Conditions: VHL Gene Mutation VHL VHL Syndrome VHL Gene Inactivation Von Hippel Von Hippel-Lindau Disease Von Hippel's Disease Von Hippel-Lindau Syndrome, Modifiers of Clear Cell Renal Cell Carcinoma Clear Cell RCC ccRCC
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 4
Healthy volunteers: no

Brief summary:
The primary objective of this study is to assess the overall response rate (ORR) of von Hippel-Lindau (VHL) disease-associated clear cell renal cell carcinoma (ccRCC) tumors in VHL participants treated with MK-3795.

Detailed description:
This open-label Phase 2 study will evaluate the efficacy, safety, PK, and PD of MK-3795 in participants with VHL disease who have at least 1 measurable VHL disease-associated ccRCC tumor (as defined by RECIST 1.1). MK-3795 will be administered orally and treatment will be continuous. Changes in VHL disease-associated non-ccRCC tumors will also be evaluated.

Arms:
arm 1: Participants receive 800 mg MK-3795 orally twice daily. Participants may continue to receive MK-3795 in the absence of unacceptable treatment related toxicity or unequivocal disease progression.

Interventions: intervention 1: MK-3795
Intervention descriptions: intervention 1: 800 mg twice daily (four 200 mg oral tablets twice daily)

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:
Document Date:
An Open-Label Phase 2 Study To Evaluate
PT2385 for the Treatment of von Hippel-Lindau
Disease-Associated Clear Cell Renal Cell
Carcinoma
NCT03108066
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Protocol PT2385-202 / MK-3795-003-05
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PROTOCOL PT2385-202
AN OPEN-LABEL PHASE 2 STUDY TO EVALUATE 
PT2385 FOR THE TREATMENT OF
VON HIPPEL-LINDAU DISEASE-ASSOCIATED
CLEAR CELL RENAL CELL CARCINOMA
Protocol Number:
PT2385-202/MK-3795-003
Sponsor:
Peloton Therapeutics, Inc., a wholly owned subsidiary
of Merck & Co., Inc. (hereafter referred to as Peloton
Therapeutics)
126 East Lincoln Avenue
PO Box 2000
Rahway, New Jersey, 07065, USA
Medical Monitor:
Version:
5.0
Date:
25 July 2022
Original Protocol: 
26 October 2016
Version 2.0
01 December 2016
Version 3.0
02 December 2016
Version 4.0
05 January 2017
The information contained herein is confidential and the proprietary property of 
Peloton Therapeutics, Inc. and any unauthorized use or disclosure of such 
information without the prior written authorization of Peloton Therapeutics, Inc. 
is expressly prohibited.
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INVESTIGATOR’S AGREEMENT
I have received and read the Investigator’s Brochure for PT2385.  I have read the 
PT2385-202 protocol and agree to conduct the study as outlined.  I agree to maintain the 
confidentiality of all information received or developed in connection with this protocol.
Printed Name of Investigator
Signature of Investigator
Date
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SPONSOR APPROVAL AND SIGNATURE PAGE
SPONSOR’S APPROVAL OF PROTOCOL PT2385-202:
Medical Monitor 
Date
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PROCEDURES IN CASE OF EMERGENCY
Emergency Contact Information
Role in Study
Name
Address and Telephone Number
Clinical Study Manager
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065
Medical Monitor
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065
PPD
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1.
SYNOPSIS
Name of Sponsor/Company:
Peloton Therapeutics, Inc.
Name of Investigational Product:
PT2385
Name of Active Ingredient:
PT2385
Title of Study: 
An Open-Label Phase 2 Study To Evaluate PT2385 for the Treatment of von Hippel-Lindau
Disease-Associated Clear Cell Renal Cell Carcinoma
Study Center(s): Up to 3
Principal Investigator:
Estimated Date First Patient Enrolled: January 2017
Phase of Development: 2
Objectives: 
Primary:
To assess overall response rate (ORR) of von Hippel-Lindau (VHL) disease-associated clear cell 
renal cell carcinoma (ccRCC) tumors in VHL patients treated with PT2385 as determined by 
Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1). ORR is defined as the 
proportion of patients with a best confirmed response of complete response (CR) or partial 
response (PR).
Secondary:

To evaluate progression-free survival (PFS) in patients with VHL disease-associated ccRCC
tumors treated with PT2385

To evaluate duration of response (DOR) and time to response (TTR) in patients with VHL 
disease-associated ccRCC tumors treated with PT2385 who achieve a PR or better as 
determined by RECIST 1.1

To study the effect of treatment with PT2385 on VHL disease-associated non-ccRCC tumors 
by modifying RECIST 1.1 criteria to assess tumors in individual organ systems independently 
rather than collectively

To study the safety and tolerability of PT2385 

To study the pharmacokinetics (PK) of PT2385
Exploratory:

To evaluate changes in pharmacodynamic (PD) markers (e.g., serum erythropoietin [EPO]) in 
patients treated with PT2385
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Methodology: 
This open-label Phase 2 study will evaluate the efficacy, safety, PK, and PD of PT2385 in patients 
with VHL disease who have at least 1 measurable VHL disease-associated ccRCC tumor (as 
defined by RECIST 1.1).  PT2385 will be administered orally at a dosage of 800 mg twice daily; 
treatment will be continuous. Patients will be entered in the study after meeting all inclusion 
criteria and no exclusion criteria.  This study will be conducted with a 2-stage design, which allows 
for an early assessment of futility.  A response will be defined as either a PR or CR occurring at 
any time after initiation of treatment, based on assessment of ccRCC tumors.  All responses must 
be confirmed after the initial response is documented.  Changes in VHL disease-associated non-
ccRCC tumors will also be evaluated independently by modifying RECIST 1.1 criteria to assess
tumors in individual organ systems independently rather than collectively.
Twenty-five patients will be enrolled during the first stage.  A Data Monitoring Committee (DMC) 
will perform the safety review for the first 6 patients and the futility analysis for Stage 1 of the 
study.  The DMC will review safety and any treatment-limiting toxicities to confirm whether the 
study should continue to enroll or if modifications to the protocol are needed.  The DMC will 
review the response data from the first 25 patients to determine if at least 3 patients have a 
confirmed PR or better and that the threshold for opening Stage 2 has been met.  Treatment-
limiting toxicities will be assessed according to pre-defined criteria.
In the second stage of the study, 25 additional patients will be enrolled, to a maximum accrual of 
50 patients.
Patients will undergo clinical and laboratory evaluations every 2 weeks for the first 4 weeks and 
then every 4 weeks (i.e., 28 days) according to the Schedule of Events.  Patients will be evaluated 
radiologically for evidence of response or progression approximately 12 weeks after initiation of 
treatment and every 12 weeks thereafter while continuing in the study.  Patients with evidence of 
stable disease or disease response, i.e., CR or PR, will continue to receive treatment in the absence 
of serious toxicity.  Patients who demonstrate disease progression of renal lesions at any time will 
be withdrawn from study treatment.  Patients who discontinue study treatment for any reason will 
be followed either by telephone or office visit to for their medical history, surgical history, disease
status, and survival status.  These patients will be followed every 6 months for up to 3 years 
following completion of enrollment in the study or until the patient either withdraws consent or 
dies.
Number of patients (planned): 
50 patients
Diagnosis and main criteria for inclusion: Patients must meet all of the following criteria to be 
enrolled in this study.
1.
Has the ability to understand and willingness to sign a written informed consent form before 
the performance of any study procedures
2.
Is of age ≥18 years
3.
Has at least 1 measurable ccRCC tumor and no solid ccRCC tumor greater than 3.0 cm, based 
on radiologic diagnosis (histologic diagnosis not required); may have VHL disease-associated 
lesions in other organ systems
4.
Has a diagnosis of von Hippel-Lindau disease, based on a germline VHL alteration
5.
Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
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6.
Has normal organ and marrow function as defined below:
•
White blood cell count ≥3,000/µL, absolute neutrophil count ≥1,500/µL, hemoglobin 
level ≥9 g/dL without transfusion support within 2 weeks prior to enrollment; platelet 
count ≥100,000/µL;
•
Serum creatinine level ≤2.0 × upper limit of normal (ULN) or measured 24-hour 
creatinine clearance ≥30 mL/min; and
•
Levels of AST and ALT < 2.5 × ULN, total bilirubin < 1.5 × ULN (< 3 × ULN in patients 
with Gilbert’s disease), and alkaline phosphatase ≤2.5 × ULN 
7.
If a female patient of child bearing potential, or a male patient with a female partner of 
child-bearing potential (defined as all women physiologically capable of becoming pregnant), 
must agree to use highly effective methods of contraception during screening, during the 
period of drug administration and for 30 days after stopping study drug administration. Highly 
effective contraception methods include the following:
•
Total abstinence,
•
Male or female sterilization, or
•
Combination of any 2 of the following (a + b or a + c or b + c):
a.
Use of oral, injected or implanted hormonal methods of contraception
b.
Placement of an intrauterine device (IUD) or intrauterine system (IUS)
c.
Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository
8.
Female patients of child-bearing potential must have a negative serum pregnancy test result 
within 7 days before first administration of study drug.
Main Criteria for Exclusion:  Patients will be excluded from this study if they meet any of the 
following criteria.
1.
Has participated or plans to participate in another clinical trial of an investigational drug (or a 
medical device) within 30 days of study enrollment
2.
Has had prior treatment with or known allergy or hypersensitivity to a HIFα inhibitor
3.
Has had prior radiotherapy or systemic anti-cancer therapy for ccRCC (includes anti-VEGF 
therapy or any systemic investigational anti-cancer agent)
4.
Has a prior or concomitant non-VHL disease-associated invasive malignancy with the 
exception of adequately treated basal or squamous cell carcinoma of the skin, cervical 
carcinoma in situ or any other malignancy from which the patient has remained disease free for 
more than 2 years
5.
Has any history of metastatic disease
6.
Has any condition possibly affecting absorption, distribution, metabolism, or excretion of drugs 
that may confound the analyses conducted in this study (e.g., previous surgery on the 
gastrointestinal tract that includes removal of parts of stomach, bowel, liver, gallbladder, or 
pancreas)
7.
Has known hypersensitivity to any component in the formulation of PT2385 
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8.
Has had radiotherapy to any non-ccRCC site within 4 weeks prior to entering the study or has 
not recovered from adverse events (AE) (to ≤Grade 1 National Cancer Institute Common 
Terminology Criteria for Adverse Events Version 4.03 [NCI CTCAE 4.03]) related to agents 
administered more than 4 weeks earlier
9.
Has had any surgical procedure for VHL disease or any major surgical procedure completed 
within 4 weeks prior to entering the study or has any surgical lesions from recent major 
surgical procedures that are not well healed
10. Has an immediate need for surgical intervention for tumor treatment 
11. Has known history of positive test results for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS)
12. Has an active infection requiring systemic treatment
13. Has a bleeding diathesis or coagulopathy
14. Has had any major cardiovascular event within 6 months prior to study drug administration 
including but not limited to myocardial infarction, unstable angina, cerebrovascular accident, 
transient ischemic event, pulmonary embolism, or New York Heart Association Class III or IV 
heart failure
15. Has any other clinically significant cardiac, respiratory, or other medical or psychiatric 
condition that might interfere with participation in the trial or interfere with the interpretation 
of trial results
16. If a female patient, intends to breast feed a child during study or within 30 days after 
administration of the last dose of study drug
Investigational product, dosage and mode of administration: 
PT2385 tablets, 800 mg (four 200 mg tablets) administered orally, twice daily
Duration of treatment: 
Patients may continue to receive PT2385 in the absence of unacceptable treatment-related toxicity 
or unequivocal disease progression.
Reference therapy, dosage and mode of administration: 
None
Criteria for evaluation:
Efficacy
Primary Endpoint: Overall response rate (ORR) in VHL disease-associated ccRCC tumors, defined 
as the proportion of the best confirmed response of CR or PR (as assessed by the Independent 
Review Committee (IRC)) as determined by RECIST 1.1, modified to follow ccRCC tumors only
Secondary Endpoints:

Progression-free survival (PFS) in VHL disease-associated ccRCC tumors, defined as the 
interval from the start of study treatment until the earlier of the first documentation of disease 
progression determined by RECIST 1.1 or death from any cause, and calculated for patients 
with a best confirmed response of CR or PR

Duration of response (DOR) in VHL disease-associated ccRCC tumors, defined as the interval 
from the first documentation of response, as determined by RECIST 1.1, to the earlier of the 
first documentation of disease progression or death from any cause
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
Time to response (TTR) in VHL disease-associated ccRCC tumors, defined as the interval 
from the start of study treatment to the first documentation of a response, as determined by 
RECIST 1.1, and calculated for patients with a best confirmed response of CR or PR

Best confirmed response, PFS, DOR, and TTR for non-ccRCC tumors associated with VHL 
disease in different organ systems, by modifying RECIST 1.1 criteria to assess tumors in 
individual organsystems
Exploratory endpoints:

Changes in PD markers (e.g., serum EPO)
Safety:
Safety and tolerability will be determined by symptoms, signs, and abnormal laboratory test results
Safety assessments include the following:

Physical examinations

Vital sign measurements (including pulse oximetry)

12-lead electrocardiograms (ECG) with QTc interval determination

Clinical laboratory measurements

Concomitant medications

Incidence, intensity, and relationship of AEs and serious adverse events (SAEs)

Effects on fertility in males (orchidometry, semen analysis, and measurement of testosterone,
follicle-stimulating hormone, luteinizing hormone, and inhibin B levels)
Pharmacokinetics will be evaluated.
Statistical methods:
Sample size determination
This study will be conducted with a 2-stage design (Green and Dahlberg, 1992), which allows for 
an early assessment of futility.  If after the first 25 patients have been accrued to the study, 2 or 
fewer patients have had a confirmed response, further accrual will be temporarily suspended for up 
to a year or until at least 3 responses are seen; if at least 3 responses are not seen within 1 year after 
enrollment of the 25th patient, no further patients will be enrolled and the study will be 
discontinued.  In addition, if more than 2 of the first 6 patients enrolled experience treatment-
limiting toxicity during the first 4 weeks of their treatment, the protocol will be modified or the 
study will be stopped.  If 3 or more of the 25 patients respond, enrollment will proceed to the 
second stage of the study.
A total of 25 patients will be enrolled into the second stage of the study for a total required 
enrollment of 50 patients.  If at least 13 of the 50 patients (25 + 25) respond (CR or PR), then the 
hypothesis that PT2385 is ineffective will be rejected.
The required sample size for this 2-stage design is based on the following design parameters: The 
null hypothesis is that PT2385 is ineffective, defined as an ORR (best confirmed response of PR or 
CR) of 15% (P0 = 0.15).  The alternative hypothesis is that PT2385 is effective, defined as an ORR 
of 30% (P1 = 0.3).  The probability of falsely concluding that the agent is effective when it is truly 
ineffective is 0.05 (alpha) and the probability of falsely concluding that the agent is ineffective 
when it is truly effective is 0.2 (beta).
Efficacy Assessments
Efficacy analyses will be conducted on the Efficacy Analysis Set, i.e., for patients enrolled in the 
study who have received at least 1 dose of PT2385. Clear cell renal cell tumor response will be 
assessed according to RECIST 1.1, modified to follow ccRCC tumors only.  The ccRCC ORR will 
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be summarized.  Estimates of the ccRCC ORR along with the associated 90% and 95% exact 
binomial confidence intervals (Clopper-Pearson method) will be provided.  The binomial 
probability that the observed ccRCC ORR is > 0.15 will be calculated.  Best confirmed response 
will be summarized.  The ccRCC TTR will be calculated for patients who achieve a ccRCC CR or 
PR.  The maximum percent decrease in ccRCC tumor burden will be displayed using waterfall 
plots.  The ccRCC PFS and ccRCC DOR will be summarized descriptively using the 
Kaplan-Meier method.  The median and quartiles of ccRCC PFS and ccRCC DOR will be 
calculated along with 90% and 95% confidence intervals.
Summaries of the response endpoints will also be provided for subgroups of the Efficacy Analysis 
Set as follows: Subgroups will be defined based on site of primary tumors other than ccRCC at 
screening, blood level of PT2385 based on the PK assessments, and duration of PT2385 treatment.  
The analyses of ORR, PFS, best confirmed response, and DOR will be performed in each of these 
subgroups.
The ORR, PFS, DOR, and TTR will be summarized for the individual types of non-ccRCC tumors 
using modified RECIST 1.1 criteria.  The modification to RECIST 1.1 is to evaluate different 
organ system tumors independently (e.g., VHL disease-associated solid tumors in the pancreas, 
adrenal gland, or hemangioblastomas or retinal angiomas).
The determination of response and progression will be made by the local investigators. The 
investigator assessments will be used for decisions regarding treatment for individual patients and 
by the DMC for approval to open Stage 2 of the study. The response outcomes will also be 
reviewed and determined by an Independent Review Committee (IRC). For the primary analysis 
of ORR, the determination of response will be based on independent radiologic assessment 
conducted by the IRC. Both the investigators’ and the IRC’s assessments will be used for the 
summaries and analyses of efficacy.
Safety Assessments
Safety data analysis will be conducted for all patients receiving at least 1 dose of PT2385 (Safety 
Analysis Set). Adverse Events will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) terminology.  Analyses will consist of data summaries for AEs, SAEs, clinical 
laboratory parameters, vital sign measurements, and ECG data.  The QTc intervals will be 
summarized according to the method recorded on the electronic Case Report Form.  The number 
and percentage of patients experiencing 1 or more AEs will be summarized by the relationship to 
study drug and severity.  Laboratory parameters will be summarized using descriptive statistics, by 
post-treatment shifts relative to baseline, and data listings of clinically significant abnormal 
laboratory test results.  Vital sign measurements and ECG data will be summarized by changes
from baseline values using descriptive statistics.
Pharmacokinetic Assessments
The plasma concentrations of PT2385 and PT2639 at each collection time will be summarized.
Pharmacodynamic Assessments
Pharmacodynamic assessments will be conducted on the Efficacy Analysis Set.  Summary 
statistics will be computed for baseline biomarkers.  The change and percent change from baseline 
will be calculated for each subsequent measurement.  Summary statistics will be computed for 
each collection time point.  To investigate the effect of biomarkers on efficacy, the association of 
baseline biomarkers with ORR and PFS will be investigated using multivariate techniques, 
subgroup analyses, and regression modeling.
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2.
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
TABLE OF CONTENTS
1.
SYNOPSIS ............................................................................................... 5
2.
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES
................................................................................................................ 11
3.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS......... 16
4.
INTRODUCTION.................................................................................. 19
4.1.
Background............................................................................................. 19
4.1.1.
Von Hippel-Lindau Disease and Renal Cell Carcinoma........................ 19
4.1.1.1.
The von Hippel-Lindau Tumor Suppressor Gene .................................. 20
4.1.1.2.
HIF-2α .................................................................................................... 21
4.1.2.
PT2385.................................................................................................... 21
4.1.2.1.
Pharmacologic Activity .......................................................................... 21
4.1.2.2.
Pharmacokinetic Data............................................................................. 22
4.1.2.3.
Toxicity................................................................................................... 23
4.1.2.4.
Clinical Studies....................................................................................... 24
4.2.
Study Rationale....................................................................................... 24
5.
TRIAL OBJECTIVES AND PURPOSE................................................ 26
5.1.
Primary Objective................................................................................... 26
5.2.
Secondary Objectives ............................................................................. 26
5.3.
Exploratory Objectives ........................................................................... 26
6.
INVESTIGATIONAL PLAN................................................................. 27
6.1.
Overall Study Design.............................................................................. 27
6.2.
Number of Patients ................................................................................. 28
6.3.
Treatment Assignment............................................................................ 28
6.4.
Dose Adjustment Criteria ....................................................................... 28
6.5.
Criteria for Study Termination ............................................................... 30
7.
SELECTION AND WITHDRAWAL OF PATIENTS.......................... 31
7.1.
Informed Consent ................................................................................... 31
7.2.
Patient Eligibility.................................................................................... 31
7.2.1.
Patient Inclusion Criteria ........................................................................ 31
7.2.2.
Patient Exclusion Criteria....................................................................... 32
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7.2.3.
Patient Withdrawal Criteria.................................................................... 33
8.
TREATMENT OF PATIENTS.............................................................. 35
8.1.
Description of Study Drug...................................................................... 35
8.2.
Concomitant Medications....................................................................... 35
8.3.
Treatment Compliance............................................................................ 36
8.4.
Randomization and Blinding.................................................................. 36
9.
STUDY DRUG MATERIALS AND MANAGEMENT ....................... 37
9.1.
Study Drug.............................................................................................. 37
9.2.
Study Drug Packaging and Labeling...................................................... 37
9.3.
Study Drug Storage................................................................................. 37
9.4.
Study Drug Preparation .......................................................................... 37
9.5.
Administration........................................................................................ 37
9.6.
Study Drug Accountability..................................................................... 38
9.7.
Study Drug Handling and Disposal........................................................ 38
10.
ASSESSMENT OF EFFICACY ............................................................ 39
10.1.
Efficacy Parameters................................................................................ 39
10.1.1.
Response in VHL Disease-Associated ccRCC Tumors ......................... 39
10.1.1.1.
Response in VHL Disease-Associated Tumors...................................... 39
10.1.2.
Pharmacodynamics and Biomarker Assessments................................... 40
10.1.2.1.
Tissue Sample Collection ....................................................................... 40
11.
PHARMACOKINETIC ASSESSMENTS............................................. 41
12.
ASSESSMENT OF SAFETY................................................................. 42
12.1.
Safety Assessments................................................................................. 42
12.1.1.
Demographic/Medical History ............................................................... 42
12.1.2.
Eastern Cooperative Oncology Group Status......................................... 42
12.1.3.
Vital Signs .............................................................................................. 42
12.1.4.
Weight and Height.................................................................................. 43
12.1.5.
Physical Examination ............................................................................. 43
12.1.6.
Electrocardiogram................................................................................... 43
12.1.7.
Laboratory Assessments......................................................................... 43
12.1.7.1.
Hematology............................................................................................. 44
12.1.7.2.
Blood Chemistry..................................................................................... 44
12.1.7.3.
Iron Panel................................................................................................ 44
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12.1.7.4.
Prothrombin Time, Activated Partial Thromboplastin Time, and 
International Normalized Ratio .............................................................. 44
12.1.7.5.
Urinalysis................................................................................................ 44
12.1.7.6.
Pregnancy Screen.................................................................................... 44
12.1.7.7.
Male Fertility Analysis ........................................................................... 44
12.2.
Adverse and Serious Adverse Events..................................................... 45
12.2.1.
Definition of Adverse Events ................................................................. 45
12.2.1.1.
Adverse Events ....................................................................................... 45
12.2.1.2.
Serious Adverse Events.......................................................................... 45
12.3.
Eliciting Adverse Event Information...................................................... 46
12.4.
Assessment of Causality......................................................................... 46
12.5.
Assessment of Severity........................................................................... 46
12.6.
Recording Adverse Events ..................................................................... 47
12.7.
Reporting Serious Adverse Events......................................................... 48
12.8.
Pregnancy ............................................................................................... 49
12.8.1.
Methods of Birth Control........................................................................ 49
12.8.2.
Suspected Pregnancy .............................................................................. 49
13.
STATISTICS .......................................................................................... 51
13.1.
Determination of Sample Size................................................................ 51
13.2.
Analysis Populations .............................................................................. 51
13.3.
Statistical Analyses................................................................................. 52
13.3.1.
Handling of Missing, Unused, or Spurious Data.................................... 52
13.3.2.
Patient Characteristics and Patient Disposition...................................... 52
13.3.3.
Exposure ................................................................................................. 52
13.3.4.
Efficacy Analyses ................................................................................... 52
13.3.5.
Pharmacodynamic Analyses................................................................... 54
13.3.6.
Safety Analyses ...................................................................................... 54
13.3.6.1.
Adverse Events ....................................................................................... 54
13.3.6.2.
Clinical Laboratory Data ........................................................................ 55
13.3.6.3.
Other Safety Data ................................................................................... 56
13.3.7.
Pharmacokinetic Analyses...................................................................... 56
13.4.
Analysis Time Points.............................................................................. 56
13.4.1.
Final Analysis ......................................................................................... 56
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13.4.2.
Interim Analysis...................................................................................... 56
14.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS..................... 57
14.1.
Study Monitoring.................................................................................... 57
14.2.
Audits and Inspections............................................................................ 57
14.3.
Institutional Review Board (IRB)........................................................... 58
14.4.
Confidentiality........................................................................................ 58
14.5.
Modification of the Protocol................................................................... 58
14.6.
Protocol Deviations ................................................................................ 58
15.
QUALITY CONTROL AND QUALITY ASSURANCE ..................... 59
15.1.
Quality Assurance................................................................................... 59
15.2.
Financial Disclosure ............................................................................... 59
15.3.
Sponsor Obligations................................................................................ 59
15.4.
Investigator Documentation.................................................................... 59
15.5.
Clinical Study Insurance......................................................................... 60
15.6.
Use of Information.................................................................................. 60
16.
ETHICS .................................................................................................. 61
16.1.
Ethics Review......................................................................................... 61
16.2.
Ethical Conduct of the Study.................................................................. 61
16.3.
Written Informed Consent...................................................................... 61
17.
DATA HANDLING AND RECORDKEEPING................................... 63
17.1.
Inspection of Records ............................................................................. 63
17.2.
Retention of Records .............................................................................. 63
17.3.
Case Report Forms ................................................................................. 63
18.
PUBLICATION POLICY ...................................................................... 64
19.
LIST OF REFERENCES........................................................................ 65
20.
APPENDICES ........................................................................................ 68
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LIST OF TABLES
Table 1
Guidelines for Dose Modification .......................................................... 29
Table 2
Investigational Product ........................................................................... 35
Table 3
Adverse Event Severity Grades.............................................................. 47
Table 4
Serious Adverse Event Reporting Contact Information......................... 48
LIST OF APPENDICES
Appendix 1Schedule of Events ................................................................................. 69
Appendix 2ECOG Performance Status ..................................................................... 71
Appendix 3RECIST 1.1 Summary............................................................................ 72
Appendix 4Evaluation of Non-Renal VHL Related Disease .................................... 73
Appendix 5New York Heart Association Functional Classification......................... 74
Appendix 6Partial List of Strong CYP2C19 and CYP3A4 Inhibitors ...................... 75
Appendix 7Partial List of Substrates of CYP3A4, CYP2B6, CYP2C9, and CYP2C19
................................................................................................................ 76
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3.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
The following abbreviations and specialist terms are used in this study protocol.
Abbreviation or Specialist Term
Explanation
AE
adverse event
AIDS
acquired immunodeficiency syndrome
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
aPTT
activated partial thromboplastin time
ARNT
aryl hydrocarbon receptor nuclear translocator
ASCO
American Society of Clinical Oncology
BUN
blood urea nitrogen
Ca
calcium
CCND1
cyclin d1
ccRCC
clear cell renal cell carcinoma
Cl
chloride
CO2
bicarbonate
CR
complete response
CRF
case report form
CT
computerized tomography
DDI
drug-drug interaction
DLT
dose-limiting toxicity
DMC
Data Monitoring Committee
DOR
duration of response
ECG
electrocardiograms
ECOG
Eastern Cooperative Oncology Group
EPO
erythropoietin
Fe
iron
Flt-1/VEGFR1
fms-like tyrosine kinase-1/vascular endothelial growth 
factor receptor 1
G CSF
granulocyte colony-stimulating factor
GCP
good clinical practice
GLUT1
glucose transporter 1
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Abbreviation or Specialist Term
Explanation
HCT
hematocrit
Hgb
hemoglobin
HIF
hypoxia inducible factor
HIF-1α 
hypoxia inducible factor 1 alpha
HIF-2 α
hypoxia inducible factor 2 alpha
HIV
human immunodeficiency virus
ICH
International Council on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for 
Human Use
IRB
institutional review board
IRC
Independent Review Committee
IUD
intrauterine device
IUS
intrauterine system
K
Potassium
KDR
kinase insert domain containing receptor
KM
Kaplan-Meier 
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MPV
mean platelet volume
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
Na
Sodium
NCI CTCAE 4.03
National Cancer Institute Common Terminology Criteria 
for Adverse Events, Version 4.03
ORR
overall response rate
PBPK
physiologically-based pharmacokinetic
PD
Pharmacodynamics
PDGF
platelet-derived growth factor
PFS
progression-free survival
PK
Pharmacokinetic
Plt
Platelets
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Abbreviation or Specialist Term
Explanation
PO4 
phosphate
PR
partial response
PT
prothrombin time
RDW
red blood cell distribution width
RECIST 1.1
Response Evaluation Criteria in Solid Tumors Version 
1.1
Retic
reticulocyte count
RP2D
recommended phase 2 dose
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
TBILI
total bilirubin
TEAE
treatment-emergent adverse event
TGF-α
transforming growth factor alpha
TK
toxicokinetic
tmax
time at which maximum concentrations occurred
TTR
time to response
ULN
upper limit of normal
VEGF
vascular endothelial growth factor
VEGFA
vascular endothelial growth factor A
VEGFR2
vascular endothelial growth factor receptor 2
VHL
von Hippel-Lindau disease
WBC
white blood cells
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4.
INTRODUCTION
4.1.
Background
4.1.1.
Von Hippel-Lindau Disease and Renal Cell Carcinoma
Von Hippel-Lindau (VHL) disease is a hereditary cancer disease transmitted in an autosomal 
dominant fashion, in which affected individuals are at risk for the development of tumors in a 
number of organs.  Affected individuals have a germline mutation and/or deletion of the 
VHL gene, and are at risk for developing tumors and fluid-filled sacs (cysts) in a number of 
organs (Linehan et al, 2001; Linehan et al, 2002; Linehan et al, 1995; Clifford and Maher, 
2001; Maher and Kaelin, 1997; Kaelin, 2002).  Tumors can initially appear during young 
adulthood; however, the signs and symptoms of von Hippel-Lindau disease can present 
throughout life (Genetics Home Reference, downloaded February 23, 2016).
Patients with VHL disease are at risk for developing renal cysts and clear cell renal cell 
carcinomas (ccRCC), pheochromocytomas, pancreatic cysts, neuroendocrine tumors,
hemangioblastomas of the brain and spinal cord, retinal angiomas, inner ear endolymphatic 
sac tumors, and epididymal and broad ligament cystadenomas. Renal cell carcinoma occurs 
in 30% to 70% of individuals with VHL disease and is the leading cause of mortality
(Chittiboina and Lonser, 2015).  
Von Hippel-Lindau disease-associated renal tumors, which are uniformly ccRCC histological 
subtype, are malignant tumors that can metastasize and are generally incurable once 
metastatic (Hwang et al, 2003; Poston et al, 1995).  The clinical management of VHL
disease-associated renal tumors involves active surveillance until the largest renal tumor 
reaches approximately 3 cm, at which time nephron-sparing surgical intervention is 
recommended.  This threshold was determined by an analysis of patient data collected over a 
30-year time period; no patient with maximum renal tumor diameter less than 3 cm 
developed metastases (Walther, Choyke et al, 1999; Pavlovich et al, 2002).  Surgical 
management may involve partial or complete nephrectomy; partial nephrectomy is 
recommended whenever possible.  Patients affected with VHL disease are at risk for the 
development of up to 600 renal tumors and 1300 renal cysts.  Von Hippel-Lindau renal 
cancer surgery is often very extensive; as many as 90 tumors may be removed from a kidney 
during a single surgery.  Complications from such extensive surgery are not uncommon and 
can include significant blood loss, infection, loss of the kidney, pulmonary emboli, and death. 
A retrospective review of 30 patients who underwent a total of 34 partial nephrectomies, with 
removal of at least 20 tumors in each kidney revealed perioperative complications in > 50%
of the cases. Other complications included blood loss, significant renal function decline, and 
1 death (Fadahunsi, 2011).
Surgery does not cure VHL disease patients with ccRCC; surgery is intended to prevent the 
development of metastasis.  In the great majority of patients, the tumors continue to recur and 
repeated surgeries are required to prevent death from metastatic kidney cancer.  These 
surgeries carry significant morbidity and, sometimes, mortality.  Many patients have 
undergone 4 or 5 sequential surgeries on a single kidney, sometimes on both kidneys.  The 
extensive renal surgeries required inevitably leads to progressive decrease in renal function in 
these patients.  Many patients will develop renal insufficiency, which may lead to shortened 
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life span, and some patients require dialysis and/or renal transplantation.  Despite the most 
aggressive lifelong surveillance with the most experienced clinical/surgical team, a number 
of these patients will still go on to develop metastatic ccRCC, which is almost always fatal 
(Walther, Choyke et al 1995; Walther, Lubensky et al, 1995; Herring et al, 2001; Hwang et 
al, 2003; Drachenberg et al, 2004; Grubb et al, 2005; Bratslavsky, Liu et al, 2008; Boris et al, 
2009; Bratslavsky, Linehan et al, 2010; Liu et al, 2010; Fadahunsi et al, 2011; Gupta et al, 
2013).  The life expectancy of VHL disease patients with ccRCC is only 40 to 52 years 
(Chittiboina and Lonser, 2015).
Once the renal tumors have metastasized the treatment algorithm follows that of advanced 
sporadic ccRCC with anti-VEGF/VEGFR therapy, immune-modulators and mTOR inhibitors 
(inhibitors of the mammalian target of rapamycin).  These agents have had a limited role in 
the treatment of VHL disease or VHL disease-associated ccRCC prior to metastases.  Both 
sunitinib (a multi-kinase inhibitor) and vandetanib (a dual VEGFR/EGFR inhibitor) have 
been evaluated in Phase 2 studies in VHL disease patients (Jonasch et al, 2011; Stamatakis et 
al, 2013).  While both agents demonstrated activity, their tolerability was a major issue, 
resulting in discontinuation of treatment in a significant proportion of patients and 
discontinuation of development of the products for this disease.  Consequently, the treatment 
approach for VHL disease-associated renal tumors remains surgical resection of tumors 
greater than 3 cm in diameter.
4.1.1.1.
The von Hippel-Lindau Tumor Suppressor Gene
A study of VHL kindreds at the National Cancer Institute (NCI) led to identification of the 
VHL gene (Latif et al, 1993).  The VHL gene is a classical tumor suppressor gene and 
tumorigenesis due to VHL inactivation conforms to Knudson’s ‘two-hit’ hypothesis 
(Knudson, 1986).  The gene has 3 exons that encode the VHL protein (Latif et al, 1993).  
While VHL mutations were initially identified in the germline of patients with VHL disease, 
inactivation of the gene by somatic mutation or promoter hypermethylation has also been 
described in a high proportion of sporadic ccRCC.  The function of VHL proteins and the 
biochemical consequences of VHL gene inactivation have been studied extensively.  
Von Hippel-Lindau protein forms a complex with other cellular proteins including elongins 
B and C, and Cullin 2 (Pause et al, 1997).  This complex plays an important role in the 
degradation of cellular proteins via the ubiquitin pathway.  Inactivation of the VHL gene 
consequently leads to accumulation of proteins targeted for degradation through this 
pathway.  These proteins include the alpha subunits of a group of transcriptionally active 
proteins called the hypoxia inducible factors (HIFs) (Maxwell et al, 1999).  Accumulation of 
HIFs results in overexpression of several genes including those encoding vascular endothelial 
growth factor A (VEGFA), glucose transporter 1 (GLUT1), transforming growth factor alpha 
(TGF-α), platelet-derived growth factor (PDGF), cyclin D1 (CCND1) and erythropoietin 
(EPO) (Linehan et al, 2001; Linehan et al, 2002; Linehan et al, 1995; Clifford and Maher, 
2001).  VEGFA is an important regulator of tumor angiogenesis that supports tumor growth 
and progression.  VEGFA exerts its activity through several receptor tyrosine kinases 
expressed on endothelial cells, chief among them being the fms-like tyrosine 
kinase-1/vascular endothelial growth factor receptor 1 (Flt-1/VEGFR1) and the kinase insert 
domain containing receptor/vascular endothelial growth factor receptor 2 (KDR/VEGFR2) 
(Ferrara, 2001).  In addition to promoting angiogenesis in the tumor microenvironment, VHL
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inactivation can also directly promote tumor growth via the autocrine and paracrine effects of 
transforming growth factor alpha (TGF-α), and PDGF, which act through receptor tyrosine 
kinases such as the epidermal growth factor receptor (EGFR, a receptor for TGF-α) 
expressed on tumor cell surface.  Thus, VHL deficiency initiates a series of downstream 
events that promote tumor progression.  
4.1.1.2.
HIF-2α
A strong connection has been established among the histologic features of ccRCC, mutations 
in the VHL tumor suppressor gene and the subsequent activation of HIF-2α transcriptional 
activity (Shen and Kaelin, 2013).  More than 90% of sporadic ccRCC tumors have defective 
or deficient VHL function through deletion, mutation, or hypermethylation of the VHL gene 
(Sato et al, 2013).  Although both HIF-1and HIF-2are stabilized upon VHL loss, a 
greater role has been ascribed to HIF-2in the pathobiology of ccRCC.  As much as 40% of 
sporadic ccRCC have reduced copy number and expression of HIF-1, and HIF-2alone is 
sufficient to support the growth of ccRCC mouse xenografts (Sato et al, 2013, Kondo et al, 
2002). In this setting, HIF-2α will accumulate, even under normoxic conditions, and drive 
the expression of genes associated with tumor growth. Preclinical studies showed that HIF-
2depletion or pharmacologic antagonism is sufficient to inhibit ccRCC tumor growth 
(Kondo et al, 2002; Wallace et al, 2016; Chen et al, 2016; Cho et al, 2016).  HIF-2has 
therefore been established as an oncogenic driver in ccRCC, where VHL deficiency is the 
underlying genomic alteration.  In VHL disease, renal tumors are of clear cell histology 
(Lund et al, 1994; Poston et al, 1995).  Further, expression of HIF-2has been found to 
correlate with disease development in renal cancer, as well as in paraganglioma and 
pheochromocytoma associated with VHL disease (Mandriota et al, 2002; Pollard et al, 2006).  
Thus, HIF-2stabilization and activation appears to be common to the spectrum of 
neoplasms associated with VHL deficiency, suggesting that HIF-2α may be a major driver of 
the disease pathology.  Inhibition of this transcription factor is a novel approach that could 
lead to a significant new treatment option for patients with VHL disease.
4.1.2.
PT2385
PT2385 is a first-in-class small molecule inhibitor of HIF-2α, which impairs hypoxic 
signaling in cancer cells. 
4.1.2.1.
Pharmacologic Activity
PT2385 is a potent and selective inhibitor both in vitro and in vivo and has been shown to 
inhibit signaling by disrupting the formation of the HIF-2α: aryl hydrocarbon receptor 
nuclear translocator (ARNT) heterodimer in cells.  Thus, in tumors where HIF-2α is 
activated, PT2385 blocks the transcription of several genes involved in oncogenesis, 
Additionally, PT2385 has demonstrated anti-tumor activity in
mouse 
xenograft models of VHL mutant ccRCC, resulting in tumor stasis after oral administration at 
3 mg/kg twice daily, and nearly complete regression after oral administration at 10 mg/kg 
twice daily and 20 mg/kg once daily.  In efficacy studies comparing once and twice daily
dosing, the response was greater (3 mg/kg twice daily versus 6 mg/kg once daily) and more 
CCI
CCI
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rapid (10 mg/kg twice daily versus 20 mg/kg once daily) with twice daily dosing.  PT2385 
has shown no activity (up to 10 µM) against other Per-ARNT-Sim-B (PAS-B) domain-
containing proteins or against a large panel of receptors, ion channels, and kinases.  Studies 
to date have not revealed any cardiovascular, central nervous system or respiratory safety 
pharmacology issues with PT2385 treatment in vitro or in vivo.  Refer to the Investigator’s 
Brochure for additional information. 
Preclinical studies demonstrate that PT2385 is a potent and selective inhibitor of HIF-2α.  
Additionally, they demonstrate that inhibition of HIF-2α with PT2385 is efficacious in the 
treatment of sporadic ccRCC tumors with VHL mutations in mouse models.  Although there 
are no mouse models for evaluating PT2385 in VHL disease pathologies, the preclinical and 
clinical data for PT2385 in sporadic ccRCC support its testing in ccRCC associated with 
VHL disease, given the identical histologic and molecular characteristics of these 2 types of 
renal cancer. 
4.1.2.2.
Pharmacokinetic Data
Absorption of PT2385 following administration of an oral dose was rapid in all species, with 
the time at which maximum concentrations occurred (tmax) between 0.5 and 2 hours in most 
preclinical studies.  Oral bioavailability was high in mice and dogs (95% and 89%, 
respectively), moderate in rats (41%), and low in monkeys (16%) following a single oral 
dose.
Overall, exposure to PT2385 in rats and dogs was somewhat dose proportional up to doses of 
300 mg/kg, was less than dose proportional up to 450 or 600 mg/kg, and showed little to no 
increase with doses of 1000 mg/kg.  There was no consistent evidence of a sex difference in 
PT2385 exposure in rats and dogs.
PT2385 showed time-dependent pharmacokinetics following 28-day twice-daily dosing in rat 
and dog toxicokinetic (TK) studies. The ratio of Day 28/Day 1 PT2385 AUC0-tau (area under 
the plasma concentration curve from time over 1 dose interval) decreased as dose increased, 
which was more severe in dogs than in rats.
Tissue distribution after administration of a single oral dose of PT2385 was evaluated in rats.  
The highest concentration of PT2385 was observed in the liver followed by the heart, kidney 
lung, plasma and brain.  Permeability across the blood-brain barrier was also demonstrated 
after administration of repeat doses in mice and in rats, where concentrations of PT2385 were 
similar in plasma and brain tissue.  The in vitro plasma protein binding of PT2385 was 
moderate and ranged from 64% to 82% across species (82% for human plasma protein).   
In vitro, the primary biotransformation route of PT2385 was direct conjugation to form a 
glucuronide conjugate (PT2639), oxidative metabolism to M+16, oxidative defluorination 
and subsequent conjugation to glucuronides. No human specific metabolite was found. 
Enzyme phenotyping results suggested PT2385 was primarily metabolized via UGT2B17, 
UGT2B7, UGT2B15, CYP2C19 and CYP3A4 in human.  
PT2385 is not a potent inhibitor for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, 
CYP2D6 and CYP3A4 (IC50 > 8.8 μg/mL).  It is unlikely to significantly inhibit these CYPs 
at the clinically relevant PT2385 concentrations (maximum peak concentration [Cmax] 
~ 3.14 μg/mL).
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PT2385 induced concentration-dependent increases in CYP2B6 and CYP3A4 mRNA in 
cultured human hepatocytes. Simcyp physiologically-based pharmacokinetic (PBPK) model 
simulations indicate a weak-to-moderate CYP3A4 substrate midazolam drug-drug interaction 
(DDI) (~50% reduction in midazolam AUC) at the clinical relevant PT2385 doses. A
qualitative assessment of the DDI liability of sunitinib, cabozantinib, and axitinib when co-
administered with PT2385 was performed using literature data; the expected DDI effects 
with these kinase inhibitors are smaller than the effect predicted for midazolam.  Simulations 
also indicate that PT2385 is a weak CYP2B6 inducer (< 11% AUC reduction for CYP2B6 
substrate bupropion at the clinical relevant PT2385 doses).
4.1.2.3.
Toxicity
The nonclinical toxicology studies were designed to assess the toxicity potential of PT2385, 
with appropriate TK monitoring.  Exploratory studies assessed the tolerability of PT2385 in 
mice, rats and dogs.  Based on the findings that the putative metabolites predicted in humans 
were also observed in rat and dog hepatocytes, and oral administration of PT2385 to these 
species achieved good bioavailability, the rat and dog were selected for definitive toxicity 
studies.  The tolerability studies demonstrated a reversible dose-responsive effect on the red 
blood cell compartment.  This effect encompassed the total red blood cell count, hemoglobin 
concentration and hematocrit with reductions in all indices.  The immature red cell fraction, 
as noted by the reticulocyte count, was also impacted in a reversible manner. 
The definitive toxicity studies were designed to assess the safety and reversibility of effects 
from PT2385 administration.  Twice-daily PT2385 was administered orally for 28 days to 
rats and dogs in GLP studies.  Overall results demonstrated PT2385 to be clinically well 
tolerated for up to 28 days with twice-daily administration.  There were no deaths in either 
toxicity study.  A recoverable mild anemia was identified in both studies, similar to the pilot 
experiments.  In both the rat and dog studies, a hepatocellular hypertrophy was observed 
histologically, indicative of an adaptive response.  This effect was completely reversible 
following removal of the test item.  Based on metabolism studies examining CYP3A4 and 
CYP2B6 mRNA induction in human hepatocytes, this effect may relate to induction of 
hepatic enzymes.  This histological finding corresponded with a dose-dependent increase in 
liver weights and a reduction in plasma concentrations from Day 1 to Day 28 in both the rat 
and dog.  
From the 28-day studies, the only identified target organs for toxicity were the testes and 
epididymis in male rats.  The effect was dose responsive on the seminiferous tubule 
epithelium and ranged from mild to marked in severity.  Following the recovery period, the 
testes did not demonstrate recovery of effect, while the epididymis demonstrated a partial 
recovery of effect.  Possibly, a longer recovery period that captured the entire cycle of 
spermatogenesis (63 days) could have afforded complete recovery.  No target organs were 
identified in female rats.
PT2385 did not have a consistent effect on the testes of male dogs, however sporadic effects 
were noted.  These changes were considered related to the young age of the animals.  No 
target organs were identified in female dogs. 
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Assessment of genotoxicity included in vitro bacterial mutagenicity and chromosomal 
aberration assays.  Both assays were conducted with and without metabolic activation and 
both yielded negative results with PT2385.
PT2385 will be administered orally at a dosage of 800 mg twice daily.  This dose was 
identified in the initial study of PT2385 in humans, a Phase 1 study in patients with advanced 
clear cell renal cell carcinoma, as the recommended Phase 2 dose (RP2D) (Courtney et al, 
2016).  The starting dose in that study was 100 mg twice daily based on the identification of 
the mid dose, 200 mg/kg/day, as the highest non-severely toxic dose because of associated 
minimal to moderate changes in the testes and epididymis that were not completely 
reversible.  
4.1.2.4.
Clinical Studies
PT2385 has not previously been studied in patients with VHL disease.  Clinical studies of 
PT2385 in ccRCC are ongoing. Under Protocol PT2385-101, patients with advanced ccRCC 
who had been treated with at least 1 prior treatment with a VEGF inhibitor were treated with 
PT2385 twice daily in a 3+3 Phase 1 design to determine the maximum tolerated dose 
(MTD)/RP2D and to evaluate safety, PK, and pharmacodynamics (PD).  The 26 patients 
enrolled in the dose-escalation portion received PT2385 at oral dosages of 100 to 1800 mg
twice daily.  No dose limiting toxicities (DLTs) were observed at any dose level.  Exposure
generally increased with dose up to the 800 mg dose, without a further increase from 800 to 
1800 mg.  At 800 mg, PT2385 was rapidly absorbed with a Cmax of 3.14 µg/mL and a t1/2 of 
17 hours.  The targeted Cmin of 280 ng/mL was exceeded in the majority of patients receiving 
a twice daily dose of ≥800 mg.  Circulating plasma levels of EPO rapidly decreased within 
24 hours in most patients receiving ≥800 mg and remained suppressed during the 16-week 
sampling period.  Based on safety, PK, and EPO PD data, the RP2D has been defined as oral 
800 mg twice daily.  An additional 25 patients were enrolled in an expansion cohort at the 
RP2D.  As of August 15, 2016, the most common adverse events (AEs) of any severity have 
been anemia, peripheral edema, and fatigue.  One patient had a complete response (CR), 4 
patients had a partial response (PR), and 16 patients had stable disease (SD) for more than 16 
weeks.  PT2385 administration was safe and well tolerated, and has demonstrated early 
evidence of clinical activity in these heavily pre-treated patients with advanced ccRCC 
(Courtney et al, 2016).  
A Phase 1 food effect study of PT2385 was conducted in healthy female volunteers.  The 
most common AEs were headache, injection site bruising, and nausea.  The presence of food 
had a mild effect (19% to 37% increase) on the exposure to PT2385 in this study; little to no 
effect was observed in exposure to PT2639, the major metabolite, in the presence of food.
4.2.
Study Rationale
This study is part of the clinical program to investigate PT2385 as a treatment for VHL 
disease-associated ccRCC.
Patients affected with VHL, a rare hereditary cancer syndrome, are at risk to develop ccRCC 
as well as pheochromocytomas; pancreatic cysts; neuroendocrine tumors; 
hemangioblastomas of the brain and spinal cord; retinal angiomas; inner ear endolymphatic 
sac tumors; and epididymal and broad ligament cystadenomas.  The current treatment 
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paradigm is based upon frequent monitoring and surgery, as no therapies are approved for 
treatment of VHL disease.  Although effective in limiting metastatic disease spread, surgery 
is associated with significant morbidity, particularly in patients undergoing multiple surgical 
interventions.  Development of systemic options that can delay or obviate the need for 
surgery is, therefore, desirable.  
Patients enrolled in this present study will be treated with oral PT2385, 800 mg twice daily. 
Overall response rates in this patient population will provide insight into the efficacy of 
PT2385 as reduction in tumor size relates to preclusion or delay of surgery-associated 
morbidity and mortality. 
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5.
TRIAL OBJECTIVES AND PURPOSE
This open-label Phase 2 study will evaluate the efficacy, safety, tolerability, PK, and PD of 
PT2385 for the treatment of VHL disease-associated ccRCC.
5.1.
Primary Objective
To assess overall response rate (ORR) of von Hippel-Lindau (VHL) disease-associated 
ccRCC tumors in VHL patients treated with PT2385 as determined by Response Evaluation 
Criteria in Solid Tumors Version 1.1 (RECIST 1.1, Appendix 3); ORR is defined as the 
proportion of patients with a best confirmed response of complete response (CR) or partial 
response (PR).
5.2.
Secondary Objectives
•
To evaluate progression-free survival (PFS) in patients with VHL disease-associated 
ccRCC tumors treated with PT2385
•
To evaluate duration of response (DOR) and time to response (TTR) in patients with 
VHL disease-associated ccRCC tumors treated with PT2385 who achieve a PR or 
better as determined by RECIST 1.1
•
To study the effect of treatment with PT2385 on VHL disease-associated non-ccRCC 
tumors by modifying RECIST 1.1 criteria to assess tumors in individual organ 
systems independently rather than collectively
•
To study the safety and tolerability of PT2385 
•
To study the pharmacokinetics (PK) of PT2385
5.3.
Exploratory Objectives
•
To evaluate changes in pharmacodynamic (PD) markers (e.g., serum EPO) in patients 
treated with PT2385 
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6.
INVESTIGATIONAL PLAN
6.1.
Overall Study Design
This open-label Phase 2 study will evaluate the efficacy, safety, PK, and PD of PT2385 in 
patients with VHL disease who have at least 1 measurable VHL disease-associated ccRCC 
tumor (as defined by RECIST 1.1).  PT2385 will be administered orally at a dosage of 
800 mg twice daily.  Treatment will be continuous; the drug will be administered twice daily 
every day.  Patients will be entered in the study after meeting all inclusion criteria and no 
exclusion criteria.  This study will be conducted with a 2-stage design, which allows for an 
early assessment of futility.  A response will be defined as either a PR or CR occurring at any 
time after initiation of treatment, based on assessment of ccRCC tumors.  All responses must 
be confirmed after the initial response is documented.  Changes in VHL disease-associated 
non-ccRCC tumors will also be evaluated independently by modifying RECIST 1.1 criteria 
to assess tumors in individual organ systems independently rather than collectively.
Twenty-five patients will be enrolled during the first stage.  A Data Monitoring Committee 
(DMC) will perform the safety review for the first 6 patients and the futility analysis for 
Stage 1 of the study.  The DMC will review safety and any treatment-limiting toxicities to 
confirm whether the study should continue to enroll or if modifications to the protocol are 
needed.  The DMC will review the response data from the first 25 patients to determine if at 
least 3 patients have a confirmed PR or better in ccRCC tumors and that the threshold for 
opening Stage 2 has been met.  Treatment-limiting toxicities will be assessed according to 
Section 6.4.  Study termination criteria are presented in Section 6.5.
In the second stage of the study, 25 additional patients will be enrolled, to a maximum 
accrual of 50 patients.
Patients will undergo clinical and laboratory evaluations every 2 weeks for the first 4 weeks 
and then every 4 weeks (i.e., 28 days) according to the Schedule of Events.  Patients will be 
evaluated radiologically for evidence of response or progression approximately 12 weeks 
after initiation of treatment and every 12 weeks thereafter while continuing in the study.  
Patients with evidence of stable disease or disease response, i.e., CR or PR, will continue to 
receive treatment in the absence of serious toxicity.  Patients who demonstrate disease 
progression of their ccRCC tumors at any time will be withdrawn from study treatment. 
Patients who need surgical intervention for VHL-disease associated non-ccRCC tumors, and 
who do not meet the RECIST 1.1 criteria for progression of the ccRCC tumors, while 
participating in the study, may be allowed to resume study drug administration, as long as 
study drug has been withheld no more than 8 weeks, and there is no progression of ccRCC 
tumors.  Patients with non-ccRCC tumors that meet the RECIST 1.1 criteria for progression 
will be withdrawn from study treatment.
Patients who undergo resection of non-renal VHL disease-associated lesions, and who do not 
meet the RECIST 1.1 criteria for progression of those lesions, may resume treatment with 
PT2385 once the surgical incisions have adequately healed, and if in the opinion of the 
Principal Investigator, the patient is likely to experience clinical benefit.  
Patients who discontinue from study treatment for any reason will be followed every 6 
months either by telephone or office visit to determine their medical history, surgical history,
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disease status, and survival status.  These patients will be followed for up to 3 years 
following the completion of enrollment in the study or until the patient either withdraws 
consent or dies.
6.2.
Number of Patients
A total of 50 patients will be enrolled in the study:  25 patients will be enrolled in the first 
stage; 25 patients will be enrolled in the second stage.
6.3.
Treatment Assignment
After meeting all inclusion and no exclusion criteria, enrolled patients will be assigned to 
treatment with open-label PT2385.  The treatment will be administered orally at a dosage of 
800 mg twice daily (four 200 mg PT2385 tablets twice daily).
6.4.
Dose Adjustment Criteria
For patients who experience a treatment-limiting toxicity and require dose modification, the 
guidelines in Table 1 will be used to determine the dose modification required.  If the 
Investigator believes that the guidelines should not apply, he/she will contact the Sponsor’s 
medical monitor to discuss the circumstances and the appropriate dose modification.
Patients requiring surgical intervention for non-renal lesions during the course of the study 
should have study drug treatment interrupted.  Study drug may be restarted when the surgical 
incision has adequately healed, provided there is no evidence of progression of ccRCC, and 
study drug interruption has been for no more than 8 weeks.  Patients with non-renal lesions 
that meet the RECIST 1.1 criteria for progression will be withdrawn from study treatment.
Patients requiring study drug interruption for more than 3 weeks will be withdrawn from 
study treatment, except in the instance of interruption for surgery as noted above.
Treatment-limiting toxicity in the first 6 patients will be defined as any of the following 
events occurring in the first 28 days of treatment, graded using the National Cancer Institute 
Common Terminology Criteria for Adverse Events Version 4.03 (NCI CTCAE 4.03):

Hematologic

Febrile neutropenia (absolute neutrophil count < 1,000/μL plus body 
temperature ≥38.5°C)

Grade 4 neutropenia lasting for > 5 days (in the absence of growth factor 
support)

Grade 3 thrombocytopenia with bleeding

Grade 4 thrombocytopenia

Grade 4 anemia unexplained by underlying disease

Gastrointestinal

Grade 3 or 4 nausea, vomiting, or diarrhea that persists for > 48 hours despite 
optimal antiemetic or antidiarrheal treatment
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
Hepatic

Grade 3 or greater increase in transaminase levels, if confirmed upon repeat 
testing within 48 hours

Grade 3 or 4 increase in transaminase levels if accompanied by a Grade 2 
increase in bilirubin level and an alkaline phosphatase level > 2 × upper limit 
of normal (ULN)

Other

Any other study drug-related Grade 3 or 4 non-hematologic toxicity, except 
for Grade 3 asymptomatic hypoxia unless considered clinically significant by 
the Investigator

Any study drug-related Grade 3 or 4 laboratory toxicity that does not resolve 
within 48 hours and is considered clinically significant by the Investigator.
Table 1
Guidelines for Dose Modification
Toxicity
Occurrence
Action
Hematologic
•
ANC < 1,000/μL + body temperature 
≥38.5°C, or
•
Gr 4 neutropenia for > 5 days, or
•
Gr 3 thrombocytopenia with bleeding, 
or
•
Gr 4 thrombocytopenia, or
•
Gr 4 anemia unexplained by underlying 
disease
1st
Hold study drug.  Once toxicity has resolved 
to < Gr 2 or baseline, restart PT2385 at a 25% 
reduction of the assigned dose.
2nd
Hold study drug.  Once toxicity has resolved 
to < Gr 2 or baseline, restart PT2385 at a 50%
reduction of the assigned dose 
3rd
Discontinue PT2385.
Gastrointestinal
•
Gr 3 or 4 nausea, vomiting, or diarrhea 
if persistent for > 48 hours despite optimal 
antiemetic or antidiarrheal therapy
1st
Hold study drug.  Once toxicity has resolved 
to < Gr 2 or baseline, restart PT2385 at a 25% 
reduction of the assigned dose.
2nd
Hold study drug.  Once toxicity has resolved 
to < Gr 2 or baseline, restart PT2385 at a 50% 
reduction of the assigned dose
3rd
Discontinue PT2385
Hepatic
•
≥Gr 3 increase in transaminase levels, 
if confirmed upon repeat testing within 
48 hours, or 
•
Gr 3 or 4 increase in transaminase 
levels if accompanied by a Gr 2 increase in 
bilirubin level and an alkaline phosphatase 
level < 2 × ULN
1st
Discontinue PT2385
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Toxicity
Occurrence
Action
Other
•
Any other Gr 3 toxicity, with the 
exception of Gr 3 cardiovascular, vascular 
or thrombotic events and Gr 3 
asymptomatic hypoxia unless considered 
clinically significant by the Investigator
1st
Hold study drug.  Once toxicity has resolved 
to < Gr 2 or baseline, restart PT2385 at a 25% 
reduction of the assigned dose.
2nd
Hold study drug.  Once toxicity has resolved 
to < Gr 2 or baseline, restart PT2385 at a 50% 
reduction of the assigned dose
3rd
Discontinue PT2385 
Other
•
Any study drug-related Gr 3 
cardiovascular, vascular or thrombotic 
events
•
Any other study drug-related Gr 4 non-
hematologic toxicity
•
Any study drug-related Gr 3 or 4 
laboratory toxicity that does not resolve 
within 48 hours and is considered clinically 
significant by the Investigator
1st
Discontinue PT2385
ANC = absolute neutrophil count; Gr = Grade; ULN = upper limit of normal.
6.5.
Criteria for Study Termination
If more than 2 of the first 6 patients enrolled in the first stage of the study experience 
treatment-limiting toxicity within the first 4 weeks of their treatment, the protocol will be 
modified or the study will be stopped.  If after the first 25 patients have been enrolled in the 
study, 2 or fewer patients have had a confirmed ccRCC tumor response of PR or better, 
further enrollment will be temporarily suspended for up to a year or until at least 3 confirmed 
responses are seen.  If 3 confirmed responses have not been observed within1 year after 
enrollment of the 25th patient, no further patients will be enrolled and the study will be 
stopped.
A Data Monitoring Committee (DMC) will perform the safety review for the first 6 patients 
and the futility analysis for Stage 1 of the study.  The DMC will consist of the Principal 
Investigator(s) participating in this study, the Medical Monitor, and representatives from 
Peloton.  The DMC will meet shortly after the sixth patient has been observed for 28 days 
after the administration of their initial PT2385 dose.  The DMC will review safety and any 
treatment-limiting toxicities to confirm whether the study should continue to enroll or if 
modifications to the protocol are needed.  The DMC will review the response data from the 
first 25 patients to determine if at least 3 patients have a confirmed PR or better in ccRCC 
tumors and that the threshold for opening Stage 2 has been met.  Treatment-limiting 
toxicities will be assessed according to Section 6.4.
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7.
SELECTION AND WITHDRAWAL OF PATIENTS
7.1.
Informed Consent
Written informed consent (see Section 16.3) must be obtained from the patient before any 
study related procedures are performed and whenever the study procedures change or new 
safety information becomes available that may affect the patient’s willingness to participate.
Male patients must be provided with information about the option for sperm banking before 
providing written informed consent.
7.2.
Patient Eligibility
Inclusion and exclusion criteria should be reviewed during the time period indicated for 
Screening in Appendix 1, Schedule of Events.  Patients must meet all of the inclusion and 
none of the exclusion criteria for study entry.  
7.2.1.
Patient Inclusion Criteria
Patients must meet all of the following criteria to be enrolled in this study.
1. Has the ability to understand and willingness to sign a written informed consent form 
before the performance of any study procedures
2. Is of age ≥18 years
3. Has at least 1 measurable ccRCC tumor and no solid ccRCC tumor > 3.0 cm, based 
on radiologic diagnosis (histologic diagnosis not required); may have VHL disease-
associated lesions in other organ systems
4. Has a diagnosis of von Hippel-Lindau disease, based on a germline VHL alteration
5. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
(see Appendix 2)
6. Has normal organ and marrow function as defined below:

White blood cell count ≥3,000/µL, absolute neutrophil count ≥1,500/µL, 
hemoglobin level ≥9 g/dL without transfusion support within 2 weeks prior to 
enrollment; platelet count ≥100,000/µL;

Serum creatinine level ≤2.0 × ULN or measured 24-hour creatinine clearance 
≥30 mL/min; and

Levels of AST and ALT < 2.5 × ULN, total bilirubin < 1.5 × ULN (< 3 × ULN in 
patients with Gilbert’s disease), and alkaline phosphatase ≤2.5 × ULN 
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7. If a female patient of child-bearing potential, or a male patient with a female partner 
of child-bearing potential (defined as all women physiologically capable of becoming 
pregnant), must agree to use highly effective methods of contraception during 
screening, during the period of drug administration and for 30 days after stopping 
study drug administration.  Highly effective contraception methods include the 
following:

Total abstinence,

Male or female sterilization, or

Combination of any 2 of the following (a + b or a + c or b + c):
a.
Use of oral, injected or implanted hormonal methods of contraception
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS)
c.
Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository
8. If a female patient of child-bearing potential, must have a negative serum pregnancy 
test result within 7 days before first administration of study drug.
7.2.2.
Patient Exclusion Criteria
Patients will be excluded from this study if they meet any of the following criteria.
1. Has participated or plans to participate in another clinical trial of an investigational 
drug (or a medical device) within 30 days of study enrollment
2. Has had prior treatment with or known allergy or sensitivity to a HIFα inhibitor
3. Has had prior radiotherapy or systemic anti-cancer therapy for ccRCC (includes anti-
VEGF therapy or any systemic investigational anti-cancer agent)
4. Has a prior or concomitant non-VHL disease-associated invasive malignancy with the 
exception of adequately treated basal or squamous cell carcinoma of the skin, cervical 
carcinoma in situ or any other malignancy from which the patient has remained 
disease free for more than 2 years
5. Has any history of metastatic disease
6. Has any condition possibly affecting absorption, distribution, metabolism or excretion 
of drugs that may confound the analyses conducted in this study (e.g., previous 
surgery on the gastrointestinal tract that includes removal of parts of stomach, bowel, 
liver, gallbladder, or pancreas)
7. Has known hypersensitivity to any component in the formulation of PT2385 
8. Has had radiotherapy to any non-ccRCC site within 4 weeks prior to entering the 
study or has not recovered from adverse events (AE) (to ≤Grade 1 NCI CTCAE 
4.03) related to agents administered more than 4 weeks earlier
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9. Has had any surgical procedure for VHL disease or any major surgical procedure 
completed within 4 weeks prior to entering the study or has any surgical lesions from 
recent major surgical procedures that are not well healed
10. Has an immediate need for surgical intervention for tumor treatment. 
11. Has known history of positive test results for human immunodeficiency virus (HIV) 
or known acquired immunodeficiency syndrome (AIDS)
12. Has an active infection requiring systemic treatment
13. Has a bleeding diathesis or coagulopathy
14. Has had any major cardiovascular event within 6 months prior to study drug 
administration including but not limited to myocardial infarction, unstable angina, 
cerebrovascular accident, transient ischemic event, pulmonary embolism, or New 
York Heart Association Class III or IV heart failure (see Appendix 5)
15. Has any other clinically significant cardiac, respiratory, or other medical or 
psychiatric condition that might interfere with participation in the trial or interfere 
with the interpretation of trial results
16. If a female patient, intends to breast feed a child during study or within 30 days after 
administration of the last dose of study drug.
7.2.3.
Patient Withdrawal Criteria
Patients have the right to withdraw from the study or study treatment at any time for any 
reason.  The Investigator may discontinue a patient from the study or study treatment for any 
of the following reasons:

Disease progression per RECIST 1.1 

Occurrence of an AE, development of an intercurrent illness/condition, or change in 
patient’s condition that leads the Investigator to be concerned about the patient’s 
welfare

Treatment-limiting toxicity or intolerable toxicity

Noncompliance with study procedures

Failure to comply with study drug administration instructions, to return for follow up, 
or to meet other requirements of the study

Pregnancy in a female patient during the study

Death

Withdrawal of consent
The reason for a patient’s withdrawal from the study or study treatment will be recorded in 
the case report form (CRF).  Patients who withdraw from study participation for any reason 
may not re-enter the study at any time.  
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Patients who discontinue from study treatment will be asked to complete the early 
termination and safety follow-up procedures according to the Schedule of Events, 
Appendix 1.  During the safety follow-up the patient should be evaluated for continuation or 
resolution of any treatment-related AEs/SAEs
Long-term follow-up will begin at the time a patient discontinues study treatment for any 
reason and will continue for up to 3 years following completion of enrollment in the study or 
until the patient withdraws consent or dies.
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8.
TREATMENT OF PATIENTS
8.1.
Description of Study Drug
Table 2
Investigational Product
Investigational Product
Product Name
PT2385
Dosage Form
Tablet
Unit Dose
200 mg
Route of Administration
Oral
Physical Description
White capsule-shaped tablet
Manufacturer
Peloton Therapeutics, Inc., Dallas, TX
8.2.
Concomitant Medications
Patients may not receive chemotherapy, anti-neoplastic hormonal therapy, or any 
investigational anti-neoplastic agent during the course of this study.  Immunosuppressive 
agents are prohibited during the course of study participation.  Systemic steroids may not be 
used in the study at doses greater than the equivalent of 20 mg prednisone daily with the 
exception of intermittent use for the treatment of emesis.
Patients may receive limited fraction palliative radiotherapy after 12 weeks to control local 
tumor-related symptoms if irradiation is unlikely to induce major organ toxicity and only if in 
the opinion of the Investigator, the patient does not have progressive disease.  The radiation 
field cannot encompass a target lesion.  Radiation to a target lesion is considered progressive 
disease and the patient should be removed from study treatment.
Antiemetic agents may be used for the treatment of nausea and vomiting but may not be 
administered prophylactically.  Granulocyte colony-stimulating factor (G-CSF) should be 
administered only for severe or prolonged neutropenia or for neutropenic sepsis.  There will 
be no constraint on the use of growth factors during subsequent treatment; however, 
prophylactic use is discouraged and adherence to the American Society of Clinical Oncology 
(ASCO) guidelines is recommended.  Erythropoietin should not be administered during the 
first 28 days of study drug treatment.
Patients should receive all necessary supportive care, including blood products, transfusions, 
antibiotics, pain medications, bisphosphonates, and replacement hormonal therapies (insulin, 
thyroid hormones, estrogen/progesterone) as needed, but levels should be closely monitored.
PT2385 is primarily metabolized by UGT2B17, UGT2B7, UGT2B15, CYP2C19 and 
CYP3A4.  Strong inhibitors of CYP2C19 and CYP3A4 should be avoided in patients 
receiving PT2385 (Appendix 6).
PT2385 has been shown to induce the enzymes CYP3A4 and CYP2B6 in cultured human 
hepatocytes. Simcyp PBPK model simulations indicate weak-to-moderate CYP3A4 
substrate midazolam DDIs (~50% reduction in midazolam AUC) at the clinically relevant 
PT2385 doses. Simulations also indicate that PT2385 is a weak CYP2B6 inducer (< 11% 
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AUC reduction for CYP2B6 substrate bupropion at the clinically relevant PT2385 doses).
PT2385 is not a potent inhibitor for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, 
CYP2D6 and CYP3A4 (IC50 > 8.8 μg/mL).  It is unlikely to significantly inhibit these CYPs 
at the clinically relevant PT2385 concentrations (Cmax ~ 3.14 μg/mL). A partial list of 
CYP3A4, CYP2B6, CYP2C9, and CYP2C19 substrates is provided in Appendix 7.
Patients taking medications metabolized by CYP3A4 and CYP2B6 should be monitored 
carefully for decreases in drug effect.  Patients taking medications metabolized by CYP2C9 
and CYP2C19 should be monitored for potential increases in drug effect.  
All concomitant medication(s) used during the study and within 28 days before the start of 
study drug administration will be reported on the appropriate CRF page.
8.3.
Treatment Compliance
The Investigator or his/her designated and qualified representatives will dispense study drug 
only to patients enrolled in the study in accordance with the protocol.  The study drug must 
not be used for reasons other than that described in the protocol.
The number of tablets returned at a visit will be used to assess compliance; any discrepancy 
from the expected number of returned tablets will be discussed with the patient.
Patients who fail to comply with the requirements of the study may be withdrawn from the 
study.  
8.4.
Randomization and Blinding
There will be no randomization or blinding in this open-label study.
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9.
STUDY DRUG MATERIALS AND MANAGEMENT
9.1.
Study Drug
PT2385 tablets are supplied by Peloton Therapeutics, Inc. as immediate-release 200 mg
tablets for oral administration. Each PT2385 tablet contains PT2385, lactose monohydrate, 
microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, polysorbate 80, 
and magnesium stearate.
9.2.
Study Drug Packaging and Labeling
The 200 mg strength of PT2385 will be supplied in 100-cc high-density polyethylene bottles 
with induction-seal liners and a child-resistant closure.  Each bottle of study drug will contain 
60 tablets of a single strength (200 mg) of PT2385.
Bottles provided to the site will be labeled with the following information: 
1. PT2385, 200 mg
2. Protocol PT2385-202
3. Lot number 
4. Contains 60 200 mg PT2385 tablets 
5. Instructions: Take orally as directed 
6. CAUTION: New Drug – limited by federal law to investigational use
7. FOR ORAL USE ONLY
8. Store at controlled room temperature 15°C to 30°C (59°F to 86°F)
9. Peloton Therapeutics, Inc., Dallas, TX
9.3.
Study Drug Storage
PT2385 must be stored in a secure location at controlled room temperature, 15°C to 30°C 
(59°F to 86°F).
9.4.
Study Drug Preparation
PT2385 will be provided to each site pharmacy and the Investigator or designee will provide 
tablets to each patient with clear instructions on the number of tablets to be taken each day 
until the next study visit.
9.5.
Administration
Following confirmation of eligibility, enrolled patients will be assigned to open-label
PT2385.  Four PT2385 200 mg tablets will be taken orally twice daily (for a total of 8 tablets 
or 1600 mg daily), with doses approximately 12 hours apart.  Study drug may be 
administered without regard to food.
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Missed doses may be made up if taken within 4 hours after the scheduled administration 
time.  Study drug may not be taken within 8 hours before the scheduled time for 
administration of the next dose.  Patients who vomit after study drug administration should 
not retake that study drug dose but should resume taking study drug with the next scheduled 
dose.
9.6.
Study Drug Accountability
The dispensing pharmacist or designated qualified individual will write the date dispensed 
and the patient’s identification number or initials on the Drug Accountability Source 
Documents.  All medication supplied will be accounted for on the Drug Accountability 
Record.  
9.7.
Study Drug Handling and Disposal
All partially used or unused study drug supplies will be destroyed at the site in accordance 
with approved written site procedures, or returned to Peloton Therapeutics or its designee as 
described in the pharmacy manual.  The Investigator will maintain a record of the amount 
and dates when unused supplies were either destroyed or returned to Peloton Therapeutics or 
a designated vendor for destruction.  All records will be retained as noted in Section 17.2.
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10.
ASSESSMENT OF EFFICACY
10.1.
Efficacy Parameters
Primary endpoint: Best confirmed response in VHL disease-associated ccRCC tumors, 
defined as the proportion of the best confirmed response of CR or PR (as assessed by the 
Independent Review Committee (IRC)) as determined by RECIST 1.1, modified to follow 
ccRCC tumors only. ORR is defined as the proportion of patients with a best confirmed 
response of CR or PR.
Secondary endpoints:

Progression-free survival (PFS) in VHL disease-associated ccRCC tumors, defined as the 
interval from the start of study treatment until the earlier of the first documentation of 
disease progression determined by RECIST 1.1 or death from any cause, and calculated 
for patients with a best confirmed response of CR or PR

Duration of response (DOR) in VHL disease-associated ccRCC tumors, defined as the 
interval from the first documentation of response, as determined by RECIST 1.1, to the 
earlier of the first documentation of disease progression or death from any cause, and 
calculated for the patients with a best confirmed response of CR or PR

Time to response (TTR) in VHL disease-associated ccRCC tumors, defined as the 
interval from the start of study treatment to the first documentation of a response, as 
determined by RECIST 1.1, and calculated for patients with a best confirmed response of 
CR or PR 

Best confirmed response, PFS, DOR, and TTR for non-ccRCC tumors associated with 
VHL disease in different organ systems, by modifying RECIST 1.1 criteria to assess 
tumors in individual organsystems (Appendix 4)
Exploratory endpoint:

Changes in PD markers (e.g., serum EPO)
10.1.1.
Response in VHL Disease-Associated ccRCC Tumors
Anti-tumor activity will be assessed by non contrast or contrast computerized tomography 
(CT) or magnetic resonance imaging (MRI) at baseline, within 7 days before the Week 13 
visit and every 12 weeks thereafter.  Patients will be imaged using the same technique at 
baseline and each follow up assessment. 
Response assessments will be made using RECIST 1.1 (Appendix 3), modified to follow 
ccRCC tumors only.  Best confirmed response and PFS will be determined for all patients.  
DOR and TTR will be determined for all patients with a best confirmed response of PR or 
CR.  The ORR for VHL disease-associated ccRCC tumors will be determined.
10.1.1.1.
Response in VHL Disease-Associated Tumors
Best confirmed response rate, PFS, DOR, and TTR for tumors associated with VHL disease 
in other (non-renal) organ systems (pancreas or adrenal gland, or hemangioblastomas or 
retinal angiomas) will be evaluated by modifying RECIST 1.1 criteria.  Tumors will be 
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assessed in individual organ systems independently (Appendix 4).  The ORR for each of the 
other VHL disease-associated non-ccRCC tumors will be determined.
10.1.2.
Pharmacodynamics and Biomarker Assessments
Blood samples for analysis of PD effects (biomarkers) will be obtained at the Week 1, Day 
1 visit before and 6 hours after study drug administration. Pharmacodynamic biomarkers to 
be assessed may include, but are not limited to, levels of EPO and VEGFA.  Whole blood
samples will be collected for single nucleotide polymorphism analyses of genes (231)
encoding proteins that may be involved in the transport or metabolism of PT2385.
Details for the collection, processing, storage, and shipment of samples for the determination 
of PD effects can be found in the study laboratory manual.
10.1.2.1.
Tissue Sample Collection
Archival tumor tissue samples will be obtained whenever possible from all patients.  
Additionally, fresh tissue samples will be obtained from consenting patients in whom tumor 
tissue is accessible (patients who undergo tumor excision during the study).  Tumor tissue 
samples will be analyzed for HIF-2α and HIF-1α expression by immunohistochemistry..  
Tumor tissue samples may be subjected to mRNA analyses for the expression of HIF-1, 
HIF-2and target genes that have been found in preclinical studies to be associated with the 
sensitivity of ccRCC tumors to HIF-2a antagonism (Chen et al, 2016). Genomic DNA from 
tumor tissues may also be analyzed to confirm the loss of heterozygozity of VHL, and to 
assess the status of genes, such as PBRM1, BAP1, TP53, SETD2, and TCEB1, that have been 
found to be altered in ccRCC (Sato et al, 2013). Data from these analyses will be used 
retrospectively to evaluate their utility as predictors of clinical benefit from treatment with 
PT2385.  
Details for the collection, processing, storage and shipment of tissue samples can be found in 
the study laboratory manual.
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11.
PHARMACOKINETIC ASSESSMENTS
Blood samples for the determination of plasma concentrations of PT2385 and its primary 
metabolite PT2639 will be collected at the Week 1, Day 1 visit before and 6 hours after study 
drug administration and at the Week 3, Week 5 and every 4 weeks through the Week 17 
visits before study drug administration (Schedule of Events, Appendix 1).  The date and time 
of collection of all PK blood samples should be recorded.
Validated liquid chromatography/mass spectrometry methods will be used to assay the 
samples for plasma concentrations of PT2385 and PT2639.  Additional metabolites, if 
detected, may be assessed using non-validated methods.  Details for the collection, 
processing, storage, and shipment of samples can be found in the study laboratory manual.
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12.
ASSESSMENT OF SAFETY
12.1.
Safety Assessments
Safety assessments include the following:

Physical examinations

Vital sign measurements (including pulse oximetry)

12-lead electrocardiograms (ECG) with QTc interval determination

Clinical laboratory measurements

Concomitant medications

Incidence, intensity, and relationship of AEs and serious adverse events (SAEs)

Effects on fertility in males (orchidometry, semen analysis, and measurement of
testosterone, follicle-stimulating hormone, luteinizing hormone, and inhibin B levels)
Safety and tolerability will be determined by symptoms, signs, and abnormal laboratory test 
results.  The Investigator will monitor the laboratory test findings.  Abnormalities of 
laboratory test results may or may not, in the opinion of the Investigator, be considered 
clinically significant.  All clinically significant abnormal laboratory test results will be 
reported on the Adverse Event CRF and will be followed until a return to normal or baseline 
levels.  Abnormal laboratory values that require intervention must be reported on the Adverse 
Event CRF.  Any laboratory test result that is abnormal during the course of the study but not 
considered clinically significant will be followed at the discretion of the Investigator.  
12.1.1.
Demographic/Medical History
Demographic data include gender, age, race, and ethnicity, and will be collected during the 
time period indicated for Screening in Appendix 1.  Medical and surgical history will be 
recorded during Screening and will include documentation of the date/year of VHL 
diagnosis, documentation of prior therapies for VHL and documentation of all currently 
active and relevant medical and surgical conditions.
12.1.2.
Eastern Cooperative Oncology Group Status
Eastern Cooperative Oncology Group (ECOG) Status performance status will be assessed 
using the grading system shown in Appendix 2, at the time points indicated in Appendix 1.
12.1.3.
Vital Signs
Vital signs (blood pressure, pulse, respirations, pulse oximetry and temperature) will be 
assessed as noted in Appendix 1.  All blood pressure measurements should be taken after the 
patient has rested in a seated position for at least 3 minutes.
Monitoring of oxygen saturation
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Oxygen saturation should be measured by pulse oximetry at each visit and at any time a 
patient presents with any new or worsening respiratory symptoms.  Readings at rest and on 
exertion should be obtained at each time point.  The extent of the exertion should be based on 
the judgment of the Investigator, but should remain consistent for each individual patient 
throughout the study. If the patient’s status changes, the Investigator can alter the extent of 
exertion based on their medical judgment. If a patient shows changes on pulse oximetry
(oxygen saturation < 92%) or other pulmonary disease related signs (e.g., hypoxia, fever) or 
symptoms (e.g., dyspnea, cough, fever) consistent, the patient should be immediately 
evaluated to rule out pulmonary toxicity. Evaluation may include chest x-ray, arterial blood 
gas analysis, pulmonary function testing including diffusion capacity, and co-oximetry as 
well as evaluations for specific causes of hypoxia/dyspnea, such as CT scan, CT angiogram 
or ventilation-perfusion scan.
12.1.4.
Weight and Height
Weight will be measured and recorded at each study visit according to the Schedule of 
Events (Appendix 1).  Height will be assessed during Screening only.
12.1.5.
Physical Examination
The physical examination will include evaluation of the head, eyes, ears, nose, and throat 
(HEENT), cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, and 
neurological systems.  Physical examinations should be performed according to the Schedule 
of Events (Appendix 1).  Funduscopic exams must be performed at Screening, Baseline, and 
every 12 weeks during the treatment period.  Before administration of the first dose of study 
drug, any new or worsened abnormalities (other than those due to protocol required 
procedures) should be recorded as medical history.  After the initiation of study drug 
administration, any clinically significant new or worsened abnormalities noted on the 
physical examination will be recorded as AEs.  No rectal or pelvic examination is required.
12.1.6.
Electrocardiogram
A 12-lead ECG will be obtained after 5 to 15 minutes of rest in the supine position using 
equipment at the site and according to the schedule in Appendix 1.  The Investigator or 
designee will evaluate the ECG for abnormalities.
12.1.7.
Laboratory Assessments
Clinically significant abnormal laboratory findings identified during the screening period 
should be recorded as medical history in the CRF.
Laboratory samples will be collected according to the schedules in Appendix 1.
Clinically significant abnormal laboratory test results should be followed until a return to 
normal or baseline values.
Details for the collection, processing, storage, and shipment of samples can be found in the 
study laboratory manual.
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12.1.7.1.
Hematology
Hematology tests will include RBC count, white blood cell (WBC) count, hemoglobin (Hgb), 
hematocrit (HCT), WBC differential count (neutrophils, lymphocytes, eosinophils, 
monocytes, and basophils), mean corpuscular hemoglobin concentration (MCHC), mean 
corpuscular hemoglobin (MCH), mean corpuscular volume (MCV), mean platelet volume 
(MPV), red blood cell distribution width (RDW), platelet count (Plt), and reticulocyte count 
(retic).
12.1.7.2.
Blood Chemistry
Blood chemistry tests will include sodium (Na), potassium (K), magnesium (Mg), chloride 
(Cl), bicarbonate (CO2), calcium (Ca), phosphate (PO4), blood urea nitrogen (BUN), 
creatinine, total protein, glucose, lactate dehydrogenase (LDH) (Week 1 only), aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total 
bilirubin (TBILI), and albumin.
12.1.7.3.
Iron Panel
Blood samples will be collected for an iron panel to include: iron (Fe), ferritin, transferrin 
saturation, and total iron binding capacity. 
12.1.7.4.
Prothrombin Time, Activated Partial Thromboplastin Time, and 
International Normalized Ratio
Blood samples collected during screening will be used to determine prothrombin time (PT), 
activated partial thromboplastin time (aPTT), and international normalized ratio (INR) to 
assess coagulation.  
12.1.7.5.
Urinalysis
Urinalysis will include appearance, glucose, ketones, blood, protein, nitrite, bilirubin, 
specific gravity, pH, urobilinogen, and leukocytes.  If the results are positive for blood or 
protein, a microscopic examination should be included.
12.1.7.6.
Pregnancy Screen
A serum pregnancy test must be performed within 7 days before the first study drug 
administration.  A urine pregnancy test will be performed according to the schedule in 
Appendix 1.
12.1.7.7.
Male Fertility Analysis
Fertility tests for male patients will include orchidometry, semen analysis, and measurement 
of testosterone, follicle-stimulating hormone, luteinizing hormone, and inhibin B levels, 
according to the Schedule of Events, Appendix 1.  Male patients must be provided with 
information about the option for sperm banking before providing written informed consent.
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12.2.
Adverse and Serious Adverse Events
12.2.1.
Definition of Adverse Events
12.2.1.1.
Adverse Events
An AE is defined as any untoward medical occurrence in a patient regardless of its causal 
relationship to study treatment.  An AE can be any unfavorable and unintended sign 
(including any clinically significant abnormal laboratory test result), symptom, or disease 
temporally associated with the use of the study drug, whether or not it is considered to be 
study drug related.  Included in this definition are any newly occurring events and any 
previous condition that has increased in severity or frequency since the administration of 
study drug.  Disease progression is a study endpoint and consequently, should not be reported 
as an AE.  However, if a patient dies from disease progression with no other immediate 
causes, “disease progression” should be reported as an SAE (Section 12.7).
All AEs that are observed or reported by the patient during the study (from the time of 
administration of the first dose of study drug until the final visit indicated in Appendix 1) 
must be reported, regardless of their relationship to study drug or their clinical significance.
12.2.1.2.
Serious Adverse Events
An SAE is any AE occurring at any dose and regardless of causality that meets any of the 
following criteria.

Results in death

Is life-threatening

Requires inpatient hospitalization > 24 hours or prolongation of existing 
hospitalization

Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions

Is a congenital anomaly or birth defect in an offspring of a patient taking study drug

Is an important medical event 
The term “life-threatening” refers to an event in which the patient is at immediate risk of 
death at the time of the event.  The term does not refer to an event that hypothetically might 
cause death if it were more severe.
Important medical events are those that may not meet any of the criteria defined above; 
however, they may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient and may require medical or surgical intervention to prevent 
one of the other outcomes listed in the SAE definition.
Pregnancy is not considered an AE; however, information will be collected for any 
pregnancies that occur during the study (from the time the first dose of study drug is 
administered until the final visit indicated in Appendix 1).  Certain pregnancy outcomes will 
require submission as an SAE.  
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The Investigator is responsible for reporting to Peloton Therapeutics or designee all AEs and 
SAEs that are observed or reported by the patient during the study (from the time the first 
dose of study drug is administered until the final visit indicated in Appendix 1), regardless of 
their relationship to study drug or their clinical significance.  All SAEs reported or observed 
during the study must be followed to resolution or until the Investigator deems the event to 
be chronic or the patient to be stable.  Peloton Therapeutics or designee may contact the 
Investigator to obtain additional information on any SAE that has not resolved at the time the 
patient completes the study.
12.3.
Eliciting Adverse Event Information 
At every study visit, patients must be asked a standard, non-directed question, such as, “How 
do you feel?” or “How have you been feeling since your last visit?” to elicit any medically 
related changes in their well-being.  They may also be asked if they have been hospitalized, 
had any accidents, used any new medications, or changed concomitant medication regimens 
(including prescription drugs, over-the-counter medications, vitamins, herbal products, and 
minerals).  Responses should be recorded in the source documents.
In addition to patient observations, AEs must be documented for any clinically significant 
diagnosis resulting from abnormal laboratory test values, physical examination findings, or 
ECG abnormalities, or from other documents that are relevant to patient safety.
12.4.
Assessment of Causality 
The Investigator must use the following classifications and criteria to characterize the 
relationship or association of PT2385 in causing or contributing to the AE:
Unrelated: This relationship suggests that there is no association between the study drug and 
the reported event.
Unlikely: This relationship suggests that the temporal sequence of the event with study drug 
administration makes a causal relationship improbable and/or other factors also provide 
plausible explanations.
Possible: This relationship suggests that treatment with the study drug caused or contributed 
to the AE.  That is, the event follows a reasonable temporal sequence from the time of study 
drug administration, and/or, follows a known response pattern to the study drug, but could 
have been produced by other factors.
Probable: This relationship suggests that a reasonable temporal sequence of the event with 
study drug administration exists and, based upon the known pharmacological action of the 
drug, known or previously reported adverse reactions to the drug or class of drugs, or 
judgment based on the Investigator’s clinical experience, the association of the event with 
study drug administration seems likely.
12.5.
Assessment of Severity
The Investigator will grade the severity of the AEs as Grades 1, 2, 3, 4, or 5 based on NCI 
CTCAE 4.03 or subsequent versions released during the study.  If the CTCAE do not apply, 
severity should be defined as shown in Table 3.
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Table 3
Adverse Event Severity Grades
Grade
Description
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.
2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living.
3
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of daily 
living.
4
Life-threatening consequences; urgent intervention indicated.
5
Death related to AE.
The NCI CTCAE 4.03 will be provided to the Investigator.
12.6.
Recording Adverse Events
All conditions present before administration of the first dose of study drug should be 
documented as medical history.  All drug-related (possible or probable, see Section 12.4) 
AEs and abnormal laboratory test results reported or observed during the study must be 
followed to resolution (either return to baseline or within normal limits).  All other AEs will 
be followed through the final visit indicated in Appendix 1.  Information to be collected 
includes type of event, date of onset, date of resolution, Investigator-specified assessment of 
severity and relationship to study drug, seriousness, as well as any action taken.  
While an AE is ongoing, changes in the severity (e.g., worsening and improving) should be 
noted in the source documents but, when documenting the AE, only the total duration and 
greatest severity should be recorded in the CRF.  AEs characterized as intermittent require 
documentation of onset and duration.
AEs resulting from concurrent illnesses, reactions to concurrent illnesses, reactions to 
concurrent medications, or progression of disease states must also be reported.  Preexisting 
conditions (present before the start of the AE collection period) are considered concurrent 
medical conditions and should NOT be recorded as AEs.  However, if the patient experiences 
a worsening or complication of such a concurrent condition, the worsening or complication 
(except disease progression) should be recorded as an AE.  Investigators should ensure that 
the AE term recorded captures the change in the condition (e.g., “worsening of…”).
Each AE should be recorded to represent a single diagnosis.  Accompanying signs (including 
abnormal laboratory test values or ECG findings) or symptoms should NOT be recorded as 
additional AEs.  If a diagnosis is unknown, sign(s) or symptom(s) should be recorded as an 
AE(s).  Changes in laboratory test values or ECG parameters are only considered to be AEs 
if they are judged to be clinically significant (i.e., if some action or intervention is required or 
if the Investigator judges the change to be beyond the range of normal physiologic 
fluctuation).  If abnormal laboratory test values or ECG findings are the result of pathology 
for which there is an overall diagnosis (e.g., increased creatinine levels in renal failure), only 
the diagnosis should be reported as an AE.
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Elective procedures (surgeries or therapies) that were scheduled before the start of AE 
collection are not considered AEs.  These elective procedures should not be recorded as AEs, 
but should be documented in the patient’s source documents as elective (e.g., elective 
periodontal surgery).  However, if a pre-planned procedure is performed early (e.g., as an 
emergency) because of a worsening of the preexisting condition, the worsening of the 
condition should be captured as an AE.
12.7.
Reporting Serious Adverse Events
Any AE that meets the previously described criteria for “serious” must be reported to the 
Sponsor’s designee within 24 hours from the time when site personnel first learn about the 
event.  To report the SAE, fax or email the completed SAE form to SCRI Development 
Innovations Pharmacovigilance Department (contact information listed in Table 4) within 24 
hours of awareness.  For questions regarding SAE reporting, SCRI Development Innovations 
Safety personnel can be contacted by phone, fax or email, see Table 4.
Table 4
Serious Adverse Event Reporting Contact Information
The Investigator must continue to follow the patient until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the 
patient dies.  Within 24 hours of receipt of new information, the updated follow-up SAE 
form, along with any supporting documentation (e.g., patient discharge summary or autopsy 
reports), should be faxed to SCRI Development Innovations Pharmacovigilance Department
(Table 4).
Peloton Therapeutics or designee will notify regulatory agencies of any fatal or 
life-threatening unexpected events associated with the use of the study drug as soon as 
possible but no later than 7 calendar days after the initial receipt of the information.  Initial 
notification will be followed by a written report within the timeframe established by the 
appropriate regulatory agency.  For other SAEs that do not meet the fatal or life-threatening 
unexpected criteria, but are deemed by the Investigator to be associated with the use of the 
study drug (that is, “possible” or “probable” in causality assessment), Peloton Therapeutics 
or designee will notify the appropriate regulatory agencies in writing within the timeframe 
established by those regulatory agencies.  Peloton Therapeutics or designee will provide 
copies of any reports to regulatory agencies regarding serious and unexpected SAEs to the 
Investigators for their information and submission to their institutional review board (IRB), 
as appropriate.
Principal Investigators are responsible for informing their IRB of any SAEs at their site, as 
appropriate.  Serious AE correspondence with regulatory authorities or IRBs must be 
submitted to Peloton Therapeutics or designee for recording in the study file.
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12.8.
Pregnancy
Female patients of child-bearing potential are defined as patients who are not surgically 
sterile (no history of bilateral tubal ligation, hysterectomy, or bilateral 
salpingo-oophorectomy), do not have fallopian inserts with confirmed blockage, have not 
had reproductive potential terminated by radiation, and have not been postmenopausal for at 
least 1 year.
12.8.1.
Methods of Birth Control
During screening, while taking study drug, and until 30 days after taking the final dose of 
study drug, female patients of child-bearing potential and male patients who have female 
partners of child-bearing potential (defined as all women physiologically capable of 
becoming pregnant) must practice one of the following methods of birth control:

Total abstinence,

Male or female sterilization, or

Combination of any 2 of the following (a + b or a + c or b + c):
a.
Use of oral, injected or implanted hormonal methods of contraception
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS)
c.
Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository
12.8.2.
Suspected Pregnancy
During the study, all females of child-bearing potential must be instructed to contact the 
Investigator immediately if they suspect they might be pregnant (e.g., late or missed 
menstrual period).  Male patients must be instructed to contact the Investigator if a sexual 
partner suspects she may be pregnant.
If a patient or Investigator suspects that the patient may be pregnant, study drug 
administration must be held until the results of a serum pregnancy test are available.  If 
pregnancy is confirmed, the patient must discontinue taking study drug.  The Investigator
must immediately report a pregnancy associated with study drug exposure and record the 
event.  The protocol-required early termination procedures noted in Appendix 1 must be 
performed.  Other appropriate follow-up procedures should be considered if indicated.
Pregnancy is not considered an AE; however, the Investigator must follow a pregnant patient, 
or the pregnant female partner of a male patient (if consenting), and report follow-up 
information regarding the course of the pregnancy, including perinatal and neonatal outcome.  
Infants resulting from such pregnancies should be followed for a minimum of 8 weeks.  
Peloton Therapeutics or designee may contact the Investigator to request additional 
information throughout the course of the pregnancy.
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The following post-pregnancy outcomes must be considered SAEs and will require 
additional reporting in the CRF and on an SAE form.

Congenital anomaly/birth defect

Stillbirth

Spontaneous miscarriage
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13.
STATISTICS
This section describes the statistical methodology to be used in the analysis of protocol 
endpoints.  These methods will be documented in a formal statistical analysis plan (SAP) 
detailing the analyses to be performed, which will be developed before the final database 
lock.  The SAP will serve as the final arbiter of all statistical analyses.  The SAP will 
describe the analysis of all safety, efficacy, PK, and PD response variables.  Any changes to 
the methodology described in the final approved SAP will be presented and discussed in the 
clinical study report.
13.1.
Determination of Sample Size
This study will be conducted with a 2-stage design (Green and Dahlberg, 1992) which allows 
for an early assessment of futility.  If after the first 25 patients have been enrolled to the 
study, 2 or fewer patients have had a confirmed response, further enrollment will be 
temporarily suspended for up to a year or until at least 3 responses are seen; if 3 responses 
are not seen within 1 year after enrollment of the 25th patient, no further patients will be 
enrolled and the study will be discontinued.  In addition, if more than 2 of the first 6 patients 
enrolled experience treatment-limiting toxicity during the first 4 weeks of their treatment, the 
protocol will be modified or the study will be stopped.  If 3 or more of the 25 patients 
respond, enrollment will proceed to the second stage of the design.
A total of 25 patients will be enrolled into the second stage of the study for a total required 
enrollment of 50 patients.  If at least 13 of the 50 patients (25 + 25) respond (CR or PR), then 
the hypothesis that PT2385 is ineffective will be rejected.
The required sample size for this 2-stage design is based on the following design parameters: 
The null hypothesis is that PT2385 is ineffective, defined as an ORR (best confirmed 
response of PR or CR) of 15% (P0=0.15).  The alternative hypothesis is that PT2385 is
effective, defined as an ORR of 30% (P1=0.3).  The probability of falsely concluding that the 
agent is effective when it is truly ineffective is 0.05 (alpha) and the probability of falsely 
concluding that the agent is ineffective when it is truly effective is 0.2 (beta).
13.2.
Analysis Populations
The analysis populations include the following:  
Enrolled Population: The Enrolled Population is defined as all patients who have been 
screened and have provided written informed consent.  This population will be used for the 
summary of patient disposition and data listings.
Efficacy Analysis Set:  The Efficacy Analysis Set is defined as all patients who have been 
enrolled and received at least 1 dose of PT2385.  This population is the primary population 
for analysis of efficacy.
Safety Analysis Set:  The Safety Analysis Set is defined as all patients who have been 
enrolled and received at least 1 dose of PT2385.  This population is the primary population 
for the summaries of demographics, baseline data, safety data, and exposure.
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13.3.
Statistical Analyses
All statistical summaries and analyses will be performed in SAS® Version 9.1 or higher 
(SAS Institute Inc., Cary, NC, USA) on a PC platform.
Results will be reported using summary tables, figures, and data listings.  No inferential 
statistical analyses will be performed.  For continuous variables, the number of patients with 
non missing data (n), mean, standard deviation, median, minimum, and maximum will be 
presented.  For discrete data, the frequency and percent distribution will be presented.  
Unless otherwise indicated, percentages will be calculated based upon the number of patients 
in the Safety Analysis Set as the denominator.  Graphical methods will be used, as 
appropriate, to illustrate study endpoints.
Summaries will be provided for the total number of patients in the population of interest and 
for selected variables, and subsets of patients in the population of interest.
Data recorded on the electronic case report forms and any derived data will be presented by 
patient in data listings.
13.3.1.
Handling of Missing, Unused, or Spurious Data
The handling of dropouts and missing disease status assessments for the efficacy variables is 
described in their definitions. Missing data will not be estimated or carried forward for any 
of the other summaries.
If only a partial date is available and is required for a calculation of whether a medication is 
concomitant or an AE is treatment emergent, the start and stop dates will be imputed 
according to a predefined standard.  Any partial dates will be displayed in data listings 
without imputation of missing days and/or months (e.g., MAR2011, 2009).  No other 
imputation of missing data will be performed.
13.3.2.
Patient Characteristics and Patient Disposition
Demographics (including gender, age, race, and ethnicity), disease characteristics, and other 
baseline data (e.g., medical history, concomitant medications) will be summarized using 
descriptive statistics.  The number of patients who enter, who complete treatment, who 
complete long-term follow-up, who withdraw from treatment prematurely (along with the 
reason), and who withdraw from the long-term follow-up prematurely (along with the 
reason) will be tabulated.
13.3.3.
Exposure
All study drug administration data will be summarized for the Safety Analysis Set.  The 
duration of PT2385 exposure in weeks, defined as (date of administration of last dose minus 
date of administration of first dose of PT2385 plus 1) divided by 7 and the total amount of 
PT2385 administered will be summarized.
13.3.4.
Efficacy Analyses
The primary summaries of all response data will be based on the Efficacy Analysis Set.
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Response of ccRCC tumors will be measured by contrast enhanced computerized 
tomography (CT) or magnetic resonance image (MRI) scan and assessed according to 
RECIST 1.1, modified to follow ccRCC tumors only.
Response assessments of ccRCC CR and PR should be confirmed by a second assessment.  
Where confirmed responses are required, the date of the first assessment will be used in all 
analyses.  In the case that the confirmation assessment is not available, the assessment at the 
next scheduled time point will be used for confirmation.  If there are no assessments, the 
response will be taken to be unconfirmed and a non response.
The ccRCC ORR is defined as the proportion of patients for whom the best confirmed
ccRCC response is CR or PR, determined by RECIST 1.1.  Estimates of the ccRCC ORR 
along with the associated 90% and 95% exact binomial confidence intervals (Clopper 
Pearson) will be provided.  The binomial probability that the observed ccRCC ORR is > 0.15 
will be calculated.  Best confirmed ccRCC response will be summarized.
The ccRCC PFS is defined the interval from the start of study treatment until the earlier of 
the first documentation of ccRCC disease progression determined by RECIST 1.1 or death 
from any cause, whichever occurs first.  Renal cell carcinoma PFS will be right censored for 
patients who meet one of the following conditions: 1) no post baseline disease assessments, 
2) non protocol systemic anticancer treatment started before documentation of disease 
progression or death, 3) surgery that is considered to affect response before documentation of 
disease progression or death, 4) death or disease progression after more than 1 missed disease 
assessment visit, 5) alive and does not have documentation of disease progression before a 
data analysis cutoff date.  The Kaplan-Meier (KM) method will be used to estimate the 
distribution of ccRCC PFS.  Quartiles including the median will be estimated by KM method 
along with their 95% confidence intervals.  A figure showing the estimated ccRCC PFS 
distribution will be provided.  KM cumulative estimators along with the associated 95% CIs 
will be provided for ccRCC PFS rates at 26, 39 and 52 weeks.  Duration of follow up for
ccRCC PFS will be summarized according to the KM estimate of potential follow up also 
termed “reverse Kaplan-Meier.”
The ccRCC DOR will be calculated for patients who achieve a ccRCC CR or PR.  For such 
patients, the ccRCC DOR is defined as the interval from first documentation of response, as 
determined by RECIST 1.1, to the earlier of the first documentation of disease progression or 
death from any cause.  Dates of progression and censoring will be determined as described 
for the analysis of ccRCC PFS.  Kaplan-Meier methods will be used to estimate the 
distribution of ccRCC DOR.  Quartiles including the median will be estimated by KM 
method along with their 95% confidence intervals.  KM cumulative estimators along with the 
associated 95% CIs will be provided for ccRCC DOR rates at 26, 39 and 52 weeks.  These 
estimates will be used as estimates of durable response.
The ccRCC TTR will be calculated for patients who achieve a ccRCC CR or PR.  Renal cell 
carcinoma TTR is defined as the interval from the start of study treatment to the first 
documentation of a ccRCC response of PR or better, as determined by RECIST 1.1.
The maximum percent decrease in ccRCC total tumor burden will be displayed using 
waterfall plots.
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Summaries of the response endpoints will also be provided for subgroups of the Efficacy 
Analysis Set as follows: Subgroups will be defined according to blood level of PT2385 based 
on the PK assessments and duration of PT2385 treatment. The analyses of ccRCC ORR,
ccRCC PFS, ccRCC best confirmed response, ccRCC DOR, and ccRCC TTR will be 
performed in each of these subgroups.
The ORR, PFS, best confirmed response, DOR, and TTR will be summarized for the non-
ccRCC tumors associated with VHL disease based on the subgroups of patients in the 
Efficacy Analysis Set who have the particular type of tumor.  The determination of best 
response and date of progression will be determined by modifying RECIST 1.1 criteria to 
assess tumors in individual organ systems independently (e.g., VHL disease-associated solid 
tumors in the pancreas or adrenal gland, or hemangioblastomas or retinal angiomas).
The determination of response and progression will be made by the local investigators. The 
investigator assessments will be used for decisions regarding treatment for individual patients 
and by the DMC for approval to open Stage 2 of the study. The response outcomes will also 
be reviewed and determined by an Independent Review Committee (IRC). For the primary 
analysis of ORR, the determination of response will be based on independent radiologic 
assessment conducted by the IRC. Both the investigators’ and the IRC’s assessments will be 
used for the summaries and analyses of efficacy.
13.3.5.
Pharmacodynamic Analyses
Blood samples for assessment of pharmacodynamic parameters such as EPO will be obtained 
in conjunction with PK samples, before (pre-dose) and 6 hours after study drug 
administration at the Week 1 visit and only before study drug administration at the Week 3 
and 5 visits.
The value, change from baseline, and percent change from baseline will be listed and 
summarized for each scheduled time-point during the study for each of the pharmacodynamic 
parameters.
To investigate the effect of these potential biomarkers on efficacy, the association of baseline 
pharmacodynamic parameters with ORR and PFS will be investigated using exploratory 
multivariate techniques, subgroup analyses, and regression modeling.
The summaries will be based on the Safety Analysis Set.  The exploratory analyses will be 
performed for the Efficacy Analysis Set.
13.3.6.
Safety Analyses
Safety data analysis will be conducted for all patients in the Safety Analysis Set.  Analyses 
will consist of data summaries for AEs/SAEs, clinical laboratory parameters, vital signs, and 
ECGs.  
13.3.6.1.
Adverse Events
Adverse events occurring from the time the patient gives consent but prior to study drug 
administration will be captured on the Medical History CRF.  All AEs occurring on or after 
the first day of treatment and within 30 days after administration of the last dose of study 
drug will be considered to be a treatment-emergent adverse event (TEAE).
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Adverse events will be coded according to the latest Version of the Medical Dictionary for 
Regulatory Activities (MedDRA).  The severity of AEs will be coded according to NCI 
CTCAE 4.03.  Treatment-related AEs are AEs that are not stated as unrelated to PT2385.
An overall summary of TEAEs will summarize the number (%) of patients with at least 1 of 
the following.

TEAE

PT2385 related TEAE

Grade 3 or higher TEAE

Grade 3 or higher PT2385 related TEAE

Grade 5 TEAE

SAE

Leading to discontinuation of PT2385
Summaries of the following TEAEs will be provided by system organ class and preferred 
term.

All TEAEs

TEAEs by maximum severity

TEAEs grade 3 or higher

PT2385 related TEAEs

Grade 3 or higher PT2385 related TEAE

Serious TEAEs

TEAEs that led to permanent discontinuation of study of PT2385
A summary of the number of deaths within 30 days of administration of the last dose of study 
drug and deaths more than 30 days after administration of the last dose of study drug will be 
provided.
Listings will be provided of AEs identified as treatment-limiting toxicity, deaths, SAEs, and 
AEs leading to discontinuation of PT2385 tablet treatment.
13.3.6.2.
Clinical Laboratory Data
Summary statistics (n, arithmetic mean, standard deviation, median, minimum, and 
maximum) for the observed data and change from baseline will be presented for clinical 
laboratory data and abnormal clinically significant lab.  Selected laboratory values will also 
be categorized according to their NCI CTCAE 4.03 toxicity grade.  Shift tables will be 
presented for the baseline toxicity grade by the worst toxicity grade during the study and the 
toxicity grade at the end of treatment for the biochemistry and hematology parameters with 
NCI CTCAE toxicity grading.
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13.3.6.3.
Other Safety Data
Summary statistics (n, arithmetic mean, standard deviation, median, minimum, and 
maximum) for the observed data and change from baseline will be presented for vital sign 
parameters.
Summaries of ECG findings and shifts from baseline will be tabulated.
13.3.7.
Pharmacokinetic Analyses
Blood samples for calculation of concentration of PT2385 and PT2639 will be obtained 
before (pre-dose) and 6 hours after study drug administration at the Week 1 visit and only 
before study drug administration at the Week 3, Week 5, and every 4 weeks through the 
Week 17 visits.  The blood concentrations of PT2385 and PT2639 at each collection time 
will be summarized.  Figures displaying individual and mean blood concentrations will be 
provided.
13.4.
Analysis Time Points
13.4.1.
Final Analysis
The final analysis for the study will be conducted once all patients have completed the study 
and the database is clean and locked.
13.4.2.
Interim Analysis
There is one formal interim analysis for futility planned for this study.  The response data for 
the first 25 patients in Stage 1 of the study will be reviewed by a DMC.  The DMC will 
consist of the principal Investigator(s) participating in this study, the Medical Monitor, and 
representatives from Peloton.  The DMC will determine if the threshold for opening Stage 2 
has been met.
In addition, the data for the first 6 patients will be reviewed by the DMC.  The DMC will 
meet shortly after the sixth patient has been observed for 28 days after the administration of 
their initial PT2385 Tablet dose.  The DMC will review safety and any treatment-limiting 
toxicities to confirm whether the study should continue to enroll or if modifications to the 
protocol are needed.
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14.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS
14.1.
Study Monitoring
Before an investigational site can enter a patient into the study, a representative of Peloton
will visit the investigational study site to:

Determine the adequacy of the facilities

Discuss with the Investigator(s) and other personnel their responsibilities with regard 
to protocol adherence, and the responsibilities of Peloton or its representatives.  This 
will be documented in a Clinical Study Agreement between the Sponsor and the 
Investigator.
During the study, a monitor from Peloton or representative will have regular contacts with 
the investigational site, for the following:

Provide information and support to the Investigator(s)

Confirm that facilities remain acceptable

Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the case report forms, and that investigational product 
accountability checks are being performed

Perform source data verification.  This includes a comparison of the data in the case 
report forms with the patient’s medical records at the hospital or practice, and other 
records relevant to the study.  This will require direct access to all original records for 
each patient (e.g. clinic charts).

Record and report any protocol deviations not previously sent to Peloton.

Confirm AEs and SAEs have been properly documented on CRFs and confirm any 
SAEs have been forwarded the Sponsor and those SAEs that met criteria for reporting 
have been forwarded to the IRB.
The monitor will be available between visits if the Investigator(s) or other staff needs 
information or advice.
14.2.
Audits and Inspections
Authorized representatives of Peloton, a regulatory authority, an Independent Ethics 
Committee or an Institutional Review Board may visit the site to perform audits or 
inspections, including source data verification.  The purpose of a Sponsor audit or inspection 
is to systematically and independently examine all study-related activities and documents to 
determine whether these activities were conducted, and data were recorded, analyzed, and 
accurately reported according to the protocol, Good Clinical Practice guidelines of the 
International Council on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH), and any applicable regulatory requirements.  The 
Investigator should contact Peloton immediately if contacted by a regulatory agency about an
inspection.
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14.3.
Institutional Review Board (IRB)
The Principal Investigator must obtain IRB approval for the investigation.  Initial IRB 
approval, and all materials approved by the IRB for this study including the patient consent 
form and recruitment materials must be maintained by the Investigator and made available 
for inspection.
14.4.
Confidentiality
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain patient confidentiality.  All records will be kept in a secure 
storage area with limited access.  Clinical information will not be released without the 
written permission of the patient (or the patient’s guardian), except as necessary for 
monitoring and auditing by the Sponsor, its designee, the FDA or applicable regulatory 
authorities, or the IRB.
The Principal Investigator and all employees and coworkers involved with this study may not 
disclose or use for any purpose other than performance of the study, any data, record, or 
other unpublished confidential information disclosed to them for the purpose of the study.  
Prior written agreement from the Sponsor or designee must be obtained for the disclosure of 
any said confidential information to other parties.
14.5.
Modification of the Protocol
Any changes that arise after the approval of the protocol must be documented as protocol 
amendments.  The FDA must be notified of protocol amendments.  The changes will become 
effective only after approval of the Sponsor, the Principal Investigator, and the IRB.  In cases 
when the protocol is modified to enhance patient safety, changes may be implemented and 
the amendment must be immediately submitted to the IRB.
The Principal Investigator is responsible for informing the IRB of all problems involving 
risks to patients according to national legislation.  In case of urgent safety measures, the 
Sponsor will immediately notify the FDA in accordance with 21 CFR 312.32.
14.6.
Protocol Deviations
The Principal Investigator or designee must document any protocol deviation.  The IRB must 
be notified of all protocol deviations in a timely manner by the Investigator as appropriate.  
Protocol deviations will be documented by the responsible monitor during monitoring visits, 
and those observations will be communicated to the Investigator.
If there is an immediate hazard to a patient, the Principal Investigator may deviate from the 
protocol without prior Sponsor and IRB approval.  The Sponsor and IRB must be notified of 
the deviation immediately.
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15.
QUALITY CONTROL AND QUALITY ASSURANCE
15.1.
Quality Assurance
To ensure compliance with Good Clinical Practices (GCP) and all applicable regulatory 
requirements, Peloton Therapeutics may conduct a quality assurance audit.
15.2.
Financial Disclosure 
Principal Investigators and sub Investigators are required to provide financial disclosure 
information before starting the study.  In addition, the Principal Investigator and sub 
Investigators must provide the Sponsor or designee with updated information, if any relevant 
changes occur during the course of the investigation and for 1 year after the completion of 
the study.
Any potential Investigator who has a vested financial interest in the success of this study may 
not participate in this study.
15.3.
Sponsor Obligations 
The Sponsor or designee is not financially responsible for further testing/treatment of any 
medical condition that may be detected during the screening process.  In addition, in the 
absence of specific arrangements, the Sponsor or designee is not financially responsible for 
treatment of non-study-related fatalities, physical injuries, or damage to health that may 
occur during the clinical study, as well as the patient’s underlying disease.
15.4.
Investigator Documentation
Before beginning the study, the Principal Investigator will be asked to comply with ICH 
E6(R1) 8.2 and Title 21 of the Code of Federal Regulations (CFR) by providing the essential 
documents to the Sponsor or designee, which include but are not limited to the following.

An original Investigator signed Investigator agreement page of the protocol 

The IRB approval of the protocol

The IRB approved informed consent, samples of site advertisements for recruitment 
for this study, and any other written information regarding this study that is to be 
provided to the patient or legal guardians

A Form FDA 1572, fully executed, and all updates on a new fully executed Form 
FDA 1572

Curriculum vitae for the Principal Investigator and each sub Investigator listed on 
Form FDA 1572.  A curricula vitae and current licensure, as applicable, must be 
provided.  The curricula vitae must have been signed and dated by the Principal 
Investigators and sub Investigators within 2 years before study start up to indicate the 
documents are accurate and current

Completed financial disclosure forms to allow the Sponsor or designee to submit 
complete and accurate certification or disclosure statements required under US Title 
21 CFR 54.  In addition, the Investigators must provide to the Sponsor or designee a 
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commitment to update this information promptly if any relevant changes occur during 
the course of the investigation and for 1 year after the completion of the study

Laboratory certifications and normal ranges for any laboratories used by the site for 
the conduct of this study
15.5.
Clinical Study Insurance
In accordance with the respective national drug laws, the Sponsor has taken out patient 
liability insurance for all patients who give their consent and enroll in this study.  This 
insurance covers potential study related fatalities, physical injuries, or damage to health that 
may occur during the clinical study.
15.6.
Use of Information 
All information regarding PT2385 supplied by the Sponsor to the Investigator is privileged 
and confidential.  The Investigator agrees to use this information to accomplish the study and 
will not use it for other purposes without consent from the Sponsor.  Furthermore, the 
Investigator is obligated to provide the Sponsor with complete data obtained during the 
study.  The information obtained from the clinical study will be used towards the 
development of PT2385 and may be disclosed to regulatory authority(ies), other 
Investigators, corporate partners, or consultants as required.
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16.
ETHICS
16.1.
Ethics Review
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board (IRB) before study start.  Each Investigator
must provide the Sponsor or its designee a signed and dated statement that the protocol and 
informed consent have been approved by the IRB before consenting patients.  Before study 
initiation, the Investigator is required to sign a protocol signature page confirming agreement 
to conduct the study in accordance with this protocol and to give access to all relevant data 
and records to the Sponsor, its designee, and regulatory authorities as required.
The IRB chairperson or designee must sign all IRB approvals and must identify the IRB by 
name and address, the clinical protocol, and the date approval and/or favorable opinion was 
granted.
The Principal Investigator is responsible for obtaining reviews of the clinical research at 
intervals specified by the IRB, but not exceeding 1 year.  The Principal Investigator must 
supply the Sponsor or designee with written documentation of reviews of the clinical 
research.
16.2.
Ethical Conduct of the Study
This clinical study was designed and shall be implemented and reported in accordance with 
the ICH Harmonised Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (e.g., US Code of Federal Regulations Title 21), and with the ethical principles 
laid down in the Declaration of Helsinki. 
The Principal Investigator agrees to conduct the study in accordance with the ICH Guidance 
for Industry on GCP ICH E6(R1) and the principles of the Declaration of Helsinki.  The 
Principal Investigator must conduct all aspects of this study in accordance with all national, 
state, and local laws or regulations.
16.3.
Written Informed Consent
Because the study will be conducted under a United States Investigational New Drug 
Application, a signed informed consent form, in compliance with Title 21 of the United 
States CFR Part 50, will be obtained from each patient before the patient enters the study.  
An informed consent template may be provided by the Sponsor or designee to the 
Investigators.  The consent must be reviewed by the Sponsor or designee before IRB 
submission.  Once reviewed, the consent will be submitted by the Principal Investigator to 
his or her IRB for review and approval before the start of the study.  If the informed consent 
form is revised during the course of the study, all participants affected by the revision must 
sign the revised IRB approved consent form.
Before enrollment, each prospective patient will be given a full explanation of the study and 
be allowed to read the approved informed consent form.  Once the Principal Investigator or 
designee is assured that the patient understands the implications of participating in the study, 
the patient will be asked to give consent to participate in the study by signing the informed 
consent form.
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Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB approved informed consent.  Informed consent must be 
obtained before conducting any study specific procedures (i.e., all of the procedures 
described in the protocol).  The process of obtaining informed consent must be documented 
in the patient source documents.
Any changes to the proposed consent form suggested by the Investigator must be agreed to 
by the Sponsor before submission to the IRB, and a copy of the approved Version and the 
notice of approval must be provided to the Sponsor’s designated monitor after IRB approval.
The Principal Investigator or designee will provide a copy of the informed consent form 
(signed copy to be provided per applicable law) to the patient and/or legal guardian.  The 
original form will be maintained in the patient’s medical records at the site.
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17.
DATA HANDLING AND RECORDKEEPING
17.1.
Inspection of Records
Peloton will be allowed to conduct site visits to the investigation facilities for the purpose of 
monitoring any aspect of the study.  The Investigator agrees to allow the monitor to inspect 
the drug storage area, study drug stocks, drug accountability records, patient charts and study 
source documents, and other records relative to study conduct.
17.2.
Retention of Records
The Investigator will maintain all study records according to ICH GCP and applicable 
regulatory requirement(s).  Records will be retained for at least 2 years after the last 
marketing application is approved or 2 years after formal discontinuation of the clinical 
development of the investigational product.  If the Investigator withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person willing to 
accept the responsibility.  The Sponsor must be notified in writing if a custodial change 
occurs.  
17.3.
Case Report Forms
All CRF data will be entered in paper or electronic forms at the investigational site.  If an 
Electronic Data Capture (EDC) system is used to capture data electronically for all enrolled
patients, it will be 21 CFR Part 11 compliant.
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18.
PUBLICATION POLICY
Peloton Therapeutics reserves the right to review all planned communications and 
manuscripts based on the results of this study.  This reservation of the right is not intended to 
restrict or hinder publication or any other dissemination of study results, but to allow the 
Sponsor to confirm the accuracy of the data, to protect proprietary information, and to 
provide comments based on information that may not yet be available to the study 
Investigators.  Peloton Therapeutics supports communication and publication of study results 
whatever the findings of the study.  Peloton Therapeutics also encourages disclosure of any 
conflict of interest from all authors or Investigators when manuscripts are submitted for 
publication.
Those individuals who have contributed greatly to this study, as determined by Peloton 
Therapeutics, will serve on any publication committee for the study.
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19.
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APPENDICES
Appendix 1
Schedule of Events
Appendix 2
ECOG Performance Status
Appendix 3
RECIST 1.1 Summary
Appendix 4
Evaluation of Non-Renal VHL Related Disease
Appendix 5
New York Heart Association Functional Classification
Appendix 6
Partial List of Strong CYP2C19 and CYP3A4 Inhibitors
Appendix 7
Partial List of Substrates of CYP3A4, CYP2B6, CYP2C9, and CYP2C19
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Appendix 1
Schedule of Events
Assessment
Pre-Treatment 
Period
Treatment Period
Post-Treatment Period/ Early 
Termination
Screening
(Day -28 to 
Day -1)
Week 11
(Day 1)
Weeks 3 and 51
(± 1 Day)
Weeks 9, 13, 17, and 
Every 4 Weeks1
(± 2 Days)
Extended Treatment2
Every 12 Weeks
(± 1 Week)
Safety Follow-Up
28 Days After Last 
Dose of Study Drug 
Taken (± 7 Days)
Long Term 
Follow-up 
(every 6
months)16
Informed Consent
X
Assess Inclusion/Exclusion 
X
Demographics and Medical 
X
Physical Examination3
X
X
X
X
X
X
Vital Signs4
X
X 4
X
X
X
X
Weight
X
X
X
X
X
X
Height
X
ECOG
X
X
X
X
X
X
Dispense/Collect Study Drug
X
X
X
X
Hematology5
X
X
X
X
X
X
Serum Chemistry6
X
X
X
X
X
X
PT, aPTT, INR
X
Iron Panel7
X
X
X
X
X
Urinalysis8
X
X
X
X
X
X
Pregnancy Test9
X
X
X
X
X
X
ECG10
X
X10
X10
X10
Tumor Assessment11
X
X11
X
Pharmacokinetic Sample12
X
X
X
Pharmacodynamic Sample13
X
X
X
Assessment of Male Fertility14
X
X14
X14
Tissue Sample Collection15
X
Adverse Events
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
Study Drug Administration
------------------------------X------------------------------
Patient Status16
X
ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; PT/aPTT = prothrombin time/activated partial thromboplastin time.
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1.
Assessments are to be done on Day 1 of each visit week.  For the Weeks 3 and 5 visits, assessments may be ± 1 day; for the Week 9, 13, and 17 visits 
and for visits every 4 weeks thereafter, assessments may be ± 2 days.
2.
For patients deriving clinical benefit at 1 year and continuing to take study drug after 1 year, visits will be conducted at 12-week intervals.
3.
Funduscopic exams must be performed at Screening, Baseline, and every 12 weeks during the treatment period.
4.
At the Week 1 visit, patients will take their morning dose of PT2385 in the clinic.  Vital signs (pulse, blood pressure, respirations, temperature, and 
pulse oximetry) will be measured at least 30 minutes before and at 1, 2, 4, and 6 hours after study drug administration.  For all remaining clinic visits, 
vital signs should be measured during each clinic visit and the time the measurements are taken should be recorded.  Oxygen saturation (measured by 
pulse oximetry) should be measured at both rest and on exertion each time vital signs are measured; at the Week 1 visit, oxygen saturation should be 
measured before study drug administration and at 6 hours after study drug administration only.  Those patients with dyspnea or asymptomatic 
desaturation (oxygen saturation < 92%) will be further evaluated as clinically indicated; evaluation may include chest x-ray, arterial blood gas analysis, 
pulmonary function testing including diffusion capacity, co-oximetry as well as evaluation for specific causes of hypoxia/dyspnea, such as CT scan, CT 
angiogram or ventilation-perfusion scan..
5.
Hematology assessments include complete blood count, differential, platelet count and reticulocyte count.
6.
Serum chemistry assessments include glucose, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin, albumin, 
electrolytes (sodium, potassium, chloride, bicarbonate), calcium, magnesium, phosphate, blood urea nitrogen, creatinine, and total protein levels; lactate 
dehydrogenase level at Week 1 only.
7.
Iron panel assessments including iron, ferritin, transferrin saturation and total iron binding capacity should be captured at Screening, and every 4 weeks 
for the first year thereafter.
8.
Samples for urinalysis (including microscopic if abnormalities on macroscopic examination) will be obtained at Screening and the Week 1, 3, 5, 9, 13, 
and 17 visits, and every 4 weeks thereafter.
9.
Female patients of child-bearing potential will have a serum pregnancy test within 7 days before the first study drug administration; a urine pregnancy 
test will be performed at the Week 1, 3, 5, 9, 13, and 17 visits, and every 4 weeks thereafter.
10. A 12-lead ECG will be obtained, in triplicate, before and at 1.5 hours after study drug administration at the Week 1, 3, and 17 visits.
11. Tumor assessment including non-contrast or contrast computed tomography (CT), or magnetic resonance imaging (MRI) will be obtained at screening 
and within 7 days before the Week 13 visit, and every 12 weeks thereafter (e.g., before the visits for Weeks 25, 37, etc.).
12. At the Week 1 visit, patients will take their morning dose of PT2385 in the clinic and will have 4 mL of blood drawn for pharmacokinetic (PK) 
assessment before (pre-dose) and 6 hours after study drug administration.  At the Week 3, 5, 9, 13, and 17 week visits, patients will take their morning 
dose of PT2385 in the clinic.  The blood sample for PK assessment is to be obtained before study drug administration on these days.
13. Blood samples for analysis of pharmacodynamic effects of PT2385 (e.g., erythropoietin) will be obtained in conjunction with PK samples, before 
(pre-dose) and 6 hours after study drug administration at the Week 1 visit and only before study drug administration at the Weeks 3, 5, 9, 13 and 17
visits; patients should not take their dose of PT2385 until after this blood collection has occurred at these visits.  Two whole blood samples will be 
collected at the Week 1 visit only for sequencing of genes encoding proteins that may be involved in regulating PT2385 metabolism.
14. Tests (orchidometry, semen analysis, and measurement of testosterone, follicle stimulating hormone, luteinizing hormone, and inhibin B levels) are to 
be conducted at Screening, the Week 17 visit, and 13 weeks after last study drug administration for those male patients for whom a clinically significant 
effect on fertility was seen at Week 17.
15. Archival tumor tissue samples will be obtained whenever possible from all patients.  Additionally, fresh tissue sample will be obtained from consenting 
patients in whom tumor tissue is accessible (patients who undergo tumor excision during the study).
16. Long-term follow-up may be accomplished via an in person visit or telephone.  The patient will be questioned about the following since their last study 
visit or telephone contact:  medical history, surgical history, disease status, and survival status.
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Appendix 2
ECOG Performance Status
(Oken, 1982)
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 3
RECIST 1.1 Summary
Abstracted from Eisenhauer EA, et al. 2009
Time Point Response: Patients with Target (± Non-Target) Disease
Target lesions
Non-target lesions
New lesions
Overall response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = not 
evaluable
Time Point Response: Patients with Non-Target Disease Only
Non-target lesions
New lesions
Overall response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR = complete response, PD = progressive disease and NE = not evaluable
A ‘Non-CR/non-PD is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised.
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Appendix 4
Evaluation of Non-Renal VHL Related Disease
Wherever possible, non-renal lesions will be assessed using RECIST 1.1, modified to assess 
that type of lesion only.  Assessments of specific lesion types will be made as described 
below.

Pancreatic Lesions
CT/MRI of the pancreas will be obtained at baseline and follow-up and evaluated using 
RECIST 1.1.

Pheochromocytomas
Serum and urine catecholamine levels will be evaluated at baseline and follow-up visits.  

Adrenal Lesions
CT/MRI of the adrenal glands will be obtained at baseline and follow-up and evaluated 
using RECIST 1.1

CNS Hemangioblastomas
MRI of the brain and spine will be obtained at baseline and follow-up and evaluated 
using RECIST 1.1

Retinal Angiomas
Evaluation of these lesions at baseline and follow-up will include the following:
o
Fundoscopic examination with notation of the size and location of angiomas
o
Visual acuity and visual fields in patients with lesions close to the macula or affecting 
vision.

Inner Ear Endolymphatic Sac Tumors
CT/MRI of the head will be obtained at baseline and follow-up and evaluated using 
RECIST 1.1.

Epididymal Cystadenomas
The epidydimis will be assessed at baseline and follow-up using ultrasound.
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Appendix 5
New York Heart Association Functional Classification
New York Heart Association Criteria Committee, March 1994.
Class
Functional Capacity: How a patient with cardiac disease feels during physical 
activity
I
Patients with cardiac disease but resulting in no limitation of physical activity.  Ordinary 
physical activity does not cause undue fatigue, palpitation, dyspnea or anginal pain.
II
Patients with cardiac disease resulting in slight limitation of physical activity.  They are 
comfortable at rest.  Ordinary physical activity results in fatigue, palpitation, dyspnea or 
anginal pain.
III
Patients with cardiac disease resulting in marked limitation of physical activity.  They are 
comfortable at rest.  Less than ordinary activity causes fatigue, palpitation, dyspnea or 
anginal pain.
IV
Patients with cardiac disease resulting in inability to carry on any physical activity 
without discomfort.  Symptoms of heart failure or the anginal syndrome may be present 
even at rest.  If any physical activity is undertaken, discomfort increases.
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Appendix 6
Partial List of Strong CYP2C19 and CYP3A4 Inhibitors
CYP2C19 Inhibitors
CYP3A4 Inhibitors
esomeprazole
indinavir
lansoprazole
nelfinavir
omeprazole
ritonavir
pantoprazole
clarithromycin
cimetidine
itraconazole
fluoxetine
ketoconazole
nefazodone
saquinavir
suboxone
telithromycin
For a comprehensive list see: http://medicine.iupui.edu/clinpharm/ddis/main-table/
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Appendix 7
Partial List of Substrates of CYP3A4, CYP2B6, CYP2C9, and CYP2C19
CYP3A4 Substrates
CYP2B6 Substrates
CYP2C9 Substrates
CYP2C19 Substrates
clarithromycin
artemisinin
ibuprofen
esomeprazole
erythromycin
bupropion
naproxen
Lansoprazole
quinidine
efavirenz
tolbutamide
Omeprazole
alprazolam
ketamine
glipizide
Pantoprazole
diazepam
meperidine
losartan
Phenytoin
midazolam
methadone
irbesartan
Amitriptyline
cyclosporine
nevirapine
glyburide
Carisoprodol
indinavir
propofol
glipizide
Citalopram
nelfinavir 
selegiline
celecoxib
Clopidogrel
ritonavir
sorafenib
fluoxetine
cyclophosphamide
cisapride
rosiglitazone
Imipramine
chlorpheniramine
tamoxifen
Labetalol
terfenadine
valproic acid
Nilutamide
amlodipine
zafirlukast
Progesterone
diltiazem
Propranolol
nifedipine
Teniposide
atorvastatin
Voriconazole
lovastatin
simvastatin
estradiol
testosterone
carbamazepine
codeine
fentanyl
haloperidol
ondansetron
For a comprehensive list see: http://medicine.iupui.edu/clinpharm/ddis/main-table/
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