composition/excipients of AC176. 
15. Psychological, familial, sociological, or geographical conditions that do not permit 
compliance with the protocol and/or follow-up procedures outlined in the protocol. 
3.3 
Discontinuation from Study Treatment 
Patients will be discontinued from study treatment for any of the following reasons: 
• 
Disease progression (Patients who are receiving clinical benefit in the opinion of the 
treating Investigator may be allowed to stay on study after consultation with the 
Medical Monitor) 
• 
Irreversible or intolerable toxicity or clinically significant abnormal laboratory values 
thought to be related to drug toxicity 
• 
Conditions requiring therapeutic intervention not permitted by the protocol 
• 
Intercurrent illness (this will be at the Investigator’s discretion) 
• 
Inability of the patient to comply with study requirements 
• 
Patient lost to follow-up 
• 
Patient requests to discontinue treatment 
• 
Patient withdraws consent from study treatment or study participation altogether 
• 
Study termination. 
After discontinuation from protocol treatment, patients must be followed for adverse events 
(AEs) for 30 days after their last dose of study drug.  All new AEs occurring during this period 
must be reported and followed until resolution unless, in the opinion of the Investigator, these 

 
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AEs are not likely to improve because of the underlying disease.  In this case, the Investigator 
must record his or her reasoning for this decision in the patient’s medical records and indicate 
that the outcome is not resolved on the AE pages on the electronic case report form (eCRF). 
All patients who have Grade 3 or 4 laboratory abnormalities (per CTCAE Version 5.0) at the 
time of treatment discontinuation must be followed until the laboratory values have returned to 
Grade 1 or 2 unless, in the opinion of the Investigator, it is not likely that these values are to 
improve.  In this case, the Investigator must record his or her reasoning for making this decision 
in the patient’s medical records and indicate that the outcome is not resolved on the AE pages on 
the eCRF. 
3.4 
Study Completion 
The study duration includes the recruitment period and 12-month follow-up of the last patient.  
Patients may remain on treatment in the absence of disease progression at the completion of the 
study through a single patient investigational new drug (IND) application or 
an expansion protocol, depending on the number of patients. 
The Sponsor has the right to close this study or part of the study at any time, which may be due 
(but not limited to) the following reasons: 
• If the risk-benefit ratio becomes unacceptable, as evidenced by emerging data. 
• If the study conduct does not suggest proper completion of the trial within a reasonable 
time frame. 
The Investigator has the right to close his/her center at any time. 
For any of the above closures, the following guidelines apply: 
- 
Closures should occur only after consultation between involved parties. Final 
decision on the closure must be provided in writing.  
- 
All affected institutions must be informed as applicable according to local law. 
- 
All study materials (except documentation that has to remain stored at site) must be 
returned to the Sponsor.  The Investigator will retain all other documents until 
notification is given by the Sponsor for destruction. 
- 
In the event of a partial study closure, ongoing patients, including those in post-study 
follow-up, must be taken care of in an ethical manner. 
Details for individual patient withdrawal can be found in Section 3.3. 
4. 
STUDY REGISTRATION 
The patient must willingly consent after being informed of the procedures to be followed, the 
experimental nature of the treatment, and the potential benefits, alternatives, side-effects, risks, 
and discomforts.  Human protection committee (Institutional Review Board [IRB]) approval of 
this protocol and any associated ICFs is required.  Eligible patients who wish to participate in the 
study will be enrolled. 
Registration must occur prior to the initiation of protocol therapy.  Patient registration and dose 
level assignment will be performed by Sarah Cannon Development Innovations, LLC 
(Development Innovations).  The Development Innovations designee will document the patient 

 
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Sponsor/Development Innovations Study Number: AC176-001/GU 207 
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identification number, dose level, and date of enrollment on the Registration Form and in the 
electronic data capturing (EDC) system, and will send the completed form back to the site as 
soon as possible, but no later than 24 hours following the registration request. 
5. 
STUDY DESIGN 
This is a Phase I, first-in-human, open-label, multi-center dose-escalation (Part A) study 
followed by an expansion cohort (Part B) of AC176 given as a single agent.  During Part A 
Dose-Escalation, successive cohorts of patients will be treated with increasing doses of AC176 to 
evaluate safety and tolerability.  
In Part A Dose-Escalation, AC176 will be given orally (PO).  The starting dose will be 30 mg 
and will follow a 3+3 design, (see Figure 1).  If suggested by emerging safety or PK findings, or 
as appropriate based on other data from previous cohorts, and approved by the SRC, alternative 
dose levels, intervals or schedules may be evaluated.  Alternative dosing schedules may be tested 
concurrently provided the total dose is not greater than that of the dose level being evaluated.   
Prostate cancers with androgen receptor (AR) mutations are more dependent on the AR pathway 
for their growth.  Degradation of AR makes these cancers more susceptible to cell death.  Thus, 
AR-mutated cancers may respond to AR degradation at lower doses than their wildtype 
counterparts.  As more data emerges from Part A, and the tested cohorts are cleared and deemed 
safe, patients with known AR point mutations, may be eligible to enroll in Backfill cohorts.  The 
Backfill patients will be enrolled to further characterise the objectives for the study.  The total 
number of patients enrolled in the Backfill cohort will not total more than 12 patients when 
combined with the number of patients already treated in the same cohort.  Toxicity for the 
patients enrolled in a Backfill cohort will be managed according to the Dose Modification 
Section 6.  Up to approximately 70 patients are expected to be enrolled in Part A dose-escalation, 
plus the backfill patients. 
The recommended dose for the Expansion cohorts will be determined in the Part A Dose-
Escalation part of the study.  Up to two dose cohorts may be explored in Part B with 
approximately 30 patients each.  One cohort will be for patients with AR point mutations.  The 
other cohort will be for patients without AR point mutations.  The Sponsor and SRC will 
determine the dose and schedule(s) for the Expansion cohorts based on tolerability and emerging 
data.  
Patients enrolled in Backfill (Part A) and Expansion cohorts (Part B) will be pre-screened for AR 
mutation status, unless patients provide documentation that they have the AR point mutation.   
All patients will retrospectively undergo central laboratory testing for AR mutation confirmation 
at C1D1 per the SOA. 
The Dose-Escalation phase will identify a maximum tolerated dose (MTD), if possible, with 
safety and tolerability data.  The Expansion portion of the study will support the selection of a 
dose for future clinical studies (i.e., recommended Phase 2 dose [RP2D]). 
The study schema is presented in Figure 1. 
 

 
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Final Protocol:  10 July 2023 Version 4.0  
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Figure 1 
Study Schema 
 
 
At the starting dose, the dosing frequency of AC176 is QD.  
If suggested by safety or PK findings, or as appropriate based on other data from previous 
cohorts, AC176 may be administered at a different dosing schedule.  Any change to the dosing 
frequency should be made before the first administration of the impacted dose level, and be 
applied to all patients within that dose cohort for the duration of their study treatment. 
5.1 
Treatment Plan 
AC176 will be self-administered (by the patient) on a continuous daily dosing schedule.  AC176 
should be taken at the same time immediately after a meal in the morning (if QD dosing).  
AC176 should be swallowed whole with a glass of water.  Patients should not chew or crush it.   
If vomiting occurs, the patient should be instructed not to retake the dose.  Patients should take 
the next scheduled dose of AC176.  If vomiting persists, the patient should contact the 
Investigator. 
If the patient misses a dose of study drug, the patient should take the dose as soon as possible, 
but not less than 12 hours (if QD dosing) or 6 hours (if BID dosing) before the next dose is due.  
If the next dose is due sooner than the above timeframes, the patient should skip the missed dose 
and take the next dose as scheduled. 
At each new cycle, patients will be dispensed sufficient supplies until the next visit.   
AC176 drug compliance will be assessed at the beginning of each new cycle.  The research staff 
will count and document the amount of study drug taken and returned by the patient. 
 

 
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5.1.1 
Dose-Escalation Procedure (Part A) 
The dose-escalation cohorts with 6 dose levels are shown in Figure 1.  However, dose levels may 
be adjusted and additional dose levels may be tested if suggested by the acquired clinical data 
and they are deemed safe by the Safety Review Committee (SRC; see Section 5.1.6).   
A new formulation of AC176 30 mg tablets will be introduced into this study after corresponding 
submission to Health Authority has been filed and the Pharmacy Manual has been updated, 
accordingly.  The introductory dose of the 30 mg tablet formulation will not be more than a 
cleared dose level with the capsule formulation.  The SRC will determine the AC176 dose level 
introducing the new formulation.  
The 3+3 Dose-Escalation Design 
A 3+3 dose-escalation design will be used.  Each cohort will enroll up to 6 evaluable patients per 
dose level.  Evaluation of a cohort of at least 3 patients completing 1 cycle of treatment and 
evaluable for dose-limiting toxicities (DLTs) is required prior to the dosing of patients at the next 
dose level.  Dose-escalation decisions will take into account the safety profile of prior dose 
groups and available PK data.  In order for sufficient PK and biopsy data to be collected at doses 
below the MTD, additional patients may be enrolled at lower doses during the 3+3 
dose-escalation phase.  These additional patient enrollment at dose levels that already tested and 
cleared is generally known as “backfilling” (see Section 5.1.2).  
The 3+3 dose-escalation procedure is shown in Table 4. 
 
Table 4 
Dose-Escalation (3+3) Design 
Number of Patients with a DLT 
Action 
0 of 3 patients 
Escalate to next dose level 
1 of 3 patients 
Accrue 3 additional evaluable patients at the current dose 
level (for a total of up to 6 evaluable patients)a 
1 of 6 patients 
Escalate to the next dose level  
2 or more patients in a dose level group of 
up to 6 patients 
The MTD has been exceeded 
DLT = dose-limiting toxicity; MTD = maximum-tolerated dose 
a For a patient to be considered “evaluable,” he must have met the minimum safety evaluation requirements of the study, and/or 
experienced a DLT. 
 
5.1.2 
Backfill Cohorts  
Pending the totality of clinical data, including but not limited, to safety and PK data, Part A 
cohorts which have been cleared and deemed safe may be expanded by enrolling patients into 
Backfill cohorts.  This expanded enrollment of patients in cohorts that have cleared dose-
escalation and are deemed safe is referred to as Backfilling and will further characterise the 
objectives for the study.  The total number of patients enrolled to a Backfill cohort will not total 
more than 12 patients when combined with the number of patients already treated in the same 
cohort. 

 
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Final Protocol:  10 July 2023 Version 4.0  
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Prostate cancers with AR mutations are more dependent on the AR pathway for their growth.  
Degradation of AR makes these cancers more susceptible to cell death.  Thus, AR-mutated 
cancers may respond to AR degradation at lower doses than their wildtype counterparts.  To 
enroll a patient to a Backfill cohort, there must be documentation of the AR point mutations.  
Patients who have not had AR mutation testing may have the testing performed after signing a 
pre-screening informed consent form (ICF) (see Section 7.2).  
The backfill patient data will be reviewed at quarterly safety meetings.  The safety data of the 
Backfill cohort at a specific dose level will be considered in their totality, considering the data of 
all patients dosed at that dose level.  Toxicity for the patients enrolled into the Backfill cohort 
will be managed in accord with the protocol dose modification criterion described in the protocol 
(Section 6).  Additional safety review meetings may be organized as deemed appropriate.  
5.1.3 
Dose-Limiting Toxicity 
Toxicity will be assessed using NCI CTCAE Version 5.0 unless otherwise specified. 
A toxicity will be considered dose-limiting if it occurs during the first cycle of treatment with 
AC176 during the dose-escalation phase (excluding Backfill cohort patients).  Dose-limiting 
toxicities (DLTs) will not include any toxicity related to underlying disease (including disease 
progression), intercurrent illness, concomitant medications, or extraneous causes.  DLTs will be 
defined as follows: 
• Any Grade 5 toxicity  
• Hematologic: 
o Grade 4 neutrophil count decrease for >7 days; or febrile with neutrophil count 
decrease (ANC <1000/mm3 with a single temperature of >38.3°C [101°F] or a 
sustained temperature of ≥ 38°C [100.4°F] for more than 1 hour) 
o Grade 4 platelet count decrease; or Grade 3 platelet count decrease associated 
with clinically significant bleeding, including any bleeding that warrants a platelet 
transfusion, related to drug 
o Grade 4 anemia related to drug (life-threatening consequences requiring urgent 
interventions) 
• Non-Hematologic: 
o Grade 3 or 4 non-hematologic toxicity, with the exception of: 
 Alopecia; 
 Grade 3 nausea, vomiting, or diarrhea if well-controlled by supportive care 
within 72 hours; 
 Grade 3 skin rash that improves in ≤7 days, with or without supportive 
care; 
 Grade 3 fatigue that improves in ≤7 days, with or without supportive care; 
 Grade 3 endocrinopathies that only require treatment with hormone 
replacement therapy; 

 
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 Grade 3 non-hematologic laboratory abnormalities, other than liver 
function tests, will not be considered a DLT unless they are associated 
with clinical manifestations which lead to medical intervention and/or 
hospitalization. 
o Potential drug-induced liver injury consistent with Hy’s Law (Appendix F), 
defined as AST and/or ALT >3 × ULN with concurrent total bilirubin >2 × ULN 
without findings of cholestasis (alkaline phosphatase [ALP] >2 × ULN) 
o Grade 3 or higher electrolyte abnormality that lasts >72 hours, unless the patient 
has clinical symptoms, in which case all Grade 3 or higher electrolyte 
abnormalities regardless of duration should count as a DLT 
Determination of Dose-Limiting Toxicities 
The patient population used for determination of DLTs will consist of patients who have met the 
minimum safety evaluation requirements of the study, and/or who have experienced a DLT.  
Minimum safety requirements will be met if, during Cycle 1 of treatment, the patient receives at 
least 75% of planned total doses of AC176 and is observed for at least one cycle following the 
first dose of AC176.  The minimum safety requirements must be met for a patient to be included 
in the MTD-determining population. 
Patients who discontinue treatment early due to disease progression or withdrawal will be asked 
to have all end-of-treatment (EOT) safety evaluations performed as described in the protocol (see 
Section 7.6).  If a patient withdraws from treatment during Cycle 1 due to any reason other than a 
DLT and does not meet the minimum requirements for inclusion in the MTD-determining 
population described above, that patient will be replaced. 
5.1.4 
Maximum-Tolerated Dose 
The MTD is the highest dose at which ≤1 of 6 patients experiences a DLT during Cycle 1 of 
therapy.  If 2 or more patients in a dosing group of ≤6 patients experience a DLT, the MTD has 
been exceeded.  If 2 or more patients in a dose level group of up to 6 patients experience a DLT 
and only 3 patients were evaluated at the previous (i.e., next lower) dose, then an additional 3 
patients will be evaluated at this next lower dose; and, if 0 or 1 have DLTs, then this previous 
dose level will be declared the MTD.  If 2 or more patients have DLTs, there will be further de-
escalation according to the same scheme. 
5.1.5 
Intra-Patient Dose Adjustment 
Patients may be permitted an intra-patient dose-escalation of AC176 to a higher dose level that 
has been cleared and deemed safe by the SRC if they have completed at least 2 cycles at their 
assigned dose level and continued on study with no ≥ Grade 2 treatment-related AEs. The 
highest dose the patient can be escalated to is the highest dose level that has been cleared for 
DLT and is considered to be safe for this patient by the Investigator.  The Investigator must 
consult with the Medical Monitor to confirm that the patient has been tolerating their AC176 
dose.  The patient data will continue to be collected for evaluation of safety and clinical activity, 
and all assessments will continue according to the Schedule of Assessments (see applicable SOA 
Table 2 or Appendix H). 

 
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5.1.6 
Safety Review Committee 
After each dose level during the dose-escalation, an SRC will evaluate the safety, tolerability, 
and available PK data for AC176 to decide the next dose.  The SRC has discretion to consider 
the MTD or other doses as the RP2D.  However, the RP2D will be no greater than the MTD. 
The SRC will consist of: 
• 
Coordinating Investigator, who will chair the committee, or delegate 
• 
Principal Investigator or delegate from the Investigational sites 
• 
Medical Monitor(s) for the study or delegate(s). 
In addition, the Sponsor Safety Physician or delegates(s) may be invited.  The Study 
Pharmacologist, Study Statistician, Patient Safety Scientist, Project Manager and other experts 
may also be invited as appropriate. 
Further internal or external experts may be consulted by the SRC as necessary.  The Sponsor 
Safety Physician (if applicable), Medical Monitors, or delegates should always be present at the 
SRC if there are safety issues for discussion.  The SRC will be consulted throughout the study on 
issues related to study safety.   
5.1.7 
Expansion Cohorts (Part B) 
The recommended dose for the Expansion Cohorts will be determined in the Part A Dose-
Escalation part of the study.  The opening of the Expansion Cohorts will be determined by the 
Sponsor after review of the emerging safety and tolerability data from the dose-escalation phase.  
Two cohorts may be explored in Part B and will involve approximately 30 patients each with AR 
point mutations and 30 patients without AR point mutations.  The Sponsor and SRC will 
determine the dose, schedule (e.g., BID dosing, intermittent scheduled dosing days, change in 
number of days in a cycle) and cohort open time for the expansion phase.   
5.2 
Treatment Duration 
The start of the study is defined as the date when the first patient in the whole study signs 
informed consent. 
The end of the study is defined as the date of the last visit (including all follow-up visits) of the 
last patient in the whole study. 
Patients will be evaluated for toxicity at the start of each cycle.  Restaging will occur with 
CT/MRI or bone imaging as defined in the applicable SOA (see Table 2 or Appendix H).  
Patients will continue on treatment until disease progression as defined in Appendix B and 
Appendix C or intolerance of side effects. 
5.3 
Concomitant Medications 
Patients will be asked about prior medications during screening and instructed not to take any 
additional medications during the course of the study without prior consultation with the study 
team.  At each visit, the patient will be asked about any new medications he or she is taking or 
has taken after the start of study drug treatment.  The patients will be asked to take AC176 in the 
morning immediately after a meal, and other concomitant medications in the evening; or at least 
4 hours apart from taking AC176, if possible. 

 
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5.3.1 
Permitted Concomitant Medications 
Supportive care per institutional standard, such as anti-emetics, is allowed during the study. 
Medications may be administered for maintenance of existing conditions prior to study 
enrollment or for a new condition that develops while on study, including but not limited to the 
following: 
• 
Bisphosphonate use, as recommended according to practice guidelines 
• 
Receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor use, as 
recommended according to practice guidelines 
• 
Growth factors or transfusions are allowed as clinically indicated, except the 2 weeks 
prior to the first dose of study treatment and during the Cycle 1 DLT evaluation 
period. 
• 
Patients receiving coumarin-derivatives are permitted on study but will be monitored 
carefully.  Should a thrombotic event occur while the patient is receiving treatment, 
the patient may continue, but low-molecular-weight heparin (LMWH) will be the 
preferred treatment.  
Supportive care and other medications considered necessary for the patient’s safety and well-
being may be given at the discretion of the Investigator, with the exception of those listed in 
Section 5.3.2. 
5.3.2 
Prohibited Concomitant Medications 
The following treatments are prohibited while on this study: 
• 
No other investigational therapy should be given to patients.  No anticancer agents 
other than the study treatments should be given to patients.  If such agents are 
required for a patient, then the patient must first be withdrawn from the study. 
• 
No routine prophylactic antiemetics or pre-medications will be given.  However, 
these medications may be administered for symptoms when they occur and may be 
given prophylactically afterward. 
6. 
DOSE MODIFICATIONS 
If toxicity occurs, it will be graded using the NCI CTCAE Version 5.0, and appropriate 
supportive care treatment will be administered to decrease the signs and symptoms thereof.  
Dose adjustments will be based on the organ system exhibiting the greatest degree of toxicity.  
Patients who experience a DLT during Cycle 1 can continue on the study at the next lower dose 
if the toxicity resolves to Grade 1 or baseline.  
A dose may be delayed for a patient for up to 2 weeks because of AEs.  Continuing treatment 
after a delay of more than 2 weeks may be allowed if the treating physician and the Medical 
Monitor agree that continuing treatment is in the best interest of the patient.  
Patients whose treatment is delayed will resume treatment when toxicity has improved to 
≤ Grade 1 or baseline.   
If toxicities occur that are ≤ Grade 2, they should be managed symptomatically, if possible, and 
the patient should continue treatment without a dose reduction.  If toxicities occur that are ≥ 
Grade 3 refer to Table 5 and Table 6 for dose modification guidelines. 

 
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A maximum of 2 dose reductions are allowed in this study.  However, dose reductions below the 
30-mg starting dose will not be allowed.  If more than 2 dose reductions of AC176 are necessary 
for a patient, the patient will be discontinued from study treatment, unless the treating physician 
and the Medical Monitor agree that continued treatment at lower doses is in the best interest of 
the patient. 
6.1 
Dose Modifications Due to Hematologic Toxicity 
Dose modifications due to hematologic toxicity are described in Table 5. 
 
Table 5 
Dose Modifications Due to Hematologic Toxicities 
Event 
AC176 Dosea 
Neutrophil Count Decrease 
(ANC) 
 
ANC <0.5 × 109/L (Grade 4) 
Hold dose until recovery to ≤ Grade 2 (ANC ≥1.0 × 
109/L)b,  
• If resolved in ≤7 days, then resume without a dose 
reduction. 
• If resolved in >7 days but <2 weeks, then resume dose 
at one lower dose level. 
Recurrence of  
ANC <0.5 × 109/L (Grade 4) 
Hold dose until recovery to ≤ Grade 2 (ANC ≥1.0 × 
109/L), then resume at 1 lower dose levelb. 
Platelet Count Decrease 
 
Platelets <50 × 109/L  
(Grade 3) 
 
Hold dose until improvement to platelets ≥75 × 109/Lb 
• If resolved in ≤7 days, then resume without a dose 
reduction. 
• If resolved in >7 days but <2 weeks, then resume dose 
at 1 lower dose level. 
Other severe and non-life-
threatening toxicities 
(≥Grade 3) 
Hold or maintain dose at the treating physician’s 
discretion. 
Monitor at least weekly and manage accordingly. 
a Any patients who require a treatment delay of more than 2 weeks due to treatment-related toxicity will be discontinued from 
study treatment unless the treating physician and the Medical Monitor agree that continued treatment at lower doses is in the 
best interest of the patient. 
b Hold AC176 treatment; perform at least weekly complete blood count (CBC) with differentials until toxicity resolves (ANC 
recovery ≥1.0 × 109/L and platelets ≥75 × 109/L). 
Re-treatment criteria = ANC recovery ≥1.0 × 109/L and platelets ≥75 × 109/L. 
 

 
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6.2 
Dose Modifications Due to Non-Hematologic Toxicity 
Dose modifications due to non-hematologic toxicities are shown in Table 6. 
Table 6 
Dose Modifications due to Grade 3 or 4 Non-Hematologic Toxicities 
Toxicity Grade 
AC176 Dosea 
Grade 3 (except nausea, vomiting, alopecia, diarrhea, 
rash, and fatigue) 
Holda until recovery to ≤ Grade 1 or baseline 
Toxicity resolves in ≤7 days 
Resume at original dose.   
Toxicity resolves >7 day and <2 weeks 
Reduce by 1 dose level. 
Toxicity does not resolve to ≤ Grade 1 or baseline 
within 2 weeks 
Discontinue treatment.  If in the patient’s best 
interest, dose may be resumed at a lower dose 
only after discussion and agreement with 
Medical Monitor. 
Recurrence of the above same toxicity 
Holda until recovery to ≤ Grade 1 or baseline 
Toxicity resolves ≤7 days 
Resume at original dose or reduce by 1 dose 
level at the Investigator’s discretionb 
Toxicity resolves >7 days 
Discontinue treatment.  If in the patient’s best 
interest, dose may be resumed at 1 reduced 
dose level only after discussion and agreement 
with Medical Monitor 
Grade 4 (except asymptomatic electrolyte 
abnormalities that respond to treatment and resolve 
to ≤ Grade 2 within 72 hours, nausea, vomiting, 
alopecia, diarrhea, rash, and fatigue) 
Discontinue treatment.   
Grade 4 asymptomatic electrolyte abnormalities that 
respond to treatment and resolve to ≤ Grade 2 within 
72 hours 
Holda 
Once resolved as mentioned, treatment may 
continue at 1 reduced dose level at the 
Investigator’s discretion and upon discussion 
with Medical Monitor 
Grade 3 or 4 nausea, vomiting diarrhea, rash, or 
fatigue  
Hold and institute maximum supportive 
treatment until recovery to ≤ Grade 1, baseline 
or tolerable Grade 2 
Toxicity resolves ≤7 days 
Resume at original dose.   
Toxicity resolves >7 day and <2 weeks 
Reduce by one dose levelb 

 
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Toxicity Grade 
AC176 Dosea 
Toxicity does not resolve to ≤ Grade 1 or baseline, 
or tolerable Grade 2 by 2 weeks 
Discontinue treatment.  If in the patient’s best 
interest, dose may be resumed at a lower dose 
only after discussion and agreement with 
Medical Monitor 
Recurrence of the above same toxicity 
Hold and institute maximum supportive 
treatment until recovery to ≤ Grade 1, baseline 
or tolerable Grade 2 
Toxicity resolves ≤7 days 
Resume at original dose or reduce by one dose 
level at the Investigator’s discretionb 
Toxicity resolves >7 days 
Discontinue treatment.  If in the patient’s best 
interest, dose may be resumed at a lower dose 
only after discussion and agreement with 
Medical Monitor 
a AC176 should be held until toxicity resolves to ≤ Grade 1 or baseline.  Any patients who develop irreversible Grade 3/4 
non-hematologic toxicity that does not resolve to ≤ Grade 1 or baseline within 2 weeks after maximum supportive treatment 
should be removed from the study unless the treating physician and the Medical Monitor agree that continued treatment at 
lower doses is in the best interest of the patient. 
b No more than 2 dose reductions of AC176 are allowed unless the treating physician and the Medical Monitor agree that 
continued treatment at lower doses is in the best interest of the patient. 
 
6.2.1 
Specific Recommendations for Liver Function Test Abnormalities 
For patients with Grade 3 liver enzyme elevations (AST/ALT), AC176 should be held until the 
values recover to ≤ Grade 1 or baseline.  Patients with an elevation of AST/ALT ≥3 × ULN in 
conjunction with a bilirubin ≥2 × ULN may remain in the study if a correctable, non-drug related 
cause of the liver test evaluations can be documented; otherwise, the patient must be 
discontinued from the study. 
7. 
STUDY ASSESSMENTS AND EVALUATIONS 
7.1 
Overview 
All patients should visit the study center on the days specified within this protocol.  The 
complete Schedule of Assessments for this study is presented at the beginning of this protocol 
(see Table 2 or the appropriate SOA table in Appendix H).  The key procedures required in this 
study include: 
• Reporting of all AEs occurring after the main ICF has been signed 
• Laboratory assessments (blood and urine based) 
• Immature platelet fraction testing (blood based), at sites with the capability, and if 
clinically indicated  
• PK samples throughout the study 
• Baseline and on-treatment blood biomarker assessments 

 
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• Tumor biopsy biomarker assessments 
• Tumor assessments (based on CT/MRI and bone scans according to Response Evaluation 
Criteria in Solid Tumors (RECIST) Version 1.1 and PCWG3 (see Appendix B). 
• PSA assessments 
Treatment cycle is presented in the SOA table or assigned at patient enrollment.  Multiple 
procedures may be scheduled at the same time point relative to AC176 dosing.  Priority should 
be given to PK collection at the time specified.  Vital signs and ECG assessments should be 
performed prior to specimen collections. 
7.2 
Pre-Screening AR Mutation Status for Backfill Patients and Expansion Cohorts 
Prostate cancers with AR mutations are more dependent on the AR pathway for their growth.  
Degradation of AR makes these cancers more susceptible to cell death.  Thus, AR-mutated 
cancers may respond to AR degradation at lower doses than their wildtype counterparts.   
Pre-screening, as described in Table 1, for AR mutation status is required in the Backfill and 
Expansion cohorts.  If patients provide historic ctDNA testing results of a positive AR point 
mutation, then pre-screening ctDNA testing for AR mutation status by ctDNA testing is not 
needed.  All patients will retrospectively undergo central laboratory testing for AR mutation 
confirmation at Cycle 1 Day 1 per the SOA.  
Patients who have not had AR point mutation testing must agree to sign a pre-screening ICF to 
collect a blood sample for ctDNA.  Confirmation of the AR point mutation does not guarantee 
eligibility for a backfill cohort or the expansion cohort. 
Depending on the AR point mutation status, patients may proceed with further screening 
procedures for Backfill or Expansion cohorts, as appropriate, after signing a separate ICF for the 
study.   
7.3 
Screening 
At enrollment, each potential research subject will provide written informed consent ≤28 days 
prior to initiation of treatment and prior to starting any study-specific procedures.  Upon 
signature of the ICF, patients will be assigned a unique subject number as enrollment (screening) 
occurs. 
The screening assessments described in Table 1 will be collected, reviewed, and determined to 
be acceptable by the site Principal Investigator or designee after obtaining informed consent 
prior to the initiation of treatment.  Patients who do not meet all inclusion criteria, or who meet 
an exclusion criterion, may be rescreened once.  Rescreening is at the discretion of the 
Investigator but requires Sponsor approval and agreement.   
The following information will be collected and procedures will be performed ≤28 days prior to 
initiation of treatment: 
• Written informed consent prior to any other study-related procedures 
• Medical history, concomitant therapy, and demographics 
• Adverse events 
• ECHO 

 
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• Serology infection test (Hepatitis B Virus Surface Antigen (HBsAg), Anti-HBc, Hepatitis 
B DNA, Hepatitis C Virus antibody, Hepatitis C RNA, Human Immunodeficiency Virus 
1 [HIV-1], Human Immunodeficiency Virus 2 [HIV-2]) 
• Pre-treatment biopsy (optional) 
• Testosterone blood level 
• PSA level 
• CT scan/MRI of chest, abdomen, and pelvis 
• Bone scan  
 
The following screening parameters should be recorded ≤14 days prior to initiation of treatment: 
• Physical examination (including height and weight) 
• ECOG performance status 
• 12-lead ECG triplicate 
• Vital signs (blood pressure, body temperature, pulse rate, and respiration rate) 
• Hematology 
• Biochemistry (sodium, potassium, phosphate, chloride, creatinine, calcium, venous 
bicarbonate HCO3, albumin, total protein, AST, ALT, ALP, total bilirubin, lactate 
dehydrogenase, serum glucose, creatinine kinase [CK: if CK is elevated, then CK-MB, 
troponin I, and myoglobin should be reactively tested, with further follow-up as clinically 
warranted], serum urea nitrogen, and serum uric acid) 
• Thyroid stimulating hormone [TSH] and free T4 
• Urinalysis 
If these assessments are performed within 72 hours of initiation of treatment, they do not need to 
be repeated on Cycle 1 Day 1, with the exception of ECOG performance status, an abbreviated 
physical examination (head, eyes, ears, nose and throat, as appropriate), vital signs, and triplicate 
ECGs.   
Relevant concomitant diagnoses and/or therapies present at study entry and/or during screening 
that are relevant to the patient’s safety during the study (as judged by the Investigator) will be 
recorded in the eCRF (see Section 5.3 for details on concomitant medications).   
7.4 
Assessments During Study Treatment 
Patients will remain on treatment as long as, in the opinion of the Investigator, they are deriving 
benefit and the criteria listed in Section 7.6 are not met.  Please refer to the applicable SOA table 
for detailed outlines of each visit during the treatment period for each part of the study. 

 
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7.4.1 
Response Assessments  
Patients will be evaluated for response to treatment every 2 cycles ±5 days up to 24 weeks (if 28 
day cycle) or up to 18 weeks (if 21 day cycles), then every 12 (or 9, respectively) weeks ±5 days, 
and, if clinically indicated, imaging of any other known or suspected sites of disease (e.g., brain).  
The following assessments will be performed in addition to determination of elevated PSA levels 
(which will be taken on prior to dosing on Cycle 1 Day 1 as PSA baseline and on Day 1 of each 
subsequent cycle): 
• CT/MRI scans of chest  
• CT/MRI scan of the abdomen and pelvis  
• Bone scan - technetium only  
Lymph nodes and bone lesions should be evaluated using PCWG3 criteria (Appendix B) not 
RECIST v1.1.  Patients with progressive disease or unacceptable toxicity should be discontinued 
from the study; patients with stable disease (SD) or response to therapy may continue treatment. 
7.4.2 
PSA Progression 
PSA progression is defined as ≥25% increase and ≥2 ng/mL increase above the nadir or baseline 
value for patients who had a PSA decrease on treatment, which is confirmed by a second value 
3 or more weeks later.   
For patients without a decrease on treatment, PSA progression is defined as a ≥25% increase and 
an absolute increase of ≥2 ng/mL after 12 weeks.   
PSA progressions must be confirmed at the next study visit 4 weeks later.  PSA will be collected 
at screening and on Day 1 of each treatment cycle.   
7.4.3 
PSA Response 
PSA response is defined as the proportion of patients achieving a ≥50% decline from baseline to 
the lowest post-baseline PSA results, confirmed by a second consecutive PSA assessment at least 
3 weeks later.  Ignore early rises (before 12 weeks) in determining PSA response. 
− 
A patient will be regarded as having a single PSA visit response if their PSA level at 
any post-dose visit is reduced by 50% or more compared with baseline 
− 
A patient will be regarded as having a confirmed PSA response if they have a reduction 
in PSA level of 50% or more compared with baseline that is confirmed at the next 
assessment at least 3 weeks later (i.e., decrease relative to baseline of at least 50% 
documented on 2 consecutive occasions at least 3 weeks apart). 
7.5 
Follow-Up Periods and Study Completion 
7.5.1 
End-of-Treatment Visit 
The EOT visit will be performed as soon as possible (preferably within 7 days but no later than 
14 days) after permanent discontinuation of the study treatment for any reason, or when the 
Investigator decided with the patient to permanently discontinue the study treatment, or when the 
Investigator became aware that the study treatment had been discontinued. 

 
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The assessments of the EOT visit will then be performed at the next planned visit.  If the patient 
finishes treatment without having progressive disease (PD), tumor assessment/imaging must be 
performed at the time of treatment discontinuation unless it has been done within the past 
4 weeks. 
7.5.2 
Thirty-Day Safety Follow-up 
All patients will be followed during the off-treatment period until all treatment-related toxicity 
resolves, or for at least 30 days post-study drug discontinuation, or until the start of another anti-
cancer treatment.  Any concomitant medications received up to 30 days after the last dose of 
study medication should be recorded. 
7.5.3 
Extended Follow-Up Period 
If treatment was discontinued for reasons other than disease progression, additional follow-up 
visits after the 30-day safety follow-up visit will be performed for tumor assessment by imaging 
as on treatment until PD or another withdrawal criterion is met: 
• Start of a new anti-cancer therapy 
• Lost to follow-up 
• Death 
• Patient withdrawal 
• End of the whole study. 
Additional PSA assessments after the 30-day safety follow-up visit will be performed as on 
treatment until PD or another withdrawal criterion is met. 
These visits may also be performed by telephone interview or via written correspondence in case 
the patient is unable to visit the Investigator. 
7.6 
Early Patient Termination/Patient Withdrawal 
Patients who discontinue treatment early due to disease progression, unacceptable toxicity, 
intolerability, or withdrawal of consent will be asked to have all EOT safety evaluations 
performed as described in the protocol (see the applicable SOA table).  If a patient withdraws 
from treatment during Cycle 1 due to any reason other than a DLT and does not meet the 
minimum requirements for inclusion in the MTD-determining population described in 
Section 5.1.4, that patient will be replaced. 
7.7 
Pharmacokinetic Assessments 
Serial blood (plasma) samples will be collected to assess the pharmacokinetics of AC176.  Any 
residual plasma from the collected pharmacokinetic samples may be used for metabolite 
analysis, when an assay becomes available.   
Meal consumption prior to full 24-hour PK collections will be collected.  The last meal 
consumed prior to dosing on the day of full PK collections during Cycle 1 should be recorded. 
If the sample cannot be collected at the visit as scheduled, it should be collected at the next visit 
whenever possible.  Additional unscheduled PK samples may be drawn during the study if it is 
deemed clinically indicated for the patient and/or based on newly emerged data from clinical 

 
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studies of AC176.  Similarly, if any PK timepoint is later deemed unnecessary per acquired 
clinical PK data, such timepoint may be removed from PK schedule by the Sponsor. 
With Sponsor approval the required 10 hour and 12 hour PK sample collections may be omitted 
if not feasible. 
The schedule for PK assessments is found in Appendix G. 
7.8 
Biomarker Assessments 
7.8.1 
Optional Fresh Biopsies 
Fresh tumor biopsies at baseline and on-treatment are optional.  All fresh biopsies will be 
processed according to the laboratory manual. 
Evaluable baseline and on-treatment biopsy samples will be used to evaluate the amount of AR 
degradation during treatment.  If possible, sites should collect pre- and on-treatment biopsies 
from the same tumor lesion.  Accessible lesions are defined as tumor lesions that can be biopsied 
and that are amenable to repeat biopsy unless clinically contraindicated or the patient has 
withdrawn consent.   
If a patient agrees to baseline biopsy and on-treatment biopsies, the equivalent of four 18-gauge 
core needle biopsies will be freshly taken between screening and the day before the first study 
drug treatment.  Another equivalent of four 18-gauge core needle biopsies will be collected on 
Cycle 2 Day 1 (+ 5 days). 
Biopsies should be obtained through non-significant risk procedures.  Sampling should be 
undertaken by experienced physicians in appropriate settings.   
Instructions regarding sample collection, handling/processing and shipping are provided in the 
Laboratory Manual. 
7.8.2 
Biomarker Blood Samples 
Blood samples for ctDNA will be taken at pre-screening, if applicable, on Cycle 1 Day 1, and on 
Cycle 2 Day 1, Cycle 5 Day 1, and Cycle 8 Day 1, and at the EOT visit.  Blood samples for 
ARv7 (CTC) will be collected pre-dose on Cycle 1 Day 1 and at the EOT visit.  Instructions 
regarding sample collection, handling/processing, and shipping are provided in the Laboratory 
Manual. 
A blood sample for ctDNA will be required at pre-screening for patients enrolling in Backfill and 
Expansion cohorts without AR point mutation documentation.  The separate pre-screen ICF must 
be signed by the patient prior to collection of the pre-screening ctDNA sample (see Section 7.2).   
In addition to the biomarkers listed above, other biomarkers deemed relevant to gain further 
knowledge about the biology of the disease or about the study drug may be assayed, based on 
newly emerging data from the study and/or literature data.  For similar reasons, unscheduled 
sampling may be allowed if deemed clinically relevant. 

 
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8. 
DRUG FORMULATION, AVAILABILITY, ADMINISTRATION, AND 
TOXICITY INFORMATION 
8.1 
AC176 
 
Investigational Product 
Dosage Form and Strength 
Manufacturer 
AC176 
Refer to the Pharmacy Manual 
Accutar Biotechnology, Inc. 
 
8.1.1 
Labeling, Packaging, and Supply 
AC176 will be supplied by Accutar Biotechnology, Inc. in bottles that contain 30 capsules or 
tablets of AC176 30 mg each.  AC176 should be used only as directed by the Investigator.  Store 
capsule bottles at 36-48°F (2-8°C) and tablet bottles between 59–77°F (15–25°C).  Both capsule 
and tablet bottles need to be protected from light. 
At the start of each cycle, patients will be dispensed sufficient supplies until the next visit.  Study 
drug compliance will be assessed at each patient visit by review of the dosing diary.  The 
research staff will count and document the amount of study drug taken and returned by the 
patient.  The batch number of the study drug dispensed to the patient should be entered on the 
eCRF, if applicable. 
The Immediate packaging will contain a statement to conform with US Food and Drug 
Administration (FDA) IND requirements as follows: “Caution: New Drug - Limited by federal 
(or United States) law to investigational use.” 
All study drugs must be kept in a secure place under appropriate storage conditions.  Storage 
conditions for AC176 are included on the investigational product label. 
The Sponsor or its representative must be granted access on reasonable request to check drug 
storage, dispensing procedures, and accountability records. 
8.1.2 
Preparation and Administration of AC176 
AC176 is administered PO.  Patients will be instructed to take one dose of AC176 at the same 
time immediately after a meal. For once-a-day dosing, patients will be instructed to take 1 dose 
of AC176 immediately after a meal in the morning and other concomitant medications in the 
evening; or at least 4 hours apart from taking AC176, if possible.  AC176 should be taken whole 
with liquid(s).  For BID dosing, patients will be instructed to take 1 dose of AC176 immediately 
after a meal in the morning and 1 dose of AC176 immediately after a meal in the evening.  
The time of day for administration of AC176 should be consistent.  If the patient misses a dose 
of study drug, the patient should take the dose as soon as possible, but not less than 12 hours (if 
on QD frequency) or 6 hours (if on BID frequency) before the next dose is due.  If the next dose 
is due sooner than the above timeframe, the patient should skip the missed dose and take the next 
dose as scheduled.  
8.1.3 
Precautions and Risks Associated with AC176 
Precautions and risks are located in the IB. 

 
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8.2 
Accountability for All Study Drugs 
The Principal Investigator (or designee) is responsible for accountability of all used and unused 
study drug supplies at the site. 
All study drug inventories must be made available for inspection by the Sponsor or its 
representative, e.g., Development Innovations, and regulatory agency inspectors upon request. 
Throughout the study and at its completion, Development Innovations Drug Accountability 
Record Forms will be completed by the site and sent to the Development Innovations Regulatory 
Department.  Study drug supplies must not be destroyed unless prior approval has been granted 
by the Sponsor or its representative.  Please contact the Sponsor or its representative regarding 
disposal of any study drug. 
9. 
RESPONSE EVALUATIONS AND MEASUREMENTS 
Response and progression will be evaluated in this study using RECIST Version 1.1 and 
PCWG3 criteria (see Appendix B and Appendix C).  Lesions are either measurable or non-
measurable according to the criteria.  The term “evaluable” in reference to measurability will not 
be used, as it does not provide additional meaning or accuracy. 
Lymph nodes and bone lesions should be evaluated using PCWG3 criteria (see Appendix B) not 
RECIST v 1.1.   
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Statistical Design 
This is a Phase I, first-in-human, open-label dose-escalation study of AC176 given as a single 
agent.  There are two parts to this study: Part A, Dose-Escalation and Part B, Expansion cohorts.  
Approximately 70 patients are expected to be enrolled in the Part A Dose-Escalation cohorts, 
including the Backfill patients, and up to 60 patients, to the Part B Expansion cohorts.  Up to 130 
patients overall may enter the study. 
In this study, AC176 will be given PO.  The starting dose will be 30 mg.  If suggested by safety 
or PK findings, or as appropriate based on other data from previous cohorts, then an alternative 
dosing schedule may be considered.  However, the total daily dose would remain the same.  The 
study will identify a MTD if possible, with safety and tolerability data (see Section 5.1.4); while 
the totality of data collected on AC176 may be used to suggest a RP2D. 
10.2 
Sample Size Considerations 
The Phase I dose-escalation will enroll 3 patients at the 30 mg starting dose level following a 
standard 3+3 cohort design until the MTD, if possible, is determined in this population.   
Currently, 6 dose levels are planned.  The MTD will be defined based on DLTs.  If 1 patient 
experiences a DLT at a given dose level, then that dose level will be expanded to 6 patients.  
Evaluation of a cohort of at least 3 patients completing 1 cycle of treatment is required prior to 
proceeding to the next dose level.  In addition, dose level(s) which have been cleared and 
deemed safe may be expanded (refer to Section 5.1.2 Backfill cohorts). 
Assuming 6 dose levels will be studied with a maximum of 6 patients enrolled per dose level, 
Backfilled patients may increase each cohort to a total of 12 patients, and up to approximately 70 

 
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patients may be accrued during dose-escalation.  The total number of patients enrolled to a 
Backfill cohort will not total more than 12 patients when combined with the number of patients 
previously enrolled in the same cohort.  Up to 70 patients are expected to be enrolled in Part A 
dose-escalation cohorts, plus the backfill patients. 
Depending on the totality of emerging data from safety, tolerability, PK, biomarker and 
preliminary anti-tumor activity, the recommended dose for expansion cohorts will be determined 
in Part A, dose-escalation.  Two expansion cohorts may be explored in Part B expansion.  The 
cohorts will encompass up to 30 patients with AR point mutations and 30 patients without AR 
point mutations.  Guided by tolerability and emerging data, the Sponsor and SRC will determine 
the dose and schedule(s) for the expansion cohorts. 
10.3 
Analysis Population 
The following analysis populations will be used: 
• Full Analysis Set (FAS)/ Safety Analysis Set (SAS) is defined as all patients who have 
received at least one dose of study treatment.  Patients will be included in the cohort in 
which they have been actually treated. 
• Efficacy Evaluable Set (EFF) is defined as all patients who have received any dose of 
study treatment and have at least one adequate post-baseline response assessment. 
• PK Analysis Set includes patients who were dosed with AC176 and have any sample 
collection of blood with measurable concentration of AC176 in plasma. 
10.4 
Data Analysis 
Descriptive statistics, including mean, median, standard deviations and ranges for all continuous 
measures will be tabulated and reported.  Percentages and frequencies for all categorical 
measures will also be presented.  Time to events endpoints will be reported using Kaplan-Meier 
estimates, with 95% confidence intervals (CIs) for median time to event. 
10.4.1 
Demographics and Baseline Characteristics 
Demographic and baseline disease characteristics will be summarized in order to assess the 
comparability of the treatment groups descriptively.  Data to be tabulated will include 
demographic features such as age, sex and race, as well as disease-specific characteristics. 
The number and percentages of patients screened, randomized, treated, completed the 
treatment/study and withdrawn from treatment/study for any reasons will be presented overall 
and also by dose level. 
10.4.2 
Efficacy Analysis 
All efficacy analyses will be performed using the EFF. 
Measurement of PSA levels, bone scans and CT/MRI scans will be performed for all patients at 
screening, during the study, and at follow-up visits before a subsequent anti-cancer therapy or 
death. 
• PSA response rate, PSA confirmed response is defined as the proportion of participants 
with a reduction in the PSA level of ≥50% from baseline to the lowest post-baseline PSA 
results, measured twice, at least 3 weeks apart by the PCWG3 criteria. 

 
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• Objective Response Rate (ORR), defined as the proportion of patients with confirmed 
complete response (CR) or partial response (PR) (i.e., 2 CRs or PRs at least 4 weeks 
apart) according to the PCWG3-modified RECIST Version 1.1 criteria (see Appendix B). 
• Duration of Response (DoR), defined as the time from the date of first documented 
response (the first CR or PR which has been subsequently confirmed) until date of 
documented progression or death in the absence of disease progression. 
• Time-to-Progression (TTP) based on PCWG3-modified RECIST v1.1 and/or PCWG3 
PSA criteria (≥25% increase and ≥2 ng/mL increase above the nadir or baseline value for 
patients who had a PSA decrease on treatment, which is confirmed by a second value 3 or 
more weeks later.  For patients without a decrease on treatment, PSA progression is 
defined as ≥25% increase and an absolute increase of ≥2 ng/mL after 12 weeks.), defined 
as the time from start of study treatment to disease progression. 
• Radiographic Progression-Free Survival (rPFS), based on PCWG3-modified RECIST 
v1.1 criteria.  rPFS is defined as the time from the first study drug administration to first 
objective evidence of radiographic disease progression assessed by the Study 
Investigator, or death, whichever occurs first.   
• Progression-free Survival (PFS), based on PCWG3-modified RECIST v1.1 and/or 
PCWG3 PSA criteria.  PFS is defined as the time from first study drug administration 
until objective disease progression (based on bone or CT/MRI scans), or PSA, or death, 
whichever occurs first.   
For ORR, patients without a post-baseline tumor assessment will be classed as not evaluable 
(NE) and considered as non-responders, and estimates and the associated 95% CIs (based on the 
Clopper-Pearson method) in each dose level will be calculated.   
For TTP, Kaplan-Meier curves will be generated and the median time to event, and the 
associated 95% CIs will be provided.   
10.4.3 
Safety Analysis 
Safety will be assessed through the analysis of the reported incidence of treatment-emergent 
AEs.  Treatment-emergent AEs are those with an onset on or after the initiation of therapy and 
will be graded according to NCI CTCAE Version 5.0. 
The AEs will be coded using the current version of Medical Dictionary for Regulatory Activities 
(MedDRA; https://www.meddra.org/about-meddra/) and summarized using system organ class 
and preferred term by dose level for all patients in the Safety Analysis Set.  In addition, 
summaries of serious adverse events (SAEs), AEs leading to dose modification (dose hold, 
reduction, and discontinuation), AEs by maximum NCI CTCAE grade, and AEs related to study 
treatment will also be presented by dose level. 
Other safety endpoints, including laboratory results, vital signs, ECG, and ECOG findings, will 
be summarized for all patients in the Safety Analysis Set. 
Concomitant medications will be coded using the World Health Organization Drug Dictionary 
(WHO DD; https://www.who-umc.org/), and they will be listed and summarized by dose level. 

 
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10.4.4 
Pharmacokinetics 
Plasma concentrations of AC176 will be used to calculate the PK parameters.  These parameters 
will be listed by individual patient and summarized by descriptive statistics (means, medians, 
ranges, standard deviations and coefficients of variation as appropriate) by cohort. 
Further details on the PK analyses will be documented in the Statistical Analysis Plan (SAP). 
10.5 
Analysis Time Points 
10.5.1 
Final Analysis 
The final analysis of the study will occur after the last visit of the last patient. 
10.5.2 
Interim Analysis 
No formal interim analysis is planned. 
10.5.3 
Safety Review 
An SRC will be established by Development Innovations for this study with members as 
described in the SRC section (Section 5.1.6).   
Once there are evaluable patients at a dose level, the SRC will review and assess all available 
safety data and any other relevant data from the cohort to make a decision on how the study 
should proceed.  Any dose interruptions and reductions will be taken into account.  When 
available, emerging PK data for plasma exposure will be evaluated to inform the dose-escalation 
or dosing regimen decisions on at least a prior dose level lagging basis. 
The decision may be to: 
• Proceed with dose-escalation 
• Expand the cohort  
• De-escalate the dose to a previous lower dose level or to an intermediate lower dose level 
• Stop the dose-escalation part of the study 
When there are other patients that are ongoing at the time of this review, the SRC may decide to 
defer their decision until these further patients become evaluable. 
Any patient started on treatment in error, as he failed to comply with all of the eligibility criteria 
but meets the criteria of an evaluable patient, will be reviewed on a case-by-case basis by the 
SRC to determine if the patient should be included or excluded in the evaluation of dose-
escalation. 
The decisions and decision-making of the SRC on the next dose level will be documented and 
provided to the Investigators prior to dosing any new patients. 
The SRC will be consulted throughout the study on issues related to study safety.  The timing, 
frequency, or need for safety evaluations may be revised, in consultation with the SRC, in 
response to emerging data.   

 
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11. 
SAFETY REPORTING AND ANALYSES 
Safety assessments will consist of monitoring and recording protocol-defined AEs and SAEs, 
and measurement of protocol-specified hematology, clinical chemistry, and urinalysis variables, 
measurement of protocol-specified vital signs, and other protocol-specified tests that are deemed 
critical to the safety evaluation of the study drug. 
The Principal Investigator is responsible for recognizing SAEs and reporting them to the 
Development Innovations Safety Department (see Section 11.1.5), and the Development 
Innovations Safety Department in turn notifies the Sponsor (see Section 11.4).  It is the 
Sponsor’s responsibility to report relevant SAEs to the applicable local, national, or international 
regulatory bodies.  In addition, Investigators must report SAEs and follow-up information to 
their responsible IRBs according to the policies of each IRB. 
The Principal Investigator is also responsible for ensuring that every staff member involved in 
the study is familiar with the content of this section. 
11.1 
Definitions 
11.1.1 
Adverse Events 
Adverse event means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug-related.  An AE can be any unfavorable and unintended 
sign (e.g., an abnormal laboratory finding), symptom, or disease temporarily associated with the 
use of a drug, without any judgment about causality.  An AE can arise with any use of the drug 
(e.g., off-label use, use in combination with another drug) and with any route of administration, 
formulation, or dose, including overdose. 
11.1.2 
Serious Adverse Event 
An AE or a suspected adverse reaction (SAR) is considered “serious” if it results in any of the 
following outcomes: 
• Death 
• A life-threatening AE 
• Inpatient hospitalization of at least 24 hours or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• A congenital anomaly/birth defect 
Important medical events 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.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in hospitalization, or development of drug dependency or drug 
abuse. 
It is important to distinguish between “serious” and “severe” AEs, as the terms are not 
synonymous.  Severity is a measure of intensity; however, an AE of severe intensity need not 
necessarily be considered “serious.”  Seriousness serves as the guide for defining regulatory 

 
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reporting obligations and is based on patient/event outcome or action usually associated with 
events that pose a threat to a patient’s life or vital functions.  For example, nausea that persists 
for several hours may be considered “severe” nausea but may not be considered an SAE.  On the 
other hand, a stroke that results in only a limited degree of disability may be considered only a 
mild stroke but would be considered an SAE.  “Severity” and “seriousness” should be 
independently assessed when recording AEs on the eCRF screen and SAEs on the SAE Report 
Form. 
11.1.3 
Adverse Reaction 
An adverse reaction means any AE caused by a drug.  Adverse reactions are a subset of all SARs 
where there is a reason to conclude that the drug caused the event. 
11.1.4 
Suspected Adverse Reaction 
Suspected adverse reaction (SAR) means any AE for which there is a reasonable possibility that 
the drug caused the AE.  “Reasonable possibility” means that there is evidence to suggest a 
causal relationship between the drug and the AE.  An SAR implies a lesser degree of certainty 
about causality than adverse reaction, which means any AE caused by a drug. 
11.1.5 
Recording and Reporting of Adverse Events 
Recording of Adverse Events 
All AEs of any patient during the course of the research study will be recorded in the eCRF, and 
the Investigator will give his or her opinion as to the relationship of the AE to the study drug 
treatment (i.e., whether the event is related or unrelated to study drug administration). 
All AEs should be documented.  A description of the event, including its date of onset and 
resolution, whether it constitutes an SAE or not, any action taken (e.g., changes to study 
treatment), and outcome should be provided along with the Investigator’s assessment of causality 
(i.e., the relationship to the study treatment).  For an AE to be a suspected treatment-related 
event, there should be at least a reasonable possibility of a causal relationship between the 
protocol treatment and the AE.  Adverse events will be graded according to the NCI CTCAE 
Version 5.0, and changes will be documented. 
If the AE is serious, it should be reported immediately to Development Innovations Safety 
Department.  Other untoward events occurring in the framework of a clinical study are to be 
recorded as AEs (i.e., AEs that occur prior to assignment of study treatment that are related to a 
protocol-mandated intervention, including invasive procedures such as biopsies, medication 
washout, or no treatment run-in). 
Any clinically significant signs and symptoms, abnormal test findings, changes in physical 
examination, hypersensitivity, and other measurements that occur will be reported as AEs and 
reported on the relevant eCRF screen. 
Test findings will be reported as an AE if the test result requires an adjustment in the study drug 
or discontinuation of treatment and/or test findings require additional testing or surgical 
intervention, a test result or finding is associated with accompanying symptoms, or a test result is 
considered to be an AE by the Investigator. 
Reporting Period for Adverse Events 

 
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All AEs regardless of seriousness or relationship to AC176 treatment (called study treatment), 
spanning from the signing of the ICF until 30 calendar days after discontinuation or completion 
of study treatment as defined by the study for that patient after his last dose of study drug, are to 
be recorded on the corresponding screen(s) included in the eCRF. 
All AEs resulting in discontinuation from the study should be followed until resolution or 
stabilization.  All new AEs occurring during this period must be reported and followed until 
resolution unless, in the opinion of the Investigator, the AE or laboratory abnormality/ies is/are 
not likely to improve because of the underlying disease.  In this case, the Investigator must 
record his or her reasoning for this decision in the patient’s medical record. 
Thirty days after completion of protocol-specific treatment or discontinuation, only AEs, SAEs, 
or deaths assessed by the Investigator as treatment-related are to be reported. 
11.1.6 
Assessment of Adverse Events 
All AEs and SAEs, whether volunteered by the patient, discovered by study personnel during 
questioning, or detected through physical examination, laboratory test, or other means, will be 
reported appropriately.  Each reported AE or SAE will be described by its duration (i.e., start and 
end dates), regulatory seriousness criteria if applicable, suspected relationship to the study drug 
(see following guidance), and actions taken. 
To ensure consistency of AE and SAE causality assessments, Investigators should apply the 
following general guideline: 
YES:  There is a plausible temporal relationship between the onset of the AE and 
administration of the study treatment, and the AE cannot be readily explained by the 
patient’s clinical state, intercurrent illness, or concomitant therapies, and/or the AE 
follows a known pattern of response to the study drug, and/or the AE abates or resolves 
upon discontinuation of the study drug or dose reduction and, if applicable, reappears 
upon re-challenge. 
NO:  Evidence exists that the AE has an etiology other than the study drug (e.g., pre-
existing medical condition, underlying disease, intercurrent illness, or concomitant 
medication), and/or the AE has no plausible temporal relationship to study drug 
administration (e.g., cancer diagnosed 2 days after first dose of study drug). 
11.2 
Serious Adverse Event Reporting by Investigators 
Adverse events classified by the treating Investigator as “serious” require expeditious handling 
and reporting to the Development Innovations Safety Department in order to comply with 
regulatory requirements.  Determination of “life-threatening” or “serious” is based on the 
opinion of either the Sponsor or the Investigator. 
Serious AEs occurring at any time from the signing of the ICF through the 30-day follow-up 
period after the last study treatment must be reported as SAEs on the Development Innovations 
SAE Report Form and followed until resolution (with autopsy report if applicable).  The 
Development Innovations Safety Department must be notified of all SAEs, regardless of 
causality, within 24 hours of the first knowledge of the event by the treating physician or 
research personnel. 
To report an SAE, the SAE Report Form should be completed with the necessary information. 

 
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The SAE Report Form should be sent to the Development Innovations Safety Department via fax 
or e-mail using the following contact information (during both business and non-business hours): 
Sarah Cannon Development Innovations Safety Department 
Safety Dept. Fax #:      1-866-807-4325 
Safety Dept. Email:     CANN.SAE@SCRI-Innovations.com 
Transmission of the SAE report should be confirmed by the site personnel submitting the report. 
Follow-up information for SAEs and information on non-serious AEs that become serious should 
also be reported to the Development Innovations Safety Department as soon as it is available; 
these reports should also be submitted using the Development Innovations SAE Report Form.  
The detailed SAE reporting process will be provided to the sites in the SAE reporting guidelines 
contained in the study reference manual. 
11.3 
Recording of Adverse Events and Serious Adverse Events 
11.3.1 
Diagnosis versus Signs and Symptoms 
All AEs should be recorded individually in the patient’s own words (verbatim) unless, in the 
opinion of the Principal Investigator or designated physician, the AEs constitute components of a 
recognized condition, disease, or syndrome.  In the latter case, the condition, disease, or 
syndrome should be named rather than each individual sign or symptom.  If a constellation of 
signs and/or symptoms cannot be medically characterized as a single diagnosis or syndrome at 
the time of reporting, each individual event should be recorded as an AE or SAE as appropriate 
on the relevant form(s) (SAE Report Form and/or AE eCRF screen).  If a diagnosis is 
subsequently established, it should be reported as follow-up information is available.  If a 
diagnosis is determined subsequent to the reporting of the constellation of symptoms, the 
signs/symptoms should be updated to reflect the diagnosis. 
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (e.g., as per RECIST criteria for solid tumors; see Appendix B), should not be reported 
as an SAE. 
11.3.2 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between patient evaluation 
time points.  Such events should be recorded only once on the SAE Report Form (if applicable) 
and/or the AE eCRF screen.  Changes in AE grading of persistent AEs should be entered 
separately in the AE eCRF. 
A recurrent AE is one that occurs and resolves between patient evaluation time points and 
subsequently recurs.  All recurrent AEs should be recorded on an SAE Report Form (if 
applicable) and/or AE eCRF screen. 
11.3.3 
Abnormal Laboratory Values 
If an abnormal laboratory value or vital sign is associated with clinical signs and/or symptoms, 
the sign or symptom should be reported as an AE or SAE, and the associated laboratory value or 
vital sign should be considered additional information that must be collected on the relevant 
eCRF screen.  If the laboratory abnormality is a sign of a disease or syndrome, only the diagnosis 
needs to be recorded on the SAE Report Form (if applicable) and/or AE eCRF screen. 

 
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Abnormal laboratory values will be reported as clinically significant and as an AE if the 
laboratory result(s) require an adjustment in the study drug or discontinuation of treatment, 
and/or laboratory findings require additional testing or surgical intervention, a laboratory result 
or finding is associated with accompanying symptoms, or a laboratory result is considered to be 
an AE by the Investigator. 
11.3.4 
Deaths 
Deaths that occur during the protocol-specified AE reporting period that are attributed by the 
Investigator solely to progression of disease will be recorded on the “End of Study” eCRF 
screen.  All other on-study deaths, regardless of attribution, will be recorded on an SAE Report 
Form and expeditiously reported to the Development Innovations Safety Department. 
When recording a SAE with an outcome of death, the event or condition that caused or 
contributed to the fatal outcome should be recorded as the single medical concept on the SAE 
Report Form and Adverse Event eCRF screen.  If the cause of death is unknown and cannot be 
ascertained at the time of reporting, record “Death NOS” (“death, cause unknown”) on the eCRF 
Adverse Event screen.  During post-study survival follow-up, deaths attributed to progression of 
disease will be recorded on the “Follow-up Summary” and “Death Page” eCRF screens. 
11.3.5 
Hospitalization, Prolonged Hospitalization, or Surgery 
Any AE that results in a hospitalization of >24 hours or prolongation of pre-existing a 
hospitalization should be documented and reported as an SAE unless specifically instructed 
otherwise in this protocol.  There are some hospitalizations that do not require reporting as an 
SAE. 
Treatment within or admission to the following facilities is not considered to meet the criteria of 
“inpatient hospitalization” (although if any other SAE criteria are met, the event must still be 
treated as an SAE and immediately reported): 
• Emergency department or emergency room 
• Outpatient or same-day surgery units 
• Observation or short-stay unit 
• Rehabilitation facility 
• Hospice or skilled nursing facility 
• Nursing homes, custodial care, or respite care facility 
Hospitalization during the study for a pre-planned surgical or medical procedure (one which was 
planned prior to entry in the study) does not require reporting as an SAE. 
11.3.6 
Pre-Existing Medical Conditions 
A pre-existing medical condition is one that is present at the start of the study.  Such conditions 
should be recorded on the General Medical History of the eCRF screen.  A pre-existing medical 
condition should be recorded as an AE or SAE only if the frequency, severity, or character of the 
condition worsens during the study.  When recording such events on an SAE Report Form and/or 
AE eCRF screen, it is important to convey the concept that the pre-existing condition has 
changed by including applicable descriptors. 

 
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11.3.7 
New Cancers 
The development of a new primary cancer should be regarded as an AE and will generally meet 
at least one of the seriousness criteria (see Section 11.1.2).  New primary cancers are those that 
are not the primary reason for the administration of the study treatment and have developed after 
the inclusion of the patient into the study.  They do not include metastases of the original cancer.  
Symptoms of metastasis or the metastasis itself should not be reported as an AE/SAE, as they are 
considered to be disease progression. 
11.3.8 
Pregnancy, Abortion, Birth Defects/Congenital Anomalies 
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, this must be reported to the Development Innovations Safety Department 
immediately.  Every effort should be made to follow the pregnancy for the final pregnancy 
outcome. 
Congenital anomalies/birth defects always meet SAE criteria and should therefore be 
expeditiously reported as an SAE using the previously described process for SAE reporting.  A 
Pregnancy Form should also have been previously completed, and will need to be updated to 
reflect the outcome of the pregnancy. 
11.3.9 
AC176 Overdose 
Any dose in excess of the dose specified according to the protocol will constitute an overdose.  
Symptomatic and non-symptomatic overdose must be recorded in the eCRF system.  Any 
accidental or intentional overdose with the study treatment that is symptomatic, even if not 
fulfilling a seriousness criterion, is to be reported to the Development Innovations Safety 
Department no greater than 24 hours from first knowledge of the event following the same 
process described for SAE reporting (see Section 11.2) if the overdose is symptomatic. 
For information on how to manage an overdose of AC176, see the IB. 
11.4 
Sponsor Serious Adverse Event Reporting Requirements 
The Development Innovations Safety Department will forward SAE information to Accutar 
Biotechnology, Inc., within 1 business day of Development Innovations Safety Department 
personnel becoming aware of the SAE. 
The Sponsor is responsible for reporting relevant SAEs to the competent authority, other 
applicable regulatory authorities, and participating Investigators, in accordance with 
International Council for Harmonisation (ICH) guidelines and FDA regulations.  
11.4.1 
Sponsor Assessment of Unexpected 
Development Innovations is responsible for assessing an AE or suspected AE as “unexpected.” 
An AE or SAR is considered “unexpected” when the following conditions occur: 
• Event(s) is not mentioned in the IB (or current US Package Insert [USPI]) 
• Event(s) is not listed at the specificity or severity that has been observed 
• An event(s) is not consistent with the General Investigative Plan or in the current 
application 

 
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• Includes AEs or SARs that may be anticipated from the pharmacological properties of the 
study drug or that occur with members of the drug class, but have not previously been 
observed under investigation. 
When applicable, a unexpected adverse event (UAE) may also apply to an event that is not listed 
in the current USPI or an event that may be mentioned in the USPI but differs from the event 
because of greater severity or specificity. 
Known as suspected unexpected serious adverse reactions (SUSARs), these events suspected (by 
the Investigator or Sponsor) to be related to the study drug are unexpected (not listed in the IB or 
USPI) and are serious (as defined by the protocol) and require expedient submission to relevant 
health authorities within 7 days (for fatal or life-threatening events) or 15 days (for all serious 
events) or as defined by law.  The term SUSAR is used primarily in the reporting of events to 
regulatory authorities. 
Expected AEs are those events that are listed or characterized in the USPI or current IB. 
11.4.2 
Sponsor Reporting for Clinical Studies under an Investigational New Drug 
Application 
All written IND Safety Reports will be submitted to the FDA by the Sponsor, Accutar 
Biotechnology, Inc. 
12. 
QUALITY ASSURANCE AND QUALITY CONTROL 
12.1 
Monitoring 
Site monitoring shall be conducted to ensure that patient protection, study procedures, 
laboratory, study intervention administration, and data collection processes are of high quality 
and meet Sponsor, Good Clinical Practice (GCP), ICH and, when appropriate, regulatory 
guidelines. 
12.2 
Audits and Inspections 
The Investigator will permit study-related quality audits and inspections by Development 
Innovations or its representative(s), government regulatory authorities, and the IRB(s) of all 
study-related documents (e.g., source documents, regulatory documents, data collection 
instruments, case report forms).  The Investigator will ensure the capability for review of 
applicable study-related facilities.  The Investigator will ensure that the auditor or inspector or 
any other compliance or Quality Assurance reviewer is given access to all study-related 
documents and study-related facilities. 
At the discretion of the Sponsor or its delegate, source document verification may be performed 
on partial or all data items as defined in study documents and/or plans. 
Participation as an Investigator in this study implies the acceptance of potential inspection by the 
Sponsor or its representative, government regulatory authorities, and IRB(s). 
13. 
ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS 
This research study will be conducted according to the standards of GCP outlined in the ICH E6 
Tripartite Guideline and Code of Federal Regulations (CFR) Title 21 part 312, applicable 

 
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government regulations, institutional research policies and procedures, and any other local 
applicable regulatory requirement(s). 
13.1 
Institutional Review Board Approval 
The clinical study protocol, ICF, IB, available safety information, patient documents (e.g., 
dosing diary), patient recruitment procedures (e.g., advertisements), information about payments 
(i.e., Principal Investigator payments) and compensation available to the patients, and 
documentation evidencing the Principal Investigator’s qualifications should be submitted to the 
IRB for ethical review and approval if required by local regulations, prior to the study start. 
The Principal Investigator/Sponsor and/or designee will follow all necessary regulations to 
ensure appropriate, initial, and on-going IRB study review.  The Principal Investigator/Sponsor 
(as appropriate) must submit to and, where necessary, obtain approval from the IRB for all 
subsequent protocol amendments and changes to the ICF.  Investigators will be advised by the 
Sponsor or designee whether an amendment is considered substantial or non-substantial and 
whether it requires submission for approval or notification only to an IRB. 
Safety updates for AC176 will be prepared by the Sponsor or its representative as required for 
distribution to the Investigator(s) and submission to the relevant IRB. 
13.2 
Regulatory Approval 
As required by local regulations, the Sponsor will ensure all legal aspects are covered and that 
approval of the appropriate regulatory bodies has been obtained, prior to study initiation.  If 
required, the Sponsor will also ensure that the implementation of substantial amendments to the 
protocol and other relevant study documents happen only after approval by the relevant 
regulatory authorities. 
13.3 
Informed Consent 
Informed consent is a process by which a patient voluntarily confirms his or her willingness to 
participate in a particular study after having been informed of all aspects of the study that are 
relevant to the patient's decision to participate.  Informed consent is documented by means of a 
written, signed, and dated ICF. 
The ICF will be submitted for approval to the IRB that is responsible for review and approval of 
the study.  Each ICF must include all of the relevant elements currently required by the FDA, as 
well as local county authority or state regulations and national requirements. 
Before recruitment and enrollment into the study, each prospective candidate will be given a full 
explanation of the research study.  Once the essential information has been provided to the 
prospective candidate, and the Investigator is sure that the individual candidate understands the 
implications of participating in this research study, the candidate will be asked to give consent to 
participate in the study by signing an ICF.  A notation that written informed consent has been 
obtained will be made in the patient’s medical record.  A copy of the ICF, to include the patient’s 
signature, will be provided by the Investigator to the patient. 
If an amendment to the protocol substantially alters the study design or the potential risks to the 
patient, the patient’s consent to continue participation in the study should be obtained. 

 
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13.3.1 
Confidentiality 
13.3.1.1 Patient Confidentiality 
Confidentiality of patients’ personal data will be protected in accordance with the Health 
Insurance Portability and Accountability Act of 1996 (HIPAA).  HIPAA regulations require that 
in order to participate in the study, a patient must sign an authorization form for the study that he 
or she has been informed of the following: 
• What protected health information (PHI) will be collected from patients in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• That health information may be further disclosed by the recipients of the information, and 
that if the information is disclosed the information may no longer be protected by federal 
or state privacy laws 
• That the information collected about the research study will be kept separate from the 
patient’s medical records, but the patient will be able to obtain the research records after 
the conclusion of the study 
• Whether the authorization contains an expiration date 
• The rights of a research patient to revoke his or her authorization. 
In the event that a patient revokes authorization to collect or use his or her PHI, the Investigator, 
by regulation, retains the ability to use all information collected prior to the revocation of patient 
authorization.  For patients that have revoked authorization to collect or use PHI, attempts should 
be made to obtain permission to collect at least vital status (i.e., that the patient is alive) at the 
end of their scheduled study period. 
In compliance with ICH GCP guidelines and applicable parts of 21 CFR, it is a requirement that 
the Investigator and institution permit authorized representatives of the Sponsor, Development 
Innovations, the regulatory authorities, and the IRB direct access to review the patient’s original 
medical records at the site for verification of study-related procedures and data. 
One measure to protect confidentiality is that only a unique study number will identify patients 
in the eCRF database system or other documents submitted to the Sponsor or delegate and 
Development Innovations.  This information, together with the patient’s year of birth, will be 
used in the database for patient identification.  Patient names or addresses will not be entered in 
the eCRF database system.  No material bearing a patient’s name will be kept on file by the 
Sponsor or Development Innovations.  Patients will be informed of their rights within the ICF. 
13.3.1.2 Investigator and Staff Information 
Personal data of the Investigators and sub-Investigators may be included in the Sponsor and/or 
Development Innovations databases and shall be treated in compliance with all applicable laws 
and regulations.  When archiving or processing personal data pertaining to the Investigator or 
sub-Investigator, the Sponsor and/or Development Innovations shall take all appropriate 
measures to safeguard and prevent access to this data by any unauthorized party. 

 
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13.4 
Financial Information 
The finances for this clinical study will be subject to a separate written agreement between the 
Sponsor and applicable parties.  Any Investigator financial disclosures as applicable to 21CFR 
Part 54 shall be appropriately provided. 
14. 
RESEARCH RETENTION AND DOCUMENTATION OF THE STUDY 
14.1 
Amendments to the Protocol 
Amendments to the protocol shall be planned, documented, and signature-authorized prior to 
implementation. 
If an amendment to the protocol is required, the amendment will be originated and documented 
by the Sponsor or its representative.  All amendments require review and approval of all 
pharmaceutical companies and the Principal Investigator supporting the study.  The written 
amendment must be reviewed and approved by the Sponsor and submitted to the IRB at the 
Investigator’s facility for the board’s approval. 
Amendments specifically involving change to study design, risk to patient, increase to dosing or 
exposure, patient number increase, or addition or removal of new tests or procedures shall be 
reviewed and approved by the IRB of record for the Investigator’s facility. 
The amendment will be submitted formally to the FDA or other regulatory authorities by the 
Sponsor as applicable, and IRB approval, obtained, specifically when an increase to dosing or 
patient exposure and/or patient number has been proposed or when the addition or removal of an 
Investigator is necessitated. 
Items requiring a protocol amendment with IRB and/or the FDA or other regulatory authorities’ 
approval include, but are not limited to, the following: 
• Change to study design 
• Risk to patients 
• Increase to dose or patient exposure to drug 
• Patient number increase 
• Addition or removal of tests and/or procedures 
• Addition/removal of an Investigator. 
It should be further noted that if an amendment to the protocol substantially alters the study 
design or the potential risks to the patients, their consent to continue participation in the study 
should be obtained. 

 
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14.2 
Documentation Required to Initiate the Study 
Before the study can begin, certain documentation required by FDA regulations and ICH GCP 
must be provided by the Investigator.  The required documentation should be submitted to: 
Sarah Cannon Development Innovations, LLC 
Regulatory Department 
1100 Dr. Martin L. King Jr. Blvd. Suite 800 
Nashville, TN  37203 
Documents required at a minimum to begin a study include but are not limited to the following: 
• A signature-authorized protocol and contract 
• A copy of the official IRB approval of the study and the IRB members list 
• Current curricula vitae for the Principal Investigator and any associate Investigator(s) 
who will be involved in the study 
• Indication of appropriate accreditation for laboratories (as required) to be used in the 
study and the normal ranges for tests to be performed by those laboratories 
• Original Form FDA 1572 (Statement of Investigator), appropriately completed and 
signed 
• A copy of the IRB -approved ICF containing permission for audit by representatives of 
the Sponsor, Development Innovations, the IRB, and the FDA and other regulatory 
agencies (as applicable) 
• Financial disclosure forms for all Investigators listed on Form FDA 1572 (if applicable, 
i.e., for covered trials) 
• Verification of Principal Investigator acceptability from local and/or national debarment 
list(s). 
14.3 
Study Documentation and Storage 
The Principal Investigator must maintain a list of appropriately qualified persons to whom he has 
delegated study duties and should ensure that all persons assisting in the conduct of the study are 
informed of their obligations.  All persons authorized to make entries and/or corrections on the 
eCRFs are to be included on this document.  All entries in the patients’ eCRFs are to be 
supported by source documentation where appropriate. 
Source documents are the original documents, data, records, and certified copies of original 
records of clinical findings, observations, and activities from which the patients’ eCRF data are 
obtained.  These can include but are not limited to hospital records, clinical and office charts, 
laboratory, medico-technical department and pharmacy records, diaries, microfiches, ECG 
traces, copies or transcriptions certified after verification as being accurate and complete, 
photographic negatives, microfilm or magnetic media, X-rays, and correspondence. 
The Principal Investigator and study staff members are responsible for maintaining a 
comprehensive and centralized filing system (e.g., regulatory binder or Investigator study file 
[ISF]) of all essential study-related documentation, suitable for inspection at any time by 
representatives from the Sponsor and/or applicable regulatory authorities.  The ISF must consist 
of those documents that individually or collectively permit evaluation of the conduct of the study 

 
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and the quality of the data produced.  The ISF should contain at a minimum all relevant 
documents and correspondence as outlined in ICH GCP Section 8 and 21 CFR Part 312.57, 
including key documents such as the IB and any amendments, the protocol and any amendments, 
signed ICFs, copies of completed eCRFs, IRB approval documents, Financial Disclosure forms, 
patient identification lists, enrollment logs, delegation of authority log, staff qualification 
documents, laboratory normal ranges, and records relating to the study drug including 
accountability records.  Drug accountability records should, at a minimum, contain information 
regarding receipt, shipment, and disposition.  Each form of drug accountability record, at a 
minimum, should contain the Principal Investigator name, the date the drug was 
shipped/received, and the date, quantity, and batch/code or lot number for the identity of each 
shipment.  In addition, all original source documents supporting entries in the eCRF must be 
maintained and readily available. 
The Sponsor shall maintain adequate investigational product and financial interest records as per 
21 CFR Part 54.6 and Part 312.57 for no less than 2 years after the last marketing application has 
been approved by FDA or, in the event that the marketing application has not been approved by 
FDA, for no less than 2 years after the last shipment/delivery of the drug for investigational use 
or the drug is discontinued and the FDA has been notified of the discontinuation. 
The IRB shall maintain adequate documentation/records of IRB activities as per 21 CFR Part 
56.115 for at least 3 years after completion of the research. 
The Investigator shall maintain adequate records of drug disposition, case histories, and any 
other study-related records as per 21 CFR Part 312.62 for no less than 2 years after the last 
marketing application has been approved by FDA or, in the event that the marketing application 
has not been approved by FDA, for no less than 2 years after the last shipment/delivery of the 
drug for investigational use or the drug is discontinued and FDA has been notified of the 
discontinuation. 
To enable evaluations and/or audits from regulatory authorities or from the Sponsor or its 
representative, the Investigator additionally agrees to keep records, including the identity of all 
participating patients (sufficient information to link records, e.g., eCRF and medical records), all 
original signed ICFs, copies of all eCRF records, SAE reporting forms, source documents, 
detailed records of treatment disposition, and related essential regulatory documents.  The 
documents listed above must be retained by the Investigator for as long as needed to comply with 
national and international regulations (generally 2 years after discontinuing clinical development 
or after the last marketing approval).  Sponsor or its representative will notify the 
Investigator(s)/institutions(s) when the study-related records are no longer required. 
If the Investigator relocates, retires, or for any reason withdraws from the study, the Sponsor or 
its representative must be prospectively notified.  The study records must be transferred to an 
acceptable designee, such as another Investigator, another institution, or to Development 
Innovations.  The Investigator must obtain the Sponsor’s written permission before disposing of 
any records, even if retention requirements have been met.  All study files will be maintained by 
the Sponsor or its representative throughout the study and will be transferred to the Sponsor at 
the conclusion of the study, if applicable. 

 
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14.4 
Data Collection 
The study eCRF is the primary data collection instrument for the study.  Case report forms will 
be completed using the English language and should be kept current to enable the Sponsor to 
review the patients’ status throughout the course of the study. 
In order to maintain confidentiality, only study number, patient number, and year of birth will 
identify the patient in the eCRF system.  If the patient’s name appears on any other document 
(e.g., laboratory report), it must be obliterated on the copy of the document to be supplied to 
Development Innovations and be replaced instead with the patient number and other identifier as 
allowed per institutional policy.  The Investigator will maintain a personal patient identification 
list (patient numbers with corresponding patient identifiers) to enable records to be identified and 
verified as authentic.  Patient data/information will be kept confidential and will be managed 
according to applicable local, state, and federal regulations. 
All data requested by the eCRF system must be supported by and be consistent with the patient’s 
source documentation.  All missing data must be explained.  When a required laboratory test, 
assessment, or evaluation has not been done or an “Unknown” box is not an option on the eCRF, 
a note should be created verifying that the test was “Not Done” or the result was “Unknown.”  
For any entry errors made, the error(s) must be corrected, and a note explaining the reason for 
change should be provided. 
The Investigator will electronically sign and date the patient eCRF indicating that the data in the 
eCRF have been assessed.  Each completed eCRF will be signed and dated by the Principal 
Investigator, once all data for that patient are final. 
14.5 
Disclosure and Publication Policy 
All information provided regarding the study, as well as all information collected/documented 
during the course of the study, will be regarded as confidential.  The Sponsor reserves the right 
to release literature publications based on the results of the study.  Results from the study will be 
published/presented as per the Sponsor’s publication process. 
Inclusion of the Investigator in the authorship of any multi-center publication will be based upon 
substantial contribution to the study design, the analysis or interpretation of data, or the drafting 
and/or critically revising of any manuscript(s) derived from the study.  The Investigator 
acknowledges that the study is part of a multi-center study and agrees that any publication by the 
Investigator of the results of the study conducted at the research site shall not be made before the 
first multi-center publication.  In the event there is no multi-center publication within fifteen 
(15) months after the study has been completed or terminated at all study sites and all data have 
been received, the Investigator shall have the right to publish his/her results from the study, 
subject to the notice requirements described herein and subject to acknowledgement of the 
Sponsor as appropriate.  The Investigator shall provide the Sponsor thirty (30) days to review a 
manuscript or any poster presentation, abstract or other written or oral material that describes the 
results of the study for the purpose only of determining if any confidential or patentable 
information is disclosed thereby.  If the Sponsor requests in writing, the Investigator shall 
withhold any publication or presentation an additional sixty (60) days solely to permit the 
Sponsor to seek patent protection and to remove any Development Innovations confidential 
information from all publications. 

 
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15. 
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Harris et al. 2009 
Harris WP, Mostaghel EA, Nelson PS, Montgomery B. Androgen deprivation therapy: progress 
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Jeon et al. 2020 
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Scher et al. 2016  
Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, et al. Trial design and 
objectives for castration-resistant prostate cancer: updated recommendations from the Prostate 
Cancer Clinical Trials Working Group 3. J Clin Oncol. 2016;34(12):1402-18. 
Tukachinsky et al. 2009 
Tukachinsky H, Madison RW, Chung JH, Gjoerup OV, Severson EA, Dennis L, et al. Genomic 
analysis of circulating tumor DNA in 3,334 patients with advanced prostate cancer identifies 
targetable BRCA alterations and AR resistance mechanisms. Clin Cancer 
Res. 2021:27(11):3094-3105. 

 
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16. 
APPENDICES 
Appendix A: Eastern Cooperative Oncology Group (ECOG) Performance Status Criteria 
 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous activity, but ambulatory and 
able to carry out work of a light or sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but unable to carry out 
any work activities.  Up and about more than 50% of waking hours. 
3 
In bed >50% of the time.  Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally confined to 
bed or chair. 
5 
Dead 
 

 
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Appendix B: Guidelines for Evaluation of Objective Tumor Response Using RECIST 
Version 1.1 (Response Evaluation Criteria in Solid Tumors) in Soft Tissue 
and PCWG3 (Prostate Cancer Working Group Criteria 3) in Bone Lesions 
Introduction 
This appendix details the general implementation of RECIST v1.1 (Response Evaluation Criteria 
in Solid Tumors version 1.1) guidelines (Eisenhauer et al 2009) for the study with regards to 
Investigator assessment of tumor burden and PCWG3 guidelines (Scher et al. 2016). 
Definition of Measurable and Non-measurable Lesions 
Measurable: 
Tumor lesions:  To be considered measurable disease, tumor lesions must be accurately 
measured in at least 1 dimension (longest diameter in the plane of measurement is to be 
recorded) with a minimum size of: 
• 10 mm by computed tomography (CT scan slice thickness/interval no greater than 
5 mm); up to 5 lesions (with a maximum of 2 lesions per organ) per PCWG3 
• 10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable) 
• 20 mm by chest X-ray 
 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will be measured 
and followed.  Per PCWG3 - Nodal disease should be measured in the short axis and recorded 
by location: pelvic disease should be classified as locoregional, and extrapelvic disease 
(retroperitoneal, mediastinal, thoracic, or other) as metastatic.  Nodes ≥1.5 cm in the short axis 
are considered pathologic and measurable.  As per RECIST v1.1, lymph nodes ≥1.0 and less than 
1.5 cm in the short axis may be pathologic and should be recorded as non-target lesions.  Nodes 
less than 1.0 cm in the short axis are considered nonpathologic.   
 
Non-measurable: 
• 
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph 
nodes with ≥10 to <15mm short axis at baseline). 
• 
Truly non-measurable lesions include the following: leptomeningeal disease, ascites, 
pleural/pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin 
or lung, and abdominal masses/abdominal organomegaly identified by physical examination 
that is not measurable by CT or MRI. 
• 
Previously irradiated lesions or lesions subjected to other local-regional therapy. 
 

 
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Special Consideration Regarding Lesion Measurability: 
Cystic lesions 
Cystic lesions thought to represent cystic metastases can be considered measurable lesions if 
they meet the criteria for measurability from a radiological point of view, but if non-cystic 
lesions are present in the same patient, these should be selected as target lesions. 
Definition of Target and Non-Target Lesions 
Target lesions: 
A maximum of 5 measurable lesions (with a maximum of 2 lesions per organ), representative of 
all involved organs should be identified as target lesions at baseline. Pathological lymph nodes 
which are defined as measurable and may be identified as target lesions must meet the criterion 
of a short axis of ≥15 mm by CT scan. Target lesions should be selected on the basis of their size 
(longest diameter for non-nodal lesions or short axis for nodal lesions), but in addition should be 
those that lend themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion, which can be measured reproducibly, should be selected. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum of diameters.  If lymph nodes are 
selected as measurable lesions, only the short axis is added into the sum, even if the nodes 
regress to below 10 mm in the study.  The baseline sum of diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the disease. 
Special cases: 
• If a target lesion has completely disappeared, the longest diameter should be recorded as 
0 mm. 
• If a target lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned.  If an accurate measure can be given, this 
should be recorded, even if it is below 5 mm. 
• When nodal disease is included in the sum of target lesions and the nodes decrease to 
“normal” size (<10 mm), they may still have a measurement reported on scans. This 
measurement should be recorded even though the nodes are normal in order to not 
overstate progression should it be based on increase in size of the nodes. 
• If a target lesion splits into two or more parts, then record the sum of the diameters of 
those parts.  If two or more target lesions merge then the sum of the diameters of the 
combined lesion should be recorded for one of the lesions and 0 mm recorded for the 
other lesion(s). 
• Similarly, as lesions coalesce, a plane between them may be maintained that would aid in 
obtaining maximal diameter measurements of each individual lesion. If the lesions have 
truly coalesced such that they are no longer separable, the vector of the longest diameter 
in this instance should be the maximal longest diameter for the ‘coalesced lesion’. 
 

 
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Non-target lesions: 
All other lesions (or sites of disease) including pathological lymph nodes (those with short axis 
≥10 mm but <15 mm) should be identified as non-target lesions (NTLs) and should also be 
recorded at baseline.  Nodes that have a short axis ˂10 mm are considered non-pathological and 
should not be recorded or followed.  In addition, it is possible to record multiple NTLs involving 
the same organ as a single item on the case record form (e.g., “multiple enlarged pelvic lymph 
nodes” or “multiple liver metastases”). 
Methods of Assessment  
The same method of assessment and the same technique should be used to characterize each 
identified and recorded lesion at baseline and during follow-up visits.  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. 
CT, MRI:  CT scanning with IV contrast 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 5 mm or less.  When CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion should 
be twice the slice thickness. If IV contrast cannot be administered (for example, in the situation 
of allergy to contrast), a non-contrast CT of the chest is still preferred over MRI or chest X-ray. 
MRI is also acceptable and can be used when CT is not feasible or is medically contraindicated. 
Clinical lesions:   Clinical lesions will only be considered measurable when they are superficial 
and ≥10 mm 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. 
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. 
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examination can, however, be used to identify the presence 
of new lesions.  If new lesions are identified by ultrasound in the course of the study, 
confirmation by CT or MRI is advised. 
Endoscopy, Laparoscopy, Tumor markers, Cytology, Histology:  The utilization of these 
techniques alone will not be used for objective tumor response measurements. 
FDG-PET:  FDG-PET scans may be used as a method for identifying new lesions in the 
assessment of progression, according with the following algorithm: New lesions will be recorded 
where there is positive FDG uptake (defined as when an uptake greater than twice that of the 
surrounding tissue is observed) not present on baseline FDG-PET scan or in a location 
corresponding to a new lesion by CT/MRI at the same visit.  If there is no baseline FDG-PET 
scan available, and no evidence of new lesions by CT/MRI then follow-up CT/MRI assessments 
should be continued, scheduled as per protocol or clinical indicated, in order to confirm new 
lesions. 

 
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Tumor response evaluation 
This section provides the definitions of the criteria used to determine objective tumor response. 
Evaluation of target lesions: 
Complete Response (CR) 
Disappearance of all target lesions since baseline.  Any pathological lymph 
nodes must have a reduction in short axis to <10 mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of the diameters of target lesions, taking as 
reference the baseline sum of diameters. 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD. 
Progressive Disease (PD) 
At least a 20% increase in the sum of diameters of target lesions, taking as 
reference the smallest sum on study or nadir (this includes the baseline sum if 
that is the smallest on study).  In addition to the relative increase of 20%, the 
sum must also demonstrate an absolute increase of at least 5 mm. 
Not Evaluable (NE) 
Only relevant if any of the target lesions were not assessed or not evaluable.  
Note:  If the sum of diameters of assessed lesions meets the progressive disease 
criteria, progressive disease overrides not evaluable as a target lesion response. 
 
Evaluation of non-target lesions 
Complete Response (CR) 
Disappearance of all non-target lesions since baseline.  All lymph nodes must be 
non-pathological in size (<10 mm short axis). 
Non-CR/Non-PD 
Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above normal limits.  
Progression (PD) 
Unequivocal progression of existing non-target lesions indicative of a substantial 
worsening in non-target disease.  Unequivocal progression may be due to an 
important progression in one lesion only or in several lesions.  In all cases the 
progression MUST be clinically significant for the physician to consider changing 
(or stopping) therapy. 
Not Evaluable (NE) 
Only relevant when one or some of the non-target lesions were not assessed and, 
in the Investigator's opinion, they are not able to provide an evaluable overall non-
target lesion assessment at this visit. 
Note:  For patients without target lesions at baseline, this is relevant if any of the 
non-target lesions were not assessed at this visit and the progression criteria have 
not been met. 
 
To achieve “unequivocal progression” on the basis of non-target lesions, there must be an overall 
level of substantial worsening in non-target disease such that, even in presence of SD or PR in 
target lesions, the overall tumor burden has increased sufficiently to merit discontinuation of 
therapy.  A modest “increase” in the size of one or more non-target lesions is usually not 
sufficient to qualify for unequivocal progression status. 

 
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New lesions:  The presence of one or more new lesions is assessed as disease progression.  A 
lesion identified at a follow-up assessment in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.  The finding of a new 
lesion should be unequivocal: i.e. not attributable to differences in scanning technique, change in 
imaging modality or findings thought to represent something other than tumor.  If a new lesion is 
equivocal, for example because of its small size, the treatment and tumor assessments should be 
continued until the new lesion has been confirmed.  If repeat scans confirm there is a new lesion, 
then the progression date should be declared using the date of the initial scan. 
Evaluation of overall response 
Target lesions 
Non-Target lesions 
New Lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
NE 
No 
PR 
PR 
Non-PD or NE 
No 
PR 
SD  
Non-PD or NE 
No 
SD 
NE 
Non-PD or NE 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, NE = not evaluable 
Special notes on response evaluation 
Missing assessments and non-evaluable designation:  When no imaging/measurement is done at 
all at a particular time point, the patient is not evaluable (NE) at that time point.  If only a subset 
of lesion measurements are made at an assessment, usually the case is also considered NE at that 
time point, unless a convincing argument can be made that the contribution of the individual 
missing lesion(s) would not change the assigned time point response.  This would be most likely 
to happen in the case of PD. 
Symptomatic progression:  Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of PD at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document objective progression 
even after discontinuation of treatment.  Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping study treatment. 
Confirmation of response:  Confirmation of response (by repeat scans after 4 weeks or as 
specified in the protocol) is required for studies in which response rate is the primary endpoint, 
but is not required in randomized studies or studies with primary survival endpoints (i.e., where 
response is not a primary endpoint). 

 
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REFERENCES 
Eisenhauer et al 2009 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R.  New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).  Eur J Cancer. 
2009;45:228-47. 
ASSESSMENT OF BONE LESION PROGRESSION USING PCWG3 
CRITERIA 
The same method of assessment and the same technique should be used to characterize each 
identified and recorded lesion at baseline and during follow-up visits.   
Baseline imaging 
The use of 99mTc-methylene diphosphonate radionuclide bone scintigraphy should be used, with 
the presence or absence of metastasis recorded.  A quantitative measure of disease burden, such 
as lesion number, the bone scan index, or lesion area, is recommended.  Changes in lesions 
considered metastatic on bone scintigraphy should be followed, assessed, and recorded.  
Areas/lesions on bone scans that are suggestive can be assessed further with CT or MRI and 
followed separately, but this supplemental imaging should not be used to establish lesions for the 
purposes of the trial. 
Bone scan progression 
For progression, pseudoprogression should be excluded in the absence of symptoms or other 
signs of progression.  The 2+2 rule (at least two new lesions on the first post-treatment scan, with 
at least 2 additional lesions on the next scan) should be used to distinguish flare from true 
progression.  If at least 2 additional new lesions are seen on the next (confirmatory) scan, the 
date of progression is the date of the first post-treatment scan (i.e. when the first 2 new lesions 
were documented).   
For scans after the first post-treatment scan, at least 2 new lesions relative to the first post-
treatment scan should be confirmed on a subsequent scan.  The date of progression will be the 
date of the scan that first documents the second lesion.  Changes in intensity of uptake alone do 
not constitute either progression or regression.  The proportion of patients who have not 
progressed at fixed time points (6 or 12 months) should be reported. 
Bone lesions 
• Bone scan, PET scan or plain films are not considered adequate imaging techniques to 
measure bone lesions.  However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, can 
be considered measurable if the soft tissue component meets the definition of measurability 
described above. 
• Blastic bone lesions are considered non-measurable. 

 
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OVERALL RADIOLOGICAL VISIT ASSESSMENT 
Table 7 provides the definitions how the visit responses for soft tissue (according to RECIST1.1 
criteria) and bone progression status (according to PCWG3 criteria) are combined to give an 
overall radiological objective visit response. 
 
Table 7 
Overall radiological response – RECIST v1.1 and bone progression 
(PCWG3) 
Overall visit soft tissue 
response (RECIST 1.1) 
Bone progression status 
(PCWG3) 
Overall radiological 
response 
CR 
No bone lesions at baseline 
CR 
CR, target lesions were present 
at baseline 
Non-PD or NE 
PR  
CR, only non-target lesions 
present at baseline 
Non-PD or NE 
Non-CR/Non PD  
PR 
Non-PD or NE 
PR 
SD 
Non-PD or NE 
SD 
No soft tissue lesions at 
baseline 
Non-PD or NE 
Non-PD 
PD  
Any 
PD 
Any 
PD 
PD 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, NE = not evaluable 
 

 
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Appendix C: Prostate Cancer Working Group 3 (PCWG) PSA Criteria 
Baseline/Study Entry 
PSA progression requirements for study entry 
Patients must have measurable PSA ≥1.0 ng/mL as the minimum starting level for trial entry if 
the confirmed rise is the only indication of progression (excluding pure small cell carcinoma).  It 
is recommended to estimate a pretreatment PSA doubling time (PSADT) if at least 3 values are 
available ≥4 weeks apart.  Treatment or enrollment onto a trial should not be delayed to estimate 
PSADT.  
On-Study Disease Assessments 
• 
PSA results are to be collected on Day 1 of each treatment cycle 
− 
Continue through early rises for a minimum of 12 weeks unless there is other evidence 
of progression, as favorable effects on PSA may be delayed for ≥12 weeks 
− 
Ignore PSA rises before 12 weeks in determining PSA response 
 
Patients with PSA progression are allowed and encouraged to continue treatment until 
symptomatic or radiographic progression. 
Disease Progression will be defined as follows: 
1) Bone Scan and Radiographic Progression 
Appearance of 2 or more new lesions on bone scan, and, for the first reassessment only, a 
confirmatory scan performed 6 or more weeks later that shows a minimum of 2 or more 
additional new lesions.  The date of progression is the date of the first scan that shows the 
change.  
Or  
Soft tissue disease progression by modified RECIST v1.1.  
Note that for some treatments, a lesion may increase in size before it decreases. 
2) PSA Progression 
PSA progression is defined as ≥25% increase and ≥2 ng/mL increase above the nadir or baseline 
value for patients who had a PSA decrease on treatment, which is confirmed by a second value 
3 or more weeks later.   
For patients without a decrease on treatment, PSA progression is defined as ≥25% increase and 
an absolute increase of ≥2 ng/mL after 12 weeks.   
PSA progressions must be confirmed at the next study visit 4 weeks later.  PSA will be collected 
at screening and on Day 1 of each treatment cycle.   

 
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Appendix C:  PCWG3 Criteria (continued) 
 
3) Symptomatic Progression 
Symptomatic progression is defined as evidence of unequivocal symptomatic or clinical 
progression defined by at least 1 of the following:  
• A marked escalation in cancer-related pain that is assessed by the Investigator to indicate 
the need for other systemic therapy or palliative radiotherapy.  Ignore early changes 
(≤12 weeks) in pain or health-related quality of life in absence of compelling evidence of 
disease progression.  Confirm progression of pain or health-related quality of life 
≥3 weeks later  
• An immediate need for initiation of new anticancer treatment or surgical or radiological 
intervention for complications due to tumor progression  
• A marked deterioration in ECOG performance status to Grade 3 or higher or  
• It is felt to be in the best interest of the patient to come off study due to clinical 
progression 
 
Reference: Scher et al. 2016 
 

 
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Appendix D: Guidelines for Fertile Male Patients 
Acceptable Contraception Methods: 
Fertile male subjects, defined as all males physiologically capable of conceiving offspring, with 
female partners of childbearing potential must use condoms plus spermicidal agent during the 
study treatment period and for 90 days after the last dose of the study drug, and should not father 
a child during this period. 
Male subjects must also refrain from donating sperm during their participation in the study and for 
90 days after the last dose of the study drug. 
Pregnancies 
Pregnancy outcomes must be collected for the female partners of any males who took study drug 
in this study.  Consent to report information regarding these pregnancy outcomes should be 
obtained from the mother. 
 

 
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Appendix E: New York Heart Association Classification of Cardiac Disease 
The following table presents the New York Heart Association classification of cardiac disease. 
Class 
Functional Capacity 
Objective Assessment 
I 
Subjects with cardiac disease but without resulting limitations of physical 
activity.  Ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea, or anginal pain. 
No objective evidence of 
cardiovascular disease. 
II 
Subjects with cardiac disease resulting in slight limitation of physical 
activity.  They are comfortable at rest.  Ordinary physical activity results in 
fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
minimal cardiovascular 
disease. 
III 
Subjects with cardiac disease resulting in marked limitation of physical 
activity.  They are comfortable at rest.  Less than ordinary activity causes 
fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
moderately severe 
cardiovascular disease. 
IV 
Subjects with cardiac disease resulting in inability to carry on any physical 
activity without discomfort.  Symptoms of heart failure or the anginal 
syndrome may be present even at rest.  If any physical activity is undertaken, 
discomfort is increased. 
Objective evidence of 
severe cardiovascular 
disease. 
Source:  The Criteria Committee of New York Heart Association.  Nomenclature and Criteria for Diagnosis of 
Diseases of the Heart and Great Vessels.  9th Ed. Boston, MA:  Little, Brown & Co; 1994:253-256. 
 

 
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Appendix F: Hy’s Law 
Reference:  FDA Guidance for Industry (issued July 2009) “Drug-induced liver injury: 
Premarketing clinical evaluation” 
Introduction 
This Appendix describes the process to be followed in order to identify and appropriately report 
cases of Hy’s Law (HL).  It is not intended to be a comprehensive guide to the management of 
elevated liver biochemistries.  Specific guidance on managing liver abnormalities can be found 
in Section 6.2.1 of the clinical study protocol. 
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The Investigator is responsible for determining whether a subject meets potential 
Hy’s Law (PHL) criteria at any point during the study. 
The Investigator participates, together with Accutar Biotechnology, Inc. clinical project 
representatives, in review and assessment of cases meeting PHL criteria to agree whether HL 
criteria are met.  Hy’s Law criteria are met if there is no alternative explanation for the elevations 
in liver biochemistry other than drug-induced liver injury (DILI) caused by the investigational 
medicinal product. 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for reporting 
adverse events (AEs) and serious adverse events (SAEs) according to the outcome of the review 
and assessment in line with standard safety reporting processes. 
Definitions 
Potential Hy’s Law (PHL) 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥3 × the upper limit of 
normal (ULN) together with total bilirubin (TBL) ≥2 ×ULN at any point during the study 
following the start of study medication, irrespective of an increase in alkaline phosphatase 
(ALP). 
Hy’s Law (HL) 
Aspartate aminotransferase or ALT ≥3 × ULN together with TBL ≥2 × ULN, where no other 
reason other than the investigational product can be found to explain the combination of 
increases, e.g., elevated ALP indicating cholestasis, viral hepatitis, another drug. 
For PHL and HL the elevation in transaminases must precede or be coincident with (i.e., on the 
same day) the elevation in TBL, but there is no specified time frame within which the elevations 
in transaminases and TBL must occur. 
Identification of potential Hy’s Law cases 
In order to identify cases of PHL it is important to perform a comprehensive review of laboratory 
data for any subject who meets any of the following identification criteria in isolation or in 
combination: 
• AST ≥3 × ULN 
• ALT ≥3 × ULN 

 
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• TBL ≥2 × ULN 
When a subject meets any of the identification criteria, in isolation or in combination, the central 
laboratory, if applicable, will immediately send an alert to the Investigator. 
Where the identification criteria are met in samples analyzed by a local laboratory, the 
Investigator will: 
• Notify the Sponsor’s representative 
• Request a repeat of the test (new blood draw) by the local laboratory 
• Complete the appropriate unscheduled laboratory case report form (CRF) module(s) and 
the original laboratory test CRF form 
When the identification criteria are met from central or local laboratory results the Investigator 
will without delay determine whether the subject meets PHL criteria (see “Definitions”) by 
reviewing laboratory reports from all previous visits (including both central and local laboratory 
results). 
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will: 
• Notify the Sponsor’s representative 
• Determine whether the subject meets PHL criteria (see “Definitions”) by reviewing 
laboratory reports from all previous visits 
• Promptly enter the laboratory data into the laboratory CRF 
Follow-up 
Potential Hy’s Law criteria not met 
If the subject does not meet PHL criteria the Investigator will: 
• Inform the Sponsor’s representative that the subject has not met PHL criteria 
• Perform follow-up on subsequent laboratory results according to the guidance provided 
in the clinical study protocol 
Potential Hy’s Law criteria met 
If the subject does meet PHL criteria the Investigator will: 
• Determine whether PHL criteria were met at any study visit prior to starting study 
treatment (see Section 11 Safety Reporting) 
• Notify the Sponsor’s representative that the subject has met PHL criteria 
The Investigator will contact the Medical Monitor to provide guidance, discuss, and agree on an 
approach for the study subjects’ follow-up and the continuous review of data.  Subsequent to this 
contact the Investigator will: 
• Monitor the subject until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically indicated 
• Investigate the etiology of the event and perform diagnostic investigations as discussed 
with the Medical Monitor.   
• Complete the liver CRF modules as information becomes available 

 
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• If at any time (in consultation with the Medical Monitor) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures. 
Review and assessment of potential Hy’s Law cases 
The instructions in this section should be followed for all cases where PHL criteria are met. 
No later than 3 weeks after the biochemistry abnormality was initially detected, the Investigator 
will contact the Medical Monitor in order to review available data and agree on whether there is 
an alternative explanation for meeting PHL criteria other than DILI caused by the investigational 
product.  The Accutar Biotechnology, Inc. Clinical Lead or equivalent and Medical Monitor will 
also be involved in this review, together with other subject-matter experts as appropriate. 
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below. 
If there is an agreed-upon alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE: 
• If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF. 
• If the alternative explanation is an AE/SAE, record the AE/SAE in the CRF accordingly 
and follow the reporting standard practices. 
If it is agreed upon that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the investigational product: 
Report an SAE (report term Hy’s Law) according to the Sponsor’s standard processes. 
• The “Medically Important” serious criterion should be used if no other serious criteria 
apply. 
• As there is no alternative explanation for the HL case, a causality assessment of “related” 
should be assigned. 
If there is an unavoidable delay of over 3 weeks in obtaining the information necessary to assess 
whether or not the case meets the criteria for HL, then it is assumed that there is no alternative 
explanation until such time as an informed decision can be made: 
• Report an SAE (report term Potential Hy’s Law) applying serious criteria and causality 
assessment as per above. 
• Continue follow-up and review according to the agreed-upon plan.  Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are met.  Update the SAE report according to the outcome of the 
review, amending the reported term if an alternative explanation for the liver 
biochemistry elevations is determined. 

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 84 of 121 
Actions required when potential Hy’s Law criteria are met before and after starting study 
treatment 
This section is applicable to subjects with liver metastases who meet PHL criteria on study 
treatment having previously met PHL criteria at a study visit prior to starting study treatment. 
At the first on-study treatment occurrence of PHL criteria being met, the Investigator will 
determine if there has been a significant change in the subjects’ condition compared with the last 
visit where PHL criteria were met. 
• If there is no significant change, no action is required. 
• If there is a significant change, notify the Sponsor’s representative. 
A “significant” change in the subject’s condition refers to a clinically relevant change in any of 
the individual liver biochemistry parameters (ALT, AST, or TBL) in isolation or in combination, 
or a clinically relevant change in associated symptoms.  The determination of whether there has 
been a significant change will be at the discretion of the Investigator; this may be in consultation 
with the Medical Monitor if there is any uncertainty. 
Actions required for repeat episodes of potential Hy’s Law 
This section is applicable when a subject meets PHL criteria on study treatment, and has already 
met PHL criteria at a previous on-study treatment visit. 
The requirement to conduct follow-up, review, and assessment of a repeat occurrence(s) of PHL 
is based on the nature of the alternative cause identified for the previous occurrence. 
The investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question: 
Was the alternative cause for the previous occurrence of PHL criteria being met found to be the 
disease under study (e.g., chronic or progressing malignant disease, severe infection, or liver 
disease), or did the subject meet PHL criteria prior to starting study treatment and at first on-
study treatment visit, as described in “Actions required when potential Hy’s Law criteria are met 
before and after starting study treatment”. 
• If No: Follow the process described in “Potential Hy’s Law criteria not met”. 
• If Yes: Determine if there has been a significant change in the subject’s condition 
compared with when PHL criteria were previously met. 
If there is no significant change, no action is required. 
If there is a significant change, follow the process described in “Follow-up”. 
A “significant” change in the subject’s condition refers to a clinically relevant change in any of 
the individual liver biochemistry parameters (ALT, AST, or TBL) in isolation or in combination, 
or a clinically relevant change in associated symptoms.  The determination of whether there has 
been a significant change will be at the discretion of the Investigator; this may be in consultation 
with the Medical Monitor if there is any uncertainty. 

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 85 of 121 
Appendix G: PK Sampling Timepoint Schedules 

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 86 of 121 
Table 8 
PK Sampling Timepoints Once Daily (QD Dosing) 
 
Timepoints relative to AC176 dosing*  
ECG* 
(in triplicate) 
Cycle 1 Day 1 
Pre-dose 
X 
1 hour (±5 minutes) 
- 
2 hour (±5 minutes) 
- 
3 hour (±10 minutes) 
- 
4 hour (±10 minutes) 
X 
6 hour (±20 minutes) 
- 
8 hour (±1 hour) 
X (if feasible) 
10 hour (±1 hour) 
- 
12 hour (±1 hour) 
- 
24 hour (±1 hour) 
- 
Cycle 1 Day 15 
Pre-dose 
X 
1 hour (±5 minutes) 
- 
2 hour (±5 minutes) 
- 
3 hour (±10 minutes) 
- 
4 hour (±10 minutes) 
X 
6 hour (±20 minutes) 
- 
8 hour (±1 hour) 
X (if feasible) 
10 hour (±1 hour)  
- 
12 hour (±1 hour) 
- 
24 hour (±1 hour) 
- 
Cycle 2 Day 1 
Pre-dose** 
X** 
Cycle 4 Day 1 
Pre-dose** 
X 
Cycle 6 Day 1 
Pre-dose** 
X 
* Depending on emerging PK data, the SRC may alter the timepoints for PKs and ECGs. ** For the Expansion cohort, this 
timepoint is needed to be collected, the rest of the time points are not needed.  With Sponsor approval the required 10 hour and 
12 hour PK sample collections may be omitted, if not feasible. 
Meal consumption prior to PK collections will be collected.  The last meal consumed prior to dosing on the day of full 24 hour 
PK collections (Cycle 1) should be recorded. 

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 87 of 121 
Additional unscheduled PK samples may be drawn during the study if it is deemed clinically indicated for the patient and/or 
based on newly emerged data from clinical studies of AC176.  Similarly, if any PK timepoint is later deemed unnecessary per 
acquired clinical PK data, such timepoint may be removed from the PK schedule.  
 

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 88 of 121 
Table 9 
PK Sampling Timepoints ‒ Intermittent Dosing 7 days On / 7 days Off (28 days 
per cycle) 
 
Timepoints relative to AC176 dosing* 
ECG* 
(in triplicate) 
Cycle 1 Day 1 
Pre-dose 
X 
1 hour (±5 minutes) 
- 
2 hour (±5 minutes) 
X 
3 hour (±10 minutes) 
- 
4 hour (±10 minutes) 
- 
6 hour (±20 minutes) 
- 
8 hour (±1 hour) 
X (if feasible) 
10 hour (±1 hour) 
- 
12 hour (±1 hour) 
- 
24 hour (±1 hour) 
- 
Cycle 1 Day 8 
Pre-dose 
X 
1 hour (±5 minutes) 
- 
2 hour (±5 minutes) 
 - 
3 hour (±10 minutes) 
- 
4 hour (±10 minutes) 
X 
6 hour (±20 minutes) 
- 
8 hour (±1 hour) 
X (if feasible) 
10 hour (±1 hour) 
- 
12 hour (±1 hour) 
- 
24 hour (±1 hour) 
- 
Cycle 2 Day 8 
Pre-dose** 
X** 
Cycle 4 Day 8 
Pre-dose** 
X 
Cycle 6 Day 8 
Pre-dose** 
X 
* 7 days on and 7 days off, e.g., C1D1 to C1D7 receive AC176.  Dose interrupted C1D8 to C1D14.  AC176 dose to continue 
Cycle 1 on C1D15 to C1D21 and interrupted C1D22 to C1D28.  From Cycle 2, the patients will be dosed for 7 days and 
interrupted 7 days. ** For the Expansion cohort, this timepoint is needed to be collected, the rest of the time points are not 
needed. With Sponsor approval the required 10 hour and 12 hour PK sample collections may be omitted, if not feasible.  
Meal consumption prior to PK collection will be collected.  The last meal consumed prior to dosing on the day of 
full 24 hour PK collections (Cycle 1) should be recorded.  If the sample cannot be collected at the visit as scheduled, 
it should be collected at the next visit whenever possible.

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 89 of 121 
Table 10 
PK Sampling Timepoints – Intermittent Dosing 4 Days On / 3 Days Off 
(28 days per cycle) 
 
Timepoints relative to AC176 dosing*  
ECG* 
(in triplicate) 
Cycle 1 Day 1 
Pre-dose 
X 
1 hour (±5 minutes) 
- 
2 hour (±5 minutes) 
- 
3 hour (±10 minutes) 
- 
4 hour (±10 minutes) 
X 
6 hour (±20 minutes) 
- 
8 hour (±1 hour) 
X (if feasible) 
10 hour (±1 hour) 
- 
12 hour (±1 hour) 
- 
24 hour (±1 hour) 
- 
Cycle 1 Day 4 
Pre-dose 
X 
1 hour (±5 minutes) 
- 
2 hour (±5 minutes) 
- 
3 hour (±10 minutes) 
- 
4 hour (±10 minutes) 
X 
6 hour (±20 minutes) 
- 
8 hour (±1 hour) 
X (if feasible) 
10 hour (±1 hour) 
- 
12 hour (±1 hour) 
- 
24 hour (±1 hour) 
- 
Cycle 1 Day 8 
Predose 
- 
Cycle 2 Day 5 (if feasible) 
Pre-dose** 
X** 
Cycle 4 Day 5 (if feasible) 
Pre-dose** 
X 
Cycle 6 Day 5 (if feasible) 
Pre-dose** 
X 

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 90 of 121 
* Depending on emerging PK data, the SRC may alter the timepoints for PKs and ECGs. ** For the Expansion 
cohort, this timepoint is needed to be collected, the rest of the time points are not needed.  With Sponsor approval 
the required 10 hour and 12 hour PK sample collections may be omitted, if not feasible.  Meal consumption prior to PK 
collection will be collected. The last meal consumed prior to dosing on the day of full 24 hour PK collections (Cycle 1) should be 
recorded.  If the sample cannot be collected at the visit as scheduled, it should be collected at the next visit whenever possible.  
Additional unscheduled PK samples may be drawn during the study if it is deemed clinically indicated for the patient and/or 
based on newly emerged data from clinical studies of AC176.  Similarly, if any PK timepoint is later deemed unnecessary per 
acquired clinical PK data, such timepoint may be removed from PK schedule. 

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 91 of 121 
Table 11 
PK Sampling Timepoints – Intermittent Dosing 5 Days On and 2 Days Off  
(28 days per cycle) 
 
Timepoints relative to AC176 dosing*  
ECG* 
(in triplicate) 
Cycle 1 Day 1 
Pre-dose 
X 
1 hour (±5 minutes) 
- 
2 hour (±5 minutes) 
- 
3 hour (±10 minutes) 
- 
4 hour (±10 minutes) 
X 
6 hour (±20 minutes) 
- 
8 hour (±1 hour) 
X (if feasible) 
10 hour (±1 hour) 
- 
12 hour (±1 hour) 
- 
24 hour (±1 hour) 
- 
Cycle 1 Day 5 
Pre-dose 
X 
1 hour (±5 minutes) 
- 
2 hour (±5 minutes) 
- 
3 hour (±10 minutes) 
- 
4 hour (±10 minutes) 
X 
6 hour (±20 minutes) 
- 
8 hour (±1 hour) 
X (if feasible) 
10 hour (±1 hour) 
- 
12 hour (±1 hour) 
- 
24 hour (±1 hour) 
- 
Cycle 1 Day 8 
Predose 
- 
Cycle 2 Day 6 (if 
feasible) 
Pre-dose** 
X** 
Cycle 4 Day 6 (if 
feasible) 
Pre-dose** 
X 
Cycle 6 Day 6 (if 
feasible) 
Pre-dose** 
X 
* Depending on emerging PK data, the SRC may alter the timepoints for PKs and ECGs. ** For the Expansion cohort, this 
timepoint is needed to be collected, the rest of the time points are not needed.  With Sponsor approval the required 10 hour and 
12 hour PK sample collections may be omitted if not feasible.   

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 92 of 121 
Meal consumption prior to PK collection will be collected.  The last meal consumed prior to dosing on the day of full 24 hour 
PK collections (Cycle 1) should be recorded. 
Additional unscheduled PK samples may be drawn during the study if it is deemed clinically indicated for the patient and/or 
based on newly emerged data from clinical studies of AC176.  Similarly, if any PK timepoint is later deemed unnecessary per 
acquired clinical PK data, such timepoint may be removed from PK schedule.

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 93 of 121 
Table 12 
PK Sampling Timepoints – Intermittent Dosing 2 Weeks On / 2 Weeks Off (28 
days per cycle) 
 
Timepoints relative to AC176 dosing*  
ECG* 
(in triplicate) 
Cycle 1 Day 1 
Pre-dose 
X 
1 hour (±5 minutes) 
- 
2 hour (±5 minutes) 
- 
3 hour (±10 minutes) 
- 
4 hour (±10 minutes) 
X 
6 hour (±20 minutes) 
- 
8 hour (±1 hour) 
X (if feasible) 
10 hour (±1 hour) 
- 
12 hour (±1 hour) 
- 
24 hour (±1 hour) 
- 
Cycle 1 Day 8 
Pre-dose 
X 
1 hour (±5 minutes) 
- 
2 hour (±5 minutes) 
- 
3 hour (±10 minutes) 
- 
4 hour (±10 minutes) 
X 
6 hour (±20 minutes) 
- 
8 hour (±1 hour) 
X (if feasible) 
10 hour (±1 hour) 
- 
12 hour (±1 hour) 
- 
24 hour (±1 hour) 
- 
Cycle 2 Day 15 
Pre-dose** 
X** 
Cycle 4 Day 15 
Pre-dose** 
X 
Cycle 6 Day 15 
Pre-dose** 
X 
* Depending on emerging PK data, the SRC may alter the timepoints for PKs and ECGs. ** For Expansion cohort, this timepoint 
is needed to be collected, the rest of the time points are not needed.  With Sponsor approval the required 10 hour and 12 hour PK 
sample collections may be omitted, if not feasible.   
Meal consumption prior to PK collection will be collected.  The last meal consumed prior to dosing on the day of full 24 hour PK 
collections (Cycle 1) should be recorded.   

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 94 of 121 
If the sample cannot be collected at the visit as scheduled, it should be collected at the next visit whenever possible.  Additional 
unscheduled PK samples may be drawn during the study if it is deemed clinically indicated for the patient and/or based on newly 
emerged data from clinical studies of AC176.  Similarly, if any PK timepoint is later deemed unnecessary per acquired clinical 
PK data, such timepoint may be removed from PK schedule.  

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 95 of 121 
Table 13 
PK Sampling Timepoints – Intermittent Dosing 2 Weeks On / 1 Week Off (21 
days per cycle) 
 
Timepoints relative to AC176 dosing*  
ECG* 
(in triplicate) 
Cycle 1 Day 1 
Pre-dose 
X 
1 hour (±5 minutes) 
- 
2 hour (±5 minutes) 
- 
3 hour (±10 minutes) 
- 
4 hour (±10 minutes) 
X 
6 hour (±20 minutes) 
- 
8 hour (±1 hour) 
X (if feasible) 
10 hour (±1 hour) 
- 
12 hour (±1 hour) 
- 
24 hour (±1 hour) 
- 
Cycle 1 Day 8 
Pre-dose 
X 
1 hour (±5 minutes) 
- 
2 hour (±5 minutes) 
- 
3 hour (±10 minutes) 
- 
4 hour (±10 minutes) 
X 
6 hour (±20 minutes) 
- 
8 hour (±1 hour) 
X (if feasible) 
10 hour (±1 hour) 
- 
12 hour (±1 hour) 
- 
24 hour (±1 hour) 
- 
Cycle 2 Day 15 
Pre-dose** 
X** 
Cycle 4 Day 15 
Pre-dose** 
X 
Cycle 6 Day 15 
Pre-dose** 
X 
* Depending on emerging PK data, the SRC may alter the timepoints for PKs and ECGs. ** For the Expansion cohort, this 
timepoint is needed to be collected, the rest of the time points are not needed.  With Sponsor approval the required 10 hour and 
12 hour PK sample collections may be omitted, if not feasible.   
Meal consumption prior to PK collection will be collected.  The last meal consumed prior to dosing on the day of full 24 hour PK 
collections (Cycle 1) should be recorded.  If the sample cannot be collected at the visit as scheduled, it should be collected at the 

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 96 of 121 
next visit whenever possible.  Additional unscheduled PK samples may be drawn during the study if it is deemed clinically 
indicated for the patient and/or based on newly emerged data from clinical studies of AC176.  Similarly, if any PK timepoint is 
later deemed unnecessary per acquired clinical PK data, such timepoint may be removed from PK schedule.  

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 97 of 121 
Table 14 
PK Sampling Timepoints – 3 Weeks On / 1 Week Off  (28 days per cycle) 
 
Timepoints relative to AC176 dosing*  
ECG* 
(in triplicate) 
Cycle 1 Day 1 
Pre-dose 
X 
1 hour (±5 minutes) 
- 
2 hour (±5 minutes) 
- 
3 hour (±10 minutes) 
- 
4 hour (±10 minutes) 
X 
6 hour (±20 minutes) 
- 
8 hour (±1 hour) 
X (if feasible) 
10 hour (±1 hour) 
- 
12 hour (±1 hour) 
- 
24 hour (±1 hour) 
- 
Cycle 1 Day 8 
Pre-dose 
X 
1 hour (±5 minutes) 
- 
2 hour (±5 minutes) 
- 
3 hour (±10 minutes) 
- 
4 hour (±10 minutes) 
X 
6 hour (±20 minutes) 
- 
8 hour (±1 hour) 
X (if feasible) 
10 hour (±1 hour) 
- 
12 hour (±1 hour) 
- 
24 hour (±1 hour) 
- 
Cycle 2 Day 22 
Pre-dose** 
X** 
Cycle 4 Day 22 
Pre-dose 
X 
Cycle 6 Day 22 
Pre-dose 
X 
* Depending on emerging PK data, the SRC may alter the timepoints for PKs and ECGs. ** For the Expansion cohort, this 
timepoint is needed to be collected, the rest of the time points are not needed.  With Sponsor approval the required 10 hour and 
12 hour PK sample collections may be omitted, if not feasible.   
Meal consumption prior to PK collection will be collected.  The last meal consumed prior to dosing on the day of full 24 hour PK 
collections (Cycle 1) should be recorded.  If the sample cannot be collected at the visit as scheduled, it should be collected at the 
next visit whenever possible.  Additional unscheduled PK samples may be drawn during the study if it is deemed clinically 

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 98 of 121 
indicated for the patient and/or based on newly emerged data from clinical studies of AC176.  Similarly, if any PK timepoint is 
later deemed unnecessary per acquired clinical PK data, such timepoint may be removed from PK schedule.  
  
  

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 99 of 121 
Table 15 
PK Sampling Timepoints – Twice Daily (BID) Dosing (28 days per cycle) 
 
Timepoints relative to AC176 dosing* 
ECG* 
(in triplicate) 
Cycle 1 Day 1 
Pre-dose 
X 
1 hour (±5 minutes) 
- 
2 hour (±5 minutes) 
- 
3 hour (±10 minutes) 
- 
4 hour (±10 minutes) 
X 
6 hour (±20 minutes) 
- 
8 hour (±1 hour) 
X (if feasible) 
10 hour (±1 hour) 
- 
12 hour (±1 hour) 
- 
24 hour (±1 hour) 
- 
Cycle 1 Day 15 
Pre-dose 
X 
1 hour (±5 minutes) 
- 
2 hour (±5 minutes) 
-  
3 hour (±10 minutes) 
- 
4 hour (±10 minutes) 
X 
6 hour (±20 minutes) 
- 
8 hour (±1 hour) 
X (if feasible) 
10 hour (±1 hour)  
- 
12 hour (±1 hour) 
- 
24 hour (±1 hour) 
- 
Cycle 2 Day 1 
Pre-dose** 
X** 
Cycle 4 Day 1 
Pre-dose** 
X 
Cycle 6 Day 1 
Pre-dose** 
X 
* Depending on emerging PK data, the SRC may alter the timepoints for PKs and ECGs. ** For the Expansion cohort, this 
timepoint is needed to be collected, the rest of the time points are not needed.  With Sponsor approval the required 10 hour and 
12 hour PK sample collections may be omitted, if not feasible.   
Meal consumption prior to PK collection will be collected.  The last meal consumed prior to dosing on the day of full 24 hour PK 
collections (Cycle 1) should be recorded. 

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 100 of 121 
If the sample cannot be collected at the visit as scheduled, it should be collected at the next visit whenever possible.  Additional 
unscheduled PK samples may be drawn during the study if it is deemed clinically indicated for the patient and/or based on newly 
emerged data from clinical studies of AC176.  Similarly, if any PK timepoint is later deemed unnecessary per acquired clinical 
PK data, such timepoint may be removed from PK schedule.  

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 101 of 121 
Appendix H: Schedule of Assessments for Intermittent Dosing 

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 102 of 121 
Table 16 
SOA 3 (GU 207 Schedule of Assessments) – Intermittent Dosing:  2 Weeks On / 1 Week Off, 21 Day Cycle   
 
Dose-Escalation, Backfill and Expansion Cohorts 
AC176 Treatment Period 
(1 Cycle =21 days) 
EOTp 
30-Day 
Safety FUq 
FU for PDr 
 
Cycle 
C1 
C2 
C3+ 
 
 
 
Treatment day 
1 
8 
15 (±2) 
1 (±2) 
1 (±2) 
 
±5 days 
±5 days 
Written ICF for main study 
See Table 1 for pre-screening/screening proceduresa 
 
Physical examination and weightb 
X 
 
X 
X 
X 
X 
X 
 
Vital signsc 
X 
 
X 
X 
X 
X 
X 
 
Safety laboratory (hematology, [including 
PT/PTT/(INR or aPTT)], immature platelet 
functiond, biochemistry, urinalysis)c,d 
X 
 
X 
X 
X 
X 
X 
 
CBC onlyc 
 
X 
 
 
 
 
 
 
Concomitant therapy 
X 
 
Adverse events (AEs)/Serious adverse events 
(SAEs) 
X 
 
ECOG performance statusc 
X 
 
X 
X 
X 
X 
X 
 
12-lead electrocardiograms (triplicate)e,f 
X 
X 
X 
X 
Xe 
Xe 
 
 
Pharmacokineticsg,h 
X 
X 
 
Xg,h 
(C2 D15 only) 
Xg,h 
C4 D15& 
C6 D15 only 
 
 
 
(Optional) Tumor biopsyi 
 
 
 
X (+ 5 days) 
 
 
 
 
Blood sampling for biomarkers (ctDNA)j 
X (pre-
dose) 
 
 
X 
C5 & C8 
only 
X 
 
  
ARv7 blood samplek 
(CTC) 
X (pre-
dose) 
 
 
 
 
X 
 
 
AC176 dosingl 
Two weeks on / One week off 
Days 1-14 only 
 
D1-14  
D1-14 
 
 
 
Review patient dosing diaryl 
 
 
X 
X 
X 
X 
 
 
PSAm 
X (pre-
dose) 
 
 
X 
X 
X 
 
Xm 
Tumor assessment CT/MRI and bone scansn,o  
Every 2 cycles (6 weeks) ±5 days up to 24 weeks, then every 9 
weeks ±5 days 
Xn,o 
 
X 

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 103 of 121 
SOA-3 Footnotes  
Treatment cycles are 21 days (3 weeks).  Patients may continue treatment with AC176 as long as they are deriving clinical benefit according to the Investigator’s judgment. 
a Pre-screening if applicable and screening procedures are described in Table 1.  Written ICF for the main study must be obtained before undertaking any study-related procedures 
and prior to the initiation of study treatment. 
b Physical examinations and weight will be done at Cycle 1 Day 1, Cycle 1 Day 15, on Day 1 of each subsequent treatment cycle, at the end-of-treatment (EOT) visit, and at the 
30-day safety follow-up (FU) visit.  ECOG performance status will be done at screening and at all subsequent visits. 
c The following screening parameters should be done as indicated above: physical examination (including height and weight), Eastern Cooperative Oncology Group (ECOG) 
performance status, triplicate electrocardiograms (ECGs),vital signs, hematology (including absolute lymphocyte count, absolute neutrophil count, red blood cell count, 
reticulocytes, hemoglobin, hematocrit, platelet counts, prothrombin time/partial thromboplastin time (or aPTT [activated/PTT] )/ international normalized ratio [PT/PTT/INR]), 
biochemistry (sodium, potassium, phosphate, chloride, creatinine, total calcium, venous bicarbonate [HCO3], albumin, total protein, aspartate aminotransferase [AST], alanine 
aminotransferase [ALT], alkaline phosphatase [ALP], total bilirubin, lactate dehydrogenase, glucose, creatine kinase [CK-if CK is elevated, and if it is clinically significant at 
the PI’s discretion), then CK-MB, troponin I, and myoglobin should be reactively tested, with further follow-up as clinically warranted], urea nitrogen, and uric acid), and 
urinalysis. Vital signs (blood pressure, body temperature, pulse rate, and respiration rate) are checked at every visit prior to blood work and administration of treatment at the 
discretion of the Investigator.  Safety laboratory assessments including hematology, biochemistry, coagulation and urinalysis will be performed locally.  On Cycle 1 Day 8, the 
CBC may be performed by local laboratory as long as it can be entered into the eCRF and is approved by the Investigator.  If some examinations cannot be completed at the 
study site, corresponding examinations should be used in replacement (e.g., CO2 vs HCO3), and this does not need to be reported as a protocol deviation. 
d Immature platelet fraction (IPF) testing will be evaluated when a patient experiences platelet count decrease, or anytime at the discretion of the physician and if the test can be 
run at the site.  CBC counts should be collected at the same time as the IPF collection.  IPF is not required at screening 
e Triplicate 12-lead ECGs will be done before treatment on Cycle 1 Day 1 and Cycle 1 Day 15; before treatment on Day 1 of each subsequent cycle, at the EOT, and at any other 
time the Investigator deems it necessary.  ECGs should be assessed before the patient takes the study drug that day, before other procedures, and after the patient has rested for at 
least 3 minutes.  Each recording should be separated by at least 30 seconds.   
f Additional triplicate ECGs will be performed on Cycle 1 Day 1 and Day 8 just before the 4 hour post-dose and 8 hour PK blood samples are collected.  Refer to Appendix G for 
additional ECG collections required during PK blood collections.  
g Pharmacokinetic (PK) sampling will be collected on Cycle 1 Day 1 and 8 pre-dose and post-dose at: 1 and 2 hours (±5 minutes), 3 and 4 hours (±10 minutes), 6 (±20 minutes), 
and 8, 10, and 12 hours (±1 hour), and 24-hours post dose (±1 hour).  In addition to the pre-dose ECGs collected on Cycle 1 Day 1 and 8, triplicate ECGs will also be obtained 
on Cycle 1 Day 1 pre-dose and Day 8 just before the 8-hour (if feasible) post-dose PK blood samples are collected.   
 
On Cycle 2 Day 15, Cycle 4 Day 15, and Cycle 6 Day 15, a pre-dose PK sample will be collected from all patients.  Triplicate ECGs will be obtained before the pre-dose PK 
collection on Day 15 of Cycle 2, 4, and 6.  If the sample cannot be collected at the visit as scheduled, it should be collected at the next visit whenever possible.  Additional 
unscheduled PK samples may be drawn during the study if it is deemed clinically indicated for the patient and/or based on newly emerged data from clinical studies of AC176.  
Meal consumption prior to the full 24 hour PK collection will be collected.  The last meal consumed prior to dosing on the day of full PK collections during Cycle 1 should be 
recorded.  The visit days and sampling time points are outlined in Appendix G, Table 13.  
h Expansion Cohort PKs samples should be collected pre-dose on Cycle 2 Day 15, Cycle 4 Day 15 and Cycle 6 Day 15. Triplicate ECGs will be obtained before the pre-dose PK 
collection on Day 15 of Cycle 2. No full day PK are required. Additional unscheduled PK samples may be drawn during the study if it is deemed clinically indicated for the 
patient and/or based on newly emerged data from clinical studies of AC176.  The visit days and sampling time points are outlined in Appendix G. 
i Fresh tumor biopsies on treatment are optional.  If patient agrees to anon-treatment biopsies, the biopsy will be collected on Cycle 2 Day 1 (+ 5 days) (see Section 7.8.1). 
j All patients will retrospectively undergo central laboratory testing for AR mutation confirmation at predose C1D1.  Blood samples for ctDNA will be collected prior to dosing at 
predose Cycle 1 Day 1, and on Cycle 2 Day 1, Cycle 5 Day 1, and Cycle 8 Day 1, and at EOT as outlined in Section 7.8.2. 
k Blood samples for ARv7 testing will be collected prior to dosing at Cycle 1 Day 1 and at EOT as outlined in Section 7.8.2.   
l Dosing and schedule of AC176 will be determined by the Safety Review Committee and communicated separately as each new cohort opens for recruitment.  Patients will be 
instructed to take one dose of AC176 at the same time every day immediately after a meal. The patients will be asked to take AC176 in the morning immediately after a meal, 
and other concomitant medications in the evening; or at least 4 hours apart from taking AC176, if possible. 
 
Study drug compliance will be assessed at each patient visit by review of the dosing diary. 

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 104 of 121 
m Prostate-specific antigen (PSA) blood samples will be taken prior to dosing Cycle 1 Day 1 (unless collected within the previous 72 hours), and at Day 1 of every cycle, and at 
the EOT visit if not taken in the previous 4 weeks, and at progression.  Additional PSA assessments after the 30-day safety follow-up visit will be performed as on treatment 
until PD or another withdrawal criterion is met.. 
n CT/MRI scans of the chest, abdomen and pelvis should be taken ≤4 weeks prior to initiation of treatment.  CT/MRI scans of the chest, abdomen, and pelvis should be taken 
every 2 cycles (6 weeks) ±5 days up to 18 weeks, then every 9 weeks ±5 days, and at the End of Study visit (if scans were not taken in the previous 6 weeks) and, if clinically 
indicated, imaging of any other known or suspected sites of disease (e.g., brain).  Lymph nodes should be evaluated using PCWG3 criteria and not RECIST v1.1.  
o Bone scans - technetium only - ≤4 weeks prior to initiation of treatment, every 2 cycles (6 weeks) ±5 days up to 24 weeks, then every 9 weeks ±5 days, and at the End of Study 
visit if scans were not taken in the previous 6 weeks.  Bone lesions should be evaluated using PCWG3 criteria and not RECIST v1.1. 
p An EOT visit should be performed for all patients who permanently discontinue study treatment.  If the decision to permanently discontinue treatment is made at a scheduled 
visit, the EOT visit should be performed instead of the scheduled visit (preferably within 7 days and no later than 14 days after the last treatment). 
q All patients will be followed during the off-treatment period until all treatment-related toxicity resolves, or for at least 30 days post-study drug discontinuation, or until the start 
of another anti-cancer treatment.  Any concomitant medications received up to 30 days after the last dose of study medication should be recorded. 
r Follow-up for PD visits for tumor assessment by imaging (CT scan/MRI/bone scan, if applicable) for patients who discontinue study treatment without having PD based on 
RECIST v1.1 (see Appendix B) should be performed as on treatment until PD or another withdrawal criterion is met (see Section 7.5.3).  At these visits, serious adverse events 
(SAEs) occurring during the study that are considered to be related to study treatment or procedures will be followed until resolution. 

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 105 of 121 
Table 17 
SOA 4 (GU 207 Schedule of Assessments) - Intermittent Dosing:  3 Weeks On and 1 Week Off, OR 2 Weeks On 
and 2 Weeks off, 28 Day Cycle 
 
Dose-Escalation, Backfill and Expansion Cohorts 
AC176 Treatment Period 
(1 Cycle =28 days) 
EOTp 
30-Day 
Safety 
FUq 
FU for 
PDr 
 
Cycle 
C1 
C2 
C3+ 
 
 
 
Treatment day 
1 
8 
15 (±2) 
1 (±2) 
1 (±2) 
 
±5 days 
±5 days 
Written ICF for main study 
See Table 1 for pre-screening/screening proceduresa 
 
 
Physical examination and weightb 
X 
 
X 
X 
X 
X 
X 
 
Safety laboratory (hematology, [including 
PT/PTT/(INR or aPTT)], immature platelet 
function, biochemistry, urinalysis)c,d 
X 
 
X 
X 
X 
X 
X 
 
CBC onlyd 
 
X 
 
 
 
 
 
 
ECOG performance statusc 
X 
 
X 
X 
X 
X 
X 
 
Vital signsc 
X 
 
X 
X 
X 
X 
X 
 
Adverse events (AEs)/Serious adverse events 
(SAEs) 
X 
 
Concomitant therapy 
X 
 
12-lead electrocardiograms (triplicate)e,f 
X 
 
X 
X 
Xe 
Xe 
 
 
Pharmacokineticsg,h  
Refer to Table 12 or Table 14 
Xg,h 
C2 D15 or 
Day 22 per 
schedule only  
Xg,h 
C4 D15 or 
D22 & C6 
D15 or D22 
per schedule 
only 
 
 
 
(Optional) Tumor biopsyi 
 
 
 
X (+ 5 days) 
 
 
 
 
Blood sampling for biomarkers (ctDNA)j 
X  
(pre-dose) 
 
 
X 
C5 & C8 
only 
X 
 
  
ARv7 blood samplek 
(CTC) 
X  
(pre-dose) 
 
 
 
 
X 
 
 
AC176 dosing  
See footnote l 
 
 
 
Review patient diaryl 
 
 
X 
X 
X 
X 
 
 
PSAm 
X 
(pre-dose) 
 
 
X 
X 
X 
 
Xq 
Tumor assessment CT/MRI and bone scansn,o  
Every 2 cycles (8 weeks) ±5 days up to 24 weeks, then every 12 
weeks ±5 days 
Xr,s 
 
X 

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 106 of 121 
SOA 4 Footnotes  
Treatment cycles are 28 days (4 weeks).  Patients may continue treatment with AC176 as long as they are deriving clinical benefit according to the Investigator’s judgment. 
a Pre-screening if applicable and screening procedures are described in Table 1.  Written ICF for the main study must have been obtained before undertaking any study-related 
procedures and prior to the initiation of study treatment. 
b Physical examinations including weight will be done at Cycle 1 Day 1, Cycle 1 Day 15, on Day 1 of each subsequent treatment cycle, at the end-of-treatment (EOT) visit, and at 
the 30-day safety follow-up (FU) visit.  ECOG performance status will be done at screening and at all subsequent visits. 
c The following screening parameters should be done as indicated above: physical examination (including height and weight), Eastern Cooperative Oncology Group (ECOG) 
performance status, triplicate electrocardiograms (ECGs),vital signs, hematology (including absolute lymphocyte count, absolute neutrophil count, red blood cell count, 
reticulocytes, hemoglobin, hematocrit, platelet counts, prothrombin time/partial thromboplastin time (or aPTT [activated/PTT] )/ international normalized ratio [PT/PTT/INR]), 
biochemistry (sodium, potassium, phosphate, chloride, creatinine, total calcium, venous bicarbonate [HCO3], albumin, total protein, aspartate aminotransferase [AST], alanine 
aminotransferase [ALT], alkaline phosphatase [ALP], total bilirubin, lactate dehydrogenase, glucose, creatine kinase [CK-if CK is elevated, and if it is clinically significant at 
the PI’s discretion), then CK-MB, troponin I, and myoglobin should be reactively tested, with further follow-up as clinically warranted], urea nitrogen, and uric acid), and 
urinalysis.  Vital signs (blood pressure, body temperature, pulse rate, and respiration rate) are checked at every visit prior to blood work and administration of treatment at the 
discretion of the Investigator.  Safety laboratory assessments including hematology, biochemistry, coagulation and urinalysis will be performed locally.  On Cycle 1 Day 8, the 
CBC may be performed by local laboratory as long as it can be entered into the eCRF and is approved by the Investigator.  If some examinations cannot be completed at the 
study site, corresponding examinations should be used in replacement (e.g., CO2 vs HCO3), and this does not need to be reported as a protocol deviation.  
d Immature platelet fraction (IPF) testing will be evaluated when a patient experiences platelet count decrease, or anytime at the discretion of the physician and if the test can be 
run at the site.  CBC counts should be collected at the same time as the IPF collection.  IPF is not required at screening. 
e Triplicate 12-lead ECGs will be done at screening (≤14 days prior to first dose), before treatment on Cycle 1 Day 1 and Cycle 1 Day 15; before treatment on Day 1 of each 
subsequent cycle, at the EOT, and at any other time the Investigator deems it necessary.  ECGs should be assessed before the patient takes the study drug that day, before other 
procedures, and after the patient has rested for at least 3 minutes.  Each recording should be separated by at least 30 seconds.  
f Additional triplicate ECGs will be performed on Cycle 1 Day 1 and Day 15 just before the 2 hour and 4 hour post-dose PK blood samples are collected.  Refer to Appendix G 
for additional ECG collections required during PK blood collections. 
g PK sampling timepoints will be based on dosing schedule (refer to Appendix G, Table 12 or Table 14):  
 
Table 12:  2 weeks on and 2 weeks off: Pharmacokinetic(PK) sampling will be collected on Cycle 1 Day 1 and 8 pre-dose and post-dose at: 1 and 2 hours (±5 minutes), 3 and 4 
hours (±10 minutes), 6 (±20 minutes), and 8 hours, 10 and 12 hours (±1 hour), and 24-hours post dose (±1 hour).  In addition to the pre-dose ECGs collected on Cycle 1 Day 1 
and 8, triplicate ECGs will also be obtained on Cycle 1 Day 1 and 8 just before the 4-hour and 8-hour post-dose PK blood samples are collected.  On Cycle 2 Day 15, Cycle 4 
Day 15, and Cycle 6 Day 15, a pre-dose PK sample will be collected from all patients.  Triplicate ECGs will be obtained before the pre-dose PK collection on Day 15 of Cycle 
2, Cycle 4 and Cycle 6. 
 
Table 14:  3 weeks on and 1 week off: Pharmacokinetic(PK) sampling will be collected on Cycle 1 Day 1 and 8 pre-dose and post-dose at: 1 and 2 hours (±5 minutes), 3 and 4 
hours (±10 minutes), 6 (±20 minutes), 8, 10 and 12 hours (±1 hour), and 24-hours post dose (±1 hour).  In addition to the pre-dose ECGs collected on Cycle 1 Day 1 and 8, 
triplicate ECGs will also be obtained on Cycle 1 Day 1 and 8 just before the 4-hour and 8-hour post-dose PK blood samples are collected.  On Cycle 2 Day 22, Cycle 4 Day 22, 
and Cycle 6 Day 22, a pre-dose PK sample will be collected from all patients.  Triplicate ECGs will be obtained before the pre-dose PK collection on Day 22 of Cycle 2, Cycle 4 
and Cycle 6. 
h Expansion Cohort (Part B) PKs sample collections are different from Part A cohort collections.  For 3 weeks on and 1 week off dosing schedule: the Expansion Cohort PKs are 
collected on Day 22 of Cycle 2, Cycle 4, Cycle 6. Triplicate ECGs will be obtained before the pre-dose PK collection on Day 22 of Cycle 2.  For 2 weeks on and 2 week off 
dosing schedule: the Expansion Cohort PKs are collected on Day 15 of Cycle 2, 4, and 6. Triplicate ECGs will be obtained before the pre-dose PK collection on Day 15 of 

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 107 of 121 
Cycle 2.  No full day PKs are required for the Expansion cohort. Additional unscheduled PK samples may be drawn during the study if it is deemed clinically indicated for the 
patient and/or based on newly emerged data from clinical studies of AC176.  The visit days and sampling time points are outlined in Appendix G. 
i Fresh tumor biopsies at on treatment are optional.  If patient agrees to an on-treatment biopsy, it will be collected on Cycle 2 Day 1 (+ 5 days) (see Section 7.8.1). 
j All patients will retrospectively undergo central laboratory testing for AR mutations confirmation at C1D1.  Blood samples for ctDNA will be collected prior to dosing at 
predose Cycle 1 Day 1, and on Cycle 2 Day 1, Cycle 5 Day 1, and Cycle 8 Day 1, and at EOT as outlined in Section 7.8.2. 
k Blood samples for ARv7 testing will be collected prior to dosing at Cycle 1 Day 1 and at EOT as outlined in Section 7.8.2.   
l Dosing and schedule of AC176 will be determined by the Safety Review Committee and communicated separately as each new cohort opens for recruitment.   
 
Patients dosing schedule may include:  
1) 
2 weeks on 2 weeks off, e.g., C1D1 to C1D14 receive AC176. Dose is interrupted C1D15 to C1D28. AC176 dose to continue C2D1 to C2D14. Dose is interrupted 
C2D15 to C2D28, etc.  
2) 
3 weeks on 1 week off, e.g., C1D1 to C1D21 receive AC176. Dose is interrupted C1D22 to C1D28. AC176 dose to continue C2D1 to C2D21. Dose is interrupted C2D22 
to C2D28, etc. 
 
Patients will be instructed to take one dose of AC176 at the same time every day immediately after a meal. The patients will be asked to take AC176 in the morning immediately 
after a meal, and other concomitant medications in the evening; or at least 4 hours apart from taking AC176, if possible. 
 
Study drug compliance will be assessed at each patient visit by review of the dosing diary. 
m Prostate-specific antigen (PSA) blood samples will be taken prior to dosing Cycle 1 Day 1 (unless collected within the previous 72 hours), and at Day 1 of every cycle, and at 
the EOT visit if not taken in the previous 4 weeks, and at progression.  Additional PSA assessments after the 30-day safety follow-up visit will be performed as on treatment 
until PD or another withdrawal criterion is met. 
n CT/MRI scans of the chest, abdomen and pelvis should be taken ≤4 weeks prior to initiation of treatment.  CT/MRI scans of the chest, abdomen, and pelvis should be taken 
every 2 cycles (8 weeks) ±5 days up to 24 weeks, then every 12 weeks ±5 days, and at the End of Study visit (if scans were not taken in the previous 8 weeks) and, if clinically 
indicated, imaging of any other known or suspected sites of disease (e.g., brain).  Lymph nodes should be evaluated using PCWG3 criteria and not RECIST v1.1.   
o Bone scans - technetium only - ≤4 weeks prior to initiation of treatment, every 2 cycles (8 weeks) ±5 days up to 6 cycles (24 weeks), then every 3 cycles (12 weeks) ±5 days, 
and at the End of Study visit if scans were not taken in the previous 8 weeks.  Bone lesions should be evaluated using PCWG3 criteria and not RECIST v1.1. 
p An EOT visit should be performed for all patients who permanently discontinue study treatment.  If the decision to permanently discontinue treatment is made at a scheduled 
visit, the EOT visit should be performed instead of the scheduled visit (preferably within 7 days and no later than 14 days after the last treatment). 
q All patients will be followed during the off-treatment period until all treatment-related toxicity resolves, or for at least 30 days post-study drug discontinuation, or until the start 
of another anti-cancer treatment.  Any concomitant medications received up to 30 days after the last dose of study medication should be recorded. 
r Follow-up for PD visits for tumor assessment by imaging (CT scan/MRI/bone scan, if applicable) for patients who discontinue study treatment without having PD based on 
RECIST v1.1 (see Appendix B) should be performed as on treatment until PD or another withdrawal criterion is met (see Section 7.5.3).  At these visits, serious adverse events 
(SAEs) occurring during the study that are considered to be related to study treatment or procedures will be followed until resolution. 

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 108 of 121 
Table 18 
SOA 5 (GU 207 Schedule of Assessments) - Intermittent Dosing with 7, 5, or 4 Days on Followed by 7, 2, or 3 
Days Off, Respectively, 28 Day Cycle  
 
Dose-Escalation, Backfill and Expansion Cohorts 
AC176 Monotherapy Treatment Period 
(1 Cycle =28 days) 
EOTt 
30-Day 
Safety FUu 
FU for 
PDv 
 
Cycle 
C1 
C2 
C3+ 
 
 
 
Treatment day 
1 
8 
15 (±2) 
1 (±2) 
1 (±2) 
 
±5 days 
±5 days 
Written ICF for main study 
See Table 1 for pre-screening/screening proceduresa 
 
 
Physical examination and weightb 
X 
 
X 
X 
X 
X 
X 
 
Safety laboratory (hematology, [including 
PT/PTT/(INR or aPTT)], immature platelet 
function, biochemistry, urinalysis)c,d 
X 
 
X 
X 
X 
X 
X 
 
Vital signsd 
X 
 
X 
X 
X 
X 
X 
 
CBC onlyd 
 
X 
 
 
 
 
 
 
Concomitant therapy 
X 
 
ECOG performance statusc 
X 
 
X 
X 
X 
X 
X 
 
12-lead electrocardiograms (triplicate)h,i 
 
 
X 
X 
Xe 
Xe 
 
 
Adverse events (AEs)/Serious adverse events 
(SAEs) 
X 
 
Pharmacokineticsj 
See Appendix G: Table 9, Table 10 or Table 11  
 
 
 
(Optional) Tumor biopsym 
 
 
 
X (+ 5 days) 
 
 
 
 
Blood sampling for biomarkers (ctDNA)n 
X (pre-
dose) 
 
 
X 
C5 & C8 
only 
X 
 
  
ARv7 blood sampleo 
(CTC) 
X (pre-
dose) 
 
 
 
 
X 
 
 
AC176 dosing 
 
See footnote l  
 
 
 
Review patient diaryp 
 
 
X 
X 
X 
X 
 
 
PSAq 
X (pre-
dose) 
 
 
X 
X 
X 
 
Xq 
Tumor assessment CT/MRI and bone scansr,s  
Every 2 cycles (8 weeks) ±5 days up to 24 weeks, then every12 
weeks ±5 days 
Xr,s 
 
X 

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 109 of 121 
SOA Footnotes  
Treatment cycles are 28 days (4 weeks).  Patients may continue treatment with AC176 as long as they are deriving clinical benefit according to the Investigator’s judgment. 
a Pre-screening if applicable and screening procedures are described in Table 1.  Written ICF for the main study must have been obtained before undertaking any study-related 
procedures and prior to the initiation of study treatment. 
b Physical examinations including the measurements of height (screening only) and weight will be done at screening, Cycle 1 Day 1, Cycle 1 Day 15, on Day 1 of each 
subsequent treatment cycle, at the end-of-treatment (EOT) visit, and at the 30-day safety follow-up (FU) visit.  ECOG performance status will be done at screening and at all 
subsequent visits. 
c The following screening parameters should be done ≤14 days prior to first dose of study drug administration: physical examination (including height and weight), Eastern 
Cooperative Oncology Group (ECOG) performance status, triplicate electrocardiograms (ECGs),vital signs, hematology (including absolute lymphocyte count, absolute 
neutrophil count, red blood cell count, reticulocytes, hemoglobin, hematocrit, platelet counts, prothrombin time/partial thromboplastin time (or aPTT [activated/PTT] )/ 
international normalized ratio [PT/PTT/INR]), biochemistry (sodium, potassium, phosphate, chloride, creatinine, total calcium, venous bicarbonate [HCO3], albumin, total 
protein, aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase [ALP], total bilirubin, lactate dehydrogenase, glucose, creatine kinase [CK-if 
CK is elevated, and if it is clinically significant at the PI’s discretion), then CK-MB, troponin I, and myoglobin should be reactively tested, with further follow-up as clinically 
warranted], urea nitrogen, and uric acid), and urinalysis. Vital signs (blood pressure, body temperature, pulse rate, and respiration rate) are checked at every visit prior to blood 
work and administration of treatment at the discretion of the Investigator.  Safety laboratory assessments including hematology, biochemistry, coagulation and urinalysis will be 
performed locally.  On Cycle 1 Day 8, the CBC may be performed by local laboratory as long as it can be entered into the eCRF and is approved by the Investigator.  If some 
examinations cannot be completed at the study site, corresponding examinations should be used in replacement (e.g., CO2 vs HCO3), and this does not need to be reported as a 
protocol deviation. 
d Immature platelet fraction (IPF) testing will be evaluated when a patient experiences platelet count decrease, or anytime at the discretion of the physician and if the test can be 
run at the site.  CBCs should be collected at the same time as the IPF collection.  IPF is not required at screening. 
e Triplicate 12-lead ECGs will be done at screening (≤14 days prior to first dose), before treatment on Cycle 1 Day 1 and Cycle 1 Day 15; before treatment on Day 1 of each 
subsequent cycle, at the EOT, and at any other time the Investigator deems it necessary.  ECGs should be assessed before the patient takes the study drug that day, before other 
procedures, and after the patient has rested for at least 3 minutes.  Each recording should be separated by at least 30 seconds.  
f Additional triplicate ECGs will be performed on Cycle 1 Day 1 and Day 15 just before the 2 hour and 4 hour post-dose PK blood samples are collected.  Refer to Appendix G 
for additional ECG collections required during PK blood collections. 
g Pharmacokinetic (PK) sampling will be based on dosing schedule (see Appendix G, Table 9, Table 11, Table 10): 
1. 
7 days on and 7 days off (Table 9): Pharmacokinetic(PK) sampling will be collected on Cycle 1 Day 1 and 8 pre-dose and post-dose at: 1 and 2 hours (±5 minutes), 3 and 
4 hours (±10 minutes), 6 (±20 minutes), and 8 hours, 10 and 12 hours (±1 hour), and 24-hours post dose (±1 hour).  In addition to the pre-dose ECGs collected on Cycle 
1 Day 1 and 8, triplicate ECGs will also be obtained on Cycle 1 Day 1 and 8 just before the 4-hour and 8-hour post-dose PK blood samples are collected.  On Cycle 2 
Day 8, Cycle 4 Day 8, and Cycle 6 Day 8, a pre-dose PK sample will be collected from all patients.  Triplicate ECGs will be obtained before the pre-dose PK collection 
on Day 8 of Cycle 2, Cycle 4, and Cycle 6.  
2. 
5 days on and 2 days off (Table 11): Pharmacokinetic (PK) sampling will be collected on Cycle 1 Day 1 and 5 pre-dose and post-dose at: 1 and 2 hours (±5 minutes), 3 
and 4 hours (±10 minutes), 6 (±20 minutes), 8, 10 and 12 hours (±1 hour), and 24-hours post dose (±1 hour).  In addition to the pre-dose ECGs collected on Cycle 1 Day 
1 and 5, triplicate ECGs will also be obtained on Cycle 1 Day 1 and 5 just before the 4-hour and 8-hour post-dose PK blood samples are collected.  On Cycle1 Day 8, 
Cycle 2 Day 6, Cycle 4 Day 6, and Cycle 6 Day 6, a pre-dose PK sample will be collected from all patients.  Triplicate ECGs will be obtained before the pre-dose PK 
collection on Day 6 of Cycle 2, Cycle 4, and Cycle 6. 
3. 
4 days on and 3 days off (Table 10): pharmacokinetic (PK) sampling will be collected on Cycle 1 Day 1 and 4 pre-dose and post-dose at: 1 and 2 hours (±5 minutes), 3 
and 4 hours (±10 minutes), 6 (±20 minutes), 8,10 and 12 hours (±1 hour), and 24-hours post dose (±1 hour).  In addition to the pre-dose ECGs collected on Cycle 1 Day 1 
and 4, triplicate ECGs will also be obtained on Cycle 1 Day 1 and 4 just before the 4-hour and 8-hour post-dose PK blood samples are collected. On Cycle 1 Day 8, 
Cycle 2 Day 5, Cycle 4 Day 5, and Cycle 6 Day 5, a pre-dose PK sample will be collected from all patients.  Triplicate ECGs will be obtained before the pre-dose PK 
collection on Day 5 of Cycle 2, Cycle 4, and Cycle 6. 
If the sample cannot be collected at the visit as scheduled, it should be collected at the next visit whenever possible.  Additional unscheduled PK samples may be drawn during 
the study if it is deemed clinically indicated for the patient and/or based on newly emerged data from clinical studies of AC176.  Meal consumption prior to PK collection will 

 
CONFIDENTIAL 
Study Drug: AC176 
 
Sponsor/Development Innovations Study Number: AC176-001/GU 207 
Final Protocol:  10 July 2023 Version 4.0  
Page 110 of 121 
be collected.  The last meal consumed prior to dosing on the day of full PK collections during Cycle 1 should be recorded.  The visit days and sampling time points are outlined 
in Appendix G.   
h Expansion Cohort (Part B) PKs sample collections are different from Part A cohort collections.   
1. 
For 7 days on and 7 days off: The Expansion Cohort PKs are collected pre-dose on Cycle 2 Day 8, Cycle 4 Day 8, and Cycle 6 Day 8. Triplicate ECGs will be obtained 
before the pre-dose PK collection on Day 8 of Cycle 2.  
2. 
For 5 days  on and 2 days off dosing schedule: the Expansion Cohort PKs are collected on Day 6 of Cycle 2, 4, and 6. Triplicate ECGs will be obtained before the pre-
dose PK collection on Day 6 of Cycle 2.  
3. 
For 4 days on and 3 days off dosing schedule: the Expansion Cohort PKs are collected on Day 5 of Cycle 2, 4, and 6. Triplicate ECGs will be obtained before the pre-
dose PK collection on Day 5 of Cycle 2.  
 Additional unscheduled PK samples may be drawn during the study if it is deemed clinically indicated for the patient and/or based on newly emerged data from clinical studies 
of AC176.  The visit days and sampling time points are outlined in Appendix G. 
i Fresh tumor biopsies on treatment are optional.  If patient agrees to an on-treatment biopsies, the biopsy will be taken  on Cycle 2 Day 1 (+ 5 days) (see Section 7.8.1). 
j All patients will retrospectively undergo central laboratory testing for AR mutation confirmation at C1D1.  Blood samples for ctDNA will be collected prior to dosing at predose 
Cycle 1 Day 1, and on Cycle 2 Day 1, Cycle 5 Day 1, and Cycle 8 Day 1, and at EOT as outlined in Section 7.8.2. 
k Blood samples for ARv7 testing will be collected prior to dosing at Cycle 1 Day 1 and at EOT as outlined in Section 7.8.2. 
l Patients dosing schedule may include: 
1. 
7 days on and 7 days off, e.g., C1D1 to C1D7 receive AC176.  Dose interrupted C1D8 to C1D14.  AC176 dose to continue Cycle 1 on C1D15 to C1D21 and interrupted 
C1D22 to C1D28.  From Cycle 2, the patients will be dosed for 7 days and interrupted 7 days.  
 
2. 
Patients will be dosed 5 days on and 2 days off, e.g., C1D1 to C1D5 receive AC176.  Dose interrupted C1D6 to C1D7.  AC176 dosed to continue Cycle 1 on C1D8 to 
C1D12 and interrupted C1D13 to C1D14.  C1D15 to C1D19 receive AC176.  Dose interrupted C1D20 to C1D21.  AC176 dosed to continue Cycle 1 on C1D22 to 
C1D26 and interrupted C1D27 to C1D28.  
3. 
Patients will be dosed one week 4 days on and one week 3 days off, e.g., C1D1 to C1D4 receive AC176.  Dose interrupted C1D5 to C1D7.  AC176 dosed to continue 
Cycle 1 on C1D8 to C1D11 and interrupted C1D12 to C1D14.  C1D15 to C1D18 receive AC176.  Dose interrupted C1D19 to C1D21.  AC176 dosed to continue Cycle 1 
on C1D22 to C1D25 and interrupted C1D26 to C1D28.  
 
Patients will be instructed to take one dose of AC176 at the same time every day immediately after a meal.  The patients will be asked to take AC176 in the morning 
immediately after a meal, and other concomitant medications in the evening; or at least 4 hours apart from taking AC176, if possible. Study drug compliance will be assessed at 
each patient visit by review of the dosing diary. 
m Prostate-specific antigen (PSA) blood samples will be taken ≤4 weeks prior to initiation of treatment, prior to dosing Cycle 1 Day 1 (unless collected within the previous 72 
hours), and at Day 1 of every cycle, and at the EOT visit if not taken in the previous 4 weeks, and at progression.  Additional PSA assessments after the 30-day safety follow-up 
visit will be performed as on treatment until PD or another withdrawal criterion is met. 
n CT/MRI scans of the chest, abdomen and pelvis should be taken ≤4 weeks prior to initiation of treatment.  CT/MRI scans of the chest, abdomen, and pelvis should be taken 
every 2 cycles (8 weeks) ±5 days up to 24 weeks, then every 12 weeks ±5 days, and at the End of Study visit (if scans were not taken in the previous 8 weeks) and, if clinically 
indicated, imaging of any other known or suspected sites of disease (e.g., brain).  Lymph nodes should be evaluated using PCWG3 criteria and not RECIST v1.1.   
o Bone scans - technetium only - ≤4 weeks prior to initiation of treatment, every 2 cycles (8 weeks) ±5 days up to 6 cycles (24 weeks), then every 3 cycles (12 weeks) ±5 days, 
and at the End of Study visit if scans were not taken in the previous 8 weeks.  Bone lesions should be evaluated using PCWG3 criteria and not RECIST v1.1. 
p An EOT visit should be performed for all patients who permanently discontinue study treatment.  If the decision to permanently discontinue treatment is made at a scheduled 
visit, the EOT visit should be performed instead of the scheduled visit (preferably within 7 days and no later than 14 days after the last treatment). 
q All patients will be followed during the off-treatment period until all treatment-related toxicity resolves, or for at least 30 days post-study drug discontinuation, or until the start 
of another anti-cancer treatment.  Any concomitant medications received up to 30 days after the last dose of study medication should be recorded. 
r Follow-up for PD visits for tumor assessment by imaging (CT scan/MRI/bone scan, if applicable) for patients who discontinue study treatment without having PD based on 
RECIST v1.1 (see Appendix B) should be performed as on treatment until PD or another withdrawal criterion is met (see Section 7.5.3).  At these visits, serious adverse events 
(SAEs) occurring during the study that are considered to be related to study treatment or procedures will be followed until resolution. 

 
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Appendix I: Clinical Protocol Summary of Changes 
Version 4.0, 10 July 
 2023  
Additions to the text are bolded, and deletions from the text are crossed-off.  Only the parts of 
sections with changes are presented.  Please note that formatting changes and minor changes to 
punctuation, spelling, and abbreviations that do not affect meaning are not noted in this 
summary.   
Clinical Study Approval Page  
Su Young Kim, MD, PhD has replaced Antonieta Sosa as the Sponsor Representative.  
Benjamin Garmezy, MD has replaced Meredith McKean, MD, MPH as Study Chair.  
Section 1.1.2.1 Rationale for Switching to AC176 Tablets and Section 5.1.1 Dose-Escalation 
(Part A)  
The formulation for the investigational product AC176, is switching from a 30 mg capsule to a 
smaller 30 mg tablet.  The rationale for this decision is described in Section 1.1.2.1, and further 
details are provided in Section 5.1.1. 
Synopsis and Section 5.0 Study Design 
Sections of the Synopsis, Section 5.0 and other applicable areas (e.g., Section 10.1 of the 
protocol have been modified to include the following changes: 
Up to 130 patients are planned to be enrolled into this study, from 36 patients.   
Backfill and Expansion Cohorts have been added.  Up to approximately 70 patients are 
expected to be enrolled in Part A Dose-Escalation plus the Backfill cohorts.  
Alternative dosing and schedules have been added.   
In Part A Dose-Escalation, AC176 will be given orally (PO).  The starting dose will be 30 mg 
and will follow a 3+3 design, see Figure 1.  If suggested by emerging safety or PK findings, 
or as appropriate based on other data from previous cohorts, and approved by the Safety 
Review Committee (SRC), an alternative dosing level and/or dosing schedule may be 
considered, which could include twice daily (BID) or intermittent dosing.  Alternative 
dosing schedules may be tested concurrently, provided the total dose is not greater than 
that of the dose level being evaluated.   
Prostate cancers with androgen receptor (AR) mutations are more dependent on the AR 
pathway for their growth.  Degradation of AR makes these cancers more susceptible to cell 
death.  Thus, AR-mutated cancers may respond to AR degradation at lower doses than 
their wildtype counterparts.  As more data emerges from Part A, and the tested cohorts are 
cleared and deemed safe, patients with known AR point mutations may be eligible to enroll 
in Backfill cohorts.  The backfill patients will be enrolled to further characterise the 
objectives for the study.  The total number of patients enrolled in the Backfill cohort will 
not total more than 12 patients when combined with the number of patients already 
enrolled in the same cohort.  Toxicity for the patients enrolled in a Backfill cohort will be 

 
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managed according to the Dose Modification Section 6.  Up to approximately 70 patients 
are expected to be enrolled in Part A dose-escalation plus the backfill patients. 
The recommended dose for the Expansion cohort will be determined in the Part A Dose-
Escalation part of the study.  Up to two cohorts may be explored in Part B with 
approximately 30 patients each.  One cohort will be for patients with AR point mutations.  
The other cohort will be for patients without AR point mutations.  The Sponsor and SRC 
will determine the dose and schedule(s) for the Expansion cohorts based on tolerability and 
emerging data.   
Patients enrolled in Backfill (Part A) and Expansion cohorts (Part B) will be pre-screened 
for AR mutation status, unless patients can provide documentation that they have the AR 
point mutation.  All Patients will retrospectively undergo central laboratory testing for AR 
mutation confirmation at Cycle 1 Day 1 per the Schedule of Assessments (SOA).   
 
3.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
16. Treatment with any of the following: 
• 
More than 2 lines of chemotherapy in the CRPC setting. 
Section 5.1.2 Backfill Cohorts 
This section provides the details for the Backfill Cohorts, the number of patients to be enrolled, 
the eligibility requirements, and how the cohorts will be implemented. Also refer to Section 7.2 
Section 5.1.3 Dose-Limiting Toxicity 
The following clarification was made: 
A toxicity will be considered dose-limiting if it occurs during the first cycle of treatment with 
AC176 during the dose-escalation phase (excluding Backfill cohort patients).  Dose-limiting 
toxicities (DLTs) will not include any toxicity related to underlying disease (including 
disease progression), intercurrent illness, concomitant medications, or extraneous causes.   
Determination of Dose-Limiting Toxicities 
The following statement was added to this section:  The minimum safety requirements must 
be met for a patient to be included in the MTD-determining population. 
Section 5.1.5 Intra-Patient Dose Adjustment 
The following clarifications were made: 
Patients may be permitted an intra-patient dose-escalation of AC176 to a higher dose level that 
has been cleared and deemed safe by the SRC if they have completed at least 2 cycles at their 
assigned dose level and continued on study with no ≥ Grade 2 treatment-related AEs.  The 
highest dose the patient can be escalated to is the highest dose level that has been cleared for 
DLT and is considered to be safe for this patient by the Investigator.  The Investigator must 
consult with the Medical Monitor to confirm that the patient has been tolerating their AC176 
dose.  The patient data will continue to be collected for evaluation of safety and clinical activity, 

 
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and all assessments will continue according to the Schedule of Assessments (see applicable SOA 
Table 1 or Appendix H). 
Section 5.1.7 Expansion Cohorts (Part B) 
This section provides the details for the Expansion Cohorts, the number of patients to be 
enrolled, the eligibility requirements, and how the cohorts will be implemented.  Also refer to 
Section 7.2 
Section 7.1 
Overview 
The key procedures required in this study include: 
• Immature platelet fraction testing (blood based), at sites with the capability, and if 
clinically indicated  
Section 7.2 
Pre-Screening AR Mutation Status for Backfill Patients and Expansion 
Cohorts 
Prostate cancers with AR mutations are more dependent on the AR pathway for their 
growth.  Degradation of AR makes these cancers more susceptible to cell death.  Thus, AR-
mutated cancers may respond to AR degradation at lower doses than their wildtype 
counterparts.   
Pre-screening for AR mutation status is required in the Backfill and Expansion cohorts.  If 
patients provide historic ctDNA testing results of a positive AR point mutation, then pre-
screening ctDNA testing for AR mutation status by ctDNA testing is not needed.  All 
patients will retrospectively undergo central laboratory testing for AR mutation 
confirmation at Cycle 1 Day 1 per the SOA.  
Patients who have not had AR point mutation testing must agree to sign a pre-screening 
ICF to collect a blood sample for ctDNA.  Confirmation of the AR point mutation does not 
guarantee eligibility for a backfill cohort or the expansion cohort. 
Depending on the AR point mutation status, patients may proceed with further screening 
procedures for Backfill or Expansion cohorts, as appropriate, after signing a separate ICF 
for the study.   
Section 7.5.3 Extended Follow-Up Period 
The following clarification has been added: 
If treatment was discontinued for reasons other than disease progression, additional follow-
up visits after the 30-day safety follow-up visit will be performed for tumor assessment by 
imaging as on treatment until PD or another withdrawal criterion is met. 
Section 7.7 
Pharmacokinetic Assessments 
The following has been added to this section: 
Meal consumption prior to PK collections will be collected.   
If the sample cannot be collected at the visit as scheduled, it should be collected at the next 
visit whenever possible.  Additional unscheduled PK samples may be drawn during the 

 
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study if it is deemed clinically indicated for the patient and/or based on newly emerged 
data from clinical studies of AC176.  Similarly, if any PK timepoint is later deemed 
unnecessary per acquired clinical PK data, such timepoint may be removed from PK 
schedule by the Sponsor. 
Section 7.8.2 Biomarker Blood Samples 
This section has been revised as follows: 
Blood samples for ctDNA will be taken at pre-screening, if applicable, on Cycle 1 Day 1, and 
on Cycle 2 Day 1, Cycle 5 Day 1, and Cycle 8 Day 1, and at the EOT visit.  Blood samples for 
ARv7 will be collected pre-dose on Cycle 1 Day 1 and at the EOT visit.  Instructions 
regarding sample collection, handling/processing, and shipping are provided in the 
Laboratory Manual. 
A blood sample for ctDNA will be required at pre-screening for patients enrolling in 
Backfill and Expansion cohorts without AR point mutation documentation.  The separate 
pre-screen ICF must be signed by the patient prior to collection of the pre-screening ctDNA 
sample (see Section 7.2).   
In addition to the biomarkers listed above, other biomarkers deemed relevant to gain 
further knowledge about the biology of the disease or about the study drug may be assayed, 
based on newly emerging data from the study and/or literature data.  For similar reasons, 
unscheduled sampling may be allowed if deemed clinically relevant. 
Section 8.1.1. Labeling, Packaging, and Supply 
AC176 will be supplied by Accutar Biotechnology, Inc. in bottles that contain 30 capsules or 
tablets of AC176 30 mg each.  AC176 should be used only as directed by the Investigator.  Store 
capsule bottles at 36-48°F (2-8°C) and tablet bottles between 59–77°F (15–25°C).  Both 
capsule and tablet bottles need to be protected from light. 
Section 8.1.2 Preparation and Administration of AC176 
This section has been revised and clarified as follows: 
AC176 is administered PO.  Patients will be instructed to take one dose of AC176 at the same 
time immediately after a meal.  For once-a-day dosing, patients will be instructed to take 1 
dose of AC176 immediately after a meal in the morning and other concomitant medications 
in the evening; or at least 4 hours apart from taking AC176, if possible.  AC176 should be 
taken whole with liquid(s).  For BID dosing, patients will be instructed to take 1 dose of 
AC176 immediately after a meal in the morning and 1 dose of AC176 immediately after a 
meal in the evening.  
The time of day for administration of AC176 should be consistent.  If the patient misses a 
dose of study drug, the patient should take the dose as soon as possible, but not less than 12 
hours (if on QD frequency) or 6 hours (if on BID frequency) before the next dose is due.  If 
the next dose is due sooner than the above timeframe, the patient should skip the missed 
dose and take the next dose as scheduled.  

 
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Section 10.1 Statistical Design 
This is a Phase I, first-in-human, open-label dose-escalation study of AC176 given as a 
single agent.  There are two parts to this study: Part A, Dose-Escalation and Part B, 
Expansion cohorts.  Approximately 70 patients are expected to be enrolled in the Part A 
Dose-Escalation cohorts including the Backfill patients, and up to 60 patients, in the Part B 
Expansion cohorts.  Up to 130 patients overall may enter the study. 
Section 10.2 Sample Size Considerations 
This section has been updated to reflect the addition of Backfill patients and Expansion Cohort 
patients. 
Currently, 6 dose levels are planned.  The MTD will be defined based on DLTs.  If 1 patient 
experiences a DLT at a given dose level, then that dose level will be expanded to 6 patients.  
Evaluation of a cohort of at least 3 patients completing 1 cycle of treatment is required prior 
to proceeding to the next dose level.  In addition, dose level(s) which have been cleared and 
deemed safe may be expanded (refer to Section 5.1.2 Backfill cohorts). 
Assuming 6 dose levels will be studied with a maximum of 6 patients enrolled per dose level, 
Backfilled patients may increase each cohort to a total of 12 patients, and up to 
approximately 70 patients may be accrued during dose-escalation. The total number of 
patients enrolled to a Backfill cohort will not total more than 12 patients when combined 
with the number of patients previously enrolled in the same cohort.  Up to 70 patients are 
expected to be enrolled in Part A dose-escalation cohorts plus the backfill patients. 
Depending on the totality of emerging data from safety, tolerability, PK, biomarker and 
preliminary anti-tumor activity, the recommended dose for expansion cohorts will be 
determined in Part A, dose-escalation.  Two expansion cohorts may be explored in Part B 
expansion.  The cohorts will encompass up to 30 patients with AR point mutations and 30 
patients without AR point mutation.  Guided by tolerability and emerging data, the 
Sponsor and SRC will determine the dose and schedule(s) for the expansion cohorts. 
A new Study Schema (Figure 5) has been added. 
Section 3.1 
Inclusion Criteria 
Specific criteria were added for the Backfill and Expansion Cohorts as follows: 
Inclusion Criteria –Backfill Cohorts 
2. Patients may enroll to a Backfill cohort if they have documentation of the AR point 
mutation.  Patients who have not had AR mutation testing may have the testing 
performed after signing a pre-screening informed consent form (ICF [see Section 7.2]). 
Additionally, patients must meet the main inclusion criteria listed above to be enrolled. 
Inclusion Criteria – Part B Expansion Cohorts 
2. Patients are required for AR mutation testing after signing a pre-screening ICF (see 
Section 7.2), unless the patients have documentation of the AR point mutation.  
Additionally, patients must meet the main inclusion criteria listed above to be enrolled. 
 

 
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Section 3.2 
Exclusion Criteria 
Exclusion criteria were clarified and/or the order of the criteria were moved as follows: 
1. Treatment with any of the following: 
• 
Palliative radiation for the alleviation of pain due to bone metastasis will be allowed 
after the DLT evaluation period. 
7. Any of the following cardiac criteria experienced currently or within the last 6 months: 
a. Any clinically important abnormalities (as assessed by the Investigator) in 
rhythm, conduction, or morphology of resting electrocardiograms (ECGs), e.g., 
complete left bundle branch block, third-degree heart block 
b. Congestive heart failure (New York Heart Association ≥ Grade 2 [Appendix E]) 
c. Any factors that increase the risk of QTc prolongation or risk of arrhythmic 
events such as heart failure, hypokalemia, congenital long QT syndrome, family 
history of long QT syndrome or unexplained sudden death under 40 years-of-age, 
or any concomitant medication known to prolong the QT interval. 
8. Mean resting corrected QT interval (QTc) >470 msec. 
9. Left ventricular ejection fraction (LVEF) <50% or the lower limit of normal of the 
institutional standard. 
13. Presence of other active, invasive cancers other than the one treated in this study within 
3 5 years prior to screening... 
In Appendix G the following PK Sampling Timepoint tables were updated or created:  
Table 8 
PK Sampling Timepoints Once Daily (QD) Dosing 
Table 9 
PK Sampling Timepoints ‒ Intermittent Dosing 7 Days On / 7 Days Off 
Table 10 
PK Sampling Timepoints – Intermittent Dosing 4 Days On / 3 Days Off (28 days 
per cycle)  
Table 11 
PK Sampling Timepoints – Intermittent Dosing 5 Days On and 2 Days Off  
(28 days per cycle)  
Table 12 
PK Sampling Timepoints – Intermittent Dosing 2 Weeks On / 2 Weeks Off (28 
days per cycle) 
Table 13 
PK Sampling Timepoints – Intermittent Dosing 2 Weeks On / 1 Week Off (21 
days per cycle) 
Table 14 
PK Sampling Timepoints – 3 Weeks On / 1 Week Off (28 days per cycle) 
Table 15 
PK Sampling Timepoints – Twice Daily (BID) Dosing (28 days per cycle) 
In Appendix H the Schedule of Assessments (SOAs) tables were updated or created as 
follows: 
Table 1 
SOA 1 (GU 207 Schedule of Assessments) - Pre-screening (Backfill and 
Expansion Cohort Patients only) and Screening (All Patients) 

 
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Table 2 
SOA 2 (GU 207 Schedule of Assessments) - Part A [Dose-Escalation & Backfill] 
and Part B [Expansion Cohorts]) Once Daily(QD) dosing and Twice Daily (BID) 
dosing 
Table 16 
SOA 3 (GU 207 Schedule of Assessments) – Intermittent Dosing:  2 Weeks On / 
1 Week Off, 21 Day Cycle 
Table 17 
SOA 4 (GU 207 Schedule of Assessments) - Intermittent Dosing:  3 Weeks On 
and 1 Week Off, OR 2 Weeks On and 2 Weeks off, 28 Day Cycle 
Table 18 
SOA 5 (GU 207 Schedule of Assessments) - Intermittent Dosing with 7, 5, or 4 
Days and Followed by 7, 2, or 3 Days Off, Retrospectively, 28 Day Cycle 
Appendix I 
Clinical Protocol Summary of Changes 
Appendix I was created to avoid confusion for the reader.  The previous amendments and 
associated modifications have been relocated to this area from the front of the protocol.

 
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Version 3.0, 18 April 2022 
Additions to the text are bolded, and deletions from the text are crossed-off.  Only the parts of 
sections with changes are presented.  Please note that formatting changes and minor changes to 
punctuation, spelling, and abbreviations that do not affect meaning are not noted in this 
summary.   
Section 2.0 Study objectives and endpoint, Section 10.4.2 Efficacy Analysis, and Synopsis 
were amended to add radiographic progression-free survival (rPFS) and progression-free survival 
(PFS) as secondary objectives, as these are important treatment efficacy endpoints intended to be 
assessed. 
Section 3.1 Inclusion Criteria and Synopsis – amended to provide previously missing clarity 
on the appropriate histological type of cancer under study (Inclusion #3) and on how to assess 
progression (Inclusion #4) , and to add that medical castration is also expected to be ongoing 
(Inclusion #6): 
3. Patients with histological, pathological, or cytological confirmed diagnosis of advanced or 
metastatic castration resistant adenocarcinoma of the prostate excluding neuroendocrine 
differentiation or small cell featuresmCRPC who have had disease progression per Prostate 
Cancer Working Group 3 (PCWG3) (Scher et al. 2016) guidance following standard treatment, 
including approved taxane-based chemotherapy, or who are not amenable (intolerability, patient 
choice) to standard therapies, or for whom no therapy of proven efficacy exists,   
4. 
Advanced or metastatic Progressive disease per PCWG3 guidance documented by either: 
• Positive bone scan (at least 2 new lesions) or metastatic lesions on computed 
tomography (CT)/magnetic resonance imaging (MRI) (Appendix B) that can be 
followed for response.   
Or 
• If PSA criteria is the only indication of progression, then the Prostate-specific 
antigen (PSA) values with a starting value of ≥1.0 ng/mL that have increased on 
at least 2 3 occasions obtained a minimum of 1 week apart. 
6. Patients who must have had surgical or ongoing medical castration.  Surgical castration is 
defined as bilateral orchiectomy.   
Section 3.2 Exclusion Criteria and Synopsis– amended to clarify washout in a more concise 
way - 
1. Treatment with any of the following: 
• Any systemic anti-cancer therapy, chemotherapy, biologic, or hormonal agent from a 
previous treatment regimen or clinical study within 4 weeks prior to the first dose of 
study drug.  Any systemic small molecules from a previous treatment regimen or clinical 
study within 2 weeks or 5 half-lives (whichever is longer, not to exceed 4 weeks) prior to 
the first dose of study drug, except ADT for medical castration purpose.   
Section 3.3 Discontinuation of Study Treatment was amended to clarify that  

 
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Patients will be discontinued from study treatment for any of the following reasons:… 
• Irreversible or intolerable toxicity or clinically significant abnormal laboratory values 
thought to be related to drug toxicity 
Section 5 Study Design and Synopsis were amended to maintain consistency with other 
portions of the protocol - If suggested by safety or PK findings, or as appropriate based on other 
data from previous cohorts, an alternative dosing level and/or dosing schedule may be 
considered.  However, the total daily dose would remain the same.   
Section 6 Dose Modifications and subsection 6.1 and 6.2 including Table 4 were amended to 
clarify guidelines and remove redundancies.   
Table 4 Dose Modifications due to Grade 3 or 4 Non-Hematologic Toxicities was amended to 
clarify the dose modifications for Grade 3 toxicities separately from Grade 4 toxicities. 
Section 6.2.1 Specific Recommendations for Rash, Vomiting, Nausea, and Diarrhea was 
removed as no longer needed since its content was now included succinctly in section 6.2, 
Table 4. 
Section 7.2 Screening and SOA, footnote b were amended to add review of adverse events at 
Screening within 28 days of treatment and after signing the ICF. 
Section 7.2 Screening and SOA, footnote t were amended to define the serology tests to be 
taken include Hepatitis B Virus Surface Antigen (HBsAg), Anti-HBc, Hepatitis B DNA, 
Hepatitis C Virus antibody, Hepatitis C RNA, Human Immunodeficiency Virus 1 (HIV-1), 
Human Immunodeficiency Virus 2 (HIV-2). 
Section 7.2 Screening, Section 7.7.2 Biomarker Blood Samples, and SOA, footnote i and 
footnote j were amended to clarify that the first blood samples for ctDNA and CTC are to be 
taken pre-dose on Cycle 1 Day 1, and not during the Screening period. 
Section 7.3.2 PSA Progression, Section 7.4.3 Extended Follow-up Period and SOA, 
footnote l were amended to clarify that the PSA blood sample should be taken prior to dosing 
Cycle 1 Day 1 (unless collected within the previous 72 hours) and as on treatment during the 
extended follow-up visits prior to progression. 
Section 7.4.3 Extended Follow-up Period and SOA, footnote q were amended to clarify that 
response assessments should be performed as on treatment until PD or another withdrawal 
criterion is met. 
Section 10.4.3 Safety Analysis and Synopsis were amended to clarify that AEs leading to dose 
modification (including dose hold, reduction, and discontinuation) summaries will be 
presented by dose level. 
Appendix C Prostate Cancer Working Group 3 (PCWG) PSA Criteria was amended to 
correct the definition of soft tissue disease progression by modified RECIST v1.1. 

 
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Version 2.0, 12 January 2022 
Additions to the text are bolded, and deletions from the text are crossed-off.  Only the parts of 
sections with changes are presented.  Please note that formatting changes and minor changes to 
punctuation, spelling, and abbreviations that do not affect meaning are not noted in this 
summary.   
Schedule of Assessments, footnote g, Appendix G, and Synopsis 
A pre-dose PK sample will be collected with an associated ECG assessment will be collected 
Cycle 2 Day 1  
Section 3.1 Inclusion Criteria and Synopsis – amended to clarify that 
3. Patients with histological, pathological, or cytological confirmed diagnosis of advanced or 
mCRPC who have had disease progression per Prostate Cancer Working Group 3 (PCWG3) 
(Scher et al. 2016) guidance following standard treatment, including approved taxane-based 
chemotherapy, or who are not amenable (intolerability, patient choice) to standard therapies, 
or for whom no therapy of proven efficacy exists,   
5. Patients must have progressed on at least 2 prior approved systemic therapies (in any setting), 
with at least 1 being abiraterone, or enzalutamide, or apalutamide or darolutamide, and no more 
than 2 lines of chemotherapy 
8. Acceptable organ functions, as evidenced by the following laboratory data: 
• Renal function, as follows: 
o 
Creatinine ≤1.5 × the upper limit of normal (ULN), or 
Section 3.2 Exclusion Criteria – amended to clarify that 
1. Treatment with any of the following: 
More than 2 lines of chemotherapy 
 
7. 
Any of the following cardiac criteria experienced currently or within the last 6 months: 
- 
Mean resting corrected QT interval (QTc) >470480 msec 
Section 6 Dose Modifications – amended to clarify that patients who experience a DLT 
during Cycle 1 can continue on the study at the next lower dose if the toxicity resolves to 
Grade 1 or baseline.  No dose modifications are allowed during Cycle 1/the DLT 
observation period.   
Section 6.1 Dose Modifications Due to Hematologic Toxicity and Section 6.2 Dose 
Modifications Due to Non-hematologic Toxicity – amended to clarify that patients who require 
that study drug be held for more than 2 3 weeks due to treatment-related toxicity, should be 
removed from the study unless the treating physician and the Medical Monitor agree that 
continued treatment at lower doses is in the best interest of the patient. 
Section 7.2 Screening and SOA, footnote s - amended to include samples for thyroid 
stimulating hormone [TSH] and free T4 taken at Screening and as clinically indicated thereafter.  

 
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Section 7.2 Screening and SOA, footnote t - amended to include samples for serology infection 
testing taken at Screening. 
Section 7.2 Screening - amended to clarify that if these assessments are performed within 
72 hours of initiation of treatment, they do not need to be repeated on Cycle 1 Day 1, with the 
exception of ECOG performance status, an abbreviated physical examination (head, eyes, ears, 
nose and throat, as appropriate), vital signs, and triplicate ECGs.   
Section 7.3.1 Response Assessments Every 2 Cycles and SOA, footnote m – amended to 
include imaging of any other known or suspected sites of disease if clinically indicated.   
Section 7.4.3 Extended Follow-Up Period - amended to clarify that additional follow-up visits 
after the 30-day safety follow-up visit will be performed for tumor assessment by imaging 
every 12 weeks (±5 days) for the first 6 months after treatment ends if the patient has stopped 
treatment prior to disease progression before completing 6 months of treatment, and then every 
24 weeks (±5 days) thereafter until PD or another withdrawal criterion is met.   
Section 7.4.3 Extended Follow-Up Period and SOA, footnote l – amended to clarify that 
additional PSA assessments after the 30-day safety follow-up visit will be performed every 
12 weeks (±5 days) thereafter until PD or another withdrawal criterion is met. 
Section 7.6 Pharmacokinetic Assessments – amended to clarify that residual plasma from the 
collected pharmacokinetic samples may be used for metabolite analysis, and that the results of 
any such analysis will be used for exploratory purposes only.  
Section 8.1.1 Labeling, Packaging, and Supply – amended to clarify that AC176 should be 
stored at room temperature between 35–46°F (2–8°C) and protected from the light 20–22°C 
(68–72°F). 
Version 1.0, 12 November 2021 
Original protocol