Clinical trial NCT02987829
Conditions: Metastatic Castrate-resistant Prostate Cancer Adenocarcinoma, Prostate
Sponsor: Tracon Pharmaceuticals Inc.
Start date: 2017-05-23; Completion date: 2020-11-09
Enrollment: 72 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a multi-center, first-in-human, open-label, Phase 1/2A dose-escalation study in which eligible patients with metastatic castration-resistant prostate carcinoma (mCRPC) will receive oral doses of TRC253. The study will be conducted in 2 parts: part 1 (dose escalation) and part 2 (dose expansion).

Detailed description:
The patient population consists of men ≥18 years of age with adenocarcinoma of the prostate with metastatic disease. Patients who have not undergone orchiectomy must have serum testosterone levels \<50 ng/dL determined within 4 weeks prior to start of study drug, and, if applicable, must have discontinued treatment with first or second generation anti-androgens as specified in the inclusion criteria.

During Part 1 of the study, patients will be assigned sequentially to increasing TRC253 doses. The starting dose of TRC253 is 40 mg once daily, orally. TRC253 doses will be escalated in subsequent cohorts after all patients enrolled in a given cohort have completed the 28-day dose-limiting toxicity (DLT) evaluation period. Dose escalation in Part 1 will follow single-patient dose escalation design until drug-related toxicity occurs. When an initial drug-related toxicity occurs or DLT in a single patient the cohort will be expanded according to 3+3 design rules. Subsequent dose levels will enroll patients based on 3+3 design. At the maximum tolerated dose (MTD) or minimum efficacious dose (MED), up to twelve patients may be enrolled.

Part 2 will consist of two cohorts of initially up to 30 patients (Cohort 1) and up to 30 patients (Cohort 2) to receive TRC253 at the recommended Phase 2 dose (RP2D). The objective of Part 2 is to gather additional information on the safety, pharmacokinetics (PK) and pharmacodynamic (PD) characteristics, and the clinical efficacy of TRC253 in a pre-defined population of patients with metastatic castrate-resistant prostate cancer (mCRPC). Patients enrolled into Part 2 will have received prior treatment with enzalutamide or apalutamide and showed characteristics of acquired resistance based on changes in PSA serum levels. Patients will be centrally screened for the presence of the AR F876L (androgen receptor F876L) mutation from a plasma sample and enrolled into Cohort 1 (AR F876L positive) or Cohort 2 (AR F876L negative). Cohort 2 may be expanded if a specific molecular mechanism sensitizing the mCRPC to TRC253 therapy can be identified retrospectively. Additional patients may be prospectively selected for this specific molecular resistance mechanism and added to Cohort 2 upon recommendation by the medical monitor and Principal Investigators.

Arms: arm 1: 40 mg of single-agent TRC253 to be administered as oral capsules once daily arm 2: 80 mg of single-agent TRC253 to be administered as oral capsules once daily arm 3: 160 mg of single-agent TRC253 to be administered as oral capsules once daily arm 4: 240 mg of single-agent TRC253 to be administered as oral capsules once daily arm 5: 280 mg of single-agent TRC253 to be administered as oral capsules once daily arm 6: 320 mg of single-agent TRC253 to be administered as oral capsules once daily
Interventions: intervention 1: TRC253
Intervention descriptions: intervention 1: TRC253 is a high-affinity, small molecule antagonist of the androgen receptor (AR) with inhibitory activity against wild type AR and specific mutated variants of AR. TRC253 blocks AR nuclear translocation as well as AR binding to DNA and is an antagonist of transcription for wild type AR and mutated AR. TRC253 is orally active and does not have agonist activity towards either the wild type or mutated ARs. TRC253 treatment in the Hershberger assay results in complete inhibition of androgen sensitive organ development. TRC253 is efficacious in an LNCaP xenograft model driven by F876L (also known as F877L) mutant AR.

Protocol documents:
Prot_SAP_000.pdf: 


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IN CASE OF EMERGENCY 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone number 
Primary Medical Monitor 
James Freddo, MD 
4350 La Jolla Village Drive, Suite 800 
San Diego, CA 92122 
Mobile Phone: 1.858.472.2330 
Facsimile: 1.858.550.0786 
Email: jfreddo@traconpharma.com 
Secondary Medical Monitor 
Charles Theuer, MD, PhD 
4350 La Jolla Village Drive, Suite 800 
San Diego, CA 92122 
Office: 1.858.550.0780 x233 
Mobile Phone: 1.858.344.9400 
Email: ctheuer@traconpharma.com 
 


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1. 
SYNOPSIS 
Name of Sponsor/Company: TRACON Pharmaceuticals, Inc.  
Name of Investigational Product: TRC253 
Name of Active Ingredient: TRC253-HCl 
Title of Study:  
AN OPEN-LABEL PHASE 1/2A STUDY TO EVALUATE THE SAFETY, PHARMACOKINETICS, 
PHARMACODYNAMICS, AND PRELIMINARY EFFICACY OF TRC253, AN ANDROGEN RECEPTOR 
ANTAGONIST, IN PATIENTS WITH METASTATIC CASTRATION-RESISTANT PROSTATE CANCER 
Study center(s): 6 centers in Part 1, and approximately 20 centers in Part 2, in the United States 
Studied period:  
Date first patient enrolled: May 2017 
Date of determination of recommended phase 2 dose 
(RP2D): July 2018 
Estimated date last patient enrolled: April 2021 
Estimated date last patient completed: October 2021 
Phase of development: 1/2A 
 
Rationale:  
TRC253 is a high-affinity, small molecule antagonist of the androgen receptor (AR) with inhibitory 
activity against wild type AR and specific mutated variants of AR. TRC253 blocks AR nuclear 
translocation as well as AR binding to DNA and is an antagonist of transcription for wild type AR and 
mutated AR. TRC253 is orally active and does not have agonist activity towards either the wild type or 
mutated ARs. TRC253 treatment in the Hershberger assay results in complete inhibition of androgen 
sensitive organ development. TRC253 is efficacious in an LNCaP xenograft model driven by F877L 
(previously known as F876L) mutant AR and inhibited other known AR resistance mutations, including 
L702H, in preclinical models. 
Objectives 
Primary Objectives:   
• 
Assess the safety of TRC253  
• 
Determine the recommended Phase 2 dose (RP2D) of TRC253  
• 
Evaluate prostate-specific antigen (PSA) response at Week 12 according to Prostate Cancer 
Working Group 3 (PCWG3) criteria (Appendix 2)  
Secondary Objectives:   
• 
Evaluate exposure-QTcF relationship 
• 
Determine the extent of receptor occupancy 
• Evaluate preliminary anti-tumor effects of TRC253 
Exploratory Objective:   
• 
Determine effect of treatment on resistance markers  
Endpoints 
Primary Endpoint: 


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• 
Safety: adverse events, vital sign measurements, ECG, physical examinations, and clinical 
laboratory tests 
• 
RP2D of TRC253 
• 
PSA response: serum PSA at Week 12 according to PCWG3 (Appendix 2) 
 
Secondary Endpoints: 
• 
PK parameters: maximum observed plasma concentration for each patient (Cmax), observed 
plasma concentration at end of a dosing interval for each patient (Cmin), time of maximum 
observed plasma concentration (tmax), area under the plasma concentration-time curve from 
time zero to 24 hours at steady state (AUCτ), area under the plasma concentration time curve 
from time zero to the last time measured (AUClast), area under the plasma concentration time 
curve from time zero extrapolated to infinite time (AUC∞), apparent terminal elimination rate 
constant (λz), effective half-life (t1/2eff), terminal half-life (t1/2term), accumulation index (RA), total 
apparent oral clearance (CL/F), and apparent oral volume of distribution at steady state (Vss/F) 
• 
Mean (90% confidence interval [CI]) change in QTcF at Cmax and slope (90% CI) 
• 
Time to PSA progression according to PCWG3 (Appendix 2) 
• 
Radiographic PFS (rPFS) according to PCWG3 (Appendix 3) 
• 
Central read of QTcF interval in part 2 
 
Exploratory Endpoints: 
• 
Resistance markers assessed from circulating tumor cells (CTC) and circulating tumor DNA 
(ctDNA) 
• 
Standard Uptake Value (SUV) of FDHT PET scan 
 


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Study Design:  
This is a multi-center, first-in–human, open-label, Phase 1/2A dose-escalation study in which eligible 
patients with metastatic castration-resistant prostate carcinoma (mCRPC) will receive oral doses of 
TRC253. The study will be conducted in 2 parts. 
Figure 1: 
Study Design Schematic 
 
 
 
 
 
 
 
 
 
 
During Part 1 of the study, patients will be assigned sequentially to increasing TRC253 doses. The 
starting dose of TRC253 is 40 mg once daily in the morning, orally. TRC253 doses will be escalated in 
subsequent cohorts after all patients enrolled in a given cohort have completed the 28-day dose-limiting 
toxicity (DLT) evaluation period. Dose escalation in Part 1 will follow single-patient dose escalation 
design until drug-related toxicity occurs per Table 4. When an initial drug-related toxicity occurs per 
Table 4 or DLT per  
Table 6 in a single patient the cohort will be expanded according to 3+3 design rules. Cohorts may be 
expanded to include additional patients for purposes of collecting additional safety, PK, PD (FDHT-
PET), and PSA response data. A single cohort may expanded to a maximum of twelve patients to help 
inform selection of a MED, as long as that dose level remains below the MTD (see below). 
Subsequent dose levels will enroll patients based on 3+3 design, whereby 3 patients will be initially 
enrolled and treated at each dose level. If one of these 3 patients experiences a DLT during the initial 
28-day evaluation period, the dose level will be expanded to 6 patients. The MTD will have been 
exceeded if ≥ 33% of patients experience DLT at a given dose level. DLT will have occurred when a 
patient has 1 or more toxicity listed in  
Table 6 that is at least possibly related to TRC253 during the first 28 days of dosing. Patients who exit 
the study for reasons other than DLT prior to completion of the 28-day DLT evaluation period will be 
replaced to ensure an adequate safety assessment in each cohort. Patients who experience DLT who 
receive less than the prescribed dose of TRC253 due to documented toxicity during the DLT evaluation 
period will be considered evaluable for dose escalation purposes. At the MTD or MED, up to twelve 
patients may be enrolled prior to confirming the RP2D. Dose escalation will take into account all 
Part 1 
Dose Escalation 
Part 2 
Dose Expansion 
Cohort 1: mCRPC with prior 
enzalutamide or apalutamide with AR 
F877L mutation (n=15 patients)  
Cohort 2: mCRPC with prior 
enzalutamide or apalutamide – other than 
AR F877L or sole L702H mutations 
(n=30 patients)  
MTD or MED 
Starting Dose 
3+3 Dose Escalation 
Single Patient 
Escalation 
Cohort 3: mCRPC with prior 
enzalutamide or apalutamide with sole 
AR L702H mutation (n=15 patients)  


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available data including PK/PD data and the safety profile of prior cohorts, as evaluated by medical 
monitor and Principal Investigators. 
While the maximum tolerated dose was not reached, PK exposures at the 320 mg dose level 
significantly exceeded the target efficacious concentration and a decision was made not to proceed to 
400 mg. Based on review of PK and safety, the RP2D of 280 mg was chosen. 
Part 2 will consist of three cohorts of initially up to 15 patients (Cohort 1), up to 30 patients (Cohort 2), 
and up to 15 patients (Cohort 3) to receive TRC253 at the RP2D of 280 mg. The objective of Part 2 is 
to gather additional information on the safety, PK and PD characteristics, and the clinical efficacy of 
TRC253 in a pre-defined population of patients with metastatic CRPC. Patients enrolled into Part 2 will 
have received prior treatment with enzalutamide or apalutamide. Patients will be centrally screened for 
the presence of the AR F877L and AR L702H mutations from a plasma sample and enrolled into Cohort 
1 (AR F877L positive), Cohort 2 (patients without AR F877L and without sole AR L702H mutations), 
or Cohort 3 (sole AR L702H mutation positive).  
Treatment will continue until one or more of the withdrawal criterion are met; refer to Section 7.4.3. 
Patient Population: 
The patient population consists of men ≥18 years of age with adenocarcinoma of the prostate with 
metastatic disease. Patients who have not undergone orchiectomy must have serum testosterone levels 
<50 ng/dL determined within 4 weeks prior to start of study drug, and, if applicable, must have 
discontinued treatment with first or second generation anti-androgens as specified in the inclusion 
criteria. 
Inclusion Criteria 
Each potential patient must satisfy all of the following criteria to be enrolled in the study: 
 
Part 1 Only   
1. Must have received at least 2 prior therapies approved for CRPC; including a prior AR 
inhibitor (e.g., enzalutamide or apalutamide). 
Part 2 Only 
1. Must have received enzalutamide or apalutamide.  
• 
Note: additional therapies approved for CRPC prior to enzalutamide or apalutamide are 
allowed. 
 
Parts 1 and 2 
1. Histologically confirmed adenocarcinoma of the prostate with metastatic disease. 
2. Male ≥18 years of age. 
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
4. Prior orchiectomy or serum testosterone levels <50 ng/dL determined within 4 weeks prior to 
start of study drug. 
5. Adequate baseline organ function as defined below: 
Hematology 
Hemoglobin 
≥9 g/dL (or ≥90 g/L) with or without transfusion 


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Platelet count 
≥75 x 109/L with or without transfusion 
Neutrophil count 
absolute neutrophil count ≥1.0 x 109/L  
Chemistry 
Total bilirubin 
≤1.5 times laboratory upper limit of normal 
(ULN); patients with Gilbert’s syndrome can 
enroll if conjugated bilirubin is within normal 
limits 
Alanine aminotransferase and 
aspartate aminotransferase 
≤2.5 times the ULN 
Serum creatinine 
<1.5 mg/dL, or a calculated or measured 
creatinine clearance >50 mL/min/1.73 m2 
Cardiac 
Electrocardiogram QTcF  
<450 ms  
(average of 3 readings approximately 2 minutes 
apart) 
6. Ongoing androgen depletion therapy with a gonadotropin-releasing hormone (GnRH) analog 
or inhibitor, or orchiectomy (i.e., surgical or medical castration). Note: patients who have not 
undergone orchiectomy must continue GnRH analog therapy for the duration of this protocol. 
7. For patients previously treated with first generation anti-androgens (i.e., flutamide, 
nilutamide, or bicalutamide), discontinuation of flutamide or nilutamide therapy must occur 
>4 weeks (>6 weeks for bicalutamide) prior to start of study drug with no evidence of an anti-
androgen withdrawal response (i.e., no decline in serum PSA). 
8. For patients previously treated with chemotherapy, targeted therapy, immunotherapy, or 
treatment with an investigational anticancer agent, discontinuation must have occurred ≥2 
weeks, or after at least 4 half-lives, whichever is longer, prior to study drug administration. 
For enzalutamide and apalutamide, the washout period will be at least 3 weeks prior to start 
of study drug with no evidence of an anti-androgen withdrawal response (i.e., no decline in 
serum PSA). 
9. For patients previously treated with other agents approved for the treatment of prostate cancer 
(5-α reductase inhibitors, estrogens, others), discontinuation of therapy must have occurred 
≥4 weeks prior to start of study drug. 
10. Palliative radiotherapy (to bone or soft tissue lesions) must be completed >2 weeks prior to 
start of study drug (exception: palliative radiotherapy for pain may be used any time prior to 
first dose). 
11. For patients receiving bone–loss prevention treatment (e.g., bisphosphonates or denosumab), 
the patient must be on stable dose ≥4 weeks prior to start of study drug. 
12. A man who is sexually active with a woman of childbearing potential must agree to use at 
least two acceptable methods of birth control, one of which must be highly effective 
(Section 2.5.1 ) during the study and for 120 days after receiving the last dose of study drug. 
Note: a female condom and a male condom should not be used together as friction between 
the 2 can result in either product failing. All men must also not donate sperm during the study 
and for 120 days after receiving the last dose of study drug.   
13. Patient must be willing and able to adhere to the prohibitions and restrictions specified in this 
protocol. 


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14. Each patient must sign an informed consent form (ICF) indicating that he understands the 
purpose of and procedures required for the study and is willing to participate in the study. 
Consent is to be obtained prior to the initiation of any study-related tests or procedures that 
are not part of standard-of-care for the patient’s disease. 
15. Each patient must initially sign a separate pre-screening informed consent form authorizing 
collection, of the AR mutation sample(s) for genetic research. Consent must be obtained prior 
to collection of the first AR mutation sample. Participation in this genetic research is required 
for participation in the study. 
Exclusion Criteria:   
Any potential patient who meets any of the following criteria will be excluded from participating in 
the study: 
1. History of seizures. 
2. Previously documented or current brain metastases. 
3. Untreated spinal cord compression. 
4. Known positive test result for human immunodeficiency virus. 
5. History of clinically significant cardiovascular disease including, but not limited to: 
• 
Myocardial infarction or unstable angina within the 6 months prior to the first dose of 
study drug. 
• 
Clinically significant cardiac arrhythmia. 
• 
Uncontrolled (persistent) hypertension: systolic blood pressure >180 mmHg; diastolic 
blood pressure >100 mmHg. 
• 
Congestive heart failure (New York Heart Association class III-IV). 
• 
Use of pacemaker 
6. Known active or chronic hepatitis B or hepatitis C as demonstrated by hepatitis B surface 
antigen positivity and/or anti- hepatitis C virus positivity, respectively. Patients with 
clinically active or chronic liver disease, including liver cirrhosis of Child-Pugh class C, are 
also excluded. 
7. History of a different malignancy except for the following circumstances: (a) individuals with 
a history of other malignancies are eligible if they have been disease-free for at least 3 years 
or are deemed by the investigator to be at low risk for recurrence of that malignancy, (b) 
individuals with a history of treatment for the following cancers are eligible: non-muscle 
invasive bladder cancer, basal cell, or squamous cell carcinoma of the skin and resected 
melanoma in situ. 
8. Any serious underlying medical or psychiatric condition (e.g., alcohol or drug abuse), 
dementia or altered mental status or any issue that would impair the ability of the patient to 
receive or tolerate the planned treatment, to understand informed consent or that in the 
opinion of the investigator would contraindicate the patient’s participation in the study or that 
would confound the results of the study. 
9. Evidence of active viral, bacterial, or systemic fungal infection requiring systemic treatment 
within 7 days prior to the first dose of study drug. Patients requiring any systemic antiviral, 
antifungal, or antibacterial therapy for active infection must have completed treatment no less 
than 7 days prior to the first dose of study drug. 
10. Known allergies, hypersensitivity, or intolerance to TRC253 or its excipients (refer to 
Investigator's Brochure). 


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11. Enrollment in another therapeutic study. 
12. Major surgery (e.g., requiring general anesthesia) within 3 weeks before screening, or has not 
fully recovered from prior surgery (i.e., unhealed wound), or surgery planned during the time 
the patient is expected to participate in the study. Note: patients with planned surgical 
procedures to be conducted under local anesthesia may participate. 
13. Plan to father a child while enrolled in this study or within 90 days after the last dose of study 
drug. 
14. Pre-existing chronic hypokalemia or hypomagnesemia. 
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. If a 
patient's status changes (including laboratory results or receipt of additional medical records) after 
screening but before the first dose of study drug is given such that he no longer meets all eligibility 
criteria, supportive treatment may be administered, if necessary, so that eligibility criteria can be met 
and laboratory test(s) may be repeated once, to determine if the patient qualifies for the study. If 
enrollment criteria are not met after further evaluation, then the patient should be excluded from 
participation in the study. 
Dosage and Administration 
Part 1: a single dose of TRC253 will be taken on the first day (i.e., Cycle 1 Day 1) of a 7-day cycle. 
During Cycle 1, the pharmacokinetic characteristics of a single dose of TRC253 will be investigated.  
TRC253 will be administered orally once daily in the morning in 28-day cycles starting in Cycle 2. 
Starting with treatment Cycle 2 Day 1, TRC253 will be taken once daily in the morning. The proposed 
TRC253 doses are 40 mg, 80 mg, 160 mg, 240 mg, 320 mg, and 400 mg; however, intermediate dose 
levels may be implemented based on safety, tolerability, PK, PD and other observations at each dose 
level following review of data with the principal investigators at all treating sites. 
Part 2: TRC253 capsules are taken once daily in the morning starting on Cycle 1 Day 1 at the MTD or 
MED in 28-day cycles. 
On extended PK days, no food should be consumed for at least 8 hours before and 4 hours following 
TRC253 dosing. On all other days, no food should be consumed for at least 2 hours before and 1 hour 
after dosing. 
Withdrawal Criteria:  
Patients will be withdrawn from study treatment if, in the opinion of the Investigator, it is medically 
necessary, or if it is the wish of the patient. In addition, patients will be withdrawn from treatment for 
any of the following reasons: 
1. Lost to follow-up or noncompliant 
2. Withdrawal of consent 
3. The sponsor terminates the study 
4. Disease progression according to PCWG3 criteria (Appendix 2, Appendix 3) 
a. Patients may continue on study drug if in the opinion of the Investigator, patient is 
deriving benefit from continuation of therapy. Continuation of therapy must be 
approved by the Sponsor. 
5. Dose delay greater than 21 days 
Note: In part 1, only patients who have received >75% of TRC253 doses during the DLT 
evaluation period will be considered evaluable. Patients who have received ≤75% of TRC253 
doses during the DLT evaluation period due to reasons other than toxicities, such as but not 
restricted to disease progression, missed appointments, non-compliance, and patient 


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withdrawal, will be considered non-evaluable for DLT and will be replaced with a new 
patient. 
6. Patients with AST or ALT elevations >5X ULN, or who meet Hy’s Law criteria, i.e., 
concurrent elevation of AST or ALT >3X ULN and total bilirubin >2X ULN 
7. Grade 4 adverse events 
8. Patients who experience QTcF prolongation > 500 ms or > 60 ms change from baseline 
without electrolyte abnormalities and without response to TRC253 (See Section 8.5.3) 
 
If a patient discontinues study drug and withdraws from the study, the off-study visit assessments 
should be obtained.  
If a patient is lost to follow-up, every reasonable effort must be made by the study-site personnel to 
contact the patient and determine the reason for discontinuation/withdrawal. The measures taken to 
follow up must be documented. 
Study drug assigned to the withdrawn patient may not be assigned to another patient. Patients who 
withdraw for reasons other than toxicity will be replaced at the discretion of the sponsor.  
Criteria for evaluation: 
Safety evaluations: 
Safety assessments will be based on medical review of adverse event reports and the results of clinical 
laboratory tests, electrocardiograms (ECGs), vital sign measurements, and physical examinations. 
While ECG readings at the sites will be used for patient management purposes, an additional central 
read will be performed by a third-party vendor. 
Pharmacokinetic evaluations: 
Pharmacokinetic parameters of TRC253 will be derived from plasma concentration versus time data 
after single and repeated doses, as applicable.  
Biomarker evaluations: 
Part 1 
To confirm the RP2D, some patients at select dose levels will undergo positron emission tomography 
(PET) scans using 16β [18F]fluoro-α-dihydrotestosterone (FDHT), a radiopharmaceutical specifically 
designed to image binding to AR. AR-positive lesions will be determined by qualitative inspection of 
the FDHT-PET images. Imaging will occur at 1 or more centers under their existing IND and 
institutional protocol.   
Part 2 
Patients with and without AR ligand-binding-domain (LBD) mutations will be identified using ctDNA 
from plasma.  A validated and CLIA-certified Clinical Trial Assay (CTA) utilizing highly sensitive 
BEAMing emulsion PCR platform will be used to detect AR mutations. Patients who are positive for 
the AR F877L mutation will be enrolled in Cohort 1, patients without AR F877L and without sole AR 
L702H mutations will be enrolled in Cohort 2, and patients who are positive for sole AR L702H 
mutation will be enrolled in Cohort 3. Note that Cohort 1 patients may be positive for F877L alone or 
F877L associated with any other AR mutation.  


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Parts 1 and 2 
Available archival formalin-fixed paraffin-embedded (FFPE) tumor blocks or slides will be collected 
from all patients to evaluate primary response and high-risk markers, including but not limited to 
TMPRSS2-ERG, PTEN, FGFR, PI3K, BRACA1, BRCA2, and ATM. 
Whole blood will be collected from all patients to enumerate circulating tumor cells (CTCs) and assess 
the expression of high risk markers, including AR-V7. Plasma will be collected to assess the 
development of AR mutations in response to TRC253 treatment. 
Serum will be collected from all patients before, during, and after therapy and analyzed for total 
testosterone, free testosterone, dihydrotestosterone (DHT), estradiol, dehydroepiandrosterone sulfate 
(DHEA-S), androstenedione, and sex hormone-binding globulin (SHBG).  
Efficacy evaluations: 
Efficacy evaluations include disease outcome assessments, PSA, time to PSA progression, soft tissue 
disease, bone disease, and rPFS.  
Statistical methods: 
Sample size determination: 
The sample size for this study is not calculated based on statistical power but to obtain safety, PK, and 
pharmacodynamic (PD) assessments of oral doses of TRC253.  
In Part 1, dose escalation will follow a single-patient dose escalation design until initial drug-related 
toxicity occurs per Table 4. Subsequent dose levels will enroll patients based on 3+3 design 
(Section 5.1). At the maximum tolerated dose or minimum efficacious dose, up to 12 patients may be 
enrolled.  
In Part 2, dose expansion, approximately 60 patients will be enrolled in three cohorts to further 
characterize safety and PK, as well as efficacy. For example, if the true PSA response rate in cohort 2 
is 50%, the probability of observing at least 11 responders out of 30 is 95%. If the total of 30 patients 
from this example, 15 are PSA responders, then the response rate (95% CI) will be 50% (31.3%, 
68.7%). 
Safety analyses: 
All patients who receive at least one dose of study drug will be analyzed for safety. The safety 
parameters to be analyzed are adverse events (DLT, all adverse events, Grade 3 or greater adverse 
events, serious adverse events, adverse events leading to discontinuation of treatment, adverse events 
leading to death), as well as clinically significant changes in the patient’s physical examination 
findings, ECGs, vital signs measurements, and clinical laboratory results. Exposure to study drug and 
reasons for discontinuation of study treatment will be tabulated. 
Exposure-QTcF analysis of TRC253 will be performed using triplicate approximately ± 2 minute 
time points from ECG measurements performed at the time of intensive PK sampling and steady state 
PK sampling. 
In addition, there will be a central over-read of QTcF by a third-party vendor. 
Pharmacokinetic analyses: 
Descriptive statistics will be used to summarize TRC253 plasma concentrations at each sampling time 
point, by dose level/study part. Pharmacokinetic parameters of TRC253 will be determined using non-


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compartmental analysis and summarized by dose level/study part. Mean and individual plasma TRC253 
concentration time profiles will be plotted (linear and semilog) after the first dose of study drug and at 
steady state. Analysis of dose proportionality and steady state versus Day 1 accumulation ratios will be 
conducted. 
Population PK analysis of plasma concentration-time data of TRC253 will be performed using 
nonlinear mixed-effects modeling. Available baseline patient characteristics (demographics, laboratory 
variables, race, etc.) may be tested as potential covariates affecting PK parameters. Data from this study 
may be pooled with other data for the population analysis.  
Biomarker analyses: 
FDHT-PET: The maximum standard uptake value will be calculated for each lesion at each tested dose 
level and for all lesions. The percent decline in maximum standard uptake will be directly proportional 
to AR occupancy and therefore can be used to estimate EC90 which will be taken into consideration for 
the selection of the RP2D. 
Exploratory biomarkers: CTC number at baseline, and change in CTC counts will be descriptively 
summarized. Prostate-specific antigen changes at Week 12 will be correlated with expression of 
molecular markers to identify novel sensitizing mechanisms. Whole blood and plasma samples 
collected will be used to estimate frequency of expression of resistance and high risk markers. 
Associations will be made with time to clinical endpoints and expression of resistance biomarkers. 
The association of biomarkers with clinical response or relevant survival endpoints may be assessed 
using appropriate statistical methods (e.g., analysis of variance, categorical or survival models) 
depending on the endpoints. Analyses may be performed within the treatment group. Other clinical 
covariates (such as baseline tumor characteristics and patient demographics) may also be included in 
the model. Correlation of baseline biomarker expression levels with clinical response or relevant time 
to-event endpoints may be performed to identify responsive (or resistant) subgroups. Association of 
biomarkers with clinical response or relevant time-to-event endpoints will also be explored in the 
overall population.  
Pharmacokinetic/pharmacodynamic analyses 
Pharmacokinetic/pharmacodynamic (PK/PD) analyses will be performed using data from all patients 
who have sufficient data available to evaluate anti-tumor effects of TRC253. The population PK/PD 
analysis will use concentration as an independent variable. Pharmacodynamic endpoints such as percent 
decline in SUVmax-avg from baseline (estimate EC90) from FDHT-PET, time to PSA progression, and 
percent change in PSA relative to baseline will be considered using non-linear mixed-effect modeling. 
Efficacy analyses 
Patient listings will be provided for efficacy evaluations including PSA response rate, time to PSA 
progression, and rPFS.  
Post-treatment percent change in PSA relative to baseline will be reported at Week 12 (or earlier for 
those who discontinue therapy), and separately, the maximal change at any time on study will also be 
reported for each patient using waterfall plots. 
For Part 2, efficacy summaries by population cohort (PSA response, time to PSA progression, and 
rPFS) will be performed. Median time to PSA progression will be determined separately for each of 
the expansion cohorts and Kaplan-Meier curves may be plotted. If there are sufficient data, rPFS will 


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be summarized and median rPFS will be assessed. If deemed appropriate, patients receiving the same 
dose from Part 1 may also be combined with Part 2 patients. 


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TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES  
TABLE OF CONTENTS 
IN CASE OF EMERGENCY ..........................................................................................................2 
1. 
SYNOPSIS ...................................................................................................................3 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ..................................14 
TABLE OF CONTENTS ...............................................................................................................14 
LIST OF TABLES .........................................................................................................................18 
LIST OF FIGURES .......................................................................................................................19 
2. 
INTRODUCTION ......................................................................................................22 
2.1. 
Background .................................................................................................................22 
2.2. 
Summary of Nonclinical Studies ................................................................................25 
2.2.1. 
Nonclinical Pharmacology ..........................................................................................25 
2.2.2. 
Safety Pharmacology ..................................................................................................26 
2.2.3. 
Pharmacokinetics and Product Metabolism in Animals .............................................26 
2.2.4. 
Toxicology ..................................................................................................................27 
2.3. 
Overall Rationale for the Study ..................................................................................28 
2.4. 
Phase 1 and Phase 2 253PC101 Ongoing Study Results ............................................28 
2.4.1. 
Phase 1 and Phase 2 253PC101 Ongoing Study Results – Safety ..............................29 
2.4.2. 
Phase 1 and Phase 2 253PC101 Ongoing Study Results – Efficacy ..........................29 
2.4.3. 
This amendment includes a new cohort of 15 patients with sole L702H 
mutation. Phase 1 253PC101 Study Results – Pharmacokinetics ..............................30 
2.5. 
Potential Risks and Benefits to Human Patients .........................................................30 
2.5.1. 
Potential Risks ............................................................................................................30 
2.5.2. 
Potential Benefits ........................................................................................................31 
2.6. 
Conduct .......................................................................................................................31 
3. 
TRIAL OBJECTIVES ................................................................................................32 
3.1. 
Primary Objectives: ....................................................................................................32 
3.2. 
Secondary Objectives: ................................................................................................32 
3.3. 
Exploratory Objective: ................................................................................................32 
4. 
TRIAL ENDPOINTS .................................................................................................33 
4.1. 
Primary Endpoints ......................................................................................................33 
4.2. 
Secondary Endpoints ..................................................................................................33 


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4.3. 
Exploratory Endpoints ................................................................................................33 
5. 
STUDY DESIGN AND RATIONALE ......................................................................34 
5.1. 
Overview of Study Design ..........................................................................................34 
5.1.1. 
Part 1 (Dose Escalation) .............................................................................................34 
5.1.2. 
Part 2 (Dose Expansion) .............................................................................................36 
5.2. 
Dose-Limiting Toxicity ..............................................................................................37 
5.3. 
Study Design Rationale ..............................................................................................39 
5.4. 
Starting Dose Rationale ..............................................................................................39 
6. 
INVESTIGATIONAL PLAN .....................................................................................40 
6.1. 
Study Procedures ........................................................................................................40 
6.1.1. 
Trial Overview ............................................................................................................40 
6.1.2. 
Pre-Screening Period (Part 2 Only) ............................................................................40 
6.1.3. 
Screening Period .........................................................................................................40 
6.1.4. 
Treatment Period ........................................................................................................41 
6.1.5. 
End of Treatment and Follow-Up Period ...................................................................41 
7. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................51 
7.1. 
Patient Population .......................................................................................................51 
7.2. 
Patient Inclusion Criteria ............................................................................................51 
7.3. 
Patient Exclusion Criteria ...........................................................................................53 
7.4. 
Patient Completion, Discontinuation, or Withdrawal .................................................54 
7.4.1. 
Completion .................................................................................................................54 
7.4.2. 
Discontinuation of Study Treatment ...........................................................................54 
7.4.3. 
Patient Withdrawal Criteria ........................................................................................54 
7.5. 
Prohibitions and Restrictions ......................................................................................55 
8. 
STUDY DRUG INFORMATION ..............................................................................57 
8.1. 
Description of TRC253 Capsules ...............................................................................57 
8.2. 
TRC253 Packaging and Labeling ...............................................................................57 
8.3. 
TRC253 Handling, and Storage ..................................................................................57 
8.4. 
TRC253 Dose Levels ..................................................................................................57 
8.5. 
TRC253 Dosage and Administration ..........................................................................58 
8.5.1. 
TRC253 Missed Doses ...............................................................................................59 
8.5.2. 
TRC253 Dose Modification/Dose Interruptions ........................................................59 


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8.5.3. 
Management of QTcF Prolongation ...........................................................................60 
8.5.4. 
TRC253 Study Drug Accountability ..........................................................................60 
8.5.5. 
TRC253 Handling and Disposal .................................................................................61 
9. 
CONCOMITANT MEDICATIONS ..........................................................................62 
9.1. 
Permitted Medications ................................................................................................62 
9.2. 
Prohibited Medications ...............................................................................................62 
9.3. 
Precautions with Concomitant Medications ...............................................................63 
10. 
TREATMENT COMPLIANCE .................................................................................64 
10.1. 
Patient Enrollment ......................................................................................................64 
11. 
ASSESSMENT OF EFFICACY ................................................................................65 
11.1. 
Disease Outcome Assessments ...................................................................................65 
11.2. 
PSA Response and Time to PSA Progression ............................................................65 
11.3. 
Radiographic Progression-Free Survival (rPFS) ........................................................65 
12. 
ASSESSMENT OF SAFETY .....................................................................................66 
12.1. 
Safety Parameters .......................................................................................................66 
12.1.1. 
Adverse Events ...........................................................................................................66 
12.1.2. 
Clinical Laboratory Tests ...........................................................................................66 
12.1.3. 
Electrocardiograms .....................................................................................................67 
12.1.4. 
Vital Signs ..................................................................................................................67 
12.1.5. 
Physical Examination .................................................................................................67 
12.2. 
Adverse Events ...........................................................................................................67 
12.2.1. 
Definition of Adverse Event .......................................................................................68 
12.2.2. 
Serious Adverse Events ..............................................................................................68 
12.2.2.1. 
Hospitalization ............................................................................................................69 
12.3. 
Reporting Adverse Events ..........................................................................................70 
12.3.1. 
Eliciting Adverse Event Information ..........................................................................70 
12.3.2. 
Adverse Event Reporting Period ................................................................................70 
12.3.3. 
Reporting Requirements .............................................................................................70 
12.3.4. 
Recording Adverse Events in the Case Report Forms ................................................72 
12.3.5. 
Grading of Adverse Event Severity ............................................................................72 
12.3.6. 
Relationship to TRC253 Study Drug ..........................................................................72 
12.3.7. 
Expectedness Assessment ...........................................................................................74 


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12.3.8. 
Pregnancy ...................................................................................................................74 
12.3.9. 
Follow-up of Unresolved Adverse Events ..................................................................75 
12.4. 
Safety Monitoring .......................................................................................................75 
13. 
OTHER LABORATORY ASSESSMENTS ..............................................................76 
13.1. 
Pharmacokinetics ........................................................................................................76 
13.2. 
Biomarkers ..................................................................................................................76 
13.2.1. 
Part 1 Biomarkers .......................................................................................................76 
13.2.2. 
Part 2 Biomarkers .......................................................................................................76 
13.2.3. 
Parts 1 and 2 Biomarkers ............................................................................................77 
13.3. 
Archival Tumor Specimens ........................................................................................77 
13.4. 
Sample Collection and Handling ................................................................................77 
14. 
STATISTICAL METHODS .......................................................................................78 
14.1. 
Analysis Populations ..................................................................................................78 
14.2. 
Sample Size Determination ........................................................................................78 
14.3. 
Endpoint Definitions ...................................................................................................79 
14.4. 
Safety Analyses ..........................................................................................................80 
14.4.1. 
Adverse Events ...........................................................................................................80 
14.4.2. 
Clinical Laboratory Tests ...........................................................................................81 
14.4.3. 
Electrocardiogram .......................................................................................................81 
14.4.4. 
Vital Signs ..................................................................................................................81 
14.4.5. 
Physical Examination .................................................................................................81 
14.5. 
Pharmacokinetic Analyses ..........................................................................................81 
14.6. 
Biomarker Analyses ....................................................................................................82 
14.6.1. 
FDHT-PET .................................................................................................................82 
14.6.2. 
Exploratory Biomarkers ..............................................................................................82 
14.7. 
Pharmacokinetic/Pharmacodynamic Analyses ...........................................................83 
14.8. 
Efficacy Analyses .......................................................................................................83 
15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................84 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................85 
17. 
ETHICS ......................................................................................................................86 
17.1. 
Health Authorities and Independent Ethics Committees/Institutional Review 
Boards .........................................................................................................................86 


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17.2. 
Ethical Conduct of the Study ......................................................................................86 
17.3. 
Written Informed Consent ..........................................................................................86 
17.4. 
Patient Compensation .................................................................................................87 
18. 
DATA HANDLING AND RECORDKEEPING .......................................................88 
18.1. 
Inspection of Records .................................................................................................88 
18.2. 
Retention of Records ..................................................................................................88 
19. 
DEFINITION OF END TRIAL ..................................................................................90 
19.1. 
End of Trial in all Participating Countries ..................................................................90 
19.2. 
Study and Site Termination ........................................................................................90 
20. 
PUBLICATION OF TRIAL RESULTS ....................................................................91 
21. 
FINANCING AND INSURANCE .............................................................................92 
22. 
INVESTIGATOR AGREEMENT: PROTOCOL 253PC101 ....................................93 
23. 
REFERENCES ...........................................................................................................94 
APPENDIX 1. ANTICIPATED EVENTS .................................................................................95 
APPENDIX 2. OUTCOME MEASURES FOR CLINICAL TRIALS IN PROSTATE 
CANCER: PSA RESPONSE ACCORDING TO PCWG3 [8] ..................................96 
APPENDIX 3. OUTCOME MEASURES FOR CLINICAL TRIALS IN PROSTATE 
CANCER: RESPONSE BY DISEASE MANIFESTATION ACCORDING 
TO PCWG3 [8] ...........................................................................................................97 
APPENDIX 4. NATIONAL CANCER INSTITUTE (NCI) COMMON 
TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (CTCAE) ......................99 
APPENDIX 5. ECOG PERFORMANCE STATUS ................................................................100 
APPENDIX 6. MEDICATIONS THAT MAY PROLONG THE QT INTERVAL 
INCLUDE BUT ARE NOT LIMITED TO THE FOLLOWING ............................101 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................2 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................20 
Table 3: 
Molecular Activity of TRC253 Determined in Receptor Binding or Reporter 
Assays .........................................................................................................................25 
Table 4: 
Single Patient Dose Escalation ...................................................................................38 
Table 5: 
Decision Rules for 3+3 Dose Escalation ....................................................................38 
Table 6: 
3+3 Dose Escalation DLT Definition and Criteria .....................................................38 
Table 7: 
Part 1 Dose Escalation Schedule of Assessments .......................................................43 


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Table 8: 
Part 2 Dose Expansion Schedule of Assessments ......................................................47 
Table 9: 
Dose Levels ................................................................................................................57 
Table 10: Adverse Event Grading ...............................................................................................72 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic ...............................................................................................5 
Figure 2: 
PSA Changes Following Treatment With Enzalutamide in Patients with 
CRPC ..........................................................................................................................23 
Figure 3: 
Mechanisms of Resistance to AR-directed Therapies [2] ..........................................24 
Figure 4: 
Single Patient Dose Escalation Schematic .................................................................35 
Figure 5: 
3+3 Dose Escalation Schematic..................................................................................35 
Figure 6: 
Part 2 Cohorts .............................................................................................................37 
 
 
 


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Table 2: 
Abbreviations and Specialist Terms 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
AR 
androgen receptor 
AST 
aspartate aminotransferase 
BUN 
blood urea nitrogen 
CRPC 
castration-resistant prostate carcinoma 
CI 
confidence interval 
CT 
computed tomography 
CTA 
clinical trial assay 
CTC 
circulating tumor cells 
ctDNA 
circulating tumor DNA 
CYP 
cytochrome P450 
DHEA-S 
dehydroepiandrosterone sulfate 
DHT 
dihydrotestosterone 
DLT 
dose-limiting toxicity 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
eDC 
electronic Data Capture 
FDA 
Food and Drug Administration 
FDHT 
16β [18F]fluoro-α-dihydrotestosterone 
FFPE 
formalin-fixed paraffin-embedded  
FIH 
first in human 
FISH 
fluorescence in situ hybridization 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GnRH 
gonadotropin-releasing hormone analogs 
HDL 
high-density lipoprotein 
HED 
human equivalent dose 
HERG 
human Ether-à-go-go Related Gene 
IB 
Investigator’s Brochure 
IC50 
50% inhibitory concentration 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
LBD 
ligand-binding domain 
LDH 
lactate dehydrogenase 
LDL 
low-density lipoprotein 
MAD 
maximum administered dose 
MED 
minimum efficacious dose 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
PCWG3 
Prostate Cancer Working Group 3 
PD 
pharmacodynamic(s) 
PET 
positron emission tomography 


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PK 
pharmacokinetic(s) 
PLD 
phospholipidosis 
PQC 
product quality complaint 
PSA 
prostate-specific antigen 
PT 
prothrombin time 
RECIST 
Response Evaluation Criteria in Solid Tumors  
RP2D 
recommended Phase 2 dose 
rPFS 
radiographic progression-free survival 
SAE 
serious adverse event 
SET 
safety evaluation team 
SHBG 
sex hormone-binding globulin 
SUSAR 
suspected unexpected serious adverse reaction 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
Definitions of Terms  
AUC 
area under the plasma concentration-time curve 
AUC0-24h 
area under the plasma concentration-time curve from time zero to 24 hours 
AUCτ 
area under the plasma concentration-time curve from time zero to 24 hours at steady state 
AUC∞ 
area under the plasma concentration-time curve from time zero extrapolated to infinite time 
AUClast 
area under the plasma concentration-time curve from time zero to the last time measured 
CL/F 
total apparent oral clearance 
Cmax 
maximum observed plasma concentration  
Cmaxss 
maximum observed plasma concentration at steady state 
Cmin 
observed plasma concentration at end of a dosing interval for each patient 
RA 
accumulation index 
STD10 
severely toxic dose in 10% of the rats at a given dose  
SUVmax-avg 
average maximum standardized uptake value 
t1/2 
apparent elimination half-life 
t1/2eff 
effective half-life 
tmax 
time of maximum observed plasma concentration 
t1/2term  
terminal half-life 
Vss/F 
apparent oral volume of distribution at steady state 
λz 
apparent terminal elimination rate constant, determined by linear regression using the 
terminal log-linear phase of the log transformed concentration vs. time curve 
 


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2. 
INTRODUCTION 
TRC253 is a high-affinity, small molecule antagonist of the androgen receptor (AR) with 
inhibitory activity against wild type AR and specific mutated variants of AR ligand binding 
domain. TRC253 blocks AR nuclear translocation as well as AR binding to DNA and is an 
antagonist of transcription for wild type AR and mutated AR. TRC253 is orally active and does 
not have agonist activity towards either the wild type or mutated ARs. TRC253 treatment in the 
Hershberger assay results in complete inhibition of androgen sensitive organ development. 
TRC253 is efficacious in an LNCaP xenograft model driven by F877L mutant AR.  The AR 
F877L mutation results in an alteration in the ligand binding domain that does not alter the 
response of AR to androgens, but does confer resistance to current AR inhibitors. TRC253 also 
inhibits other known AR resistance mutations, including L702H, in preclinical studies.  For the 
most comprehensive nonclinical and clinical information regarding TRC253, refer to the latest 
version of the Investigator's Brochure for TRC253.  
2.1. 
Background 
Activation of AR signaling is crucial for the growth of prostate cancer at all stages of the disease. 
It is of critical importance that even castration-resistant prostate carcinomas (CRPC) are still 
dependent on functional AR. Several molecular mechanisms have been proposed to explain this 
continued addiction of CRPC to a functional AR signal transduction pathway. These molecular 
mechanisms include AR overexpression as well as AR aberrations such as gene amplification, 
constitutively active splice variants, and point mutations. Amplification of the AR leading to AR 
overexpression and mutations in the ligand-binding domain (LBD) of AR in CRPC can render 
the receptor more sensitive to growth-stimulating effects of low androgen concentrations. By 
specifically targeting the known addiction to AR signaling, the first generation cytochrome P450 
(CYP) 17A1 inhibitor abiraterone acetate and the second generation AR inhibitor enzalutamide 
have been approved for the treatment of CRPC. Patients with CRPC taking these agents 
experience a clear therapeutic benefit, including extended overall survival, as well as marked 
responses in prostate-specific antigen (PSA) suppression, radiographic tumor response, and 
extended time to progression of their disease. However, despite the initial clinical benefit, 
resistance to these AR-targeting agents, evident by rising PSA serum levels in advance of 
radiographic tumor progression, develops in nearly all men with CRPC. Three different patterns 
of PSA biomarker response have been described to characterize the sensitivity and the emerging 
resistance to the second generation AR inhibitor enzalutamide (Figure 2) [1]. 
 
 


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Figure 2: 
PSA Changes Following Treatment With Enzalutamide in Patients with 
CRPC 
 
                                           Time on Enzalutamide Therapy (Weeks) 
Abbreviations: CRPC = castration-resistant prostate cancer; PSA = prostate-specific antigen. 
Source: Rathkopf D, Scher HI. Androgen receptor antagonists in castration-resistant prostate cancer. Cancer J. 2013; 19(1):43-49. 
The emergence of an “acquired resistance” to enzalutamide is characterized by an initial decline 
of PSA serum levels of ≥50% compared to the baseline serum level at treatment week 12, 
followed by a slow PSA rise up to or close to baseline serum levels up to treatment week 60.  
The molecular mechanisms leading to intrinsic and acquired resistance to anti-androgen 
therapies of CRPC have been extensively studied, and one of the prevailing hypotheses is 
outlined in Figure 3 [2]. It appears that the selective pressure exerted by currently used 
AR-targeting therapies leads to the emergence of specific molecular resistance mechanism. 
According to this model, resistance to androgen deprivation therapy and first generation 
anti-androgens appears to be driven by AR amplification, overexpression, or mutation. Tumor 
clones acquiring these AR phenotypes remain addicted to AR and are sensitive to second 
generation anti-androgens such as enzalutamide and apalutamide.  
However, in a next step the CRPC clones acquire AR mutations or AR variants which render 
them insensitive to second generation anti-androgens. Certain mutations in the LBD of AR, 
including the recently described F877L missense mutation (i.e., substitution of phenylalanine by 
leucine at position 877 in the LBD), have been shown to mediate this acquired resistance by 
switching second generation AR antagonists to agonists and thus promoting tumor growth [3-5]. 
TRC253 has been specifically developed to inhibit these AR LBD resistance mutations arising in 
response to second generation anti-androgen therapies. Thus, TRC253 will address a currently 
unmet medical need. It is expected that treatment with TRC253 will re-sensitize these tumors to 
AR-inhibition after disease progression on a prior second generation anti-androgen therapy. To 
PSA Decline from baseline (%) 


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determine the RP2D of TRC253, positron emission tomography (PET) imaging using a 
radiolabeled analog of dihydrotestosterone (16β [18F]fluoro-α-dihydrotestosterone [FDHT]) will 
be used as a pharmacodynamic (PD) marker to define binding to AR. To maximize the clinical 
benefit of TRC253, patients will be screened for LBD mutations in Part 2 (dose expansion), and 
segregated into three cohorts: those with F877L mutant AR, those with sole L702H mutant AR, 
and those without either of these mutations. 
To better understand the resistance markers at baseline and those that may emerge during 
treatment, patients will be screened for AR alterations, including AR amplification, and 
additional high-risk markers, including ARV7 before, during, and after therapy. 
Figure 3: 
Mechanisms of Resistance to AR-directed Therapies [2] 
 
Abbreviations: ADT = androgen deprivation therapy; AR = androgen receptor. 


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2.2. 
Summary of Nonclinical Studies 
2.2.1. 
Nonclinical Pharmacology  
In vitro radioligand binding data demonstrate that TRC253 is a potent competitive binder of AR 
with high affinity for the receptor. Furthermore, TRC253 binding to AR was demonstrated to be 
selective. 
In reporter assay systems, TRC253 demonstrated potent antagonistic activity against both wild 
type AR and AR F877L. Moreover, TRC253 showed no agonistic activity in the wild type AR 
and AR F877L in these assays. In the VP-16 AR reporter assay, TRC253 inhibited androgen-
induced DNA binding of AR (wild type and F877L) without agonistic activity. TRC253 blocked 
androgen-induced nuclear translocation of the AR and did not induce translocation in the 
absence of androgen. 
The ability of TRC253 to inhibit other clinically relevant AR resistance mutations within the 
ligand binding domain was analyzed. These data demonstrate that TRC253 is an effective 
antagonist of mutations in the AR ligand binding domain, including L702H,  with nearly no 
agonist activity. 
The molecular activity of TRC253 determined in receptor binding or reporter assays as the 
estimated 50% inhibitory concentration (IC50) is summarized in the Investigator’s Brochure and 
the table below. 
Table 3: 
Molecular Activity of TRC253 Determined in Receptor Binding or Reporter 
Assays 
Androgen Receptor 
IC50 (µM) 
Method 
AR wild type 
0.0069 
Binding assay 
AR Mutations 
AR-F877L 
0.099  
Reporter assay 
AR-T878A 
6.81  
Reporter assay 
AR-L702H 
10  
Reporter assay 
AR-W742C 
12.3  
Reporter assay 
AR-H875Y 
16.8   
Reporter assay 
Abbreviations: AR = androgen receptor; IC50 = estimated 50% inhibitory concentration. 
TRC253 inhibits the androgen-dependent proliferation of wild type AR- and mutant F877L-
driven tumor cells in vitro. TRC253 did not stimulate tumor cell proliferation in the absence of 
androgen in any of the tested cell lines in vitro. 
As expected from the mechanism of action of AR inhibition, TRC253 is a potent antagonist of 
androgen-sensitive organ development in vivo. 
TRC253 treatment led to complete stasis of tumor growth inhibition in a F877L-driven xenograft 
at 30 mg/kg once daily in the morning dosing. In a tumor xenograft expressing wild type AR, 
TRC253 resulted in complete stasis at 30 mg/kg. 


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2.2.2. 
Safety Pharmacology 
Cardiovascular safety was evaluated in vitro and in Good Laboratory Practice (GLP) in vivo 
studies. In a human Ether-à-go-go Related Gene (hERG assay; non-GLP), TRC253 inhibited the 
membrane K+ current with an estimated IC50 of 2.8 μM. In a human cardiomyocyte assay, 
TRC253 reduced the amplitude of the Ca2+ transients at 0.3 to 3 µM, increased the beat rate at 3 
µM, and stopped cell beating at 10 and 30 µM, and no “arrhythmia-like” activities (such as early 
after depolarization-like or ventricular fibrillation-like) were noted. In GLP studies in beagle 
dogs dosed orally with TRC253, dose-dependent heart rate-adjusted QT prolongation occurred 
after single doses of 10, 20, and 40 mg/kg and after repeated dosing for 28 days at 7.5 and 
25 mg/kg/day but not at 2.5 mg/kg/day. After a 28-day recovery for the 25 mg/kg/day group, all 
electrocardiogram (ECG) measurements were within normal limits, indicating that 
cardiovascular effects were completely reversible. 
No notable clinical signs related to effects on the respiratory system were noted in 
Sprague-Dawley rats treated with up to 100 mg/kg/day of TRC253 in a GLP 28-day oral toxicity 
study. 
TRC253 did not induce convulsions in mice dosed orally for 3 days at 200 mg/kg/day. In a 
functional observation battery conducted as part of a GLP repeat-dose toxicity study, there were 
no central nervous system-related findings in male rats administered single oral doses up to 
100 mg/kg/day (high dose). Central nervous system safety was also confirmed by the absence of 
central nervous system -related clinical observations up to the high dose of 120 mg/kg/day in rats 
and 30 mg/kg/day in dogs in non-GLP 14-day oral toleration studies and up to the high dose of 
100 mg/kg/day in rats and 25 mg/kg/day in dogs in GLP 28-day oral toxicity studies. 
2.2.3. 
Pharmacokinetics and Product Metabolism in Animals 
In male animals (mouse, rat, dog, and monkey), TRC253 is a low clearance molecule with a 
large volume of distribution (6-20 L/kg) and high oral bioavailability (79% to 91% except in 
mouse). The apparent elimination half-life (t1/2) after an oral dose was longer in the dog and 
monkey (58 and approximately 50 hours) than in the mouse and rat (approximately 6 and 
8 hours). In vitro plasma protein binding of TRC253 (1 to 20 µg/mL) was concentration 
dependent and generally similar for male animals and male humans, with the % free fraction 
ranging from 9.2% to 18.3% and 13% to 15.4%, respectively. Consistent with the large volume 
of distribution, extensive tissue distribution was observed in rats. 
After repeated oral administration, absorption was moderate to slow in the male rat and dog 
dosed for up to 28 days (time of maximum observed plasma concentration [tmax] generally 2 to 
7 hours), in tumor-bearing castrated mice dosed for 8 days (tmax 4 hours), and in castrated rats 
dosed for 10 days (tmax 3 to 14 hours). The dose-exposure relationship was generally nonlinear 
and there was evidence of accumulation in the rat and dog. 
Limited metabolism was observed in human liver microsomes and hepatocytes (human, rat, and 
dog) in vitro. Although TRC253 is not highly metabolized, flavin-containing monooxygenases 1 
and 3 and CYP3A4 are shown to be involved in the metabolism of the compound. 
In vivo metabolism of TRC253 was studied in the male rat after a single oral administration of 
14C-TRC253. Consistent with in vitro data, limited in vivo metabolism was observed with at least 


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80% of unchanged drug recovered in the urine and feces. M5, a pharmacologically inactive 
phenolic metabolite formed by oxidative dealkylation, was predominant in plasma (9.8% of the 
total drug related radioactivity) and was also present at low levels in urine and feces. After oral 
dosing, 92.9% of the radioactive dose was recovered in urine (17.7%) and feces (75.2%) within 
96 hours post-dose. Fecal-biliary excretion of unchanged drug appears to be the major 
elimination pathway in the male rat. 
In CYP induction and inhibition studies, TRC253 was not an inducer of human CYPs 1A2, 2B6, 
or 3A4 at concentrations up to 10 µM (not assessed at 30 µM due to cytotoxicity) and was not an 
inhibitor of CYPs 1A2, 2A6, 2C8, 2C9, 2D6, 2E1, or 3A4 at concentrations up to 100 µM. 
TRC253 was a weak inhibitor of CYPs 2B6 and 2C19 (IC50 values of 52 and 97 µM, 
respectively); however, significant drug-drug interactions are not expected at the predicted 
maximum observed plasma concentration at steady state (Cmax,ss; 206 ng/mL; 0.41 M to 
2,688 ng/mL; 5.3 M) at the proposed clinical dose range 40 mg to 480 mg (highest proposed 
dose)/daily in this first-in-human study. 
In drug efflux transporter studies, TRC253 was a substrate but not an inhibitor of multi-drug 
resistance protein 1, and was neither a substrate nor an inhibitor of breast cancer resistance 
protein. 
2.2.4. 
Toxicology 
After a single oral dose up to 300 mg/kg, there was no mortality in the rat. 
In GLP repeat-dose toxicity studies, TRC253 was administered by oral gavage to male 
Sprague-Dawley rats (0, 25, 50, and 100 mg/kg/day) and male beagle dogs (0, 2.5, 7.5, and 
25 mg/kg/day) for 28 days followed by a 28-day recovery period for the control and high-dose 
groups. Microscopic findings consistent with exaggerated pharmacology (anti-androgenic) in 
animals were observed in all doses in both species. A dose-related increase in the severity and 
incidence of phospholipidosis (PLD) in numerous tissues was observed in rats at ≥50 mg/kg/day 
and in dogs at ≥7.5 mg/kg/day. Elevated urinary di-22:6-bis(monoacylglycerol)phosphate levels 
(a noninvasive biomarker for PLD), positive lysosome-associated membrane protein-2 
immunohistochemical staining, presence of vacuolated lymphocytes in blood smear evaluation, 
and transition electronic microscopy confirmed the occurrence of PLD. Findings considered to 
be effects secondary to PLD were also noted in both species. In the rat, these included vascular 
changes (vascular/perivascular infiltrates) in various tissues at ≥50 mg/kg/day, and 
degeneration/necrosis in the kidney, liver, and skeletal muscle at 100 mg/kg/day. In the dog, 
these included vacuolar degeneration of bile duct and mixed cell inflammation at 
≥7.5 mg/kg/day, and hepatocyte necrosis and portal fibrosis at 25 mg/kg/day. Following the 
recovery period, these findings were partially to fully reversible. Additional findings at 25 mg/kg 
in the dog were hyaline cast and glomerulopathy in the kidneys which completely recovered and 
necrosis in the bone marrow which partially recovered. Based on these findings, the 
No Observed Adverse Effect Level for 28-day administration was the low dose of 25 mg/kg/day 
for the male rat (Day 28: Cmax 1,390 ng/mL, area under the plasma concentration-time curve 
from time zero to 24 hours [AUC0-24h] 23,100 ng.h/mL) and 2.5 mg/kg/day for the male dog 
(Day 28: Cmax 1,360 ng/mL, AUC0-24h 25,700 ng.h/mL). 


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TRC253 did not demonstrate genotoxic potential in a GLP Ames assay or in GLP in vitro and in 
vivo micronucleus tests. 
2.3. 
Overall Rationale for the Study 
Anti-androgen therapy is an effective treatment for a large number of men with advanced 
prostate cancer. Androgen receptor antagonists such as enzalutamide and apalutamide have 
demonstrated clinical activity by (1) suppressing the rise of PSA, (2) by inducing radiographic 
tumor responses, (3) by extending time to tumor progression, and (4) in the case of enzalutamide, 
by extending survival. However, the long-term clinical benefit of AR antagonists is restricted by 
the occurrence of molecular resistance in prostate cancer, as evidenced by rising PSA in advance 
of radiographic progression.  
TRC253 was developed to address specific mechanisms of resistance to AR antagonists and to 
meet the medical need of prostate cancer patients whose disease has progressed despite and after 
treatment with enzalutamide or apalutamide.  
This study will be the first-in-human (FIH) study of TRC253 in patients with metastatic CRPC. 
The study will consist of a dose escalation phase followed by an expansion phase. The purpose 
of dose escalation is to identify a TRC253 dose and regimen that can be safely administered to 
patients with advanced prostate cancer. The purpose of dose expansion is to further characterize 
the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the RP2D as well as to 
explore clinical activity. 
2.4. 
Phase 1 and Phase 2 253PC101 Ongoing Study Results 
Twenty-two patients participated in the dose escalation portion of the study and initially enrolled 
at TRC253 doses of 40 (n=1), 80 (n=1), 160 (n=2), 240 (n=6), 280 (n=2), and 320 mg (n=10) 
and 12 have enrolled in the expansion portion.  Although only 2 patients initially enrolled at 280 
mg, 1 patient initially dosed at 240 mg dose escalated to 280 mg and 2 patients dosed at 320 mg 
dose reduced to 280 mg after the first dose; thus, a total of patients were evaluated at 280 mg 
prior to determination of the RP2D. There were no deaths, no drug-related serious adverse events 
(SAEs), and no grade 4 adverse events (AEs).   
The maximum tolerated dose was not reached.  However, the single DLT observed in the study 
of grade 3 QTcF prolongation occurred at the 320 mg dose level and steady state drug exposure 
at the 320 mg dose level significantly exceeded the target concentration.  Therefore, dose 
escalation did not proceed to the 400 mg dose level and the 280 mg dose level was explored and 
declared the RP2D based on the lack of DLT and consistent steady state exposures above the 
target concentration.  In general, TRC253 has been well-tolerated.  Three patients discontinued 
due to AEs: 1 patient discontinued due to spinal cord compression secondary to disease 
progression, and 2 patients discontinued due to QTcF prolongation, both of which were 
suspected related to TRC253.  Prolongation of QTcF of grade 1 or 2 severity has been seen in the 
majority of patients and requires serial monitoring of ECGs. 
  
 


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2.4.1. 
 Phase 1 and Phase 2 253PC101 Ongoing Study Results – Safety 
Patients have received TRC253 for up to 49 weeks of treatment.   
As of 18 Jan 2019 data are available for 34 patients with mCRPC who have received at least 1 
dose of TRC253 in part 1 or part 2.  There were no deaths, and no grade 4 adverse events (AEs).  
There were 12 SAEs (all grade 3), all considered unrelated to TRC253 investigational drug.  
There was a single dose limiting toxicity (DLT) of grade 3 QTcF prolongation in a patient who 
received 22 days of continuous daily dosing of 320 mg of TRC253.  This patient remained on 
study at a reduced of 240 mg and discontinued the study due to patient decision without further 
grade 3 toxicity.  One additional patient with a pre-existing right bundle branch block dosed at 
240 mg experienced grade 3 QTcF prolongation after 28 days of continuous daily dosing and 
continued on study without subsequent grade 3 QTcF prolongation for 12 months prior to 
discontinuing the study due to disease progression.  One additional patient dosed at 320 mg had 
> 60 msec increase in QTcF from baseline (grade 2) after 28 days of continuous daily dosing 
(cycle 3 day 1) and discontinued the trial due to this event as per institution policy.  One 
additional patient dosed at 240 mg also had > 60 msec increase in QTcF from baseline (grade 2) 
at his 28-day follow-up visit; the patient had discontinued study drug approximately 28 days 
earlier and TRC253 was not detected in plasma; therefore this event was considered unrelated to 
TRC253.  There were no DLTs and no grade 3+ toxicities at the 280 mg dose level, which was 
determined to be the recommended phase 2 dose (RP2D).  Twelve patients have enrolled in the 
dose expansion portion of the trial (part 2).  One patient initiated dosing at 240 mg daily and 
subsequently dose escalated to 280 mg.  All other patients initiated dosing at 280 mg daily.   
Overall, 3 patients have discontinued due to AEs: 1 patient discontinued due to spinal cord 
compression secondary to disease progression and 2 patients discontinued due to QTcF 
prolongation, both of which were suspected to be related to TRC253.  The most common adverse 
drug reaction that was considered at least possibly related to TRC253 study drug in the ongoing 
253PC101 study was QTcF prolongation. Twenty-two of 34 patients (65%) experienced QTcF 
prolongation: 17 (50%) with grade 1 QTcF prolongation, three (6%) with grade 2, and two 
patients (6%) with grade 3.    Other adverse events occurring in ≥ 2 patients considered at least 
possibly related to TRC253 study drug (as assessed by the clinical investigators) include: fatigue 
(7 patients, 20.59%), vomiting (3 patients, 8.82%), and diarrhea, nausea, and peripheral edema, 
increased aspartate aminotransferase (2 patients each, 5.88%).  All other adverse events 
considered at least possibly related to TRC253 study drug were grade 1 or 2 and occurred in a 
single patient.  
2.4.2. 
 Phase 1 and Phase 2 253PC101 Ongoing Study Results – Efficacy 
Two patients have had partial responses. One F877L mutation patient had a stable PSA for 8 
months, developed a RECIST defined radiographic partial response one month following dose 
escalation to 240 mg.  This patient was on study for 12 months and discontinued the study due to 
disease progression.  An additional patient without any AR mutations had a radiographic partial 
response after 3 months of daily dosing; this patient discontinued the study due to a rising PSA 
approximately 6 months later. 
The incidence of the F877L mutation in this patient population is lower than originally 
anticipated.  However, patients with the L702H mutation have shown promising anti-tumor 


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activity as follows.  One patient dosed at 160 mg had a >50% PSA decrease, and remained on 
study with radiographic stable disease for 10 months prior to withdrawing from the study for 
disease progression.  Two additional patients dosed at 280 mg had PSA declines as follows: 
30.1% PSA decline in a patient who is ongoing in cycle 8; and a 40% PSA decline by cycle 3 
day 1 in another patient; however, this patient discontinued the trial in cycle 5 due to QTcF 
prolongation (60 msec increase from baseline, grade 2). 
2.4.3. 
This amendment includes a new cohort of 15 patients with sole L702H mutation. 
Phase 1 253PC101 Study Results – Pharmacokinetics  
In Study 253PC101, TRC253 demonstrated a relatively long half-life (>24 hours); steady state 
was generally achieved after 4 weeks of daily dosing.  Plasma concentrations of TRC253 
following 1 week of daily dosing at 280 mg and 320 mg consistently exceeded the target 
concentration of 335 ng/mL associated with activity in preclinical models. 
2.5. 
Potential Risks and Benefits to Human Patients 
2.5.1. 
Potential Risks 
TRC253 
The most common adverse drug reaction that was considered at least possibly related to TRC253 
study drug in ongoing 253PC101 study was QTcF prolongation.  Two patients dosed at 320 mg 
of TRC253 discontinued due to QTcF prolongation considered related to TRC253.  The 
inclusion criterion related to QTc states that patients must have QTcF less than 450 ms to be 
eligible for enrollment.  Any QTcF greater than 450 ms (on the average of 3 readings taken 
approximately 2 minutes apart for each time point), but less than 480 ms, is considered a grade 1 
AE per CTCAE criteria version 4.03. 
Investigative sites did not list each instance of QTcF prolongation as an AE in the database; thus, 
the incidence of worst grade QTcF prolongation across all patients treated was calculated based 
on available ECG data.  All 34 patients treated on study as of the time of this writing had 
available ECG data.  Twenty-two of 34 patients (65%) experienced QTcF prolongation: 17 
(50%) with grade 1 QTcF prolongation, 3 (6%) with grade 2, and 2 patients (6%) with grade 3.  
Two patients discontinued study treatment due to QTcF prolongation and 1 patient dose reduced.  
One patient dosed at 240 mg, who had a screening QTcF of 448.5 ms and a baseline predose 
QTcF of 463.1 ms, had grade 3 QTcF prolongation (mean of 522 ms) five weeks after 
continuous daily dosing.  This patient had a pre-existing right bundle branch block that 
complicated automated the interpretation of ECG tracings.  Manual review by a cardiologist 
determined the QT interval was less than or equal to 480 ms.  This patient continued on study 
without subsequent grade 3 QTcF prolongation for 12 months prior to discontinuing for disease 
progression.  One DLT of grade 3 QTcF prolongation occurred in a patient receiving 320 mg 
three weeks after daily dosing.  This patient dose reduced to 240 mg and discontinued the study 
due to patient decision.  One additional patient dosed at 320 mg had > 60 ms increase in QTcF 
from baseline (grade 2 adverse event) after 4 weeks of daily dosing and discontinued the trial due 
to this event.  One patient dosed at 240 mg also had > 60 ms increase in QTcF from baseline 
(grade 2) 28-days following the last dose of study drug and TRC253 was not detected in plasma; 
therefore this event was considered unrelated to study drug.  At the RP2D of 280 mg, 6 out of the 


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15 patients experienced grade 1 QTcF prolongation (40%) and 1 experienced grade 2 QTcF 
prolongation (7%) and grade 3 or higher QTcF prolongation was not observed.  
Because changes consistent with PLD were observed in repeated dose toxicity studies in rat and 
dog, patients administered TRC253 may be at risk for declines in respiratory function and liver 
and kidney disease.  However, renal or liver adverse events considered related to study drug have 
not been observed to date in the 34 patients treated in Part 1 or Part 2 of the 253PC101 study. 
There is limited clinical experience with TRC253 to date. Based on the mechanism of action, 
TRC253 may induce treatment-related adverse events described for other potent inhibitors of the 
AR pathway.  The following adverse events might be anticipated: asthenia and fatigue, nausea, 
diarrhea, arthralgia and musculoskeletal pain, hot flush, peripheral edema, and hypertension. 
Other Risks 
This study treatment may involve risks to unborn children therefore patients should not father a 
baby while participating in this study. Partners of patients should not nurse while on this study.  
Men with pregnant partners and men with non-pregnant partners that are of childbearing 
potential must agree to use at least two acceptable methods of birth control, one of which must 
be highly effective, during the study, and for 120 days after stopping TRC253. The long term 
risk of infertility is unknown. 
Acceptable birth control methods considered highly effective: 
• Bilateral tubal ligation 
• Intrauterine device (IUD) 
• Vasectomy that has received medical assessment of surgical success 
• Sexual abstinence* 
* In the context of this protocol, sexual abstinence is considered a highly effective method of 
birth control only if refraining from heterosexual intercourse during the entire period of risk 
(i.e., during study treatment, including temporary breaks from treatment, and for at least 120 
days after stopping TRC253). If sexual abstinence is the highly effective method of birth 
control used, a second acceptable method is not required. 
2.5.2. 
Potential Benefits 
TRC253 is an investigational product, and its efficacy has not been established. It is possible that 
the administration of TRC253 may result in clinical benefit (i.e., tumor response or prolonged 
stable disease). 
2.6. 
Conduct 
This clinical trial will be conducted in compliance with the protocol, GCP, and the applicable 
regulatory requirements. 


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3. 
TRIAL OBJECTIVES  
3.1. 
Primary Objectives: 
• Assess the safety of TRC253  
• Determine the recommended Phase 2 dose (RP2D) of TRC253 
• Evaluate prostate-specific antigen (PSA) response at Week 12 according to Prostate 
Cancer Working Group 3 (PCWG3) criteria (Appendix 2)  
3.2. 
Secondary Objectives: 
• Evaluate exposure-QTcF relationship 
• Determine the extent of receptor occupancy 
• Evaluate the preliminary anti-tumor effects of TRC253 
3.3. 
Exploratory Objective: 
• Determine effect of treatment on resistance markers 
 


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4. 
TRIAL ENDPOINTS 
4.1. 
Primary Endpoints 
• Safety: adverse events, vital sign measurements, ECG parameters, physical 
examinations, and clinical laboratory tests 
• RP2D of TRC253 
• PSA response: serum PSA at Week 12 according to PCWG3 (Appendix 2) 
4.2. 
Secondary Endpoints 
• PK parameters: maximum observed plasma concentration for each patient (Cmax), 
observed plasma concentration at end of a dosing interval for each patient (Cmin), time 
of maximum observed plasma concentration (tmax), area under the plasma 
concentration-time curve from time zero to 24 hours at steady state (AUCτ), area 
under the plasma concentration-time curve from time zero to the last time measured 
(AUClast), area under the plasma concentration-time curve from time zero 
extrapolated to infinite time (AUC∞), apparent terminal elimination rate constant (λz), 
effective half-life (t1/2eff), terminal half-life (t1/2term), accumulation index (RA), total 
apparent oral clearance (CL/F), and apparent oral volume of distribution at steady 
state (Vss/F)  
• Mean (90% confidence interval [CI]) change in QTcF at Cmax and slope (90% CI) 
• Time to PSA progression according to PCWG3 (Appendix 2) 
• Radiographic PFS (rPFS) according to PCWG3 (Appendix 3) 
• Central read of QTcF interval in part 2 
4.3. 
Exploratory Endpoints 
• Resistance markers assessed from circulating tumor cells (CTC) and circulating 
tumor DNA (ctDNA) 
• Standard Uptake Value (SUV) of FDHT PET scan 
 
 
 
 
 
 


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5. 
STUDY DESIGN AND RATIONALE 
5.1. 
Overview of Study Design 
This is a multi-center, first-in–human, open-label, Phase 1/2A dose-escalation study in which 
eligible patients with metastatic CRPC will receive oral doses of TRC253. The study will be 
conducted in 2 parts as shown in Figure 1. 
5.1.1. 
Part 1 (Dose Escalation) 
During Part 1 of the study, patients will be assigned sequentially to increasing TRC253 doses. 
The starting dose of TRC253 is 40 mg once daily in the morning, orally (see Section 5.4 for 
starting dose justification). TRC253 doses will be escalated in subsequent cohorts after all 
patients enrolled in a given cohort have completed the 28-day DLT evaluation period. Dose 
escalation in Part 1 will follow single-patient dose escalation design until initial drug-related 
toxicity occurs per Table 4. When an initial drug-related toxicity occurs per Table 4 or DLT per  
Table 6 in a single patient the cohort will be expanded according to 3+3 design rules. Cohorts 
may be expanded to include additional patients for purposes of collecting additional safety, PK, 
PD (FDHT-PET), and PSA response data. A single cohort may expanded to a maximum of 
twelve patients to help inform selection of a MED, as long as that dose level remains below the 
MTD (see below). 
Subsequent dose levels will enroll patients based on 3+3 design, whereby 3 patients will be 
initially enrolled and treated at each dose level. If one of these 3 patients experiences a dose-
limiting toxicity (DLT) during the initial 28-day evaluation period, the dose level will be 
expanded to 6 patients. The MTD will have been exceeded if ≥ 33% of patients experience DLT 
at a given dose level. DLT will have occurred when a patient has 1 or more toxicity listed in  
Table 6 that is at least possibly related to TRC253 during the first 28 days of dosing. Patients 
who exit the study for reasons other than DLT prior to completion of the 28-day DLT evaluation 
period will be replaced to ensure an adequate safety assessment in each cohort. Patients who 
experience DLT who receive less than the prescribed dose of TRC253 due to documented 
toxicity during the DLT evaluation period will be considered evaluable for dose escalation 
purposes. At the MTD or MED, up to 12 patients may be enrolled.   
 
 
 
 
 
 
 
 
 


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Figure 4: 
Single Patient Dose Escalation Schematic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: DLT=dose-limiting toxicity, MTD=maximum tolerated dose. 
 
Figure 5: 
3+3 Dose Escalation Schematic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: DLT=dose-limiting toxicity, MTD=maximum tolerated dose. 
 
3 treated patients  
per cohort 
DLT dose level or the maximum 
allowable dose has been reached. 
Evaluate the next lower dose cohort as 
the MTD 
Continue to dose escalate per 
Table 9  
> 1/3 patient with DLT  
 
1/3 patients with DLT 
 
0/3 patients with DLT  
Add 3 additional patients 
to the same cohort 
 
 1/6 patients with DLT 
 
≥2/6 or ≥33% patients 
with DLT 
1 treated patient  
per cohort 
1/1 patients with 
Table 4 toxicity or 
DLT 
0/1 patients with 
Table 4 toxicity  
Continue to dose escalate 
per Table 9  
Add 2 additional patients and 
move to 3+3 design rules 


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Dosing during the study will occur as follows:  
• The first cohort will receive the oral TRC253 starting dose of 40 mg daily.  
• The proposed TRC253 doses are 40 mg, 80 mg, 160 mg, 240 mg, 320 mg, and 400 
mg; however, intermediate dose levels may be implemented based on safety, 
tolerability, PK, PD and other observations at each dose level with consent of the 
medical monitor and Principal Investigators. Escalation to the next dose level will 
occur with consent of the medical monitor and treating Principal Investigators 
following review of safety, tolerability, PD and other observations at previous dose 
levels.   
• Intra-patient dose escalation is allowed. A patient may dose escalate to a dose level at 
or below the maximum tolerated dose (MTD) if (1) the new dose level has been 
declared safe by the medical monitor and Principal Investigators, (2) the medical 
monitor has been consulted, (3) the disease has not progressed, and (4) the patient has 
completed three 28-day cycles of treatment at a given dose level (multiple dose 
escalations are permitted).  
The MTD, maximum administered dose (MAD), minimum efficacious dose (MED), and RP2D 
are defined as follows: 
• Maximum-tolerated Dose: MTD is the highest TRC253 dose at which the probability 
of DLT is < 33% (or < 2 out of 6).  
• Maximum-administered Dose: MAD is the highest TRC253 dose administered in 
case the MTD cannot be defined.  
• Minimum Efficacious Dose: MED is defined as the lowest TRC253 dose 
administered at which PK, mean plasma trough concentration (Ctrough) >335 ng/mL 
(623 nM) with demonstrable PD and efficacy data. In addition, data from FDHT-PET 
scans may be used to confirm the MED.  
• Recommended Phase 2 Dose: RP2D will be equal to or below the MTD (or the 
MAD) and the MED. A lower dose of TRC253 may be selected as the RP2D on the 
basis of cumulative safety, PK, PD, and efficacy data. 
5.1.2. 
Part 2 (Dose Expansion) 
Part 2 will consist of three cohorts of initially up to 15 patients (Cohort 1), up to 30 patients 
(Cohort 2), and up to 15 patients (Cohort 3) to receive TRC253 at the RP2D of 280 mg. The 
objective of Part 2 is to gather additional information on the safety, PK and PD characteristics, 
and the clinical efficacy of TRC253 in a pre-defined population of patients with metastatic 
CRPC. Patients enrolled into Part 2 will have received prior treatment with enzalutamide or 
apalutamide. Patients will be centrally screened for the presence of the AR F877L and AR 
L702H mutations from a plasma sample and enrolled into Cohort 1 (AR F877L positive), Cohort 
2 (patients without AR F877L and without sole AR L702H mutations), or Cohort 3 (sole AR 
L702H mutation positive).  Note that Cohort 1 patients may be positive for F877L alone or 
F877L associated with any other AR mutation.  


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Cohort 1: metastatic CRPC patients with prior enzalutamide or apalutamide and with 
evidence of AR F877L mutation will be enrolled at the RP2D of 280 mg (AR F877L 
mutation positive).  Note that Cohort 1 patients may be positive for F877L alone or F877L 
associated with any other AR mutation. 
Cohort 2: metastatic CRPC patients with prior enzalutamide or apalutamide without evidence 
of AR F877L and sole AR L702H mutations but with a different AR mutation or any other 
mechanism of acquired resistance will be enrolled at the RP2D of 280 mg (AR F877L and 
sole AR L702H mutation negative). 
Cohort 3: metastatic CRPC patients with prior enzalutamide or apalutamide and with 
evidence of AR L702H mutation will be enrolled at the RP2D of 280 mg (sole AR L702H 
mutation positive). 
Figure 6: 
Part 2 Cohorts 
 
 
 
5.2. 
Dose-Limiting Toxicity 
Toxicities will be graded for severity according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.03.  
The DLT evaluation period is 28 days starting from the Cycle 2 Day 1 dose of TRC253 in Part 1 
due to the anticipated long half-life.  
Only patients who have received >75% of TRC253 doses during the DLT evaluation period will 
be considered evaluable. Patients who have received ≤75% of TRC253 doses during the DLT 
evaluation period due to reasons other than toxicities, such as but not restricted to disease 
progression, missed appointments, non-compliance, and patient withdrawal, will be considered 
non-evaluable for DLT and will be replaced with a new patient. 


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Table 4: 
Single Patient Dose Escalation  
Dose Escalation Will Proceed in the Absence of the Following Toxicities: 
Toxicity Category 
Drug-Related Toxicity and Grade 
Hematologic 
Grade ≥ 3 neutropenia for > 5 days 
Grade 3 febrile neutropenia 
Grade 3 thrombocytopenia 
Non-hematologic 
Grade ≥ 2 non-hematological toxicity, with the following 
exceptions: 
• Grade 2 nausea, vomiting, or diarrhea responsive to 
symptomatic treatment 
• Grade 2 fatigue in a patient with Grade 1 fatigue at baseline 
• Transient grade 2 laboratory abnormality that the 
investigator does not believe is clinically significant 
Grade ≥ 2 QTcF prolongation or increase in QTcF of > 30 ms from 
baseline 
Missing > 7 days doses for toxicity in Cycle 2 
 
Table 5: 
Decision Rules for 3+3 Dose Escalation 
Number of patients with DLT 
in a given dose cohort 
Escalation Decision Rules 
0 out of 3 
Proceed to the next dose cohort. 
1 out of 3 
Enter more patients up to a total of 6 patients into this dose cohort. 
1 out of 6 
Proceed to the next dose cohort. 
>1 out of 3 
Stop dose escalation.   
Declare this dose cohort as the DLT dose level.   
Enroll additional patients up to a total of 6 patients into the next 
lower dose cohort, if <6 patients were treated previously. 
≥2 out of 6 
Stop dose escalation. 
Declare this dose cohort as the DLT dose level.   
Enroll additional patients up to a total of 6 patients into the next 
lower dose cohort, if <6 patients were treated previously. 
 
Table 6: 
3+3 Dose Escalation DLT Definition and Criteria 
Toxicity Category 
Drug-Related Toxicity and Grade 
Hematologic 
Grade 4 neutropenia for > 5 days 
Grade 3 febrile neutropenia 
Grade 3 thrombocytopenia with hemorrhage or Grade 4 
thrombocytopenia 
Non-hematologic 
Grade ≥ 3 non-hematological toxicity, with the following 
exceptions: 
• Grade 3 nausea, vomiting, or diarrhea lasting < 72 hours in 
the absence of maximal medical therapy 
• Grade 3 fatigue < 5 days 
Grade ≥ 3 QTcF prolongation or increase in QTcF of > 60 ms from 
baseline 


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Missing > 7 days doses for toxicity in Cycle 2 
 
Grade ≥ 1 seizure 
5.3. 
Study Design Rationale 
The purpose of Part 1 (dose escalation) is to identify a TRC253 dose and regimen that can be 
safely administered to patients with advanced cancer. The purpose of Part 2 (dose expansion) is 
to further characterize the safety, PK, and PD of the recommended dose as well as to explore 
clinical activity.  In addition, the clinical activity of TRC253 in patients with metastatic CRPC 
whose tumors harbor an acquired resistance to enzalutamide or apalutamide driven by the AR 
F877L mutation (Cohort 1), a yet unknown mechanism sensitive to TRC253 treatment 
(Cohort 2), or the sole AR L702H mutation (Cohort 3) will be explored. 
5.4. 
Starting Dose Rationale 
The TRC253 starting dose for this study is 40 mg once daily in the morning. This TRC253 
starting dose is less than the safe starting dose according to Food and Drug Administration 
(FDA) guidelines for oncology agents in cancer patients, using nonclinical safety data.  
The selection of the TRC253 starting dose is supported by toxicology results obtained in the rat 
as the most sensitive species. In the rat, the severely toxic TRC253 dose in 10% of the rats 
(STD10) was determined to be 100 mg/kg. The human equivalent dose (HED) was calculated by 
normalization of the TRC253 dose to the body surface area. A default safety factor of 10 was 
applied to provide a margin of safety for protection of human patients relative to STD10 and a 
TRC253 dose of 60 mg/m2 was determined. In consequence, for a human with a surface area of 
1.8 m2, the highest potential starting dose was calculated to be 108 mg. 
However, the final selection of the starting dose was ultimately based on the potential 
pharmacologic activity of TRC253. Pharmacologic efficacy parameters were obtained from the 
LNCaP F877L mouse xenograft model and the Hershberger assay that assessed the effect of 
TRC253 on androgen dependent organ development) to estimate the potential efficacious 
TRC253 concentration and plasma exposure in humans. Applying these parameters, a TRC253 
starting dose of 65 mg once daily was projected to achieve the median target human exposure 
(335 ng/mL) over the 24 hr dosing interval.  A dose of 40 mg per day was therefore selected to 
provide for a starting dose expected to be safe without causing complete AR receptor occupancy. 
 
 
 


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6. 
INVESTIGATIONAL PLAN 
6.1. 
Study Procedures 
6.1.1. 
Trial Overview 
The study is divided into 3-4 periods: a Pre-Screening Period (Part 2 only), a Screening Period, a 
Treatment Period, and an End of Treatment/Follow-up Period. The Schedules of Assessments 
(Table 7 and Table 8) summarize the frequency and timing of efficacy, PK, PD, biomarker, and 
safety measurements applicable to this study.  
Adverse events and concomitant therapies will be recorded from signing of informed consent 
through 28 days post dose or patient’s participation in the study if the last scheduled visit occurs 
at a later time. Follow-up toxicity assessments will be obtained monthly until study treatment-
related toxicities have resolved (baseline or ≤ Grade 1) or are deemed irreversible. 
6.1.2. 
Pre-Screening Period (Part 2 Only) 
Blood samples will be collected and screened for LBD mutations of the AR using a ctDNA 
based assay. Up to 15 patients whose blood samples test positive for the AR F877L mutation will 
be enrolled into Cohort 1.  Up to 30 patients without the AR F877L and without sole AR L702H 
mutations will be enrolled into Cohort 2.  Up to 15 patients whose blood samples test positive for 
the sole AR L702H mutation will be enrolled into Cohort 3.Note that Cohort 1 patients may be 
positive for F877L alone or associated with any other AR mutation.  
Potential patients must sign the separate ICF authorizing the collection, transfer, storage, and 
processing of the AR mutation sample(s) for genetic research. Consent must be obtained prior to 
collection of the first AR mutation sample. Participation in this genetic research is required for 
participation in the study. The status of the F877L and L702H mutations must be reported on the 
enrollment checklist in order to confirm eligibility and assignment to Cohort 1, 2, or 3.  
6.1.3. 
Screening Period 
Parts 1 and 2: 
All patients must sign the main ICF prior to the conduct of any study-related procedures. 
Screening procedures will be performed up to 28 days before the first dose of drug.  
During the Screening Period, medical history and eligibility criteria will be reviewed and a 
complete clinical evaluation will be performed, which includes a physical examination, vital 
signs measurements, physical measurements, and ECG. A brain MRI (or if contraindicated, CT) 
scan will be performed to determine eligibility.  
Laboratory tests (performed at the local laboratory) noted in the inclusion criteria (Section 7.2) 
must be within the limits specified in the inclusion criteria prior to the start of dosing.  
Prior therapies will be recorded. 


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6.1.4. 
Treatment Period 
Laboratory tests do not need to be repeated at cycle 1 day 1 if they were completed within 7 days 
prior in screening. 
Part 1 Cycle 1 
Patients will receive a single dose of TRC253 on Cycle 1 Day 1 for PK studies. No food should 
be consumed for at least 8 hours before and 4 hours after the TRC253 dosing. Blood pressure 
and heart rate will be measured prior to dose administration and hourly (± 15 minutes) for the 
first 6 hours following the first dose of study drug administration on Cycle 1 Day 1. 
To aid in selection of the RP2D, patients may undergo PET scans using FDHT, a 
radiopharmaceutical specifically designed to image binding to AR. In these patients, FDHT-PET 
scans will be obtained before initiation of therapy. Imaging will occur at 1 or more centers under 
their existing IND and institutional protocol. 
Safety, PD, biomarker, and disease evaluations will be performed as specified in the Time and 
Events Schedule for Part 1 (Table 7). 
Treatment Cycles 
TRC253 capsules will be self-administered once daily in the morning from Cycle 1 Day 1 
onwards (Cycle 2 Day 1 onwards for Part 1). On extended PK days, no food should be consumed 
for at least 8 hours before and 4 hours after the TRC253 dosing. On all other days, no food 
should be consumed for at least 2 hours before and 1 hour after dosing. 
Safety, PK, PD, biomarker, and disease evaluations will be performed at the time points 
specified in the Schedules of Assessments (Table 7 and Table 8). 
Treatment will continue until one or more of the withdrawal criterion are met (refer to 
Section 7.4.3). 
Part 1: Once the first expansion cohort reaches its primary endpoint, patients from the dose 
escalation phase of the study who continue to derive benefit from TRC253 treatment will be 
allowed to stay on treatment and will attend monthly visits, which are to occur a minimum of 
once every 4 weeks (± 2 days).  
Part 2: Once the primary endpoint is reached in the expansion cohort, patients who continue to 
derive benefit from TRC253 treatment will be allowed to stay on treatment and will attend 
monthly visits, which are to occur a minimum of once every 4 weeks (± 2 days). 
Study procedures to be performed at the monthly visits are specified in the Schedules of 
Assessments (Table 8). 
6.1.5. 
End of Treatment and Follow-Up Period 
The End of Treatment visit will be 7 days (± 2 days) after the last dose of TRC253. 
The Follow-Up visit will be 28 days (± 7 days) after the End of Treatment visit. Study 
procedures to be performed at the follow-up visit are specified in the Schedules of Assessments 
(Table 7 and Table 8). Patients who have unresolved study-related toxicities will have extended 


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follow-up once monthly until study treatment-related toxicities have resolved (baseline or 
≤ Grade 1) or are deemed irreversible.


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Table 7: 
Part 1 Dose Escalation Schedule of Assessments   
Study 
Procedures 
Notes 
Screening 
 
Cycle 1 
(7 days) 
Cycle 2 
(28 days) 
Cycles 3+ 
(28 days) 
End of 
Treatment 
Follow-
Up 
(EOT+28 
days) 
Day -28 
Day 1 
Day 4 
Day 1 
Day 8 
Day 15 
Day 22 
Day 1 
Screening/Administrative 
Sign main 
informed 
consent form 
Informed consent must be 
obtained before any study-
related procedures. 
X 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
Brain MRI 
To determine eligibility. If 
MRI is clinically 
contraindicated, a brain CT 
will be performed. 
X 
 
 
 
 
 
 
 
 
 
Medical history and demographics 
X 
 
 
 
 
 
 
 
 
 
Prior therapies 
X 
 
 
 
 
 
 
 
 
 
Study Drug Administration 
Study Drug 
Administration 
On extended PK days, no 
food should be consumed for 
at least 8 hr before and 4 hr 
after TRC253 dosing. On all 
other days, no food should be 
consumed for at least 2 hrs 
before and 1 hr after dosing. 
Patients will dose in the clinic 
on all PK days. Patients will 
track meal times on their 
home dosing logs. 
 
X 
 
Continuous daily administration from Cycle 2 Day 1 until 
one or more withdrawal criterion is met (see 
Section 7.4.3). 
 
 
Safety Assessments 
Physical 
examination 
Full physical at screening, 
and targeted physical based 
on adverse events at 
subsequent visits. 
ECOG at screening. 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
BP, heart rate, respiration, 
and body temperature. 
In addition, on cycle 1 day 1, 
blood pressure and heart rate 
will be measured prior to 
dose administration and 
hourly (±15 minutes) for the 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Study 
Procedures 
Notes 
Screening 
 
Cycle 1 
(7 days) 
Cycle 2 
(28 days) 
Cycles 3+ 
(28 days) 
End of 
Treatment 
Follow-
Up 
(EOT+28 
days) 
Day -28 
Day 1 
Day 4 
Day 1 
Day 8 
Day 15 
Day 22 
Day 1 
first 6 hours following the 
first dose. 
Physical 
measurements 
Height and weight at 
screening. Weight only is 
taken prior to each cycle and 
at EOT visit. 
X 
 
 
X 
 
 
 
X 
X 
X 
Hematology 
Hemoglobin, RBC count, 
platelet count, WBC count 
with differential and absolute 
neutrophil count. 
X 
X 
 
X 
 
X 
 
X 
X 
(X) 
Coagulation 
PT, aPTT, INR, and 
fibrinogen. 
X 
 
 
X 
 
 
 
X 
X 
(X) 
Serum 
chemistry 
Serum chemistry parameters 
are listed in Section 12.1.2. In 
addition, direct bilirubin is 
evaluated at screening if total 
bilirubin is > 1.5 ULN. Iron 
studies (serum iron, ferritin, 
and total iron binding 
capacity). 
X 
X 
 
X 
 
X 
 
X 
X 
(X) 
Fasting lipid 
panel 
Total cholesterol, HDL 
cholesterol, LDL cholesterol, 
and triglycerides. 
X 
 
 
 
 
 
 
X 
(Every 3 
cycles: C3, 
C6, etc.) 
X 
 
TSH 
X 
 
 
 
 
 
 
X 
(Every 3 
cycles: C3, 
C6, etc.) 
X 
 
Urinalysis 
Urinalysis parameters are 
listed in Section 12.1.2. If 
dipstick result is abnormal, 
microscopy will be used to 
evaluate sediment. 
X 
X 
 
X 
 
 
 
X 
X 
 
12-lead ECG 
12-lead ECGs will be 
performed in triplicate 
(approximately 2 minutes 
between recordings) pre-dose 
at all visits indicated. In 
addition, ECGs will be 
performed predose, and 2, 4, 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 


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Study 
Procedures 
Notes 
Screening 
 
Cycle 1 
(7 days) 
Cycle 2 
(28 days) 
Cycles 3+ 
(28 days) 
End of 
Treatment 
Follow-
Up 
(EOT+28 
days) 
Day -28 
Day 1 
Day 4 
Day 1 
Day 8 
Day 15 
Day 22 
Day 1 
and 8 hrs postdose (± 15 min) 
on Cycle 1 Day 1 and Cycle 3 
Day 1. Refer to Section 8.5.3  
for management of QTcF 
prolongation. 
Pharmacokinetics and Pharmacodynamics 
Blood 
pharmacokinetic 
sampling 
Pharmacokinetic plasma 
samples will be obtained 
Cycle 1 as follows: 0 (pre-
dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8 
hr (± 15 min), and 24 hr (± 1 
hr), 72 hr (Day 4), and 168 hr 
(pre-dose on Cycle 2 Day 1); 
and on Cycle 3 Day 1 as 
follows: 0 (pre-dose), 0.5, 1, 
1.5, 2, 3, 4, 6, 8 hr (± 15 min). 
Additional PK after intra-
patient dose escalation may 
be performed if deemed 
appropriate. 
 
X 
(Extended 
PK 24 
hrs) 
X 
(Trough
) 
X 
(Trough) 
X 
(Trough
) 
X 
(Trough
) 
X 
(Trough
) 
X 
(Extended 
PK 8 hrs, 
C3 only) 
 
Then, 
trough on 
even cycles 
X 
(Trough) 
X 
(Trough) 
FDHT-PET 
Imaging to determine 
receptor occupancy will be 
assessed in select patients. 
Only to be completed at 
select institutions. 
(X) 
(within 7 
days of 
C1D1) 
 
 
 
 
 
 
(X) 
(Cycle 3 
only) 
 
 
Biomarkers 
AR mutation 
testing 
See lab manual for further 
instructions. 
X 
 
 
 
 
 
 
X 
(Cycle 5 
only) 
X 
 
CTC collection 
Enumeration and molecular 
profiling. See lab manual for 
further instructions. 
 
X 
 
 
 
 
 
X  
(Every 3 
cycles: C5, 
C8, etc.) 
 
X 
 
Testosterone, 
free 
testosterone, 
DHT, estradiol, 
DHEA-S, 
The appropriate amount of 
serum should be drawn to be 
analyzed locally. 
X 
(Testoster
one only) 
X 
 
 
 
 
 
X 
(Every 3 
cycles: C5, 
C8, etc.) 
X 
 


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Study 
Procedures 
Notes 
Screening 
 
Cycle 1 
(7 days) 
Cycle 2 
(28 days) 
Cycles 3+ 
(28 days) 
End of 
Treatment 
Follow-
Up 
(EOT+28 
days) 
Day -28 
Day 1 
Day 4 
Day 1 
Day 8 
Day 15 
Day 22 
Day 1 
androstenedione
, and SHBG 
Archival Tumor 
Tissue 
If available 
(X) 
 
 
 
 
 
 
 
 
 
Disease evaluations 
Serum PSA 
 
X 
X 
 
X 
 
 
 
X 
X 
 
CT or MRI scan 
of the chest and 
abdomen/pelvis 
EOT assessments do not need 
to be repeated if they were 
performed within 28 days 
while on treatment. 
X 
 
 
 
 
 
 
X  
(C4, then 
every 3 
cycles: C7, 
C10, etc.) 
 
X 
 
Radionuclide 
bone scan 
X 
 
 
 
 
 
 
X  
(C4, then 
every 3 
cycles: C7, 
C10, etc.) 
 
X 
 
Ongoing review 
Concomitant therapy 
Continuous from signing of informed consent through 28 days after EOT visit. 
Toxicity assessment/adverse events 
The allowable window for each visit within the cycle is ± 2 days unless otherwise stated. 
The allowable window for FDHT-PET, Follow-Up visit, and all scans is ± 7 days. 
(X) for an assessment at the Follow-Up (EOT+28 days) visit indicates the assessment does not need to be performed if there were no abnormalities 
observed for the assessment at the End of Treatment visit. 
Safety assessments (except for ECG) on C1D1 do not need to be repeated if they were completed within 7 days prior in screening.


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Table 8: 
Part 2 Dose Expansion Schedule of Assessments  
Study 
Procedures 
Notes 
Pre-
Screening 
Screening 
 
Cycle 1 
 (28 days) 
Cycles 2+ 
(28 days) 
End of 
Treatment 
Follow-
Up 
(EOT+28 
days) 
 
Day -28 
Day 1 
Day 8 
Day 15 
Day 22 
Day 1 
Screening/Administrative 
Sign genetic 
research 
informed 
consent form 
Informed consent for the AR 
mutation sample must be 
obtained prior to collecting 
the sample. 
X 
 
 
 
 
 
 
 
 
Sign main 
informed 
consent form 
Informed consent must be 
obtained before any study-
related procedures. 
 
X 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
 
X 
 
 
 
 
 
 
 
Brain MRI 
To determine eligibility. If 
MRI is clinically 
contraindicated, a brain CT 
will be performed. 
 
X 
 
 
 
 
 
 
 
Medical history and demographics 
 
X 
 
 
 
 
 
 
 
Prior therapies 
 
X 
 
 
 
 
 
 
 
Study Drug Administration 
Study Drug 
Administration 
For all dosing days, no food 
should be consumed for at 
least 2 hrs before and 1 hr 
after dosing. Patients will 
dose in the clinic on all PK 
days. Patients will track meal 
times on their home dosing 
logs. 
 
 
Continuous daily administration from Cycle 1 Day 1 until one or 
more withdrawal criterion is met (see Section 7.4.3 ). 
 
 
Safety Assessments 
Physical 
examination 
Full physical at screening, 
and targeted physical based 
on adverse events at 
subsequent visits. 
ECOG at screening. 
 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
BP, heart rate, respiration, 
and body temperature. 
In addition, on cycle 1 day 1, 
blood pressure and heart rate 
will be measured prior to 
dose administration and 
 
X 
X 
X 
X 
X 
X 
X 
X 


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Study 
Procedures 
Notes 
Pre-
Screening 
Screening 
 
Cycle 1 
 (28 days) 
Cycles 2+ 
(28 days) 
End of 
Treatment 
Follow-
Up 
(EOT+28 
days) 
 
Day -28 
Day 1 
Day 8 
Day 15 
Day 22 
Day 1 
hourly (±15 minutes) for the 
first 6 hours following the 
first dose. 
Physical 
measurements 
Height and weight at 
screening. Weight only is 
taken prior to each cycle and 
at EOT visit. 
 
X 
X 
 
 
 
X 
X 
X 
Hematology 
Hemoglobin, RBC count, 
platelet count, WBC count 
with differential and absolute 
neutrophil count.  
 
X 
X 
 
X 
 
X 
X 
(X) 
Coagulation 
PT, aPTT, INR, and 
fibrinogen. 
 
X 
X 
 
 
 
X 
X 
(X) 
Serum 
chemistry 
Serum chemistry parameters 
are listed in Section 12.1.2. In 
addition, direct bilirubin is 
evaluated at screening if total 
bilirubin is > 1.5 ULN. Iron 
studies (serum iron, ferritin, 
and total iron binding 
capacity). 
 
X 
X 
 
X 
 
X 
X 
(X) 
Fasting lipid 
panel 
Total cholesterol, HDL 
cholesterol, LDL cholesterol, 
and triglycerides. 
 
X 
 
 
 
 
X (Every 3 
cycles: C3, 
C6, etc.) 
X 
 
TSH 
 
X 
 
 
 
 
X (Every 3 
cycles: C3, 
C6, etc.) 
X 
 
Urinalysis 
Urinalysis parameters are 
listed in Section 12.1.2. If 
dipstick result is abnormal, 
microscopy will be used to 
evaluate sediment. 
 
X 
X 
 
 
 
X 
X 
 
12-lead ECG 
12-lead ECGs will be 
performed in triplicate 
(approximately 2 minutes 
between recordings) pre-dose 
at all visits indicated. On 
cycle 1 day 15, ECGs in 
triplicate will be completed 
pre-dose and 6 hours post-
 
X 
X 
X 
X 
(Pre-dose 
and 6 
hours 
post-
dose) 
X 
X 
X 
X 


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Study 
Procedures 
Notes 
Pre-
Screening 
Screening 
 
Cycle 1 
 (28 days) 
Cycles 2+ 
(28 days) 
End of 
Treatment 
Follow-
Up 
(EOT+28 
days) 
 
Day -28 
Day 1 
Day 8 
Day 15 
Day 22 
Day 1 
dose (+/- 15 min). Refer to 
Section 8.5.3  for 
management of QTcF 
prolongation. 
Pharmacokinetics and Pharmacodynamics 
Blood 
pharmacokinetic 
sampling 
Plasma samples will be 
obtained pre-dose. On cycle 1 
day 15, samples will be 
obtained pre-dose and 6 hours 
post-dose (+/- 15 min). 
 
 
X 
X 
X 
(Pre-dose 
and 6 
hours 
post-
dose) 
X 
X 
X 
X 
Biomarkers 
AR mutation 
testing 
See lab manual for further 
instructions. 
X 
 
 
 
 
 
X (Cycle 5 
only) 
X 
 
CTC collection 
Enumeration and molecular 
profiling. See lab manual for 
further instructions. 
 
 
X 
 
 
 
X (Every 3 
cycles: C4, 
C7, etc.) 
 
X 
 
Testosterone, 
free 
testosterone, 
DHT, estradiol, 
DHEA-S, 
androstenedione
, and SHBG 
The appropriate amount of 
serum should be drawn to be 
analyzed locally. 
 
X 
(Testosterone 
only) 
X 
 
 
 
X (Every 3 
cycles: C4, 
C7, etc.) 
X 
 
Archival Tumor 
Tissue 
If available 
 
(X) 
 
 
 
 
 
 
 
Disease evaluations 
Serum PSA 
 
 
X 
X 
 
 
 
X 
X 
 
CT or MRI scan 
of the chest and 
abdomen/pelvis 
EOT assessments do not need 
to be repeated if they were 
performed within 28 days 
while on treatment. 
 
X 
 
 
 
 
X 
(C3, then 
every 3 
cycles: C6, 
C9, etc.) 
 
X 
 
Radionuclide 
bone scan 
 
X 
 
 
 
 
X 
(C3, then 
every 3 
X 
 


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Study 
Procedures 
Notes 
Pre-
Screening 
Screening 
 
Cycle 1 
 (28 days) 
Cycles 2+ 
(28 days) 
End of 
Treatment 
Follow-
Up 
(EOT+28 
days) 
 
Day -28 
Day 1 
Day 8 
Day 15 
Day 22 
Day 1 
cycles: C6, 
C9, etc.) 
 
Ongoing review 
Concomitant therapy 
 
Continuous from signing of informed consent through 28 days after EOT visit. 
Toxicity assessment/adverse events 
 
The allowable window for each visit within the cycle is ± 2 days unless otherwise stated. 
The allowable window for Follow-Up visit and all scans is ± 7 days. 
(X) for an assessment at the Follow-Up (EOT+28 days) visit indicates the assessment does not need to be performed if there were no abnormalities 
observed for the assessment at the End of Treatment visit. 
Safety assessments (except for ECG) on C1D1 do not need to be repeated if they were completed within 7 days prior in screening.


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7. 
SELECTION AND WITHDRAWAL OF PATIENTS 
Investigators should ensure that all study enrollment criteria have been met at screening. If a 
patient's status changes (including laboratory results or receipt of additional medical records) 
after screening but before the first dose of study drug is given such that he no longer meets all 
eligibility criteria, supportive treatment may be administered, if necessary, so that eligibility 
criteria can be met and laboratory test(s) may be repeated once, to determine if the patient 
qualifies for the study. If enrollment criteria are not met after further evaluation, then the patient 
should be excluded from participation in the study. 
7.1. 
Patient Population 
Adult male patients ≥18 years of age with histologically confirmed adenocarcinoma of the 
prostate with metastatic disease are eligible for the study. 
Screening for eligible patients will be performed within 28 days before administration of the 
study drug. 
The inclusion and exclusion criteria for enrolling patients in this study are described in the 
following 2 subsections. If there is a question about the inclusion or exclusion criteria below, the 
investigator must consult with the appropriate sponsor representative and resolve any issues 
before enrolling a patient in the study. Waivers are not allowed.  
7.2. 
Patient Inclusion Criteria 
Each potential patient must satisfy all of the following criteria to be enrolled in the study: 
Part 1 Only 
1. Must have received at least 2 prior therapies approved for CRPC; including a prior AR 
inhibitor (e.g., enzalutamide or apalutamide). 
Part 2 Only 
1. Must have received enzalutamide or apalutamide. 
• 
 (Note: additional therapies approved for CRPC prior to enzalutamide or 
apalutamide are allowed). 
Parts 1 and 2  
1. Histologically confirmed adenocarcinoma of the prostate with metastatic disease. 
2. Male ≥18 years of age. 
3. Eastern Cooperative Oncology Group performance status of 0 or 1. 
4. Prior orchiectomy or serum testosterone levels <50 ng/dL determined within 4 weeks 
prior to start of study drug. 
5. Adequate baseline organ function as defined below: 


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Hematology 
Hemoglobin 
≥9 g/dL (or ≥90 g/L) with or without transfusion 
Platelet count 
≥75 x 109/L with or without transfusion 
Neutrophil count 
absolute neutrophil count ≥1.0 x 109/L  
Chemistry 
Total bilirubin 
≤1.5 times laboratory upper limit of normal 
(ULN); patients with Gilbert’s syndrome can 
enroll if conjugated bilirubin is within normal 
limits 
Alanine aminotransferase and 
aspartate aminotransferase 
≤2.5 times the ULN 
Serum creatinine 
<1.5 mg/dL, or a calculated or measured 
creatinine clearance >50 mL/min/1.73 m2 
Cardiac 
Electrocardiogram QTcF 
<450 ms  
(average of 3 readings approximately 2 minutes 
apart) 
6. Ongoing androgen depletion therapy with a gonadotropin-releasing hormone (GnRH) 
analog or inhibitor, or orchiectomy (i.e., surgical or medical castration). Note: patients 
who have not undergone orchiectomy must continue GnRH analog therapy for the 
duration of this protocol. 
7. For patients previously treated with first generation anti-androgens (i.e., flutamide, 
nilutamide, or bicalutamide), discontinuation of flutamide or nilutamide therapy must 
occur >4 weeks (>6 weeks for bicalutamide) prior to start of study drug with no evidence 
of an anti-androgen withdrawal response (i.e., no decline in serum PSA). 
8. For patients previously treated with chemotherapy targeted therapy, immunotherapy, or 
treatment with an investigational anticancer agent, discontinuation must have occurred ≥2 
weeks, or after at least 4 half-lives, whichever is longer, prior to study drug 
administration. For enzalutamide and apalutamide, the washout period will be at least 3 
weeks prior to start of study drug with no evidence of an anti-androgen withdrawal 
response (i.e., no decline in serum PSA). 
9. For patients previously treated with other agents approved for the treatment of prostate 
cancer (5-α reductase inhibitors, estrogens, others), discontinuation of therapy must have 
occurred ≥4 weeks prior to start of study drug. 
10. Palliative radiotherapy (to bone or soft tissue lesions) must be completed >2 weeks prior 
to start of study drug (exception: palliative radiotherapy for pain may be used any time 
prior to first dose).   
11. For patients receiving bone–loss prevention treatment (e.g., bisphosphonates or 
denosumab), the patient must be on stable dose ≥4 weeks prior to start of study drug. 


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12. A man who is sexually active with a woman of childbearing potential must agree to use at 
least two acceptable methods of birth control, one of which must be highly effective 
(Section 2.5.1) during the study and for 120 days after receiving the last dose of study 
drug. Note: a female condom and a male condom should not be used together as friction 
between the 2 can result in either product failing. All men must also not donate sperm 
during the study and for 120 days after receiving the last dose of study drug.   
13. Patient must be willing and able to adhere to the prohibitions and restrictions specified in 
this protocol. 
14. Each must sign an informed consent form (ICF) indicating that he understands the 
purpose of and procedures required for the study and is willing to participate in the study. 
Consent is to be obtained prior to the initiation of any study-related tests or procedures 
that are not part of standard-of-care for the patient’s disease. 
15. Each patient must initially sign a separate pre-screening informed consent form 
authorizing collection of the AR mutation sample(s) for genetic research. Consent must 
be obtained prior to collection of the first AR mutation sample. Participation in this 
genetic research is required for participation in the study. 
7.3. 
Patient Exclusion Criteria   
Any potential patient who meets any of the following criteria will be excluded from participating 
in the study:   
1. History of seizures. 
2. Previously documented or current brain metastases. 
3. Untreated spinal cord compression. 
4. Known positive test result for human immunodeficiency virus. 
5. History of clinically significant cardiovascular disease including, but not limited to: 
• Myocardial infarction or unstable angina within the 6 months prior to the first 
dose of study drug. 
• Clinically significant cardiac arrhythmia. 
• Uncontrolled (persistent) hypertension: systolic blood pressure >180 mmHg; 
diastolic blood pressure >100 mmHg. 
• Congestive heart failure (New York Heart Association class III-IV). 
• Use of pacemaker 
6. Known active or chronic hepatitis B or hepatitis C as demonstrated by hepatitis B surface 
antigen positivity and/or anti- hepatitis C virus positivity, respectively. Patients with 
clinically active or chronic liver disease, including liver cirrhosis of Child-Pugh class C, 
are also excluded. 
7. History of a different malignancy except for the following circumstances: (a) individuals 
with a history of other malignancies are eligible if they have been disease-free for at least 


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3 years or are deemed by the investigator to be at low risk for recurrence of that 
malignancy, (b) individuals with a history of treatment for the following cancers are 
eligible: non-muscle invasive bladder cancer, basal cell, or squamous cell carcinoma of 
the skin and resected melanoma in situ. 
8. Any serious underlying medical or psychiatric condition (e.g., alcohol or drug abuse), 
dementia or altered mental status or any issue that would impair the ability of the patient 
to receive or tolerate the planned treatment, to understand informed consent or that in the 
opinion of the investigator would contraindicate the patient’s participation in the study or 
that would confound the results of the study. 
9. Evidence of active viral, bacterial, or systemic fungal infection requiring systemic 
treatment within 7 days prior to the first dose of study drug. Patients requiring any 
systemic antiviral, antifungal, or antibacterial therapy for active infection must have 
completed treatment no less than 7 days prior to the first dose of study drug. 
10. Known allergies, hypersensitivity, or intolerance to TRC253 or its excipients (refer to 
Investigator's Brochure). 
11. Enrollment in another therapeutic study. 
12. Major surgery (e.g., requiring general anesthesia) within 3 weeks before screening, or has 
not fully recovered from prior surgery (i.e., unhealed wound), or surgery planned during 
the time the patient is expected to participate in the study. Note: patients with planned 
surgical procedures to be conducted under local anesthesia may participate. 
13. Plan to father a child while enrolled in this study or within 90 days after the last dose of 
study drug. 
14. Pre-existing chronic hypokalemia or hypomagnesemia. 
7.4. 
Patient Completion, Discontinuation, or Withdrawal 
7.4.1. 
Completion 
A patient will be considered to have completed the study if assessments have been completed 
through the follow-up visit, or if he experiences an event that precludes continuation of study 
treatment (death, disease progression, unacceptable toxicity). 
7.4.2. 
Discontinuation of Study Treatment 
A patient's study treatment must be discontinued if the investigator believes that for safety 
reasons or tolerability reasons (e.g., adverse event or disease progression) it is in the best interest 
of the patient to discontinue study treatment. The follow-up visit will be 28 days (± 7 days) after 
the patient discontinues study drug. Patients who have unresolved study-related toxicities will 
have extended follow-up. 
7.4.3. 
Patient Withdrawal Criteria 
A patient will be withdrawn from the study for any of the following reasons: 
1. Lost to follow-up or noncompliant 


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2. Withdrawal of consent 
3. The sponsor terminates the study 
4. Disease progression according to PCWG3 criteria (Appendix 2, Appendix 3) 
a. Patients may continue on study drug if in the opinion of the Investigator, patient is 
deriving benefit from continuation of therapy. Continuation of therapy must be 
approved by the Sponsor. 
5. Dose delay greater than 21 days  
Note: In part 1, only patients who have received >75% of TRC253 doses during the DLT 
evaluation period will be considered evaluable. Patients who have received ≤75% of 
TRC253 doses during the DLT evaluation period due to reasons other than toxicities, 
such as but not restricted to disease progression, missed appointments, non-compliance, 
and patient withdrawal, will be considered non-evaluable for DLT and will be replaced 
with a new patient. 
6. Patients with AST or ALT elevations >5X ULN, or who meet Hy’s Law criteria, i.e., 
concurrent elevation of AST or ALT >3X ULN and total bilirubin >2X ULN 
7. Grade 4 adverse events 
8. Patients who experience QTcF prolongation > 500 ms or > 60 ms change from baseline 
without electrolyte abnormalities and without response to TRC253 (See Section 8.5.3) 
If a patient discontinues study drug and withdraws from the study, the off-study visit assessments 
should be obtained.  
If a patient is lost to follow-up, every reasonable effort must be made by the study-site personnel 
to contact the patient and determine the reason for discontinuation/withdrawal. The measures 
taken to follow up must be documented. 
Study drug assigned to the withdrawn patient may not be assigned to another patient. Patients 
who withdraw for reasons other than toxicity will be replaced at the discretion of the sponsor.  
If the patient withdraws consent, no further evaluation should be performed and no further 
attempt should be made to collect additional data. Data and samples that have already been 
collected will still be used as outlined in this study. 
7.5. 
Prohibitions and Restrictions 
Potential patients must be willing and able to adhere to the following prohibitions and 
restrictions during the course of the study to be eligible for participation: 
1. 
Refer to Section 9, Concomitant Medications, for details regarding prohibited and 
restricted therapy during the study. 
2. 
Agree to follow all requirements that must be met during the study as noted in the 
Inclusion and Exclusion Criteria (e.g., contraceptive requirements). 


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3. 
If patients need to be outdoors while on the study, they should wear clothes that 
protect skin from sun exposure, such as a long-sleeved shirt, and also a wide-brimmed 
hat and sunglasses. Patients should discuss other sun protection measures with their 
physician. 
 


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8. 
STUDY DRUG INFORMATION 
8.1. 
Description of TRC253 Capsules 
The TRC253 supplied for this study is formulated as oral capsules with a strength of 10 mg, 40 
mg, and 100 mg. The 10 mg capsules will be gray in color. The 40 mg capsules will be white in 
color. The 100 mg capsules will be red in color. It will be manufactured and provided under the 
responsibility of the sponsor.  
8.2. 
TRC253 Packaging and Labeling 
The study drug will be packaged in high-density polyethylene bottles with child-resistant 
closures. 
Study drug labels will contain information to meet the applicable regulatory requirements. 
8.3. 
TRC253 Handling, and Storage 
The study drugs must be stored at controlled room temperature in a secure area and administered 
only to patients enrolled in the clinical study in accordance with the conditions specified in this 
protocol. 
Refer to the pharmacy manual for additional guidance on study drug handling and storage. 
8.4. 
TRC253 Dose Levels 
Table 9: 
Dose Levels 
Cohort 
TRC253 Dose Levels 
Number of Evaluable Patients 
Phase 1 
1 
40 mg 
Up to 6 
2 
80 mg 
Up to 6 
3 
160 mg 
Up to 6 
4 
240 mg 
Up to 6 
5 
280 mg 
Up to 6 
6 
320 mg 
Up to 6 
Phase 2  
F877L Mutation cohort 
280 mg 
Up to 15 
Lack of F877L or sole 
L702H Mutation cohort 
280 mg 
Up to 30 
Sole L702H Mutation 
cohort 
280 mg 
Up to 15 
During Part 1 of the study, patients will be assigned sequentially to increasing TRC253 doses. 
The starting dose of TRC253 is 40 mg once daily in the morning, orally. TRC253 doses will be 
escalated in subsequent cohorts after all patients enrolled in a given cohort have completed the 
28-day DLT evaluation period. Dose escalation in Part 1 will follow single-patient dose 
escalation design until drug-related toxicity occurs per Table 4. When an initial drug-related 
toxicity occurs per Table 4 or DLT per Table 6  in a single patient the cohort will be expanded 


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according to 3+3 design rules. Any single patient cohort may be expanded to include additional 
patients for purposes of collecting additional PK, PD (FDHT-PET), and PSA response data to 
help inform selection of a MED. 
Subsequent dose levels will enroll patients based on 3+3 design, whereby 3 patients will be 
initially enrolled and treated at each dose level. If none of these 3 patients experiences a dose-
limiting toxicity (DLT) during the initial 28-day evaluation period, the dose level will be 
expanded to 6 patients. The MTD will have been exceeded if ≥ 33% of patients experience DLT 
at a given dose level. DLT will have occurred when a patient has 1 or more toxicity listed in  
Table 6 that is at least possibly related to TRC253 during the first 28 days of dosing. Patients 
who exit the study for reasons other than DLT prior to completion of the 28-day DLT evaluation 
period will be replaced to ensure an adequate safety assessment in each cohort. Patients who 
experience DLT who receive less than the prescribed dose of TRC253 due to documented 
toxicity during the DLT evaluation period will be considered evaluable for dose escalation 
purposes. At the MTD or MED, up to twelve patients may be enrolled prior to confirming the 
RP2D. Dose escalation will take into account all available data including PK/PD data and the 
safety profile of prior cohorts, as evaluated by medical monitor and Principal Investigators. 
Part 2 will consist of three cohorts of initially up to 15 patients (Cohort 1), up to 30 patients 
(Cohort 2), and up to 15 patients (Cohort 3) to receive TRC253 at the RP2D of 280 mg. The 
objective of Part 2 is to gather additional information on the safety, PK and PD characteristics, 
and the clinical efficacy of TRC253 in a pre-defined population of patients with metastatic 
CRPC. Patients enrolled into Part 2 will have received prior treatment with enzalutamide or 
apalutamide. Patients will be centrally screened for the presence of the AR F877L and AR 
L702H mutations from a plasma sample and enrolled into Cohort 1 (AR F877L positive), Cohort 
2 (patients without AR F877L and without sole AR L702H mutations), or Cohort 3 (sole AR 
L702H mutation positive).  
Patients may be moved from a lower to a higher TRC253 dose not exceeding the MTD or MED 
once it has been deemed safe by the medical monitor and Principal Investigators. 
8.5. 
TRC253 Dosage and Administration 
TRC253 will be administered orally once daily in the morning in 28-day cycles. However, in 
Part 1, a single dose of TRC253 will be taken on the first day (i.e., Cycle 1 Day 1) of a 7-day 
cycle. During Cycle 1, the pharmacokinetic characteristics of a single dose of TRC253 will be 
investigated. Starting with treatment Cycle 2 Day 1, TRC253 will be taken once daily in the 
morning. The original proposed TRC253 doses were 40 mg, 80 mg, 160 mg, 240 mg, 320 mg, 
and 400 mg; and intermediate dose levels could be implemented based on safety, tolerability, 
PK, PD and other observations at each dose level following review of data with the principal 
investigators at all treating sites. 
While the maximum tolerated dose was not reached, PK exposures at the 320 mg dose level 
significantly exceeded the target efficacious concentration and a decision was made not to 
proceed to 400 mg. Based on review of PK and safety, the RP2D of 280 mg was chosen. 
In Part 2, TRC253 capsules are taken once daily in the morning starting on Cycle 1 Day 1 at the 
MTD or MED.  


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On extended PK days, no food should be consumed for at least 8 hours before and 4 hours 
following TRC253 dosing. On all other days, no food should be consumed for at least 2 hours 
before and 1 hour after dosing. 
Study-site personnel will instruct patients on how to store study drug for at-home use as 
indicated for this protocol.  
8.5.1. 
TRC253 Missed Doses 
If a dose is missed in the morning, the patient may take the dose by 10 PM on the same day. 
Otherwise, the patient should resume dosing the next day. There should be at least 8 hours 
between doses. 
8.5.2. 
TRC253 Dose Modification/Dose Interruptions 
The phase 2 dose of TRC253 is 280 mg daily. 
Dose modifications and/or dose interruptions may be warranted for patients who experience 
toxicities. Patients with toxicities that are manageable with supportive care (i.e., nausea or 
vomiting) may not warrant dose reduction. For any occurrence of grade 2 or greater non-
hematologic toxicity, study drug may be held until toxicities have resolved or improved to grade 
1 or baseline, then resume drug at the same dose if the event was a tolerable grade 2 (at PI’s 
discretion). Dose interruption or reduction to 240 mg is also permitted for grade 2 toxicity at the 
discretion of the investigator. If the event is grade 3 or 4, the study drug dose should be reduced 
to 240 mg when resuming drug administration. For a subsequent episode of a grade 3 adverse 
event, dose reduction to 200 mg is warranted once patient has recovered. If there is no recovery 
to ≤ grade 1 or baseline after a 21 day delay, the patient should be discontinued from the study. 
Dose modifications or interruptions may be necessary for liver enzyme elevations. For grade 2 
aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation (>3 times to <5 
times the upper limit of normal), without signs of severe liver damage, stop study drug until liver 
enzymes return to baseline values. Once liver enzymes have returned to baseline values, 
treatment may be reintroduced at 240 mg. Discontinue study drug for AST or ALT elevations 
>5X ULN or for patients who meet Hy’s Law criteria (concurrent elevation of AST or ALT >3X 
ULN and total bilirubin >2X ULN). 
Dosage modification or treatment interruptions may also be necessary for patients with diarrhea 
or nausea/vomiting. Treat diarrhea at first signs with adequate hydration and antidiarrheal 
medication (e.g., loperamide), and consider treatment interruption if diarrhea continues. For 
grade ≥ 3 adverse events, first episode, patient should hold TRC253 until ≤ grade 1 or baseline, 
then may restart at 240 mg. After a second episode of a grade 3 adverse event, further dose 
reduction to 200 mg is warranted once patient has recovered. If no recovery to ≤ grade 1 or 
baseline after a 21 day delay, the patient should be discontinued from the study. 
Nausea or vomiting should be treated with supportive care including anti-emetic therapy and, if 
persistent, may require treatment interruption or dose reduction. For grade ≥ 3 adverse events, 
first episode- patient should hold TRC253 until ≤ grade 1 or baseline, then may restart at 240 mg. 
After a second episode of a grade 3 adverse event, dose further dose reduction to 200 mg is 
warranted once patient has recovered. If no recovery to ≤ grade 1 or baseline after a 21 day 
delay, patient should be discontinued from the study. 


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Further dose reductions below 200 mg may be permitted following discussion with the Sponsor. 
Additionally, in Part 2, patients should be considered for dose reduction if they experience 
toxicities outlined in Table 6. 
Dose interruptions are allowed for a maximum of 21 days; if dosing is not restarted in that time 
frame, the patient should be discontinued from the study. 
8.5.3. 
Management of QTcF Prolongation 
If > 60 ms change from baseline occurs OR QTcF > 500 ms, TRC253 should be held and 
electrolytes evaluated and repleted (if required). Other possible etiologies should be investigated 
(e.g., cardiac ischemia), and telemetry monitoring initiated if indicated. Patients who experience 
QTcF prolongation > 500 ms or > 60 ms change from baseline without electrolyte abnormalities 
should permanently discontinue treatment except in patients who are responding to the drug, in 
whom a favorable benefit-risk exists per the Investigator and where the patient re-consents to 
continued treatment. Patients discontinued due to a > 60 ms change from baseline OR QTcF > 
500 ms should also be monitored by a cardiologist, with a minimum of weekly QTcF 
assessments for at least two weeks and one QTcF assessment after four weeks. 
 If > 60 ms change from baseline occurs OR QTcF > 500 ms patients can be re-challenged at the 
same dose if there were electrolyte abnormalities present during the initial finding of QTcF 
prolongation, and after repleting electrolytes, the QTcF recovers to < 450 ms, and a favorable 
benefit-risk exists per the Investigator.  Re-challenge patients should re-consent to continued 
treatment.   
If there were no electrolyte abnormalities present initially during the finding of QTcF 
prolongation, but the patient is responding and a favorable benefit-risk exists per the Investigator 
patients should dose reduce to 240 mg and may resume treatment at this lower dose after 
recovery of the QTcF to < 450 ms. An additional dose reduction to 200 mg should be 
implemented for a subsequent >60 ms change from baseline or QTcF > 500 ms seen at the 240 
mg dose level.  
While ECG readings at the sites will be used for patient management purposes, an additional 
central read will be performed. Sites will receive clinical alerts for QTcF values > 500 ms and for 
> 60 ms changes from baseline as determined by the third-party vendor. 
8.5.4. 
TRC253 Study Drug Accountability 
The Investigator must maintain an accurate accounting of TRC253 supplied by TRACON.  
During the study, the following information must be recorded: 
• Date of receipt, quantity and lot number of the TRC253 study drug received from 
TRACON 
• ID number of the patient to whom the product is dispensed 
• The date(s) and quantity of the product dispensed 
• Dates and quantity of product returned, lost or accidentally or deliberately destroyed 


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Investigational Drug Accountability Logs should be maintained by the site and must be readily 
available for inspection. 
8.5.5. 
TRC253 Handling and Disposal 
TRC253 must be stored at controlled room temperature. The Investigator should not return (nor 
destroy) clinical study materials to TRACON unless specifically instructed to do so by 
TRACON. See pharmacy manual for further instructions regarding handling and disposal.  
 


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9. 
CONCOMITANT MEDICATIONS 
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal 
supplements; non-pharmacologic therapies such as electrical stimulation, acupuncture, special 
diets, exercise regimens, blood products) different from the study drug must be recorded in the 
eCRF beginning with 28 days prior to the first dose and for at least 28 days after the last dose. 
Recorded information will include a description of the type of the drug, treatment period, dosing 
regimen, route of administration, and its indication.   
Concomitant therapies and any medications used to treat or support adverse events or serious 
adverse events must be recorded on the eCRF and in source documents throughout the study 
beginning with start of the first dose of study drug to 28 days after the last dose of study drug. 
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered. 
No other approved or investigational anticancer treatment will be permitted during the study 
period. No other investigational drug may be used during treatment on this protocol, and 
concurrent participation in another clinical trial is not allowed. 
9.1. 
Permitted Medications 
The following concurrent medications may be administered during the study: 
• Standard supportive care therapies (antiemetics, antidiarrheals, anticholinergics, 
antispasmodics, antipyretics, antihistamines, analgesics, antibiotics and other 
antimicrobials, histamine receptor (H2) antagonists or proton pump inhibitors, and 
other medications intended to treat symptoms or signs of disease) as clinically 
indicated, according to institutional standards and as deemed necessary by the 
investigator.  
• Granulocyte colony stimulating factor and transfusions such as red blood cells and 
platelets are permitted to treat symptoms or signs of neutropenia, anemia, or 
thrombocytopenia; not allowed as prophylactic treatment during DLT period in Part 
1. 
• Documented infectious complication should be treated with oral or intravenous 
antibiotics or other anti-infective agents as considered appropriate by the treating 
investigator for a given infectious condition, according to standard institutional 
practice. 
• GnRH analog therapy 
9.2. 
Prohibited Medications 
The following concurrent medications are prohibited during the study. The sponsor must be 
notified in advance (or as soon as possible thereafter) of any instances in which prohibited 
therapies are administered. 
• Any anti-cancer medication (other than TRC253) 
• Experimental or investigational therapy 


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• Chronic doses of corticosteroids in excess of 10 mg daily of prednisone or equivalent 
is prohibited other than for the management of adverse events. 
• Immunosuppressant agents 
• Vaccination with live vaccines 
9.3. 
Precautions with Concomitant Medications 
TRC253 was not an in vitro inhibitor of CYP1A2, 2C9, 2C19, 2D6, 3A4 or a time-dependent 
inhibitor of CYP 3A4, and thus has a low drug-drug interaction risk as a perpetrator. TRC253 is 
a low CYP-mediated clearance compound. However, strong inducers or inhibitors of CYP 
enzymes should be used with caution in patients receiving TRC253. 
Medications that prolong the QT/QTc interval should be avoided when possible. Refer to a list of 
common medications that may prolong the QT interval in Appendix 6 .  


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10. 
TREATMENT COMPLIANCE 
Patients will receive instructions on compliance with study drug administration at the screening 
visit. During the course of the study, the investigator or designated study-site personnel will be 
responsible for providing additional instruction to re-educate any patient who is not compliant 
with taking the study drug. All dosing information must be recorded in the Dosage 
Administration page of the electronic case report form (eCRF).  
10.1. 
Patient Enrollment 
Sites must assign a 6-digit screening number for patients as follows: 4-digit site number 
(assigned by TRACON) followed by 01, 02, etc., sequentially. Once eligibility is confirmed, 
patients will be manually enrolled by TRACON Pharmaceuticals and assigned an eight-digit 
patient number (4-digit site number followed by 4 digits). This 8-digit number will be used to 
identify patients throughout their participation in the trial.   


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11. 
ASSESSMENT OF EFFICACY  
Efficacy evaluations include PSA response, time to PSA progression, and rPFS. For efficacy 
evaluation time points, see the Schedules of Assessments (Table 7 and Table 8). 
11.1. 
Disease Outcome Assessments 
Outcomes in this study will be assessed using the PCWG3 criteria (Appendix 2, Appendix 3).  
11.2. 
PSA Response and Time to PSA Progression 
Prostate-specific antigen will be assessed at Day 1 of each cycle and PSA response and Time to 
PSA Progression will be determined by PCWG3 criteria.  
11.3. 
Radiographic Progression-Free Survival (rPFS) 
The frequency of tumor assessments (soft tissue disease and bone disease assessments) is every 8 
weeks until the patient completes three 28-day cycles, then every 12 weeks. Only the status of 
the patient's disease (partial response, stable disease, or progressive disease) based on the 
investigator's assessment will be recorded. 
 


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12. 
ASSESSMENT OF SAFETY 
12.1. 
Safety Parameters 
Safety assessments will be based on medical review of adverse event reports and the results of 
clinical laboratory tests, ECGs, vital sign measurements, and physical examinations. For safety 
evaluation time points, see the Schedules of Assessments (Table 7 and Table 8). 
Safety parameters will be evaluated by 2 different safety committees: the TRACON Safety 
Monitoring Committee (SMC) and the Independent Safety Committee (ISC); refer to 
Section 12.4.  
12.1.1. 
Adverse Events 
Adverse events that occur between the signing of the informed consent through 28 days 
following the last dose of study drug will be recorded. All patients who receive at least 1 dose of 
study drug will be considered evaluable for safety assessment. Any clinically relevant changes 
occurring during the study must be recorded on the Adverse Event section of the eCRF.  
Adverse events reported by the patient (or, when appropriate, by a caregiver, surrogate, or the 
patient's legally acceptable representative) during the study will be followed by the investigator 
as specified in Section 12.3, Adverse Event Reporting. 
Abnormal and clinically significant laboratory tests should be recorded as adverse events. To 
meet the definition of clinically significant, the test result generally requires a change in medical 
management (e.g., new medication, unplanned treatment, additional tests, etc.). 
12.1.2. 
Clinical Laboratory Tests 
Blood samples for serum hematology, coagulation, and chemistry will be collected prior to each 
study drug administration according to the frequency specified in the Schedules of Assessments 
(Table 7 and Table 8). More frequent clinical laboratory tests may be performed if indicated by 
the overall clinical condition of the patient or by abnormalities that warrant more frequent 
monitoring. Screening laboratory results must be available to the investigator for evaluation 
before the first dose of study drug and at the start of each cycle thereafter. The investigator must 
review the laboratory reports, document this review, and ensure that any clinically relevant 
changes occurring during the study are recorded in the adverse event section of the eCRF. The 
laboratory reports must be filed with the source documents. 
The following tests will be performed by the local laboratory: 
• Hematology panel: CBC with differential and platelet count. Iron studies (serum iron, 
ferritin and total iron binding capacity) 
• Coagulation: Prothrombin Time (PT), aPTT, Internalized Normalized Ration (INR), 
and fibrinogen will be assessed 
• Serum Chemistry: Total bilirubin, alanine transaminase (ALT), aspartate 
transaminase (AST), alkaline phosphatase, lipase, amylase, total protein, albumin, 
sodium, magnesium, potassium, bicarbonate, chloride, calcium, phosphorus, blood 
urea nitrogen, creatinine, and glucose 


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• Urinalysis: Microscopic analysis and/or urine protein-creatinine ratio (UPCR) should 
be performed as clinically indicated 
• Fasting lipid panel: Total cholesterol, low-density lipoprotein cholesterol, high-
density lipoprotein cholesterol, and triglycerides 
• Thyroid-stimulating hormone 
• Testosterone, free testosterone, DHT, estradiol, DHEA-S, androstenedione, and 
SHBG 
12.1.3. 
Electrocardiograms 
QTc intervals will be determined in triplicate from ECGs taken at time points specified in the 
Schedules of Assessments by the method of Fridericia (Table 7 and Table 8). During the 
collection of ECGs, patients should be in a quiet setting without distractions (e.g., television, cell 
phones). Patients should rest in a supine position for at least 5 minutes before ECG collection 
and should refrain from talking or moving arms or legs. If blood sampling or vital sign 
measurement is scheduled for the same time point as ECG recording, the procedures should be 
performed in the following order: ECG(s), vital signs, blood draw. 
The 12-Lead ECG recordings will be obtained using an ECG machine that automatically 
calculates the heart rate and measures PR, RR, QRS, QT, and QTc intervals. ECGs will be 
performed in triplicate with approximately 2 minutes between recordings. A physician will 
review the readings, including ECG morphology and determine if additional cardiovascular 
assessments should be performed or if referral to cardiologist is warranted.  
In addition, a third-party vendor will perform central over-reads of all ECGs. The measured ECG 
intervals will be used to perform an overall concentration-QTcF analysis. 
12.1.4. 
Vital Signs 
Vital signs include temperature, heart rate, and blood pressure. Blood pressure (systolic and 
diastolic) and heart rate measurements will be assessed (supine/semi-recumbent) with a 
completely automated device. Manual techniques will be used only if an automated device is not 
available. Blood pressure and heart rate measurements should be preceded by at least 5 minutes 
of rest in a quiet setting without distractions (e.g., television, cell phones). 
12.1.5. 
Physical Examination  
The screening physical examination will include, at a minimum, patient’s height, general 
appearance, examination of the skin, ears, nose, throat, lungs, heart, abdomen, extremities, 
musculoskeletal system, lymphatic system, and nervous system. Weight will be measured at the 
start of each treatment cycle. A symptom-directed physical exam will be conducted at 
subsequent time points. 
12.2. 
Adverse Events 
All observed or volunteered adverse events regardless of suspected causal relationship to 
TRC253 study drug will be reported as described below. Medications administered and all other 


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actions taken to treat the event, the outcome, and any recurrence upon re-challenge will be 
captured on the CRF. 
12.2.1. 
Definition of Adverse Event 
An adverse event is any untoward medical occurrence in a trial patient who is administered a 
drug or biologic (medicinal product); the event may or may not have a causal relationship with 
the medicinal product. Examples of adverse events include, but are not limited to the following: 
• Clinically significant symptoms and signs including:  
− Worsening of signs and symptoms of the malignancy under trial.  
− Signs and symptoms resulting from drug overdose, abuse, misuse, withdrawal, 
sensitivity, dependency, interaction or toxicity.   
− All possibly related and unrelated illnesses, including the worsening of a 
preexisting illness.  
− Injury or accidents.  Note that if a medical condition is known to have caused the 
injury or accident (hip fracture from a fall secondary to dizziness), the medical 
condition (dizziness) and the outcome of the accident (hip fracture from a fall) 
should be reported as 2 separate adverse events.   
− Symptoms or signs resulting from exposure in utero. 
• Abnormalities in physiological testing or physical examination findings that require 
clinical intervention or further investigation (beyond ordering a repeat confirmatory 
test). 
• Laboratory abnormalities that meet any of the following (Note: merely repeating an 
abnormal test, in the absence of any of the below conditions, does not constitute an 
adverse event. Any abnormal test result that is determined to be an error does not 
require reporting as an adverse event.): 
− Test result that is associated with accompanying symptoms 
− Test result that requires additional diagnostic testing or medical/surgical 
intervention 
− Test result that leads to a change in TRC253 study drug dosing not stipulated in 
the protocol, or discontinuation from the trial, significant additional concomitant 
drug treatment, or other therapy 
− Test result that is considered to be an adverse event by the Investigator or 
TRACON 
12.2.2. 
Serious Adverse Events 
An adverse event that meets one or more of the following criteria/outcomes is classified as a 
serious adverse event: 
• Results in death 


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• Is life-threatening (i.e., at immediate risk of death) 
• Requires in patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity  
• Results in congenital anomaly/birth defect 
• Other 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 or may require medical or surgical 
intervention to prevent one of the outcomes listed above. Examples of such events are 
intensive treatment in an emergency room for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; or the development of 
drug dependence or drug abuse.  
Serious also includes any other event that the Investigator or sponsor judges to be serious, or 
which is defined as serious by a regulatory authority in the country in which the event occurred.   
Progression of the malignancy under study (including signs and symptoms of progression) 
should be reported as an SAE if it meets the criteria for seriousness.  
The onset date of an SAE is defined as the date on which the event initially met serious criteria 
(e.g., the date of admission to a hospital).  The end date is the date on which the event no longer 
met serious criteria (e.g., the date the patient was discharged from a hospital).  
12.2.2.1. Hospitalization 
Adverse events associated with in-patient hospitalization, or prolongation of an existing 
hospitalization, are considered serious. Any initial admission, even if the duration is less than 24 
hours is considered serious. In addition, any transfer within the hospital to an acute/intensive care 
unit is considered serious (e.g., transfer from the psychiatric wing to a medical floor or transfer 
from a medical floor to a coronary care unit). However, the following situations should not be 
considered serious:  
• Rehabilitation facility admission 
• Hospice facility admission 
• Respite care 
• Skilled nursing facility admission 
• Nursing home admission 
• Emergency room visit 
• Outpatient same day surgery/procedure 
• Hospitalization or prolongation of hospitalization in the absence of precipitating 
clinical adverse events as follows: 
− Admission for treatment of preexisting condition not associated with the 
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− Social admission 
− Administrative admission (e.g. for yearly physical exam) 
− Protocol-specified admission during a clinical trial 
− Optional admission not associated with a precipitating clinical adverse event (e.g. 
for elective cosmetic surgery) 
− Preplanned treatments or surgical procedures that are not related to an SAE 
− Hospitalization for observation without an AE 
• Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, 
should not be reported as AEs.  The medical condition for which the procedure was 
performed should be reported if it meets the definition of an AE (e.g., acute 
appendicitis that begins during the AE reporting period should be reported as an AE 
and the appendectomy should be recorded as a Concomitant Procedure). 
12.3. 
Reporting Adverse Events 
12.3.1. 
Eliciting Adverse Event Information 
The Investigator is to report all directly observed AEs and all AEs spontaneously reported by the 
trial patient using concise medical terminology. In addition, each trial patient will be questioned 
about adverse events at each clinic visit following initiation of treatment. The question asked will 
be, “Since your last clinic visit have you had any health problems?” 
12.3.2. 
Adverse Event Reporting Period 
The AE reporting period for this trial begins with informed consent and ends following the 
completion of the 28 day follow-up visit or at least 28 days after the last dose of TRC253 study 
drug is administered, whichever occurs later. Data for patients who screen fail will not be 
collected in the clinical database. However, if a screen fail patient experiences an AE that is 
considered related to study conduct or study procedures during the screening period, the event 
will be tracked on the Patient Screening Log and the event will be assessed for reportability. All 
events that occur following enrollment, even if the patient does not go on to receive study 
treatment, will be entered on CRFs. AEs occurring prior to the initiation of the study treatment 
will be considered “baseline-emergent adverse events” and will be recorded on the 
corresponding CRFs. 
All AEs that occur in trial patients during the AE reporting period specified in the protocol must 
be reported to TRACON, whether or not the event is considered study treatment-related. In 
addition, any known untoward event that occurs beyond the AE reporting period that the 
Investigator assesses as a suspected adverse reaction to the investigational medication/product 
should also be reported as an AE. 
12.3.3. 
Reporting Requirements 
Each AE is to be classified by the Investigator as SERIOUS or NONSERIOUS (see 
Section 12.2.2 for serious adverse event definition). This classification of the event determines 


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the reporting procedures to be followed. If an SAE occurs, reporting will follow local and 
international regulations, as appropriate. 
The Investigator must notify the Sponsor of any AE that meets one of the criteria for an SAE 
immediately upon learning of the event. Any subsequent revisions that are made to information 
pertaining to serious adverse events (e.g., change in seriousness criteria, relationship to study 
drug, etc.) should also be communicated to TRACON immediately. This notification should be 
made to: 
Primary Medical Monitor 
James Freddo, MD 
TRACON Pharmaceuticals, Inc. 
4350 La Jolla Village Drive, Suite 800 
San Diego, California 92122 
Cell Phone:  1.858.472.2330 
Email: jfreddo@traconpharma.com  
 
Secondary Medical Monitor 
Charles Theuer, MD, PhD 
TRACON Pharmaceuticals, Inc. 
4350 La Jolla Village Drive, Suite 800 
San Diego, California 92122 
Office Phone:  1.858.550.0780 x233 
Cell Phone:  1.858.344.9400 
Email: ctheuer@traconpharma.com  
 
Following this notification, the Investigator will report the SAE in the AE CRF via the data 
management system. The initial AE CRF is to be updated with followed more detailed SAE 
information within 5 calendar days of the event. 
In case the Investigator is not immediately aware of an SAE (for example, if the patient seeks 
urgent medical attention elsewhere), the Investigator is to notify the Sponsor immediately upon 
learning of it and document his/her first awareness. 
Each SAE should be followed until resolution, returns to the patient’s pre-treatment baseline 
status, or until such time as the Investigator determines that it has become stable. Information 
pertaining to follow-up of SAEs should also be sent to the TRACON Pharmaceuticals Inc. 
SAEs that are unexpected and reported as associated with use of TRC253 will be submitted to 
the US Food and Drug Administration (FDA), Competent Authorities, and Ethics Committees in 
other countries taking part in the study, as well as all participating clinical sites in all countries as 
required by applicable regulatory authorities. Investigators should report to their local IEC/IRB 
as dictated by their board’s policies and procedures. For events which are fatal or life-
threatening, unexpected, and reported as associated with use of the investigational product, a 7-
day Alert Report will be submitted to the regulatory authorities within 7 calendar days of receipt 
of the SAE information. For all other AEs that are serious, unexpected, and reported as 
associated with use of the investigational product, a written report will be made no more than 15 


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calendar days from the date TRACON learns of the event. Participating clinical sites will be 
notified of these events in parallel. 
All AEs, including SAEs, are to be reported on the AE CRFs.  
12.3.4. 
Recording Adverse Events in the Case Report Forms 
The Investigator is to report all directly observed AEs and all AEs spontaneously reported by the 
trial patient. In addition, each trial patient will be questioned about AEs. All AEs that meet the 
criteria specified in Section 12.2.1 are to be recorded on patient source documents and on the 
CRFs. AEs should be reported using concise medical terminology on the CRFs.  
12.3.5. 
Grading of Adverse Event Severity 
To report AEs on the CRFs, the Investigator will use the severity grading as described in NCI 
CTCAE (Version 4.03).   
Every effort should be made by the Investigator to assess the adverse event according to CTCAE 
criteria. However, the diagnosis term should not be altered to accommodate the CTCAE 
dictionary. If the Investigator is unable to assess severity because the term is not described in 
NCI CTCAE Version 4.03, severity of MILD, MODERATE, SEVERE, LIFE-THREATENING, 
or FATAL may be used to describe the maximum intensity of the AE. For purposes of 
consistency, these intensity grades are defined as follows:  
Table 10: 
Adverse Event Grading 
Grade 
Non-CTCAE Severity 
Definition 
1 
Mild  
Does not interfere with patient’s usual function 
2 
Moderate 
Interferes to some extent with patient’s usual function 
3 
Severe 
Interferes significantly with patient’s usual function 
4 
Life-Threatening 
Results in immediate risk of patient’s death 
5 
Fatal 
Results in patient’s death 
Note the distinction between the severity and the seriousness of an AE. A severe event is not 
necessarily a serious event. For example, a headache may be severe (interferes significantly with 
patient’s usual function) but would not be classified as serious unless it met one of the criteria for 
serious events.     
12.3.6. 
Relationship to TRC253 Study Drug 
The relationship of an AE to TRC253 study drug should be classified by the Investigator using 
the following guidelines: 
• Not related: 
− Applicable to those AEs that are clearly due to extraneous causes (concurrent 
drugs, environment, etc.) and do not meet the criteria for drug relationship listed 
under UNLIKELY, POSSIBLY, PROBABLY, and RELATED. 
• Unlikely related: 


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− Applicable to those AEs judged to be unlikely to be related to the study drug 
administration. An AE may be considered UNLIKELY RELATED when it meets 
at least two (2) of the following criteria: 
− It does not follow a reasonable temporal sequence from administration 
of the study drug. 
− It could readily have been produced by the patient’s clinical state, 
environmental or toxic factors, or other modes of therapy administered to 
the patient. 
− It does not follow a known or expected response pattern to the study 
drug. 
− It does not reappear or worsen when the study drug is re-administered. 
• Possibly related:  
− Applicable to those AEs judged to be perhaps related to the study drug 
administration. An AE may be considered POSSIBLY RELATED when it meets 
at least one (1) of the following criteria: 
a) It follows a reasonable temporal sequence from administration of the 
study drug. 
b) It could not readily have been produced by the patient’s clinical state, 
environmental or toxic factors, or other modes of therapy administered to 
the patient. 
c) It follows a known or expected response pattern to the study drug. 
• Probably related: 
− Applicable to those AEs that are felt with a high degree of certainty to be related 
to the study drug administration. An AE may be considered PROBABLY 
RELATED if it meets at least two (2) of the following criteria: 
a) It follows a reasonable temporal sequence from administration of the 
study drug. 
b) It could not be reasonably explained by the known characteristics of 
the patient’s clinical state, environmental or toxic factors, or other modes 
of therapy administered to the patient. 
c) It disappears or decreases on cessation or reduction in study drug dose. 
There are exceptions when an AE does not disappear upon discontinuation 
of the drug, yet drug relatedness clearly exists (e.g., bone marrow 
depression, fixed drug eruptions, tardive dyskinesia, etc.). 
d) It follows a known or expected response pattern to the study drug. 
• Definitely related:  


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− Applicable to those AEs that are incontrovertibly related to study drug 
administration. An AE may be assigned to this category if it meets at least the first 
three (3) of the following criteria:  
a) It follows a reasonable temporal sequence from administration of the 
study drug. 
b) It could not reasonably be explained by the known characteristics of 
the patient’s clinical state, environmental or toxic factors, or other modes 
of therapy administered to the patient. 
c) It disappears or decreases on cessation or reduction in study drug dose. 
There are exceptions when an AE does not disappear upon discontinuation 
of the drug, yet drug relatedness clearly exists (e.g., bone marrow 
depression, fixed drug eruptions, tardive dyskinesia, etc.). 
d) It follows a known or expected response pattern to the study drug. 
e) It reappears or worsens when the study drug is re-administered. 
Causality assessment should be reported for every AE. Please refer to Section 2.5.1 for TRC253 
potential risks; for complete reference, please use the most current version of the TRC253 IB. 
Note: an AE could be considered as definitely related, probably related, or possibly related to 
study drug even if not referenced in the IB if in the opinion of the investigator there is a 
reasonable possibility that the drug(s) may have caused the AE. AEs related to TRC253 study 
drug are considered Adverse Drug Reactions (ADR). 
For the purpose of analysis, AEs assessed on the CRF as “Possibly Related,” “Probably 
Related,” or “Definitely Related” will be grouped as suspected adverse reactions, and AEs 
assessed on the CRF as “Not Related” or “Unlikely Related” will be grouped as non-related AEs. 
12.3.7. 
Expectedness Assessment 
All TRC253 AEs and suspected adverse drug reactions are considered “unexpected” if not listed 
in the applicable section of the current TRC253 IB or not listed at the specificity or severity that 
has been observed and listed in the IB. For example, under this definition, hepatic necrosis would 
be unexpected (by virtue of greater severity) if the IB referred only to elevated hepatic enzymes 
or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected 
(by virtue of greater specificity) if the IB listed only cerebral vascular accidents. "Unexpected," 
as used in this definition, also refers to AEs or suspected adverse reactions that are mentioned in 
the IB as occurring with a class of drugs or as anticipated from the pharmacological properties of 
the drug, but are not specifically mentioned as occurring with the particular drug under 
investigation. 
12.3.8. 
Pregnancy 
All initial reports of pregnancy in partners of male patients must be reported to the sponsor by 
the study-site personnel within 24 hours of their knowledge of the event using the appropriate 
pregnancy notification form. Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal 
death, stillbirth, congenital anomalies, ectopic pregnancy) are considered serious adverse events 
and must be reported using the Serious Adverse Event Form.  


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Because the effect of the study drug on sperm is unknown, pregnancies in partners of male patients 
included in the study will be reported as noted above. 
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required. 
12.3.9. 
Follow-up of Unresolved Adverse Events  
All AEs should be followed until they are resolved or return to the patient’s pre-treatment 
baseline, or the Investigator assesses them as stable; every effort should be made to make this 
determination by the 28 day follow-up visit. Any increase or decrease in AE grade should be 
recorded as a new AE.  
All serious and those non-serious events assessed by the Investigator as suspected reactions (i.e., 
at least possibly related) to the investigational medication/product must be followed even after 
the patient’s withdrawal from the study until the event is either resolved, improved to the 
patient’s pre-treatment baseline or better, stable without anticipated future change, or the patient 
is lost to follow-up, or in the case of a suspected adverse reaction, later determined to not be 
related to the investigational medical product; every effort should be made to make this 
determination by the 28 day follow-up visit.   
12.4. 
Safety Monitoring 
The TRACON Clinical Team will monitor safety throughout the study via the following 
activities:  
• Surveillance and reporting of SAEs according to regulatory guidelines as outlined in 
the safety plan 
• Routine monitoring of non-serious AEs as they are recorded in the CRFs and the 
source documents at study sites 
• Periodic teleconferences with the Principal Investigators to share experiences and 
ensure communication 
• New toxicity information that may affect the treatment of patients on this study will 
be promptly communicated in writing to all participating clinical sites and institutions 
participating in this clinical trial 
• There are 2 committees monitoring safety across all studies of TRC253; a separate 
charter for each committee will define the roles and responsibilities.  
− An external Independent Safety Committee (ISC) 
− A formally chartered TRACON in-house Safety Monitoring Committee (SMC) 
 


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13. 
OTHER LABORATORY ASSESSMENTS 
13.1. 
Pharmacokinetics 
Plasma samples will be collected to evaluate the PK of TRC253. Plasma collected for PK may 
also be used for metabolic profiling. Patient confidentiality will be maintained. For PK collection 
times, see the Schedules of Assessments (Table 7 and Table 8). 
13.2. 
Biomarkers  
While the current anti-androgen therapies slow the growth of prostate cancer, resistance 
mechanisms ultimately develop, which results in lethal metastatic disease. Resistance can be 
acquired through alterations in the AR or by activation of compensatory pathways. Since the 
currently available anti-androgens target the business end of the AR, the LBD has emerged as a 
mutational hotspot. TRC253 has been developed to treat patients with AR LBD mutations, and 
thus addresses a clinically unmet need. The goals of this biomarker plan are to utilize 
FDHT-PET as a PD marker to define TRC253 binding to AR in Part 1, stratify patients based on 
AR-LBD mutation status in Part 2 utilizing companion diagnostic assay, understand resistance 
mechanisms, and measure response.   
For biomarker collection times, see the Schedules of Assessments (Table 7 and Table 8). 
13.2.1. 
Part 1 Biomarkers 
To confirm the RP2D, patients at select dose levels will undergo PET scans using FDHT, a 
radiopharmaceutical specifically designed to image binding to AR. These patients will be 
monitored using FDHT-PET scans obtained before initiation of therapy and after 4 weeks of 
therapy. AR-positive lesions will be determined by qualitative inspection of the FDHT-PET 
images. Imaging will occur at 1 or more centers under their existing IND and institutional 
protocol. 
13.2.2. 
Part 2 Biomarkers 
Mutations in the LBD have been observed in 10-20% of patients who have progressed on first 
generation therapies [6, 7]. The five clinically relevant LBD mutations include L702H, T877A, 
W741C, W874L, and F877L. Importantly, the frequency of F877L increases from 2% at baseline 
to 11% in metastatic CRPC patients who have progressed on apalutamide [1]. 
In Part 2, patients with and without AR LBD mutations will be identified using a ctDNA based 
assay.  A Clinical Trial Assay (CTA) utilizing highly sensitive BEAMing emulsion PCR 
platform will be used to detect these mutations.  The assay has been validated and CLIA 
certified.  Patients who are positive for the AR F877L mutation will be enrolled in Cohort 1, 
patients without the AR F877L and without sole AR L702H mutations but potentially positive 
for a different AR mutation or for any other mechanism of acquired resistance will be enrolled in 
Cohort 2, and patients positive for the sole AR L702H mutation will be enrolled in Cohort 3.  
Note that Cohort 1 patients may be positive for F877L alone and any other AR mutation.  
The CTA is considered a non-significant risk investigational in vitro diagnostic device (IVD). 
The noninvasive venipuncture sampling will be routinely performed throughout the trial and will 


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not present a risk to the health, safety or welfare of the patient.  The results of the assay will be 
used to place patients in cohorts to correlate activity with mutation status but will not affect what 
treatment the patient receives.  Additionally, an inaccurate test result would not pose a potential 
for serious risk to the patient. 
13.2.3. 
Parts 1 and 2 Biomarkers 
To determine the frequency of CTC and molecular alterations in CTCs, whole blood will be 
collected before, during, and after treatment for CTC enumeration and molecular 
characterization of a panel of markers including AR-V7. 
Serum will be collected from all patients before, during, and after therapy and analyzed for total 
testosterone, free testosterone, dihydrotestosterone (DHT), estradiol, dehydroepiandrosterone 
sulfate (DHEA-S), androstenedione, and sex hormone-binding globulin (SHBG) and analyzed 
locally. 
13.3. 
Archival Tumor Specimens  
Archival specimens (formalin-fixed, paraffin-embedded) of the primary cancer and/or metastatic 
cancer specimen for each study participant will be obtained, if they are available, to evaluate 
primary response and high-risk markers, including but not limited to TMPRSS2-ERG, PTEN, 
FGFR, PI3K, BRACA1, BRCA2, and ATM. It is preferable that the entire paraffin block be 
submitted, but if this is not feasible, then at least 10 unstained slides are requested for 
immunohistochemical analysis (sections of ~5 microns are preferred). Samples will be stored at 
room temperature and shipped to a third party laboratory for storage until the time of analysis.  
See separate laboratory guide for further collection and shipment information.   
13.4. 
Sample Collection and Handling 
The actual dates and times of sample collection must be recorded in the eCRF or laboratory 
requisition form.  
Refer to the Schedules of Assessments (Table 7 and Table 8) for the timing and frequency of all 
sample collections. 
Instructions for the collection, handling, storage, and shipment of samples are found in the 
laboratory manual that will be provided. Collection, handling, storage, and shipment of samples 
must be under the specified, and where applicable, controlled temperature conditions as indicated 
in the laboratory manual. 
 


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14. 
STATISTICAL METHODS 
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Specific details will be provided in the Statistical Analysis Plan. 
No formal hypothesis testing will be conducted. Data will be summarized using descriptive 
statistics. Continuous variables will be summarized using the number of observations, mean, 
standard deviation, coefficient of variation, median, and range as appropriate. Categorical values 
will be summarized using the number of observations and percentages as appropriate. 
Time-to-event endpoints will be summarized using Kaplan-Meier estimates. 
14.1. 
Analysis Populations 
The analysis populations are as follows: 
• Safety population: This population includes all patients who received at least 1 dose 
of study drug. 
• DLT evaluable analysis set: This set is a subset of the safety population. Patients 
who receive >75% of planned doses of TRC253 or who had a DLT during the DLT 
evaluation period will be included in this analysis.  
• PK analysis set: This set consists of all patients who receive at least 1 dose of study 
drug and have at least 1 post dose concentration measurement of TRC253. This group 
will be used for summaries (tables and listings) and listings of derived PK parameters. 
Note: patients will be removed from the estimation of certain PK parameters on an 
individual basis due to, for example, missing PK samples such that the PK parameters 
cannot be appropriately derived. These patients will be identified at the time of the 
analyses along with their reason for removal. 
• Efficacy analysis set: This population includes all patients who received at least 1 
dose of study drug and underwent a relevant efficacy assessment. 
14.2. 
Sample Size Determination 
The sample size for this study is not calculated based on statistical power but to obtain safety, 
PK, and PD assessments of oral doses of TRC253. In Part 1, dose escalation, patients up to six 
patients per dose level will be enrolled to evaluate for DLT. In Part 2, dose expansion, 
approximately 60 patients will be enrolled into three separate cohorts for further safety and PK 
evaluation. For example, if true PSA response rate is 50%, the probability of observing at least 
11 responders out of 30 in cohort 2 is 95%. If the total of 30 patients from this example, if 15 are 
PSA responders, then response rate (95% CI) will be 50% (31.3%, 68.7%). 


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14.3. 
Endpoint Definitions 
PSA Response at Week 12  
PSA response is defined as a ≥50% decline from baseline according to PCWG3 criteria 
(Appendix 2). An additional PSA obtained at least 4 weeks later must show ≥50% decline from 
baseline to confirm the response. 
Time to PSA Progression  
Time to PSA progression is measured from the start of treatment until the criteria for PSA 
progression according to the PCWG3 are met (Appendix 2). Patient without PSA progression 
will be censored at the last PSA assessment.  
Radiographic Progression-Free Survival (rPFS) 
Radiographic Progression-Free Survival (rPFS) is measured from the start of the treatment until 
the criteria for radiographic disease progression are met or death occurs, whichever is first. 
Patient will be censored at the last disease assessment when no rPFS event is observed. 
Pharmacokinetic Parameters 
Pharmacokinetic parameters of TRC253 will be derived from plasma concentration versus time 
data after single dose and repeat dose, as applicable. The pharmacokinetic parameters to be 
assessed are shown below. Other parameters may also be assessed.  
Cmax 
Maximum observed plasma concentration for each patient 
Cmin 
Observed plasma concentration at the end of dosing interval for each 
patient 
tmax 
Time of maximum observed plasma concentration 
AUCτ 
Area under the plasma concentration-time curve from time zero to 
24 hours (dosing interval) at steady state 
AUClast 
Area under the plasma concentration-time curve from time zero to the 
last time measured 
AUC∞ 
Area under the plasma concentration-time curve from time zero 
extrapolated to infinite time calculated as AUClast + Clast/λz, where Clast 
is the last observed measurable (non-BQL) concentration; 
extrapolations of more than 20.00% of the total AUC are reported as 
approximations 
λz 
Apparent terminal elimination rate constant, determined by linear 
regression using the terminal log-linear phase of the log transformed 
concentration vs. time curve 
t1/2term 
Apparent terminal elimination rate constant, determined by linear 
regression using the terminal log-linear phase of the log transformed 
concentration vs. time curve 


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t1/2eff 
Effective half-life 
RA 
Accumulation Index  
CL/F 
Total apparent oral clearance 
Vss/F 
Apparent oral volume of distribution at steady state  
The following requirements should be met for an acceptable calculation of t1/2term, λz, AUC∞, and 
related parameters: 
A) at least 3 data points are used in the calculation, otherwise t1/2term, λz, AUC∞, and related 
parameters are not assessable; 
B) coefficient of determination (r2adj) is at least 0.90. 
If requirement (B) is not met, t1/2term, λz, AUC∞, and related parameters will be reported as 
approximations. 
Actual sampling times will be checked for major aberrations. In case a major aberration occurs 
for an actual sampling time of >20% deviation from the scheduled time (relative to study drug 
intake), this plasma concentration will be excluded from descriptive statistics in the plasma 
concentration table. 
14.4. 
Safety Analyses 
All safety analyses are to be performed on data from the safety population, which is the same as 
all treated population. The baseline value for safety assessment is defined as the value collected 
at the time closest to, but prior to, the start of study drug administration. The safety parameters to 
be evaluated are the incidence, severity, and type of adverse events, clinically significant changes 
in the patient’s physical examination findings, vital signs measurements, and clinical laboratory 
results. Exposure duration of investigational product and reasons for discontinuation of study 
drug will be tabulated. 
14.4.1. 
Adverse Events 
The verbatim terms used in the eCRF by the investigator to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities. Treatment-emergent adverse events are 
adverse events with onset during the treatment period to 28 days after the last dose of study drug, 
or that are a consequence of a pre-existing condition that has worsened since baseline. All 
reported adverse events will be included in the analysis. For each adverse event, the percentage 
of patients who experience at least 1 occurrence of the given event will be summarized by 
treatment group. Adverse Event Reporting and graded according to the NCI-CTCAE (Version 
4.03).  
Summaries, listings, datasets, or patient narratives may be provided, as appropriate, for those 
patients who die, discontinue treatment due to an adverse event, or experience a severe or serious 
adverse event. 
Specifically, the following adverse events will be summarized: 
• Incidence of DLT (Dose escalation: Part 1) 


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• All adverse events 
• Grade 3 or greater adverse events 
• Serious adverse events (SAEs) 
• Adverse events leading to discontinuation of treatment 
• Adverse events leading to death 
14.4.2. 
Clinical Laboratory Tests 
Laboratory data will be summarized by type of laboratory test. Descriptive statistics will be 
calculated for each laboratory analyte at baseline and for observed values and changes from 
baseline at each scheduled time point. Changes from baseline results will be presented in  
pre- versus posttreatment cross-tabulations (with classes for below, within, and above normal 
ranges). A listing of patients with any laboratory results outside the reference ranges will be 
provided.  
Laboratory parameters with predefined NCI-CTCAE toxicity grades will be summarized. 
Change from baseline to the worst adverse event grade experienced by the patient during the 
study will be provided as shift tables. 
14.4.3. 
Electrocardiogram 
Summary statistics will be provided for the ECG intervals and their changes from baseline by 
dose group and cohort.  
Exposure-QTcF analysis of TRC253 will be performed using triplicate ± 5 minute time points 
ECG measurements. TRC253 plasma concentrations from Cycle 1 Day 1 and Cycle 3 Day 1 and 
at steady state timepoints will be used for the exposure-QTcF analysis. 
14.4.4. 
Vital Signs 
The incidence of abnormalities in vital signs including temperature, heart rate, and blood 
pressure will be assessed.  
14.4.5. 
Physical Examination 
Abnormal physical examination findings at screening and during the study will be provided in a 
listing. 
14.5. 
Pharmacokinetic Analyses 
All plasma concentrations below the lowest quantifiable concentration or missing data will be 
labeled as such in the concentration data presentations or SAS dataset. Concentrations below the 
lower quantifiable concentration will be treated as zero in the summary statistics. All patients 
and samples excluded from the analysis will be clearly documented in the Clinical Study Report. 
Data will be listed for all patients with available plasma concentrations per dose level/Part. 
Patients will be excluded from the PK analysis if their data do not allow for accurate assessment 
of the PK (e.g., incomplete administration of the study drug; missing information of dosing and 
sampling times; concentration data not sufficient for PK parameter calculation).  


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Descriptive statistics will be used to summarize TRC253 plasma concentrations at each sampling 
time point, by dose level/study part. Pharmacokinetic parameters of TRC253will be determined 
using non-compartmental analysis and summarized by dose level/study part. Mean and 
individual plasma TRC253 concentration time profiles will be plotted (linear and semilog) after 
the first dose of study drug and at steady state. Analysis of dose proportionality and steady state 
versus Day 1 accumulation ratios will be conducted. 
A snapshot date for PK samples to be analyzed may be defined, if required. Samples collected 
before this date will be analyzed for TRC253and included in the PK analysis. Samples collected 
after the snapshot date may be analyzed at a later date, and may be included in a PK re-analysis 
when they become available after database lock.  
Population PK analysis of plasma concentration-time data of TRC253will be performed using 
nonlinear mixed-effects modeling. Available baseline patient characteristics (demographics, 
laboratory variables, race, etc.) will be tested as potential covariates affecting PK parameters. 
Data from this study may be pooled with other data for the population analysis. Details will be 
given in a population PK analysis plan and the results of the population PK analysis will be 
presented in a separate report. 
14.6. 
Biomarker Analyses 
14.6.1. 
FDHT-PET 
The maximum standard uptake value will be calculated for each lesion at each tested dose level 
and for all lesions. The percent decline in maximum standard uptake will be directly proportional 
to AR occupancy and therefore can be used to estimate EC90 which will be taken into 
consideration to select the RP2D. 
14.6.2. 
Exploratory Biomarkers 
CTC number at baseline, and change in CTC counts will be descriptively summarized. Prostate-
specific antigen changes at Week 12 will be correlated with expression of molecular markers to 
identify novel sensitizing mechanisms. Whole blood and plasma samples collected will be used 
to estimate frequency of expression of resistance and high risk markers. Associations will be 
made with time to clinical endpoints and expression of resistance biomarkers. 
The association of biomarkers with clinical response or relevant survival endpoints may be 
assessed using appropriate statistical methods (e.g., analysis of variance, categorical or survival 
models) depending on the endpoints. Analyses may be performed within the treatment group. 
Other clinical covariates (such as baseline tumor characteristics and patient demographics) may 
also be included in the model. Correlation of baseline biomarker expression levels with clinical 
response or relevant time to-event endpoints may be performed to identify responsive (or 
resistant) subgroups. Association of biomarkers with clinical response or relevant time-to-event 
endpoints will also be explored in the overall population. Appropriate details of these exploratory 
analyses will be included in the statistical analysis plan. Results of these exploratory analyses 
will be presented in separate technical reports.  


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14.7. 
Pharmacokinetic/Pharmacodynamic Analyses 
Pharmacokinetic/pharmacodynamic (PK/PD) analyses will be performed using data from all 
patients who have sufficient data available to evaluate anti-tumor effects of TRC253. The 
population PK/PD analysis will use concentration as an independent variable. Pharmacodynamic 
endpoints such as percent decline in average maximum standardized uptake value (SUVmax-avg) 
from baseline (estimate EC90) from FDHT-PET, time to PSA progression, and percent change in 
PSA relative to baseline will be considered using non-linear mixed-effect modeling analysis. 
14.8. 
Efficacy Analyses 
Patient listings will be provided for efficacy evaluations including PSA response rate, time to 
PSA progression, and rPFS.  
Post-treatment percent change in PSA relative to baseline will be reported at Week 12 (or earlier 
for those who discontinue therapy), and separately, the maximal change at any time on study will 
also be reported for each patient and summarized using waterfall plots. 
For Part 2, efficacy summaries by population cohort will be performed. Median time to PSA 
progression will be determined separately for each of the expansion cohorts and Kaplan-Meier 
curves may be plotted. If there is sufficient data, rPFS will be summarized and median rPFS will 
be assessed. If deemed appropriate, patients receiving the same dose from Part 1 may also be 
combined with Part 2 patients.   
 
 
 
 
 


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15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
All data entered on CRFs/eCRFs must be verifiable within the patients’ source documents 
(written or electronic record). The Investigator/institution guarantees TRACON representatives 
and appropriate regulatory authorities direct access to the original source records for the duration 
of the agreed study record retention period. Printouts of source records that are electronically 
obtained and stored will not be acceptable for audit/inspection unless provided as certified exact 
copies and the data remains as meaningful and useful as in its original electronic state. All eCRF 
entries, corrections, and alterations must be made by the investigator or authorized study-site 
personnel. The investigator must verify that all data entries in the eCRF are accurate and correct. 
Legally protected patient identification and other personal health information must be securely 
stored with limited access by the participating institutions. Unless secure provisions are 
established by the institution to allow TRACON (or designee) to perform remote monitoring of 
electronic source records, TRACON (or designee) will review source records/data on site and 
will not remove any such protected health information.   
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during 
these remote contacts, study-site personnel will be available to provide an update on the progress 
of the study at the site. 


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16. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Monitoring visits to clinical investigator sites will be made by TRACON or its representatives 
periodically during the trial to ensure that GCPs and all aspects of the protocol are being 
followed.   
Representatives of the sponsor's clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. The trial site will also be subject to possible 
inspection by the institutional review board (IRB) or independent ethics committee (IEC) or 
other appropriate regulatory authority. The investigator should immediately notify the sponsor if 
he or she has been contacted by a regulatory agency concerning an upcoming inspection. 
It is important that the Investigator(s) and their relevant personnel are available during the 
monitoring visits, audits, and inspections and that sufficient attention, time, and support is 
devoted to the process.  
TRACON and its representatives will be governed by applicable regulations, good clinical 
practice standards, and internal SOPs for the conduct of monitoring visits and QA audits.    
Protocol deviations will be captured in TRACON’s electronic data capture system. 


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17. 
ETHICS 
17.1. 
Health Authorities and Independent Ethics Committees/Institutional 
Review Boards  
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any, excluding the ones that are purely administrative, with no 
consequences for patients, data or study conduct, unless required locally), the ICF, applicable 
recruiting materials, and patient compensation programs, and the sponsor has received a copy of 
this approval. This approval letter must be dated and must clearly identify the IEC/IRB and the 
documents being approved. 
All correspondence and other evidence of appropriate and timely communications with the 
IRB/IEC should be retained in the Investigator/site files. Copies of all IRB/IEC approvals should 
also be forwarded to TRACON. 
The only circumstance in which an amendment may be initiated prior to relevant approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients. In that 
event, the Investigator must notify the IRB/IEC/health authorities and TRACON in writing 
within 5 business days after the implementation. 
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB 
about the study completion. 
17.2. 
Ethical Conduct of the Study 
The investigator is responsible for ensuring the trial is performed in accordance with the 
protocol, applicable local regulatory requirements and laws, and the International Conference on 
Harmonization Guideline on Good Clinical Practice, which supports the application of ethical 
principles that have their origin in the Declaration of Helsinki (see ICH E6, §2.1).  
17.3. 
Written Informed Consent 
The informed consent form language must be agreed upon by TRACON and the IRB/IEC and 
must be in compliance with ICH GCP, local regulatory requirements, and legal requirements. 
The informed consent information must not be changed without prior approval by TRACON and 
the IRB/IEC. The informed consent form used in this trial, and any changes made during the 
course of the trial, must be approved by both the IRB/IEC and TRACON, or designee, before 
use.  
It is the responsibility of the Investigator to give each patient full and adequate verbal and written 
information regarding the objective and procedures of the trial and the possible risks involved.  
This information must be provided to each patient prior to undertaking any trial-related 
procedure. The patient will be given sufficient time to read the ICF and the opportunity to ask 
questions. After this explanation and before entry into the study, consent should be appropriately 
recorded by means of the patient’s personally dated signature. After having obtained the consent, 
a copy of the ICF must be given to the patient. 
Each patient must be informed about her right to withdraw from the trial at any time.  
Furthermore, it is the responsibility of the Investigator to ensure each patient is appropriately 


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informed before obtaining signed and dated consent. Signatures from the investigator conducting 
the informed consent discussion should also be obtained prior to undertaking any trial-related 
procedure. Consent by a legally authorized representative is not permitted. Should an impartial 
witness be needed, ICH E6 requirements for impartial witnesses will apply.  
The Investigator will retain each patient’s original signed consent form in the Investigator/site 
files. 
17.4. 
Patient Compensation 
Patients will not be compensated for participation in this trial; this will be outlined in the 
informed consent form. 


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18. 
DATA HANDLING AND RECORDKEEPING 
18.1. 
Inspection of Records 
CRFs are required and should be completed for each patient who receives treatment with 
TRC253. Screen failure CRFs will not be collected. Nevertheless, records of potential patients 
identified and screened shall be retained on site screening logs. The completed original CRFs are 
the sole property of TRACON and should not be made available in any form to third parties 
without written permission from TRACON (except for authorized representatives of the HRA 
and in accordance with HIPAA regulations). 
It is the Investigator’s responsibility to ensure completion and to review and approve all CRF 
data. The investigator will sign off on his/her data per patient. These signatures serve to attest 
that the investigator has reviewed and approved the information contained on the case report 
forms and that the information is complete, accurate, and true. At all times, the Investigator has 
final personal responsibility for the accuracy and authenticity of all clinical and laboratory data 
entered on the CRFs.   
The use of electronic CRFs (eCRFs) to capture study data using automated computerized data 
capture systems does not change the principles and requirements for collecting study data. The 
investigator still retains final personal responsibility for eCRF data and any associated data 
pertaining to it (e.g. metadata including any record of change to the originally recorded data).  
The investigator’s signed approval of the eCRF data serves to attest that the electronic data and 
all of its associated metadata (including changes) has been reviewed and accepted as complete, 
accurate, and true for each patient in the study. 
All CRF/eCRF data must be verifiable in the patient’s source records by TRACON or its 
designee. TRACON will review CRF data as compared to source records in an attempt to 
identify missing and spurious data and notify the investigator of findings so that proper 
corrections can be made. TRACON representatives (monitors and auditors), and regulatory 
inspectors shall have direct access to the original source records in its original recorded format: 
electronic or hardcopy.   
TRACON (or its designee) will perform all data management functions associated with the 
study.  Data will be captured electronically. Automated data verification (“edit checks”) will be 
used to ensure that the data are logical and consistent. Any inconsistencies will be queried for 
clarification or correction as appropriate by the clinical site.   
18.2. 
Retention of Records 
To allow for appropriate evaluations and/or audits by regulatory authorities or TRACON, the 
Investigator agrees to keep records, including the identity of all participating patients (sufficient 
information to link records, CRFs and hospital records), all original signed informed consent 
forms, copies of all CRFs, source documents, and detailed records of treatment disposition.   
Essential documents will be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product. These documents should be retained for a 


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longer period, however, if required by the applicable regulatory requirements or by an agreement 
with the sponsor.   
If the Investigator relocates, retires, or for any reason withdraws from the study, then TRACON 
should be prospectively notified. The study records must be transferred to an acceptable 
designee, such as another Investigator, another institution, or to TRACON. The Investigator must 
inform TRACON of any such transfer of responsibilities and properly identify the person or 
institution assuming the responsibility. The responsible investigator/institution must obtain 
TRACON’s written permission before disposing of any records.  


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19. 
DEFINITION OF END TRIAL 
19.1. 
End of Trial in all Participating Countries 
End of trial in all participating countries is defined as the time at which the patient enrolled in the 
study has completed treatment on study.  
For clinical investigational centers located in the EU, a declaration of the end of the clinical 
study will be made according to the procedures outlined in Directive 2001/20/ED, Article 10(c); 
for other countries, local regulations will be followed. 
19.2. 
Study and Site Termination 
Premature termination of this trial may occur because of a regulatory authority decision, change 
in opinion of the IRB/IEC, drug safety problems, or at the discretion of TRACON. In addition, 
TRACON retains the right to discontinue development of TRC253 at any time.  
TRACON reserves the right to discontinue the trial prior to inclusion of the intended number of 
patients, but intends only to exercise this right for valid scientific or administrative reasons. If a 
trial is prematurely terminated or discontinued, TRACON will promptly notify the Investigator.  
After notification, the Investigator must contact the participating patient within a 28 day time 
period. As directed by TRACON, all trial materials must be collected and all CRF data must be 
completed to the greatest extent possible.  
A study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed. 


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20. 
PUBLICATION OF TRIAL RESULTS 
Publication of trial results is discussed in the Clinical Trial Agreement.  
The sponsor is responsible for ensuring that the public has access to the appropriate information 
about the study by conforming to local and regional requirements for registration and posting of 
results. 
The study will be listed in the public database for clinical studies, www.clinicaltrials.gov. The 
summary of the study results will also be available on www.clinicaltrials.gov. 
 


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21. 
FINANCING AND INSURANCE 
Financing and Insurance are discussed in detail in the Clinical Trial Agreement.  


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22. 
INVESTIGATOR AGREEMENT: PROTOCOL 253PC101 
I understand that all information concerning this study supplied to me by TRACON 
Pharmaceuticals, Inc. is confidential information. I have read this protocol and agree to conduct 
the study according to Good Clinical Practice Guidelines and in accordance with the Clinical 
Trial Agreement. 
I understand that this protocol and all amendments must be submitted to the appropriate 
IRB/IEC. I will provide copies of the protocol and all pertinent information to all individuals 
responsible to me who assist in the conduct of this study. I will discuss this material with them to 
ensure that they are fully informed regarding the study drug, the conduct of the study, and the 
obligations of confidentiality. 
Coordinating Investigator (where required): 
 
Name (typed or printed): 
 
Institution and Address: 
 
 
 
 
 
 
 
Signature: 
 
Date: 
 
 
 
 
(Day Month Year) 
 
Principal (Site) Investigator: 
 
Name (typed or printed): 
 
Institution and Address: 
 
 
 
 
 
 
 
Telephone Number: 
 
Signature: 
 
Date: 
 
 
 
 
(Day Month Year) 
 
Note: If the address or telephone number of the investigator changes during the course of the study, written 
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required. 
 


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23. 
REFERENCES 
1. 
Rathkopf D.E., S.H.I., Androgen receptor antagonists in castration-resistant prostate 
cancer. Cancer J, 2013. 19(1): p. 43-49. 
2. 
Nelson W.G., Y.S., Resistance emerges to second-generation anti-androgens in prostate 
cancer. Cancer Discovery, 2013. 3(9): p. 971-974. 
3. 
Balbas M.D., E.M.J., Hosfield D.J., Wongvipat J., Arora V.K., Watson P.A., Chen Y., 
Greene G.L., Shen Y., Sawyers C.L., Overcoming mutation-based resistance to 
antiandrogens with rational drug design. eLife, 2013. 2(e00499): p. 21. 
4. 
Joseph JD, et al., A clinically relevant androgen receptor mutation confers resistance to 
second-generation antiandrogens enzalutamide and ARN-509. Cancer Discovery 2013. 
3(9): p. 1020-1029. 
5. 
Korpal M., K.J.M., Gao X., An F876L mutation in androgen receptor confers genetic and 
phenotype resistance to MDV3100 (enzalutamide). Cancer Discovery, 2013. 3(9): p. 
1030-1043. 
6. 
Beltran H., Y.R., Frampton G.M., et al., Targeted next-generation sequencing of 
advanced prostate cancer identifies potential therapeutic agents and disease 
heterogeneity. Eur Urol, 2013. 63(5): p. 920-926. 
7. 
Grasso C.S., W.Y.M., Robinson D.R., et al., The mutational landscape of lethal 
castration-resistant prostate cancer. Nature, 2012. 487(7406): p. 239-243. 
8. 
Scher H.I., M.M.J., Stadler W.M., 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): p. 1402-1418. 
 


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APPENDIX 1. ANTICIPATED EVENTS 
Anticipated Event 
An anticipated event is an adverse event (serious or non-serious) that commonly occurs as a 
consequence of the underlying disease or condition under investigation (disease related) or 
background regimen. 
For the purposes of this study the following events will be considered anticipated events in the 
study population of patients with metastatic, castration-resistant prostate cancer: 
• Urinary problems (including but not restricted to urinating frequently, not being able 
to urinate, difficulties to start and/or stop the flow of urine, and pain during urination) 
• Erection problems 
• Blood in urine or semen 
• Pain in the lower back, abdomen, hip, or pelvis 
• Bone pain 
• Edema in the lower extremities 
• Gastrointestinal symptoms including diarrhea, rectal urgency, fecal incontinence, 
constipation, and abdominal and/or rectal pain 
Reporting of Anticipated Events 
All adverse events will be recorded in the eCRF regardless of whether considered to be 
anticipated events and will be reported to the sponsor as described in Section 12.2.1, Adverse 
Events. Any anticipated event that meets serious adverse event criteria will be reported to the 
sponsor as described in Section 12.2.2, Serious Adverse Events. These anticipated events are 
exempt from expedited reporting as individual single cases to Health Authorities. However if 
based on an aggregate review, it is determined that an anticipated event is possibly related to 
study drug, the sponsor will report these events in an expedited manner. 
 
 


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APPENDIX 2. OUTCOME MEASURES FOR CLINICAL TRIALS IN 
PROSTATE CANCER: PSA RESPONSE ACCORDING TO 
PCWG3 [8]  
• Recognize that a favorable effect on PSA may be delayed for ≥12 weeks, even for a 
cytotoxic drug 
• Monitor PSA by cycle but plan to continue through early rises for a minimum of 12 
weeks unless other evidence of progression 
• Ignore early rises (before 12 weeks) in determining PSA response 
• Endpoints for control/relief/elimination  
− Record the percent change from baseline (rise or fall) at 12 weeks depending on 
trial design 
− Separately record the maximal change (rise or fall) at any time using a waterfall 
plot 
− Separately report the proportion of patients who have undergone radical 
prostatectomy and achieved a nadir less than 0.2 ng/mL and primary radiation 
therapy-treated patients who achieved a nadir less than 0.5 ng/mL 
− Describe absolute changes in PSA over time from baseline to best response 
• Endpoints for delay/prevention/progression:  
− After decline from baseline: record time from start of therapy to first PSA 
increase that is ≥25% and ≥2 ng/mL above the nadir, and which is confirmed by a 
second value ≥3 weeks later (i.e., a confirmed rising trend); the requirement for an 
increase of 5 ng/mL was decreased to 2 ng/mL, and the requirement for a 50% 
increase was reduced to 25% 
− Standards for reporting PSA progression date may not indicate a need to stop 
treatment 
• Recording the duration of PSA decline is of little value  
• No decline from baseline:  
− PSA progression ≥25% increase and ≥2 ng/mL increase from baseline beyond 12 
weeks 
• Relate to mechanism of drug and anticipated timing of potential 
favorable/unfavorable effects on PSA, if present 
 
 


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APPENDIX 3. OUTCOME MEASURES FOR CLINICAL TRIALS IN 
PROSTATE CANCER: RESPONSE BY DISEASE 
MANIFESTATION ACCORDING TO PCWG3 [8] 
General 
Endpoints for control/relief/elimination 
Record changes in lymph nodes, lung, liver, adrenal, and 
CNS sites separately 
Record up to five lesions per site of disease. 
Record changes in size using waterfall plot. 
Use RECIST 1.1 with caveats: 
• 
Confirm favorable change with second scan. Record 
changes in size using waterfall plot 
• 
Record complete elimination of disease at any site 
separately. Confirm favorable change with second 
scan 
• 
Record complete elimination of disease at any site 
separately 
Nodes 
Only report changes in lymph nodes that were ≥1.5 cm in the short axis 
Record changes in pelvic (regional) nodes and extrapelvic (distant/metastatic) nodes separately 
Visceral 
Use RECIST 1.1 with caveats: 
• 
Record changes in liver, lung, adrenal, and CNS separately 
• 
Only report changes in lesions ≥ 1.0 cm in the longest dimension 
Nodal and Visceral 
Endpoints for 
delay/prevention/progression 
Record changes in nodal and visceral (lung, liver, adrenal, 
and CNS) disease separately 
Use RECIST 1.1 but clearly record type of progression 
(growth of existing lesions and development of new lesions) 
separately by site 
The recommendations apply to both non-metastatic CRPC 
and metastatic CRPC 
Record up to five lesions per site of spread 
Report the proportion who have not progressed at fixed time 
points (6 or 12 months) 
Note that for some treatments, a lesion may increase in size 
before it decreases 
Nodal  
Previously normal (<1.0 cm) lymph nodes must have grown 
by ≥5 mm in the short axis from baseline or nadir and be 
≥1.0 cm in the short axis to be considered to have progressed 
Nodes that have progressed to 1.0 to less than 1.5 cm are 
pathologic, subject to clinical discretion, and nonmeasurable 
For existing pathologic adenopathy (≥1.5 cm), progression is 
defined per RECIST 1.1 
Bone Metastatic 
Endpoints for control/relief/elimination 
Record changes as improved or stable (no new lesions) or 
worse (new lesions) or resolved bone lesion 
Changes in intensity of uptake alone do not constitute 
progression or regression 
No new lesions: continue therapy in absence of other signs 
of progression 


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Endpoints for 
delay/prevention/progression 
Exclude pseudoprogression in the absence of symptoms 
or other signs of progression 
At least two new lesions on first post-treatment scan, with 
at least two additional lesions on the next scan (2+2 rule) 
If at least two additional new lesions are seen on the next 
(confirmatory) scan, the date of progression is the date 
of the first post-treatment scan, when the first two new 
lesions were documented 
 
For scans after the first post-treatment scan, at least two new 
lesions relative to the first post-treatment scan confirmed 
on a subsequent scan 
 
Date of progression is the date of the scan that first 
documents the second lesion 
Abbreviations: CNS = central nervous system; CRPC = castration-resistant prostate cancer; RECIST = Response 
Evaluation Criteria in Solid Tumors. 
Source: Scher HI, Morris MJ, Stadler WM et al. Trial design and objectives for castration-resistant prostate cancer: 
updated recommendations from the Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol. 2016; 34(12):1402-
1418. [8] 
 
 
 
 
 


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APPENDIX 4. NATIONAL CANCER INSTITUTE (NCI) COMMON 
TERMINOLOGY CRITERIA FOR ADVERSE EVENTS 
(CTCAE) 
The NCI CTCAE (Version 4.03) should be used to assess Adverse Events and may be reviewed on-line at 
the following NCI website: 
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 


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APPENDIX 5. ECOG PERFORMANCE STATUS 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, e.g., light house work, office work. 
2 
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 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
5 
Dead. 
 


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APPENDIX 6. MEDICATIONS THAT MAY PROLONG THE QT 
INTERVAL INCLUDE BUT ARE NOT LIMITED TO THE 
FOLLOWING 
Alfuzosin (Uroxatral®) 
Amoxapine 
Apomorphine (Apokyn®) 
Arformoterol (Brovana®) 
Bitter orange 
Chloroquine (Aralen®) 
Certain phenothiazine or antipsychotic 
medications, including: 
Chlorpromazine (Thorazine®) 
Clozapine (Clozaril®, FazaClo®) 
Fluphenazine (Prolixin®) 
Haloperidol (Haldol®) 
Iloperidone (Fanapt™) 
Olanzapine (Zyprexa®, Symbyax®) 
Paliperidone (Invega®) 
Perphenazine (Trilafon®) 
Pimozide (Orap®) 
Prochlorperazine (Compazine®) 
Quetiapine (Seroquel®) or quetiapine XR 
(Seroquel XR®) 
Risperidone (Risperdal®) 
Trifluoperazine (Stelazine®) 
Thioridazine (Mellaril®) 
Ziprasidone (Geodon®) 
Certain antibiotics, including: 
Azithromycin (Zithromax®) 
Ciprofloxacin (Cipro®, Cipro XR®) 
Clarithromycin (Biaxin®, Biaxin XL®) 
Erythromycin (Ery-Tab®) 
Gemifloxacin (Factive®) 
Levofloxacin (Levaquin®) 
Mefloquine (Lariam®) 
Moxifloxacin (Avelox®) 
Norfloxacin (Noroxin®) 
Ofloxacin (Floxin®) 
Telithromycin (Ketek®) 
Troleandomycin (Tao®) 
Certain arrhythmia medications, including: 
Amiodarone (Cordarone®) 
Disopyramide (Norpace®, Norpace CR®) 
Dofetilide (Tikosyn®) 
Dronedarone (Multaq®) 
Flecainide (Tambocor®) 
Ibutilide (Corvert®) 
Procainamide (Procanbid®) 
Propafenone (Rythmol®) 
Quinidine 
Sotalol (Betapace®) 
Citalopram (Celexa®) 
CortiSlim® 
Cyclobenzaprine (Flexeril®, Fexmid™) 
Ephedra 
Formoterol (Foradil®, Perforomist™, 
Symbicort®) 
Indacaterol maleate (Arcapta™) 
Lapatinib (Tykerb®) 
Lipo 6™ 
Lipovarin™ 
Lopinavir and ritonavir (Kaletra®) 
Maprotiline (Ludiomil®) 
Methadone (Dolophine®, Diskets®, 
Methadose®) 
Octreotide (Sandostatin®) 
Quetiapine (Seroquel®) or quetiapine XR 
(Seroquel XR®) 
Pentamidine (NebuPent®, Pentam®) 
Phentramine™ 
Ranolazine (Ranexa®) 


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Saquinavir (Invirase®) 
Solifenacin (VESIcare®) 
Tacrolimus (Prograf®) 
Tetrabenazine (Xenazine®) 
Tolterodine (Detrol®, Detrol LA) 
Trazodone (Desyrel®) or trazodone ER 
(Oleptro™) 
 
Certain cancer medications, including: 
Crizotinib (Xalkori®) 
Dasatinib (Sprycel®) 
Eribulin (Halaven™) 
Lapatinib (Tykerb®) 
Nilotinib (Tasigna®) 
Pazopanib (Votrient™) 
Sunitinib (Sutent®) 
Vandetanib (Caprelsa®) 
Vorinostat (Zolinza®) 
Tricyclic antidepressants, including: 
Amitriptyline (Elavil®) 
Amoxapine (Asendin®) 
Clomipramine (Anafranil®) 
Desipramine (Norpramin®) 
Doxepin (Sinequan®, Silenor®) 
Imipramine (Tofranil®, Tofranil PM®) 
Maprotiline (Ludiomil®) 
Nortriptyline (Pamelor®) 
Protriptyline (Vivactil®) 
Trimipramine (Surmontil®) 
Certain nausea and vomiting medications, 
including: 
Dolasetron (Anzemet®) 
Droperidol (Inapsine®) 
Granisetron (Kytril®, Sancuso®) 
Ondansetron (Zofran®, Zuplenz™) 
Palonosetron (Aloxi®) 
Prochlorperazine (Compazine®) 
Vardenafil (Levitra®, Staxyn™)