Clinical trial NCT03760666
Conditions: Acute Myeloid Leukemia
Keywords: DHODH Brequinar Differentiation IMPDH Inhibition
Sponsor: Clear Creek Bio, Inc.
Start date: 2018-12-20; Completion date: 2021-02-09
Enrollment: 17 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
A Phase 1b/2a multi-center, open-label, non-randomized study to assess the safety, tolerability and efficacy of dose-adjusted brequinar in adult subjects with acute myeloid leukemia (AML). Ribavirin BID may be added to brequinar twice weekly in eligible subjects.

Detailed description:
Up to 27 subjects will be entered in this Phase 1b/2a multi-center, open-label, non-randomized study to assess the safety, tolerability and efficacy of dose-adjusted brequinar in adult subjects with acute myeloid leukemia (AML). Active Cohort 2 subjects on brequinar alone twice weekly may roll over into brequinar twice weekly + ribavirin BID. Cohort 3 subjects will begin treatment with brequinar alone twice weekly then move to brequinar twice weekly + ribavirin BID as tolerated. Both the brequinar and ribavirin doses may be adjusted based on safety, tolerability, and enzyme inhibition levels.

Arms: arm 1: Brequinar and ribavirin were dosed orally; brequinar starting doses ranged from 200 mg/m2 to 500 mg/m2. Brequinar doses were adjusted by cohort for starting dose and regimen (either twice-weekly or once-weekly). In addition, the dose for each participant was also adjusted (either escalated or decreased) based on safety, brequinar PK and levels of dihydroorotate (DHO). Ribavirin 1000 mg twice a day (bid) was added in combination with brequinar for the final 3 study participants.
Interventions: intervention 1: Brequinar/Brequinar + Ribavirin
Intervention descriptions: intervention 1: The first 14 participants had brequinar monotherapy; the final 3 subjects were also exposed to a combination of brequinar + ribavirin.

Protocol documents:
SAP_002.pdf: 
CCB-01 
STUDY PROTOCOL 
A Phase 1b/2a open-label, multi-center study to assess the safety, 
efficacy and pharmacokinetics of intrapatient dose-adjusted 
brequinar and inhibition of dihydroorotate dehydrogenase 
(DHODH) in adult subjects with acute myelogenous leukemia 
(AML) 
 
NCT03760666 
 
Statistical Analysis Plan – 09/11/2019 
 




Document Number: FORM 694.01 
 
Effective Date:  13-Apr-2015 
DCN # 1372 
Document Title: Statistical Analysis Plan Template 
P a g e  | i 
Clear Creek Bio, Inc. 
Protocol #: CCB-01 
 
A Phase 1b/2a open-label, multi-center study to assess the safety, efficacy and 
pharmacokinetics of intrapatient dose-adjusted brequinar and inhibition of 
dihydroorotate dehydrogenase (DHODH) in adult subjects with acute myelogenous 
leukemia (AML)  
 
Statistical Analysis Plan 
 
 Version 1.0  
 
Document last saved: 18-Jan-2022 9:43 AM 
 
 
Prepared for: 
Clear Creek Bio, Inc. 
 585 Massachusetts Avenue, 4th Floor 
Cambridge, MA 02139 
 USA 
 
Prepared by: 
 
IQVIA Biotech 
 
1700 Perimeter Park Dr. 
 
Morrisville, NC  27560 
            USA 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clear Creek Bio, Inc. / Protocol: CCB-01 
IQVIA Biotech (Confidential) Project # YYA36071 
Document Number: FORM 694.01 
 
Effective Date:  13-Apr-2015 
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Document Title: Statistical Analysis Plan Template 
P a g e  | ii 
 
 
Statistical Analysis Plan Signatures 
 
 
 
Prepared by:  
Alka Ahuja, MS 
 
 
 
IQVIA Biotech 
 
 
 
1700 Perimeter Park Drive 
 
 
 
Morrisville, NC 27560 
 
 
 
USA 
 
 
 
Tel: +1 919-336-9323 
 
 
 
Fax: +1 919-484-7727 
 
 
 
alka.ahuja@iqvia.com 
 
 
 
 
Approved by: 
 
                           
                            
 __________________________________________    ____________ 
                                     Barbara Powers, MSN, PhD                                  
           Date 
                                     Clinical Development, Clear Creek Bio, Inc. 
 
 
 
 
__________________________________________    ___________                            
Alka Ahuja, MS 
                                                          Date 
                                    Biostatistician II, IQIVA Biotech 
 
                            
 
 
 
 


Clear Creek Bio, Inc. / Protocol: CCB-01 
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Document Number: FORM 694.01 
 
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Document Title: Statistical Analysis Plan Template 
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Table of Contents 
Statistical Analysis Plan Signatures .......................................................................................... ii 
Table of Contents ..................................................................................................................... iii 
List of Abbreviations ................................................................................................................ v 
I.Introduction ............................................................................................................................ 1 
II.Protocol Objectives ............................................................................................................... 1 
A. Primary .................................................................................................................... 1 
B. Secondary ................................................................................................................ 1 
C. Exploratory ............................................................................................................. 2 
III.Study Endpoints ................................................................................................................... 2 
A. Primary Endpoints .................................................................................................. 2 
B. Secondary Endpoints .............................................................................................. 3 
C. Exploratory Endpoints ............................................................................................ 3 
IV.Study Design ........................................................................................................................ 3 
A. Design Overview .................................................................................................... 3 
B. Study Population ..................................................................................................... 4 
C. Sample Size Predictions .......................................................................................... 4 
V.General Analytical Considerations ....................................................................................... 4 
A. Data Sources ........................................................................................................... 5 
B. Multiple Study Centers ........................................................................................... 5 
C. Definition of Baseline ............................................................................................. 5 
D. Missing Data ........................................................................................................... 5 
E. Analysis Populations ............................................................................................... 5 
F. Data Display Characteristics ................................................................................... 6 
VI.Subject Accountability......................................................................................................... 7 
A. Analysis Populations ............................................................................................... 7 
B. Disposition .............................................................................................................. 7 
C. Subject Characteristics ............................................................................................ 8 
D. Protocol Deviations ................................................................................................. 9 
VII.Safety Analyses .................................................................................................................. 9 
A. Exposure ................................................................................................................. 9 
B. DHO Plasma Levels .............................................................................................. 10 
C. Dose Limiting Toxicities ...................................................................................... 10 
D. Adverse Events ..................................................................................................... 10 
E. Deaths ................................................................................................................... 11 
F. Clinical Laboratory Results .................................................................................. 11 
G. Vital Signs ............................................................................................................. 12 
H. 12-Lead Electrocardiogram .................................................................................. 12 
I. ECOG Performance Status ................................................................................... 12 


Clear Creek Bio, Inc. / Protocol: CCB-01 
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J. Physical Examination............................................................................................ 12 
K. Concomitant Medications ..................................................................................... 12 
L. Blood Transfusions ............................................................................................... 13 
VIII.Efficacy Analyses ........................................................................................................... 13 
A. Disease Response .................................................................................................. 13 
B. Clinical Benefit ..................................................................................................... 14 
IX.Pharmacokinetic Analyses ................................................................................................. 14 
X.Exploratory Analyses .......................................................................................................... 15 
XI.Changes from Analyses Planned in Protocol..................................................................... 16 
XII.References ........................................................................................................................ 17 
 
 


Clear Creek Bio, Inc. / Protocol: CCB-01 
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List of Abbreviations 
 
 
Abbreviation 
Definition 
ANC 
Absolute neutrophil count 
AE 
Adverse event 
AML 
Acute myelogenous leukemia 
AUC0-last 
Area under curve from time 0 to time of last measurable 
concentration. 
AUC0-inf 
Area under curve from time 0 to infinity 
BOR 
Best overall response 
BSA 
Body surface area 
CI 
Confidence interval 
CL 
Systemic clearance 
Cmax 
Maximum observed plasma concentration 
CR 
Complete remission 
CRh 
CR with partial hematological recovery 
Cri 
CR with incomplete hematological recovery 
Css 
Observed concentration at steady state 
CTCAE 
Common terminology criteria for adverse events 
DHO 
Dihydroorotate 
DHODH 
Dihydroorotate dehydrogenase 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
DOR 
Duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EFS 
Event-free survival 
FISH 
Fluorescence in situ hybridization 
Hgb 
Hemoglobin 
mg 
Milligram 
m2 
Meters squared 
MedDRA 
Medical dictionary for regulatory affairs 
MLFS 
Morphologic leukemia-free state 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria 
for Adverse Events 
ORR 
Overall response rate 
OS 
Overall survival 
PK 
Pharmacokinetic(s) 
PR 
Partial remission 
PT 
Preferred term 
SAP 
Statistical analysis plan 
SI units 
International system of units 
SOC 
System organ class 
t1/2 
Elimination half-life 
Tmax 
Time to maximum plasma concentration 
TEAE 
Treatment-emergent adverse event 
TI 
Transfusion independence 
TLF 
Tables, listings, and figures 


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Document Number: FORM 694.01 
 
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Document Title: Statistical Analysis Plan Template 
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Vss 
Volume of distribution at steady state 
WHODD 
World health organization drug dictionary 
 
 
 
 
 
 
 


Clear Creek Bio, Inc. / Protocol: CCB-01 
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Document Title: Statistical Analysis Plan Template 
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I. 
Introduction 
 
This Statistical Analysis Plan (SAP) presents details of the analyses required to 
address the study aims of protocol CCB-01 version 6.0, dated 30 April 2019. The 
study is a phase 1b/2a open-label, multi-center trial with a purpose to evaluate the 
safety, efficacy, and pharmacokinetics (PK) of the drug oral brequinar in subjects 18 
years or older with relapsed/refractory acute myeloid leukemia (AML), as well as to 
determine the inhibitory level of brequinar in blocking the enzyme “dihydroorotate 
dehydrogenase” (DHODH).  
 
Safety and tolerability of brequinar will be assessed via adverse event (AE) 
monitoring, clinical laboratory safety tests, physical examinations, vital signs 
measurements, 12-lead electrocardiogram (ECG) readings, and bone marrow 
sampling. Specific efficacy endpoints of disease response, and PK profiles of 
brequinar and dihydroorotate (DHO) plasma levels will also be characterized.  
 
This SAP has been developed and approved prior to database lock and data analysis. 
All analyses will be conducted after clinical trial data are entered into the database, 
discrepancies resolved, and the database is authorized (closed to further changes). 
Any deviations from the SAP will be documented as such in the study report.  
 
Production and quality control of statistical analyses and accompanying tables, 
listings, and figures (TLFs) will be the responsibility of IQVIA Biotech located in 
Morrisville, North Carolina, United States.  
 
 
 
II. 
Protocol Objectives 
 
A. Primary 
 
The protocol lists the following primary objective:   
 
• To determine the safety and tolerability of brequinar and the DHODH 
inhibitory activity of brequinar in adult subjects with AML.  
 
B. Secondary 
 
The protocol lists the following secondary objectives: 
 
• To determine the overall response rate (ORR) including complete 
remission (CR), CR with incomplete hematologic recovery (CRi), 
morphologic leukemia-free state (MLFS), partial remission (PR) (criteria 
as defined in the ELN Guidelines, by Dohner et al., 2017) and complete 
remission with partial hematological recovery (CRh).   
 


Clear Creek Bio, Inc. / Protocol: CCB-01 
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Document Title: Statistical Analysis Plan Template 
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• To assess the rate of overall survival (OS) and event-free survival (EFS).   
• To evaluate duration of response (DOR).  
• To characterize the pharmacokinetic (PK) profile of brequinar.  
• To characterize the DHO plasma levels after oral dosing with brequinar.  
 
C. Exploratory 
 
The protocol lists the following exploratory objectives: 
 
• To assess the relationship between DHODH inhibition and the efficacy 
and safety of brequinar.   
• To evaluate molecular and cellular biomarkers that may be predictors of 
antitumor level and/or treatment resistance including cytogenetics, 
molecular profiling, and flow cytometry during and after treatment. 
• To evaluate global gene expression profiles, deoxyribonucleic acid 
(DNA)methylation profiles, and other potential prognostic markers to 
explore predictors of antitumor activity and/or resistance to treatment.    
 
 
 
III. 
Study Endpoints 
 
A. Primary Endpoints  
 
The study protocol defines primary endpoints as safety/tolerability and DHO 
level relationship with safety and therapeutic brequinar levels.  
 
Safety/tolerability, assessed at each study visit using the Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03, will be evaluated for each 
subject as follows: 
 
- Through Day 42, Grade 3 or higher, treatment-emergent, study drug-related, 
non-hematologic AE will be considered unacceptable toxicity with the following 
exceptions: 
 
Condition  
Exception Description  
Nausea/ Emesis  Grade 3 nausea and/or emesis resolving to less than or equal to Grade 2 
or baseline within 1 week after the use of an optimal antiemetic regimen 
based on standard practice. 
Diarrhea 
Grade 3 diarrhea resolving to less than or equal to Grade 1 or baseline 
within 1 week after receiving the maximal supportive therapy based on 
standard practice. 
Laboratory 
abnormalities 
Asymptomatic Grade 3 laboratory abnormalities that are not considered 
to be clinically significant. 
Mucositis 
Grade 3 with duration < 1 week. 
Fatigue 
Grade 3 with duration < 2 weeks. 
 


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- After 42 days of treatment, criteria for unacceptable safety will be expanded to 
include hematologic AEs defined as: 
 
 
• Prolonged neutropenia with ANC < 500 from start of therapy in the  
                   absence of disease.  
 
 
• > Grade 4 neutropenia. 
 
 
• And/or > Grade 4 thrombocytopenia with a hypocellular bone   
                   marrow and no greater than 5% marrow blasts lasting for > 2 weeks.  
 
- After 42 days of treatment, in expansion cohort subjects, the definition of 
unacceptable safety will include signs of hepatotoxicity (an episode of > Grade 2 
toxicity for ALT and AST).  
 
B. Secondary Endpoints 
 
The following secondary endpoints will be analyzed: 
 
•  ORR including CR, CRi, CRh, MLFS, or PR.  
•  Rates of OS and  EFS. 
•  Duration of response. 
•  PK profile of brequinar. 
•  DHO plasma profile.  
 
C. Exploratory Endpoints 
 
The following endpoints will be explored:  
 
• Relationship between DHODH inhibition and the efficacy and safety of  
   brequinar.  
• Antitumor level based on molecular and cellular biomarkers including  
   cytogenetics, molecular profiling, and flow cytometry during and after  
   treatment.  
• Global gene expression profiles, DNA methylation profiles, and other  
   potential prognostic markers to explore predictors of antitumor activity  
   and/or resistance to treatment.  
 
 
 
IV. 
Study Design 
 
A. Design Overview  
 
This will be a phase 1b/2a multi-center, open-label, non-randomized clinical trial 
to assess the safety, tolerability and efficacy of dose-adjusted brequinar in adult 
subjects with AML. The study will also assess the inhibition of DHODH and the 
PK profile of brequinar in plasma. Intra-subject dosing will be adjusted based on 
safety/tolerability, brequinar PK, and DHO levels.  


Clear Creek Bio, Inc. / Protocol: CCB-01 
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Document Title: Statistical Analysis Plan Template 
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Up to 27 subjects are planned to be entered in this trial. Cohort 1 was planned to 
have 6 subjects, but enrollment was stopped after 5 subjects when brequinar PK 
and DHO results became available. These results led to study design changes as 
described here. The sixth subject will not be enrolled in Cohort 1.  
 
Cohort 2 will enroll approximately 6 subjects, followed by an expansion cohort 
of approximately 15 subjects. All subjects in Cohort 2 will start with a 500 
mg/m2 dose once-weekly. Brequinar PK and DHO samples will be obtained for 
these subjects in Week 1 and results used to make decisions about the Week 2 
once-weekly dose. Brequinar PK and DHO samples will also be obtained for 
Week 2 and the results used to make decisions about Week 3 dose frequency 
(once or twice-weekly) and the dose. The dose will be adjusted for each subject 
to meet the twice-weekly brequinar PK and 72-hour DHO criteria, and the Week 
2 procedures may be repeated if needed until the twice-weekly dose is found.   
 
After both the brequinar PK and 72-hour DHO level meet criteria described in 
the Individual Dose Adjustment Guidelines as described in Protocol Section 8.5, 
a subject may move to twice-weekly dosing on a continuing basis as tolerated. 
The twice-weekly dose may be further adjusted using 84-hour DHO (trough ~ 84 
hours after dosing) criteria, also described in the Guidelines for Individual Dose 
Adjustment.  
 
Dosing will continue up to 12 months in the absence of unacceptable toxicity or 
disease progression, or may be discontinued with Sponsor consent after 
completing at least 6 weeks of dosing.  
 
B. Study Population 
 
Up to 27 subjects 18 years or older with relapsed/refractory AML by World 
Health Organization (WHO) classification who have exhausted available therapy 
and who meet all inclusion/exclusion criteria will be enrolled at 3- 6 sites in the 
United States.    
 
C. Sample Size Predictions 
 
Formal sample size calculations are not applicable to this phase 1b/2a dose-
adjustment and expansion study.   
 
 
 
V. 
General Analytical Considerations 
 
All analyses of safety and anti-leukemic activity for this open-label, early-phase study 
will be descriptive in nature and presented by dose group and overall, as appropriate, 
for dose-adjustment and expansion phases.  
 


Clear Creek Bio, Inc. / Protocol: CCB-01 
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Statistical code and outputs for analyses will be generated using SAS/STAT and  
            SAS/GRAPH software, version 9.3 or higher, of the SAS system for Windows.  
            Copyright © [2011] SAS Institute Inc. SAS and all other SAS Institute Inc. product  
            or service names are registered trademarks or trademarks of SAS Institute Inc., Cary,  
            NC, USA. 
 
A. Data Sources 
 
The study center staff will record completion and results of required study 
procedures in an electronic case report form (eCRF). The following external data 
obtained from third-party vendors for this study will be combined with eCRF 
data for analysis: 
 
Vendor 
Name 
Contact 
Information 
 
Data Type 
 
Schedule 
 
Reconciliation Items 
Pyxant 
TBD 
DHO 
plasma 
levels and 
brequinar 
PK results 
2 transfers during 
study 
Header data (subject 
ID, initials, visit, lab 
date, lab time) 
 
B. Multiple Study Centers 
 
Data analyses will be pooled and not controlled for center effect.     
 
C. Definition of Baseline 
 
Baseline will be defined as the last measurement collected before the first dose of 
study drug. As such, height and body surface area assessed at Screening, and pre-
dose assessments made on Cycle 1 Week 1 Day 1 for weight, vital signs, 
hematology/chemistry, and 12-lead ECG will serve as valid baseline measures. A 
missing value at Cycle 1 Week 1 Day 1 will default to the Screening 
measurement.  
 
For this study, since there is no day 0, the day immediately prior to study day 1 
will be Day -1 [calculated as Event Date – Date of First Treatment]. For events 
on or after first dose of study drug, study day will be calculated as [Event Date – 
Date of First Treatment + 1]. Thus, first day of study drug dose will be Day 1.  
 
D. Missing Data 
 
Unless stated otherwise in sections below, missing data will not be replaced with 
imputed values.   
   
E. Analysis Populations  
 
Four analysis population sets will be defined for use with various analyses, 
namely:   


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Document Title: Statistical Analysis Plan Template 
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• The Enrolled Analysis Set will include all subjects who sign informed 
consent, meet the inclusion/exclusion criteria and are enrolled in the study. 
Demographics and disposition summaries will be reported for this set of 
subjects.  
 
• The Safety Analysis Set will include all subjects who are enrolled in the 
study and receive at least one dose of brequinar. Subjects in this set will be 
used for all safety/tolerability summary tables.  
 
• The Efficacy Analysis Set will be a subset of the Safety population with 
measurable AML disease at baseline and at least one post-baseline disease 
response assessment. Subjects in this set will be used for all efficacy 
summary tables.  
 
• Pharmacokinetic Analysis Set will be a subset of the Safety population 
with at least 1 quantifiable plasma concentration collected post-dose 
without important protocol deviations/violations or events thought to 
significantly affect the PK. Summary tables for PK concentrations and 
parameters will be based on this set of subjects.  
 
F. Data Display Characteristics 
 
Data displays produced for this study will include three types—data listings, 
summary tables, and figures.   
 
Unless stated otherwise, data listings will be produced for all recorded data.  
Data listings will simply list the data recorded on the CRF or derived for each 
subject. They will be ordered by treatment, subject number, and date and time of 
assessment, where applicable.  When expedient, additional levels of ordering 
hierarchy may reflect subsets of assessments within subject. Additional listings 
may be produced for outcome measures that involve extensive procedure to 
derive analyzed outcomes.  
 
Summary tables will display summary statistics calculated for each of the 
treatment groups, and overall.  When the evolution of statistics over time is of 
interest, a group of rows that represent a cohort would generally be ordered 
chronologically.  
 
The summary statistics displayed will be a function of the type of data associated 
with the summarized assessment.  Continuous data will be summarized with the 
number of nonmissing values, mean, standard deviation (SD), minimum, median, 
and maximum.  Categorical data will be summarized with the number of 
nonmissing values. Corresponding percentages will be calculated using the 
relevant analysis population set as the denominator, unless stated otherwise.  
Some continuous variables may also be grouped into categorical levels and 
evaluated in frequency tables. 


Clear Creek Bio, Inc. / Protocol: CCB-01 
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Document Title: Statistical Analysis Plan Template 
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PK concentrations and parameters will be summarized using n (for available 
data), mean, SD, coefficient of variation percent (CV%), median, minimum, and 
maximum values. Geometric means and geometric CV% will also be calculated 
for PK parameters.  
 
All PK concentrations will be reported and analyzed with the same precision as 
the source data provided by the bio-analytical laboratory regardless of how many 
significant figures or decimals the data carry.  
 
Extra measurements (such as unscheduled or repeat assessments) will be 
included in subject listings but not in summary tables.  
 
Figures will be produced as specified in sections to follow. 
 
 
 
VI. 
Subject Accountability 
 
A. Analysis Populations 
 
       A summary table will present counts and percent of subjects in the study analysis    
       populations of Enrolled, Safety, Efficacy, and PK Analysis sets by treatment  
       group.  
 
B. Disposition 
 
All subjects who discontinue treatment or withdraw early from the study will be 
included in a listing. Disposition summaries will present number of subjects 
enrolled, number treated, and among those treated number who completed and 
discontinued treatment. Primary reason for discontinuation of treatment, 
including any of the following, will be summarized: 
- 
Adverse event 
- 
Physician/Sponsor decision 
- 
Pregnancy 
- 
Protocol defined disease progression 
- 
Study terminated by sponsor 
- 
Subject non-compliance/Protocol violation(s) 
- 
Withdrawal of consent.   
 
Counts and percentages of subjects who withdraw early from the study for any of 
the above reasons will also be calculated using all members of the relevant 
population in the relevant treatment group for the denominator. 
 
 
 


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Document Title: Statistical Analysis Plan Template 
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C. Subject Characteristics 
 
The following subject characteristics collected for the Enrolled Analysis Set will 
be presented in data listings and summarized by treatment regimen and overall: 
 
Demography:  
• Age:  Age will be calculated as the number of years elapsed between birth 
date and the date of the screening visit, adjusted for whether the birthday 
has passed as of the day of the screening visit.  
• Sex at birth 
• Ethnicity 
• Race 
 
Medical History:   
• Medical history: As noted on the Medical History eCRF, any significant 
medical conditions present prior to signing consent will be presented in a 
listing and summary table. Verbatim terms will be coded using the 
MedDRA version 21.1 and ordered by system organ class (SOC) and 
preferred term (PT). At each level of summation (SOC, PT), subjects 
reporting more than one medical condition will be counted only once.  
• AML disease information: Disease characteristics of initial diagnosis of 
AML recorded on the eCRF, along with time since initial diagnosis 
(calculated as date of informed consent – date of initial diagnosis of 
AML/365.25), will be listed and summarized.  
• AML supplemental tests: Cytogenetics and molecular data information 
recorded on the eCRF will be listed, including information on karyotypic, 
Fluorescence in situ hybridization (FISH), and gene fusion analysis, as 
well as all present mutations.  
• Prior cancer drug treatment: A listing will display all entries for prior 
cancer medications received by a subject, ordered by “Start date”. A 
summary table will summarize the following characteristics: 
- 
Number of subjects reporting at least one prior cancer drug 
treatment. 
- 
Drug treatment type (Chemotherapy, Targeted therapy, 
Immunological, Not Applicable) .  
- 
Drug treatment combined with radiotherapy (No/Yes). 
- 
Number of cycles received. 
- 
Best response under treatment (Complete remission, Complete 
remission with incomplete hematologic recovery, Complete 
remission with partial hematologic recovery, Morphologic 


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leukemia-free state, Partial remission, Stable disease, Progressive 
disease, Unknown). 
- 
Relapse (derived as ‘Yes’ if date of relapse is not blank. ‘No’ 
otherwise).  
• Prior cancer non-drug treatment: All non-drug treatments received will be 
listed in order of “Start date”. Summary statistics will be provided for: 
- 
Number of subjects reporting at least one prior cancer non-drug 
treatment. 
- 
Treatment type ( Radiation, Surgery, Other). 
- 
Intention (Palliative, Therapeutic). 
- 
Best response under treatment (Complete remission, Complete 
remission with incomplete hematologic recovery, Complete 
remission with partial hematologic recovery, Morphologic 
leukemia-free state, Partial remission, Stable disease, Progressive 
disease, Not applicable, Unknown). 
- 
Relapse (derived as ‘Yes’ if date of relapse is not blank. ‘No’ 
otherwise).  
 
D. Protocol Deviations 
 
A listing will be provided for all protocol deviations.  
 
 
 
VII. Safety Analyses  
 
To meet the primary objective of the study, all safety analyses will be performed on 
the Safety Analysis Set of subjects.   
 
A. Exposure 
 
For each subject, the assigned dose level of brequinar (mg/m2), the assigned dose 
(mg), dose day, date and time taken, whether entire dose was taken, number of 
capsules taken, total dose taken (mg), and the reason for missed dose (partial or 
complete) will be listed by treatment group and visit cycle.  
 
Summary statistics will be presented for  assigned dose level, cumulative 
assigned dose,  cumulative actual exposure (mg), total duration of treatment 
(calculated as the number of weeks from date of first drug dose to date of last 
drug dose), dose intensity (calculated as cumulative actual exposure divided by 
treatment duration, mg/week), relative dose intensity (calculated as a percent of 
cumulative actual drug dose divided by cumulative assigned dose), and any 
reason for missed dose.  


Clear Creek Bio, Inc. / Protocol: CCB-01 
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Document Title: Statistical Analysis Plan Template 
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B. DHO Plasma Levels 
 
In addition to safety/tolerability, intra-subject dosing for this study will be guided 
by DHO levels measured using a validated assay. A subject listing will include 
baseline and trough DHO levels (ng/ml), as well as the following additional 
characteristics noted at each scheduled visit: 
- 
Previous assigned dose (mg/m2). 
- 
DHO dose adjustment (dose not changed, escalated by 150 mg/m2, 
held, Cohort 1 dose escalation not permitted). 
- 
Assigned dose based on DHO (mg/m2). 
- 
PI evaluation of whether subject has acceptable safety, safety dose 
adjustment, and assigned dose.  
- 
Actual dose (mg). 
- 
Agreement between PI assessment and actual dose (No/Yes, 
reason for disagreement).  
 
       The above dose-modification characteristics will also be summarized by  
       treatment group and overall.  
  
C. Dose Limiting Toxicities 
 
AEs identified as protocol-defined DLTs will be listed and will include start and 
end dates, CTCAE grade, relationship to study drug, outcome, and action taken. 
Number and percentage of subjects reporting DLTs in each treatment group, and 
overall, will be summarized.  
 
D. Adverse Events 
 
       AEs will be collected from time of informed consent through at least 14 days    
       after the final dose of study medication. Any pre-existing condition that changes  
       in severity after dosing or abnormal laboratory finding will be recorded as an  
AE. Events that occur prior to dosing will be recorded as medical history. A 
TEAE for this study will be defined as an AE occurring after the first dose of the 
study treatment through 30 days after the last dose of study treatment.  
 
Verbatim terms on the eCRF will be coded using the MedDRA version 21.1 and 
displayed hierarchically by system organ class and preferred term. Multiple 
incidences of the same AE for a subject will be counted only once at the 
maximum CTCAE grade.  
 
All AEs (whether TEAEs or not) will be listed by treatment group and individual 
subject, and include start and end dates, if the event was serious, seriousness 
criteria, CTCAE grade, relationship to study drug, action taken with study drug, 
and any other action. All TEAEs, Serious TEAEs,  TEAEs that lead to study drug 
being permanently discontinued, and TEAEs resulting in death will be listed 
separately.  


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Document Title: Statistical Analysis Plan Template 
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All AEs (whether TEAEs or not) will be summarized by system organ class and 
preferred term for each treatment group.  
 
An overall summary table for TEAEs, and TEAEs occurring 10% or higher in the 
study population by preferred term and CTCAE grade will be provided. All 
TEAEs, grade 3 or greater TEAEs, TEAEs related to study drug (i.e., relationship 
to study drug deemed by the principal investigator as “Definite”, “Probable”, or 
“Possible”), grade 3 or greater TEAEs related to study drug, serious TEAEs,  
TEAEs leading to study drug being permanently discontinued, and TEAEs 
resulting in death will each be summarized by system organ class and preferred 
term. At each level of summation of system organ class and preferred term, 
subjects reporting more than one AE will only be counted once.  
 
E. Deaths 
 
       All deaths and the primary cause of death will be listed.  
 
F. Clinical Laboratory Results 
 
Clinical laboratory tests for safety will be performed according to the study 
schedule, samples analyzed at local laboratories, and data entered directly into 
the electronic data capture system by site users.  
 
Results for hematology and chemistry panels will be presented in separate data 
listings along with a flag for normal, abnormal not clinically significant, or 
abnormal clinically significant values. Listings will also be provided for 
pregnancy test, flow cytometry, and chromosomal/mutation testing.  
 
Beginning with the baseline results, summaries of actual values at each 
assessment time point, and change from baseline will be presented by dose level 
and overall for each hematology and chemistry parameter. Change from baseline 
will be calculated as the post-baseline measurement minus the baseline 
measurement. If either the baseline or post-baseline value is missing, the 
observation will not be included in the change from baseline summary.  
 
For hematology parameters leukocytes, hemoglobin, and platelets that can be 
graded using the NCI CTCAE criteria, shift tables that summarize counts and 
percentages of subjects by severity grade at baseline and worst post-baseline 
result will also be constructed.  
 
The percentage of blasts in bone marrow ascertained via aspiration and biopsy 
will be listed and summarized.  
 
 
 


Clear Creek Bio, Inc. / Protocol: CCB-01 
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Document Title: Statistical Analysis Plan Template 
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G. Vital Signs 
 
At designated visits, vital signs will be recorded and will include weight, 
temperature, heart rate, respiratory rate, and systolic and diastolic blood pressure. 
A listing of all vital signs, along with height and derived body surface area, will 
be provided. Additionally, data will be summarized by dose group and overall, 
using descriptive statistics at baseline, each study evaluation, and change from 
baseline to evaluation. Change from baseline will be calculated as the post-
baseline measurement minus the baseline measurement. If either value is 
missing, the observation will not be included in the change from baseline 
summary.  
 
H. 12-Lead Electrocardiogram 
 
12-lead ECG data, obtained at scheduled visits, will be listed. Counts and 
percentages of subjects with normal, abnormal clinically significant, and 
abnormal not clinically significant evaluations will be summarized at each time 
point.  
  
I. 
ECOG Performance Status 
 
ECOG performance status assessed at Screening will be listed and summarized 
for each numeric grade.  
 
J.  Physical Examination  
 
Confirmation of a physical examination, including date of assessment, will be 
listed for each scheduled time point.  
 
K. Concomitant Medications  
 
Any medication or treatment taken within two weeks prior to study entry as well 
as during the course of the study will be recorded in the eCRF. Indication for use, 
start date (if known), dose frequency, route, and whether ongoing or stopped will 
also be noted.  
 
Verbatim terms from the eCRF will be mapped to Anatomical/Therapeutic 
Chemical class and Generic drug names using the WHODD version September 
2018 Enhanced B2.  
 
For each dose cohort, a listing will display all entries for medications received by 
a subject, ordered by “Start date”. The listing will display the recorded term from 
the eCRF and, adjacent to that, the WHO Drug pharmacological subgroup and 
the anatomical main class that appears in the tables.  
 


Clear Creek Bio, Inc. / Protocol: CCB-01 
IQVIA Biotech (Confidential) Project # YYA36071 
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Document Title: Statistical Analysis Plan Template 
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A summary table will be constructed to display the anatomical main class (1st 
level) of each coded medication and, within that, the pharmacological subgroup 
(3rd level). It will include counts and percentages of subjects who reported using 
at least one medication in each pharmacological subgroup.  
 
L. Blood Transfusions  
 
Any blood transfusions received up to eight weeks prior to Cycle 1 Day 1 
(baseline event), and during the study, including start and end dates, blood 
product, total number of units received, and reason for transfusion will be listed 
and summarized.  
 
 
VIII. Efficacy Analyses 
 
The secondary objectives of the study will be addressed using the Efficacy Analysis 
Set of subjects.  
 
A. Disease Response  
 
As per criteria defined in the ELN Guidelines by Dohner et al, 2017, disease response 
will be assessed at screening and post-screening visits and included in a data listing.  
Additionally, anti-leukemic activity will be evaluated as per the following outcomes: 
 
Response Rates: The distribution of best overall response (BOR) of CR, CRi, CRh, 
MLFS, or PR will be summarized by treatment cohort and overall. Point estimates 
with two-sided exact 95%  and 90% confidence intervals (CIs) will be included for: 
- 
Overall response rate (ORR) defined as the proportion of subjects 
who achieve a best overall response of CR, CRi, CRh, MLFS, or 
PR. 
- 
Complete remission rate defined as the proportion of subjects who 
achieve a best overall response of CR.  
- 
Complete remission with incomplete hematologic recovery rate 
defined as the proportion of subjects who achieve a best overall 
response of CRi. 
- 
Complete remission with partial hematological recovery rate 
defined as the proportion subjects who achieve a best overall 
response of CRh. 
- 
Morphological leukemia-free state rate defined as the proportion of 
subjects who achieve a best overall response of MLFS. 
- 
Partial remission rate defined as the proportion of subjects who 
achieve best overall response of PR.  
 
Additional information on precise definitions of these response categories can be 
found in Section 10.3 of the protocol. 
 


Clear Creek Bio, Inc. / Protocol: CCB-01 
IQVIA Biotech (Confidential) Project # YYA36071 
Document Number: FORM 694.01 
 
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Document Title: Statistical Analysis Plan Template 
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Duration of Response: Duration of response will be defined as the time from the first 
occurrence of a qualifying response of CR, CRi, CRh, MLFS, or PR, to the date when 
progressive disease is objectively documented or death due to any cause, whichever 
occurs earlier. Following the qualifying response, subjects who are alive without 
disease progression will be right-censored at the date of last disease evaluation. A 
Kaplan-Meier graph will be plotted by treatment group and estimates of median 
duration with associated 95% CIs will be reported.  
 
Event-free Survival (EFS): Event-free survival will be determined from the first dose 
of brequinar to the date of relapse (> 5% bone marrow blasts, reappearance of blasts 
in blood, or development of extramedullary disease), disease progression, or death, 
whichever occurs first. Subjects who do not experience any of the three events will be 
right-censored at the latter date of disease evaluation or bone marrow sampling. A 
Kaplan-Meier graph will be plotted for time to the composite outcome by treatment 
group, and the estimate of medial survival time with 95% CI will be summarized.  
 
Overall Survival (OS): Overall survival will be calculated as the time from the first 
dose of study drug to the date of death or right-censoring at the date of last subject 
contact. Median time to OS, with 95% CI, will be summarized and displayed 
graphically by treatment group using the Kaplan-Meier method.  
 
B. Clinical Benefit 
 
In addition to ORR, this study will examine clinical benefit to subjects. By treatment 
group, a summary table will report counts and percent of transfusion-dependent  
subjects at baseline who, in the absence of progression, CR or PR, and independent of 
marrow response, achieve one of the following: 
- 
Erythroid response: Transfusion Independence (TI) for 8 or more 
weeks for subjects requiring at least 4 units of packed red blood 
cell transfusions in the previous 8 weeks. Only red blood cell 
transfusions given based on physician’s judgment for a 
pretreatment hemoglobin (Hgb) of < 8.5 g/dL will count in the red 
blood cell TI response evaluation.  
- 
Platelet response: TI for subjects requiring   a minimum of 4 
platelet transfusions in the previous 8 weeks.  
 
 
 
IX. 
Pharmacokinetic Analyses 
 
The plasma PK of brequinar and DHO will be characterized using non-
compartmental analysis.  Where possible, the following standard PK parameters will 
be calculated:   
• AUC0-last: Area under plasma concentration-time curve from time 0 to time 
of last measurable concentration. 


Clear Creek Bio, Inc. / Protocol: CCB-01 
IQVIA Biotech (Confidential) Project # YYA36071 
Document Number: FORM 694.01 
 
Effective Date:  13-Apr-2015 
DCN # 1372 
Document Title: Statistical Analysis Plan Template 
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• AUC0-inf: Area under plasma concentration-time curve from 0 to infinity. 
• Cmax: Maximum observed plasma concentration.  
• Css: Observed plasma concentration at steady-state. 
• CL: Systemic clearance.  
• Tmax: Time to maximum plasma concentration. 
• T1/2: Elimination half-life 
• Vss: Volume of distribution at steady state.  
 
Listings of PK concentration and parameters will be generated using the 
Pharmacokinetic Analysis Set of subjects. Concentration and PK parameters will 
also be tabulated and summarized by treatment group at baseline and scheduled 
time points using descriptive statistics.  
 
A listing of derived time interval between Brequinar dosing and pre-dose PK 
sampling will be provided.  
 
Mean concentration-time profiles by treatment group, as well as by-subject plots 
for observed concentrations of brequinar and DHO levels will be presented on 
linear and semi-logarithmic scales.  
 
Relationship between PK parameters, DHO levels, and clinical outcomes (e.g. 
efficacy, toxicity) may be explored.   
 
 
 
X. 
Exploratory Analyses 
 
This study will endeavor to explore the following aims: 
  
Relationship between DHODH inhibition and the efficacy and safety of brequinar:  
 
Identify molecular and cellular biomarkers predictive of antitumor level and/or 
treatment resistance including cytogenetics, molecular profiling and flow cytometry 
during and after treatment: 
 
Evaluate global gene expression profiles, DNA methylation profiles, and other 
potential prognostic markers as predictors of antitumor activity and/or resistance to 
treatment. 
 
 
 
 


Clear Creek Bio, Inc. / Protocol: CCB-01 
IQVIA Biotech (Confidential) Project # YYA36071 
Document Number: FORM 694.01 
 
Effective Date:  13-Apr-2015 
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Document Title: Statistical Analysis Plan Template 
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XI. 
Changes from Analyses Planned in Protocol 
 
There are no significant changes to the analyses planned in the study protocol. 
 
 
  


Clear Creek Bio, Inc. / Protocol: CCB-01 
IQVIA Biotech (Confidential) Project # YYA36071 
Document Number: FORM 694.01 
 
Effective Date:  13-Apr-2015 
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Document Title: Statistical Analysis Plan Template 
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XII. References 
 
1. CCB-01 Protocol_ver_5_16OCT2018-FINAL.pdf  
 
2. CCB-01 Protocol_ver6_30APR2019 FINAL_signed 15MAY2019.pdf 
 
3. Dohner H, Estey E, Grimwade D, Amadori S, Applebaum FR, Buchner T, et al.  
    Diagnosis and management of AML in adults: 2017 ELN recommendations from   
    an international expert panel. Blood 2017; 129(4); 424-447. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Prot_000.pdf: 
CCB-01 
STUDY PROTOCOL 
A Phase 1b/2a open-label, multi-center study to assess the safety, 
efficacy and pharmacokinetics of intrapatient dose-adjusted 
brequinar and inhibition of dihydroorotate dehydrogenase 
(DHODH) in adult subjects with acute myelogenous leukemia 
(AML) 
 
NCT03760666 
 
Original Protocol Date: 06/04/2018 V02 
Amendment 01 Date: 10/04/2018 V03 
Amendment 02 Date: 10/11/2018 V04 
Amendment 03 Date: 10/15/2018 V05 
Amendment 04 Date: 04/30/2019 V06 
Amendment 05 Date: 01/31/2020 V07 
Amendment 06 Date: 03/09/2020 V08 
 
 


Table of Contents
CCB-01 Protocol v2.0 dated 04Jun2018.......................................................................................
Approval and Revision History.........................................................................................
STUDY PROTOCOL TITLE PAGE................................................................................
TABLE OF CONTENTS..................................................................................................
LIST OF TABLES ............................................................................................................
Table 1. Exceptions to Grade 3 Nonhematologic AEs..........................................
Table 2 Intra-Subject Dose Adjustment................................................................
Table 3 Analysis Sets............................................................................................
Table 4 Efficacy Analyses.....................................................................................
LIST OF FIGURES...........................................................................................................
Figure 1 Dose Adjustment - Subject Level.......................................................................
Figure 2 Monitoring of Tumor Lysis Syndrome...............................................................
ABBREVIATIONS...........................................................................................................
1 SYNOPSIS.....................................................................................................................
STUDY PERSONNEL .....................................................................................................
2 INTRODUCTION..........................................................................................................
2.1 Background: Acute Myeloid Leukemia..........................................................
2.2 Dihydroorotate dehydrogenase (DHODH) ...................................................
2.3 Brequinar.........................................................................................................
2.4 Rationale for the Planned Trial .......................................................................
2.4.1 Brequinar Starting Dose Selection...................................................
2.5 Risk/Benefit of Brequinar ...............................................................................
2.6 Risks Associated with Participation in the Clinical Study..............................
2.7 Possible Interactions with Concomitant Medical Treatments.........................
2.7.1 CYP Interactions ..............................................................................
2.8 Steps to be Taken to Control or Mitigate Risks ..............................................
3 TRIAL OBJECTIVES....................................................................................................
3.1 Primary Objective ...........................................................................................
3.2 Secondary Objectives......................................................................................
3.3 Exploratory Objectives....................................................................................
4 TRIAL DESIGN ............................................................................................................
5 TRIAL ENDPOINTS.....................................................................................................
5.1 Primary Endpoint ............................................................................................
5.2 Secondary Endpoints.......................................................................................
5.3 Exploratory Endpoints.....................................................................................
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6 TRIAL POPULATION..................................................................................................
6.1 Number of Subjects.........................................................................................
6.2 Inclusion criteria..............................................................................................
6.3 Exclusion Criteria............................................................................................
6.4 Inclusion of Women and Minorities................................................................
7 STUDY TREATMENTS...............................................................................................
7.1 Description of Brequinar:................................................................................
7.2 Treatment Administration ...............................................................................
7.3 Safety/Tolerability...........................................................................................
7.3.1 Safety/Tolerability – Subject Level..................................................
7.3.1.1 Hematologic Toxicity........................................................
7.3.2 Safety/Tolerability – Cohort Level ..................................................
7.4 Cohort Starting Doses .....................................................................................
7.5 Individual Dose Adjustment Guidelines .........................................................
7.6 Medication/AE Diary......................................................................................
7.7 Bone Marrow Biopsy ......................................................................................
7.8 Flow Cytometry ..............................................................................................
7.9 Expansion Cohort............................................................................................
7.10 Study Drug Discontinuation..........................................................................
7.11 Brequinar Pharmacokinetics (PK) / Dihydroorotate (DHO) Plasma
Levels ....................................................................................................................
7.12 Concomitant Medication/Treatment .............................................................
7.12.1 Gastric pH ......................................................................................
7.13 Treatment Compliance..................................................................................
7.14 Storage, Stability, Labeling and Packaging ..................................................
7.14.1 Storage and Stability ......................................................................
7.14.2 Labeling and Packaging .................................................................
7.14.3 Blinding and Randomization..........................................................
7.14.4 Unblinding/Expectedness...............................................................
7.14.5 Study Drug Accountability.............................................................
8 CONDUCT OF THE TRIAL.........................................................................................
8.1 Ethical and Regulatory Considerations...........................................................
8.2 Informed Consent............................................................................................
8.3 Institutional Review Board / Ethics Committees............................................
8.4 Schedule of Events..........................................................................................
8.5 Screening Visit (Study Days -14 to -1) .........................................................
8.6 Compliance with Study Procedures ................................................................
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8.7 Early Withdrawal from the Study ...................................................................
8.8 Early Termination of the Study.......................................................................
8.9 Short Messaging Service (SMS) Medication Reminders .............................
9 ADVERSE EVENT REPORTING................................................................................
9.1 Classification of Causality ..............................................................................
9.2 Classification of Severity ................................................................................
9.3 Serious Adverse Event (SAE) Reporting ......................................................
9.4 Suspected Unexpected Serious Adverse Reactions (SUSARs) ....................
9.5 Pregnancies......................................................................................................
9.6 Hematologic Adverse Events..........................................................................
9.7 Management of Myelosuppression .................................................................
9.8 Differentiation Syndrome................................................................................
9.9 Tumor Lysis Syndrome (TLS) ......................................................................
9.10 Infection Prophylaxis ....................................................................................
9.11 Growth Factor Support..................................................................................
9.12 Management of Nausea, Vomiting, and Diarrhea.........................................
10 STATISTICAL CONSIDERATIONS.........................................................................
10.1 Study Populations for Analysis.....................................................................
10.2 Safety Analyses.............................................................................................
10.3 Efficacy Analyses..........................................................................................
10.4 Other Endpoints.............................................................................................
10.5 Sample Size Considerations..........................................................................
10.6 Randomization ..............................................................................................
10.7 Pooling of Study Centers ..............................................................................
10.8 Interim Analysis............................................................................................
11 INVESTIGATOR RESPONSIBILITIES ....................................................................
11.1 Investigator's Performance............................................................................
11.2 Confidentiality...............................................................................................
11.3 Source Documentation..................................................................................
11.4 Data Collection..............................................................................................
11.5 Case Report Forms, Investigator's Site File and Record Retention ..............
11.6 Non-Protocol Research .................................................................................
11.7 Publication.....................................................................................................
12 SPONSOR RESPONSIBILITIES................................................................................
12.1 General ..........................................................................................................
12.2  Indemnity .....................................................................................................
12.3  Data Monitoring...........................................................................................
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12.4  Audit.............................................................................................................
12.5  Confidentiality..............................................................................................
12.6  Finance .........................................................................................................
13 REFERENCES.............................................................................................................
14 APPENDICES..............................................................................................................
14.1 APPENDIX A:  CCB-01 Schedule of Events...............................................
14.2 APPENDIX B: ECOG Performance Status Criteria.....................................
14.3  APPENDIX C: Brequinar/DHO Plasma Sampling......................................
14.4  APPENDIX D: Common Terminology Criteria for Adverse Events
(CTCAE) .............................................................................................................
14.5   APPENDIX E:  Sample Subject Consent Form..........................................
CCB-01 Protocol v3.0 dated 04Oct2018.......................................................................................
Approvals and Revision History .......................................................................................
STUDY PROTOCOL TITLE PAGE................................................................................
TABLE OF CONTENTS..................................................................................................
LIST OF TABLES ............................................................................................................
Table 1. Exceptions to Grade 3 Nonhematologic AEs..........................................
Table 2. Intra-Subject Dose Adjustment...............................................................
Table 3. Analysis Sets...........................................................................................
Table 4. Efficacy Analyses....................................................................................
LIST OF FIGURES...........................................................................................................
Figure 1. Dose Adjustment – Subject Level .........................................................
Figure 2. Monitoring of Tumor Lysis Syndrome..................................................
ABBREVIATIONS...........................................................................................................
1 SYNOPSIS.....................................................................................................................
STUDY PERSONNEL .....................................................................................................
2 INTRODUCTION..........................................................................................................
2.1 Background: Acute Myeloid Leukemia..........................................................
2.2 Dihydroorotate dehydrogenase (DHODH) ...................................................
2.3 Brequinar.........................................................................................................
2.4 Rationale for the Planned Trial .......................................................................
2.4.1 Brequinar Starting Dose Selection...................................................
2.5 Risk/Benefit of Brequinar ...............................................................................
2.6 Risks Associated with Participation in the Clinical Study..............................
2.7 Possible Interactions with Concomitant Medical Treatments.........................
2.7.1 CYP Interactions ..............................................................................
2.8 Steps to be Taken to Control or Mitigate Risks ..............................................
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3 TRIAL OBJECTIVES....................................................................................................
3.1 Primary Objective ...........................................................................................
3.2 Secondary Objectives......................................................................................
3.3 Exploratory Objectives....................................................................................
4 TRIAL DESIGN ............................................................................................................
5 TRIAL ENDPOINTS.....................................................................................................
5.1 Primary Endpoint ............................................................................................
5.2 Secondary Endpoints.......................................................................................
5.3 Exploratory Endpoints.....................................................................................
6 TRIAL POPULATION..................................................................................................
6.1 Number of Subjects.........................................................................................
6.2 Inclusion criteria..............................................................................................
6.3 Exclusion Criteria............................................................................................
6.4 Inclusion of Women and Minorities................................................................
7 STUDY TREATMENTS...............................................................................................
7.1 Description of Brequinar:................................................................................
7.2 Treatment Administration ...............................................................................
7.3 Safety/Tolerability...........................................................................................
7.3.1 Safety/Tolerability – Subject Level..................................................
7.3.1.1 Hematologic Toxicity........................................................
7.3.2 Safety/Tolerability – Cohort Level ..................................................
7.3.3 Safety/Tolerability – Expansion Cohort...........................................
7.4 Cohort Starting Doses .....................................................................................
7.5 Individual Dose Adjustment Guidelines .........................................................
7.5.1 DHO Threshold................................................................................
7.6 Medication/AE Diary......................................................................................
7.7 Bone Marrow Biopsy ......................................................................................
7.8 Flow Cytometry ..............................................................................................
7.9 Expansion Cohort............................................................................................
7.10 Study Drug Discontinuation..........................................................................
7.11 Brequinar Pharmacokinetics (PK) / Dihydroorotate (DHO) Plasma
Levels ....................................................................................................................
7.12 Concomitant Medication/Treatment .............................................................
7.12.1 Gastric pH ......................................................................................
7.13 Treatment Compliance..................................................................................
7.14 Storage, Stability, Labeling and Packaging ..................................................
7.14.1 Storage and Stability ......................................................................
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7.14.2 Labeling and Packaging .................................................................
7.14.3 Blinding and Randomization..........................................................
7.14.4 Unblinding/Expectedness...............................................................
7.14.5 Study Drug Accountability.............................................................
8 CONDUCT OF THE TRIAL.........................................................................................
8.1 Ethical and Regulatory Considerations...........................................................
8.2 Informed Consent............................................................................................
8.3 Institutional Review Board / Ethics Committees............................................
8.4 Schedule of Events..........................................................................................
8.5 Study Conduct.................................................................................................
8.5.1 Screening Visit (Study Days -14 to -1) ..........................................
8.5.2 Cycle 1..............................................................................................
8.5.3 Cycle 2 (and any Dose Adjustment Cycle) ....................................
8.5.4 Maintenance Dose Cycle (visit every 2 - 4 weeks) ........................
8.5.5 Final Visit.........................................................................................
8.5.6 Follow Up Visit (2 weeks after Final Visit) ...................................
8.5.7 Unscheduled Visits...........................................................................
8.6 Compliance with Study Procedures ................................................................
8.7 Early Withdrawal from the Study ...................................................................
8.8 Early Termination of the Study.......................................................................
8.9 Short Messaging Service (SMS) Medication Reminders .............................
9 ADVERSE EVENT REPORTING................................................................................
9.1 Classification of Causality ..............................................................................
9.2 Classification of Severity ................................................................................
9.3 Serious Adverse Event (SAE) Reporting ......................................................
9.4 Suspected Unexpected Serious Adverse Reactions (SUSARs) ....................
9.5 Pregnancies......................................................................................................
9.6 Hematologic Adverse Events..........................................................................
9.7 Management of Myelosuppression .................................................................
9.8 Differentiation Syndrome................................................................................
9.9 Tumor Lysis Syndrome (TLS) ......................................................................
9.10 Infection Prophylaxis ....................................................................................
9.11 Growth Factor Support..................................................................................
9.12 Management of Nausea, Vomiting, and Diarrhea.........................................
10 STATISTICAL CONSIDERATIONS.........................................................................
10.1 Study Populations for Analysis.....................................................................
10.2 Safety Analyses.............................................................................................
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10.3 Efficacy Analyses..........................................................................................
10.4 Other Endpoints.............................................................................................
10.5 Sample Size Considerations..........................................................................
10.6 Randomization ..............................................................................................
10.7 Pooling of Study Centers ..............................................................................
10.8 Interim Analysis............................................................................................
11 INVESTIGATOR RESPONSIBILITIES ....................................................................
11.1 Investigator's Performance............................................................................
11.2 Confidentiality...............................................................................................
11.3 Source Documentation..................................................................................
11.4 Data Collection..............................................................................................
11.5 Case Report Forms, Investigator's Site File and Record Retention ..............
11.6 Non-Protocol Research .................................................................................
11.7 Publication.....................................................................................................
12 SPONSOR RESPONSIBILITIES................................................................................
12.1 General ..........................................................................................................
12.2 Indemnity ......................................................................................................
12.3 Data Monitoring............................................................................................
12.4 Audit..............................................................................................................
12.5 Confidentiality...............................................................................................
12.6 Finance ..........................................................................................................
13 REFERENCES.............................................................................................................
14 APPENDICES..............................................................................................................
14.1 APPENDIX A: CCB-01 Schedule of Events................................................
14.2 APPENDIX B: ECOG Performance Status Criteria.....................................
14.3 APPENDIX C: Brequinar/DHO Plasma Sampling.......................................
14.4 APPENDIX D: Common Terminology Criteria for Adverse Events
(CTCAE) .............................................................................................................
14.5 APPENDIX E: Sample Subject Consent Form.............................................
APPENDIX F: WMA Declaration of Helsinki.....................................................
CCB-01 Protocol v4.0 dated 11Oct2018.......................................................................................
Approvals and Revision History .......................................................................................
STUDY PROTOCOL TITLE PAGE................................................................................
TABLE OF CONTENTS..................................................................................................
LIST OF TABLES ............................................................................................................
Table 1. Exceptions to Grade 3 Nonhematologic AEs..........................................
Table 2. Intra-Subject Dose Adjustment...............................................................
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Table 3. Analysis Sets...........................................................................................
Table 4. Efficacy Analyses....................................................................................
LIST OF FIGURES...........................................................................................................
Figure 1. Dose Adjustment – Subject Level .........................................................
Figure 2. Monitoring of Tumor Lysis Syndrome..................................................
ABBREVIATIONS...........................................................................................................
1 SYNOPSIS.....................................................................................................................
STUDY PERSONNEL .....................................................................................................
SUPPORT SERVICES .....................................................................................................
2 INTRODUCTION..........................................................................................................
2.1 Background: Acute Myeloid Leukemia..........................................................
2.2 Dihydroorotate dehydrogenase (DHODH) ...................................................
2.3 Brequinar.........................................................................................................
2.4 Rationale for the Planned Trial .......................................................................
2.4.1 Brequinar Starting Dose Selection...................................................
2.5 Risk/Benefit of Brequinar ...............................................................................
2.6 Risks Associated with Participation in the Clinical Study..............................
2.7 Possible Interactions with Concomitant Medical Treatments.........................
2.7.1 CYP Interactions ..............................................................................
2.8 Steps to be Taken to Control or Mitigate Risks ..............................................
3 TRIAL OBJECTIVES....................................................................................................
3.1 Primary Objective ...........................................................................................
3.2 Secondary Objectives......................................................................................
3.3 Exploratory Objectives....................................................................................
4 TRIAL DESIGN ............................................................................................................
5 TRIAL ENDPOINTS.....................................................................................................
5.1 Primary Endpoint ............................................................................................
5.2 Secondary Endpoints.......................................................................................
5.3 Exploratory Endpoints.....................................................................................
6 TRIAL POPULATION..................................................................................................
6.1 Number of Subjects.........................................................................................
6.2 Inclusion criteria..............................................................................................
6.3 Exclusion Criteria............................................................................................
6.4 Inclusion of Women and Minorities................................................................
7 STUDY TREATMENTS...............................................................................................
7.1 Description of Brequinar:................................................................................
7.2 Treatment Administration ...............................................................................
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7.3 Safety/Tolerability...........................................................................................
7.3.1 Safety/Tolerability – Subject Level..................................................
7.3.1.1 Hematologic Toxicity........................................................
7.3.2 Safety/Tolerability – Cohort Level ..................................................
7.3.3 Safety/Tolerability – Expansion Cohort...........................................
7.4 Cohort Starting Doses .....................................................................................
7.5 Individual Dose Adjustment Guidelines .........................................................
7.5.1 DHO Threshold................................................................................
7.6 Medication/AE Diary......................................................................................
7.7 Bone Marrow Biopsy ......................................................................................
7.8 Flow Cytometry ..............................................................................................
7.9 Expansion Cohort............................................................................................
7.10 Study Drug Discontinuation..........................................................................
7.11 Brequinar Pharmacokinetics (PK) / Dihydroorotate (DHO) Plasma
Levels ....................................................................................................................
7.12 Concomitant Medication/Treatment .............................................................
7.12.1 Gastric pH ......................................................................................
7.13 Treatment Compliance..................................................................................
7.14 Storage, Stability, Labeling and Packaging ..................................................
7.14.1 Storage and Stability ......................................................................
7.14.2 Labeling and Packaging .................................................................
7.14.3 Blinding and Randomization..........................................................
7.14.4 Unblinding/Expectedness...............................................................
7.14.5 Study Drug Accountability.............................................................
8 CONDUCT OF THE TRIAL.........................................................................................
8.1 Ethical and Regulatory Considerations...........................................................
8.2 Informed Consent............................................................................................
8.3 Institutional Review Board / Ethics Committees............................................
8.4 Schedule of Events..........................................................................................
8.5 Study Conduct.................................................................................................
8.5.1 Screening Visit (Study Days -14 to -1) ..........................................
8.5.2 Cycle 1..............................................................................................
8.5.3 Cycle 2 (and any Dose Adjustment Cycle) ....................................
8.5.4 Maintenance Dose Cycle (visit every 2 - 4 weeks) ........................
8.5.5 Final Visit.........................................................................................
8.5.6 Follow Up Visit (2 weeks after Final Visit) ...................................
8.5.7 Unscheduled Visits...........................................................................
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8.6 Compliance with Study Procedures ................................................................
8.7 Early Withdrawal from the Study ...................................................................
8.8 Early Termination of the Study.......................................................................
8.9 Short Messaging Service (SMS) Medication Reminders .............................
9 ADVERSE EVENT REPORTING...................................................................................
9.1 Classification of Causality ..............................................................................
9.2 Classification of Severity ................................................................................
9.3 Serious Adverse Event (SAE) Reporting ......................................................
9.4 Suspected Unexpected Serious Adverse Reactions (SUSARs) ....................
9.5 Pregnancies......................................................................................................
9.6 Hematologic Adverse Events..........................................................................
9.7 Management of Myelosuppression .................................................................
9.8 Differentiation Syndrome................................................................................
9.9 Tumor Lysis Syndrome (TLS) ......................................................................
9.10 Infection Prophylaxis ....................................................................................
9.11 Growth Factor Support..................................................................................
9.12 Management of Nausea, Vomiting, and Diarrhea.........................................
10 STATISTICAL CONSIDERATIONS.........................................................................
10.1 Study Populations for Analysis.....................................................................
10.2 Safety Analyses.............................................................................................
10.3 Efficacy Analyses..........................................................................................
10.4 Other Endpoints.............................................................................................
10.5 Sample Size Considerations..........................................................................
10.6 Randomization ..............................................................................................
10.7 Pooling of Study Centers ..............................................................................
10.8 Interim Analysis............................................................................................
11 INVESTIGATOR RESPONSIBILITIES ....................................................................
11.1 Investigator's Performance............................................................................
11.2 Confidentiality...............................................................................................
11.3 Source Documentation..................................................................................
11.4 Data Collection..............................................................................................
11.5 Case Report Forms, Investigator's Site File and Record Retention ..............
11.6 Non-Protocol Research .................................................................................
11.7 Publication.....................................................................................................
12 SPONSOR RESPONSIBILITIES................................................................................
12.1 General ..........................................................................................................
12.2 Indemnity ......................................................................................................
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12.3 Data Monitoring............................................................................................
12.4 Audit..............................................................................................................
12.5 Confidentiality...............................................................................................
12.6 Finance ..........................................................................................................
13 REFERENCES.............................................................................................................
14 APPENDICES..............................................................................................................
14.1 APPENDIX A: CCB-01 Schedule of Events................................................
14.2 APPENDIX B: ECOG Performance Status Criteria.....................................
14.3 APPENDIX C: Brequinar/DHO Plasma Sampling.......................................
14.4 APPENDIX D: Common Terminology Criteria for Adverse Events
(CTCAE) .............................................................................................................
14.5 APPENDIX E: Sample Subject Consent Form.............................................
APPENDIX F: WMA Declaration of Helsinki.....................................................
CCB-01 Protocol v5.0 dated 16Oct2018.......................................................................................
Approvals and Revision History .......................................................................................
STUDY PROTOCOL TITLE PAGE................................................................................
TABLE OF CONTENTS..................................................................................................
LIST OF TABLES ............................................................................................................
Table 1. Exceptions to Grade 3 Nonhematologic AEs..........................................
Table 2. Intra-Subject Dose Adjustment...............................................................
Table 3. Analysis Sets...........................................................................................
Table 4. Efficacy Analyses....................................................................................
LIST OF FIGURES...........................................................................................................
Figure 1. Dose Adjustment – Subject Level .........................................................
Figure 2. Monitoring of Tumor Lysis Syndrome..................................................
ABBREVIATIONS...........................................................................................................
1 SYNOPSIS.....................................................................................................................
STUDY PERSONNEL .....................................................................................................
SUPPORT SERVICES .....................................................................................................
2 INTRODUCTION..........................................................................................................
2.1 Background: Acute Myeloid Leukemia..........................................................
2.2 Dihydroorotate dehydrogenase (DHODH) ...................................................
2.3 Brequinar.........................................................................................................
2.4 Rationale for the Planned Trial .......................................................................
2.4.1 Brequinar Starting Dose Selection...................................................
2.5 Risk/Benefit of Brequinar ...............................................................................
2.6 Risks Associated with Participation in the Clinical Study..............................
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2.7 Possible Interactions with Concomitant Medical Treatments.........................
2.7.1 CYP Interactions ..............................................................................
2.8 Steps to be Taken to Control or Mitigate Risks ..........................................................
3 TRIAL OBJECTIVES....................................................................................................
3.1 Primary Objective ...........................................................................................
3.2 Secondary Objectives......................................................................................
3.3 Exploratory Objectives....................................................................................
4 TRIAL DESIGN ............................................................................................................
5 TRIAL ENDPOINTS.....................................................................................................
5.1 Primary Endpoint ............................................................................................
5.2 Secondary Endpoints.......................................................................................
5.3 Exploratory Endpoints.....................................................................................
6 TRIAL POPULATION..................................................................................................
6.1 Number of Subjects.........................................................................................
6.2 Inclusion criteria..............................................................................................
6.3 Exclusion Criteria............................................................................................
6.4 Inclusion of Women and Minorities................................................................
7 STUDY TREATMENTS...............................................................................................
7.1 Description of Brequinar:................................................................................
7.2 Treatment Administration ...............................................................................
7.3 Safety/Tolerability...........................................................................................
7.3.1 Safety/Tolerability – Subject Level..................................................
7.3.2 Safety/Tolerability – Cohort Level ..................................................
7.3.3 Safety/Tolerability – Expansion Cohort...........................................
7.4 Cohort Starting Doses .....................................................................................
7.5 Individual Dose Adjustment Guidelines .........................................................
7.5.1 DHO Threshold................................................................................
7.6 Medication/AE Diary......................................................................................
7.7 Bone Marrow Biopsy ......................................................................................
7.8 Flow Cytometry ..............................................................................................
7.9 Expansion Cohort............................................................................................
7.10 Study Drug Discontinuation..........................................................................
7.11 Brequinar Pharmacokinetics (PK) / Dihydroorotate (DHO) Plasma
Levels ....................................................................................................................
7.12 Concomitant Medication/Treatment .............................................................
7.12.1 Gastric pH ......................................................................................
7.13 Treatment Compliance..................................................................................
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7.14 Storage, Stability, Labeling and Packaging ..................................................
7.14.1 Storage and Stability ......................................................................
7.14.2 Labeling and Packaging .................................................................
7.14.3 Blinding and Randomization..........................................................
7.14.4 Unblinding/Expectedness...............................................................
7.14.5 Study Drug Accountability.............................................................
8 CONDUCT OF THE TRIAL.........................................................................................
8.1 Ethical and Regulatory Considerations...........................................................
8.2 Informed Consent............................................................................................
8.3 Institutional Review Board / Ethics Committees............................................
8.4 Schedule of Events..........................................................................................
8.5 Study Conduct.................................................................................................
8.5.1 Screening Visit (Study Days -14 to -1) ..........................................
8.5.2 Cycle 1..............................................................................................
8.5.3 Cycle 2 (and any Dose Adjustment Cycle) ....................................
8.5.4 Maintenance Dose Cycle (visit every 2 - 4 weeks) ........................
8.5.5 Final Visit.........................................................................................
8.5.6 Follow Up Visit (2 weeks after Final Visit) ...................................
8.5.7 Unscheduled Visits...........................................................................
8.6 Compliance with Study Procedures ................................................................
8.7 Early Withdrawal from the Study ...................................................................
8.8 Early Termination of the Study.......................................................................
8.9 Short Messaging Service (SMS) Medication Reminders .............................
9 ADVERSE EVENT REPORTING................................................................................
9.1 Classification of Causality ..............................................................................
9.2 Classification of Severity ................................................................................
9.3 Serious Adverse Event (SAE) Reporting ......................................................
9.4 Suspected Unexpected Serious Adverse Reactions (SUSARs) ....................
9.5 Pregnancies......................................................................................................
9.6 Hematologic Adverse Events..........................................................................
9.7 Management of Myelosuppression .................................................................
9.8 Differentiation Syndrome................................................................................
9.9 Tumor Lysis Syndrome (TLS) ......................................................................
9.10 Infection Prophylaxis ....................................................................................
9.11 Growth Factor Support..................................................................................
9.12 Management of Nausea, Vomiting, and Diarrhea.........................................
10 STATISTICAL CONSIDERATIONS.........................................................................
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10.1 Study Populations for Analysis.....................................................................
10.2 Safety Analyses.............................................................................................
10.3 Efficacy Analyses..........................................................................................
10.4 Other Endpoints.............................................................................................
10.5 Sample Size Considerations..........................................................................
10.6 Randomization ..............................................................................................
10.7 Pooling of Study Centers ..............................................................................
10.8 Interim Analysis............................................................................................
11 INVESTIGATOR RESPONSIBILITIES ....................................................................
11.1 Investigator's Performance............................................................................
11.2 Confidentiality...............................................................................................
11.3 Source Documentation..................................................................................
11.4 Data Collection..............................................................................................
11.5 Case Report Forms, Investigator's Site File and Record Retention ..............
11.6 Non-Protocol Research .................................................................................
11.7 Publication.....................................................................................................
12 SPONSOR RESPONSIBILITIES................................................................................
12.1 General ..........................................................................................................
12.2 Indemnity ......................................................................................................
12.3 Data Monitoring............................................................................................
12.4 Audit..............................................................................................................
12.5 Confidentiality...............................................................................................
12.6 Finance ..........................................................................................................
13 REFERENCES.............................................................................................................
14 APPENDICES..............................................................................................................
14.1 APPENDIX A: CCB-01 Schedule of Events................................................
14.2 APPENDIX B: ECOG Performance Status Criteria.....................................
14.3 APPENDIX C: Brequinar/DHO Plasma Sampling.......................................
14.4 APPENDIX D: Common Terminology Criteria for Adverse Events
(CTCAE) .............................................................................................................
14.5 APPENDIX E: Sample Subject Consent Form.............................................
APPENDIX F: WMA Declaration of Helsinki.....................................................
14.6 Appendix G: Investigator's Statement and Agreement .................................
CCB-01 Protocol v6.0 dated 30Apr2019......................................................................................
Approvals and Revision History .......................................................................................
STUDY PROTOCOL TITLE PAGE................................................................................
TABLE OF CONTENTS..................................................................................................
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LIST OF TABLES ................................................................................................
Table 8-1. Exceptions to Grade 3 Nonhematologic AEs ..........................
Table 8-2. Algorithm to Set Twice-Weekly Dose.....................................
Table 8-3. Algorithm to Adjust Twice-Weekly Dose using 84h DHO
(Trough) ..................................................................................................
Table 11-1. Analysis Sets..........................................................................
Table 11-2. Efficacy AnalysesEndpoint Statistical Analysis....................
LIST OF FIGURES...............................................................................................
Figure 8-1. Algorithm to Set Twice-Weekly Dose ...................................
Figure 8-2. Algorithm to Adjust Dose Using 84h DHO ...........................
Figure 10-1. Monitoring of Tumor Lysis Syndrome.................................
ABBREVIATIONS...........................................................................................................
2 SYNOPSIS.....................................................................................................................
STUDY PERSONNEL .....................................................................................................
SUPPORT SERVICES .....................................................................................................
3 INTRODUCTION..........................................................................................................
3.1 Background: Acute Myeloid Leukemia..........................................................
3.2 Dihydroorotate dehydrogenase (DHODH) ...................................................
3.3 Brequinar.........................................................................................................
3.4 Rationale for the Planned Trial .......................................................................
3.4.1 Brequinar Starting Dose Selection...................................................
3.5 Risk/Benefit of Brequinar ...............................................................................
3.6 Risks Associated with Participation in the Clinical Study..............................
3.7 Possible Interactions with Concomitant Medical Treatments.........................
3.7.1 CYP Interactions ..............................................................................
3.8 Steps to be Taken to Control or Mitigate Risks ..............................................
4 TRIAL OBJECTIVES....................................................................................................
4.1 Primary Objective ...........................................................................................
4.2 Secondary Objectives......................................................................................
4.3 Exploratory Objectives....................................................................................
5 TRIAL DESIGN ............................................................................................................
6 TRIAL ENDPOINTS.....................................................................................................
6.1 Primary Endpoint ............................................................................................
6.2 Secondary Endpoints.......................................................................................
6.3 Exploratory Endpoints.....................................................................................
7 TRIAL POPULATION..................................................................................................
7.1 Number of Subjects.........................................................................................
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7.2 Inclusion criteria..............................................................................................
7.3 Exclusion Criteria............................................................................................
7.4 Inclusion of Women and Minorities................................................................
8 STUDY TREATMENTS...............................................................................................
8.1 Description of Brequinar.................................................................................
8.2 Treatment Administration ...............................................................................
8.3 Safety/Tolerability...........................................................................................
8.3.1 Safety/Tolerability – Subject Level..................................................
8.3.2 Hematologic Toxicity.......................................................................
8.4 Cohort Starting Doses .....................................................................................
8.5 Individual Dose Adjustment Guidelines .........................................................
8.5.1 Brequinar Exposure (BRQ PK) and 72h DHO Criteria to Set
Twice-Weekly Dosing...............................................................................
8.5.2 Dose Adjustment Using 84h DHO...................................................
8.6 Medication/AE Diary......................................................................................
8.7 Bone Marrow Biopsy ......................................................................................
8.8 Expansion Cohort............................................................................................
8.9 Study Drug Discontinuation............................................................................
8.10 Brequinar Pharmacokinetics (PK)/Dihydroorotate (DHO) Plasma
Levels/Flow Cytometry.........................................................................................
8.11 Concomitant Medication/Treatment .............................................................
8.11.1 Gastric pH ......................................................................................
8.12 Treatment Compliance..................................................................................
8.13 Storage, Stability, Labeling and Packaging ..................................................
8.13.1 Storage and Stability ......................................................................
8.13.2 Labeling and Packaging .................................................................
8.13.3 Blinding and Randomization..........................................................
8.13.4 Unblinding/Expectedness...............................................................
8.13.5 Study Drug Accountability.............................................................
9 CONDUCT OF THE TRIAL.........................................................................................
9.1 Ethical and Regulatory Considerations...........................................................
9.2 Informed Consent............................................................................................
9.3 Institutional Review Board / Ethics Committees............................................
9.4 Schedule of Events..........................................................................................
9.5 Study Conduct.................................................................................................
9.5.1 Screening Visit (Study Days -14 to -1) ..........................................
9.5.2 Treatment .........................................................................................
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9.5.3 Dose Adjustment: Cycle 1 Week 1 ..................................................
9.5.4 Dose Adjustment: Cycle 1 Week 2 ..................................................
9.5.5 Maintenance Dose Cycle..................................................................
9.5.6 Final Visit.........................................................................................
9.5.7 Telephone Follow Up Visit (2 weeks after Final Visit) .................
9.5.8 Unscheduled Visits...........................................................................
9.6 Compliance with Study Procedures ................................................................
9.7 Early Withdrawal from the Study ...................................................................
9.8 Early Termination of the Study.......................................................................
9.9 Short Messaging Service (SMS) Medication Reminders .............................
10 ADVERSE EVENT REPORTING..............................................................................
10.1 Classification of Causality ............................................................................
10.2 Classification of Severity ..............................................................................
10.3 Serious Adverse Event (SAE) Reporting ....................................................
10.4 Suspected Unexpected Serious Adverse Reactions (SUSARs) ..................
10.5 Pregnancies....................................................................................................
10.6 Hematologic Adverse Events........................................................................
10.7 Management of Myelosuppression ...............................................................
10.8 Differentiation Syndrome..............................................................................
10.9 Tumor Lysis Syndrome (TLS) ....................................................................
10.10 Infection Prophylaxis ..................................................................................
10.11 Growth Factor Support................................................................................
10.12 Management of Nausea, Vomiting, and Diarrhea.......................................
11 STATISTICAL CONSIDERATIONS.........................................................................
11.1 Study Populations for Analysis.....................................................................
11.2 Safety Analyses.............................................................................................
11.3 Efficacy Analyses..........................................................................................
11.4 Other Endpoints.............................................................................................
11.5 Sample Size Considerations..........................................................................
11.6 Randomization ..............................................................................................
11.7 Pooling of Study Centers ..............................................................................
11.8 Interim Analysis............................................................................................
12 INVESTIGATOR RESPONSIBILITIES ....................................................................
12.1 Investigator's Performance............................................................................
12.2 Confidentiality...............................................................................................
12.3 Source Documentation..................................................................................
12.4 Data Collection..............................................................................................
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12.5 Case Report Forms, Investigator's Site File and Record Retention ..............
12.6 Non-Protocol Research .................................................................................
12.7 Publication.....................................................................................................
13 SPONSOR RESPONSIBILITIES................................................................................
13.1 General ..........................................................................................................
13.2  Indemnity .....................................................................................................
13.3  Data Monitoring...........................................................................................
13.4  Audit.............................................................................................................
13.5  Confidentiality..............................................................................................
13.6  Finance .........................................................................................................
14 REFERENCES.............................................................................................................
15 APPENDICES..............................................................................................................
15.1 APPENDIX A:  CCB-01 Schedule of Events...............................................
15.2 APPENDIX B: ECOG Performance Status Criteria.....................................
15.3  APPENDIX C: Brequinar/DHO/Flow Cytometry Sampling.......................
15.4  APPENDIX D: Common Terminology Criteria for Adverse Events
(CTCAE) .............................................................................................................
15.5   APPENDIX E:  Sample Subject Consent Form..........................................
15.6  APPENDIX F:  WMA Declaration of Helsinki...........................................
15.7 APPENDIX G: Investigator's Statement and Agreement .............................
CCB-01 Protocol v7.0 dated 21Feb2020 ......................................................................................
Approvals and Revisions...................................................................................................
STUDY PROTOCOL  TITLE PAGE...............................................................................
TABLE OF CONTENTS..................................................................................................
LIST OF TABLES ................................................................................................
Table 8-1. Exceptions to Grade 3 Nonhematologic AEs ..........................
Table 8-2. Algorithm to Set Twice-Weekly Dose for Cohort 2
Replacement/ExpansionSubjects (Starting Dose 350 mg/m2) ...............
Table 8-3. Algorithm to Adjust Twice-Weekly Dose using 84h DHO
for Cohort 2Replacements and Expansion Cohort....................................
Table 11-1.Analysis Sets...........................................................................
Table 11-2.Efficacy Analyses ...................................................................
LIST OF FIGURES...............................................................................................
Figure 8-1.Algorithm to Set Twice-Weekly Dose ....................................
Figure 8-2.Algorithm to Adjust Dose Using 84h DHO ............................
Figure 10-1. Monitoring of Tumor Lysis Syndrome.................................
ABBREVIATIONS...........................................................................................................
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2 SYNOPSIS.....................................................................................................................
STUDY PERSONNEL .....................................................................................................
SUPPORT SERVICES .....................................................................................................
3 INTRODUCTION..........................................................................................................
3.1 Background .....................................................................................................
Acute Myeloid Leukemia......................................................................................
3.2 Dihydroorotate dehydrogenase (DHODH) ...................................................
3.3 Brequinar.........................................................................................................
3.4 Rationale for the Planned Trial .......................................................................
3.4.1 Brequinar Starting Dose Selection...................................................
3.5 Risk/Benefit of Brequinar ...............................................................................
3.6 Risks Associated with Participation in the Clinical Study..............................
3.7 Possible Interactions with Concomitant Medical Treatments.........................
3.7.1 CYP Interactions ..............................................................................
3.8 Steps to be Taken to Control or Mitigate Risks ..............................................
4 TRIAL OBJECTIVES....................................................................................................
4.1 Primary Objective ...........................................................................................
4.2 Secondary Objectives......................................................................................
4.3 Exploratory Objectives....................................................................................
5 TRIAL DESIGN ............................................................................................................
6 TRIAL ENDPOINTS.....................................................................................................
6.1 Primary Endpoint ............................................................................................
6.2 Secondary Endpoints.......................................................................................
6.3 Exploratory Endpoints.....................................................................................
7 TRIAL POPULATION..................................................................................................
7.1 Number of Subjects.........................................................................................
7.2 Inclusion criteria..............................................................................................
7.3 Exclusion Criteria............................................................................................
7.4 Inclusion of Women and Minorities................................................................
8 STUDY TREATMENTS...............................................................................................
8.1 Description of Brequinar.................................................................................
8.2 Treatment Administration ...............................................................................
8.3 Safety/Tolerability...........................................................................................
8.3.1 Safety/Tolerability – Subject Level..................................................
8.3.2 Hematologic Toxicity.......................................................................
8.4 Cohort Starting Doses .....................................................................................
8.5 Individual Dose Adjustment Guidelines .........................................................
548
560
561
562
562
562
562
563
564
565
566
566
566
567
567
568
568
568
568
569
570
570
570
570
571
571
571
572
573
574
574
574
575
576
577
577
578


8.5.1 Brequinar Exposure \(BRQ PK\) and 72h DHO Criteria to Set
Twice-Weekly Dosing...............................................................................
8.5.2 Dose Adjustment Using 84h DHO...................................................
8.6 Medication/AE Diary......................................................................................
8.7 Bone Marrow Biopsy ......................................................................................
8.8 Expansion Cohort............................................................................................
8.9 Study Drug Discontinuation............................................................................
8.10 Brequinar Pharmacokinetics (PK)/Dihydroorotate (DHO) Plasma
Levels/Flow Cytometry.........................................................................................
8.11 Concomitant Medication/Treatment .............................................................
8.11.1 Gastric pH ......................................................................................
8.12 Treatment Compliance..................................................................................
8.13 Storage, Stability, Labeling and Packaging ..................................................
8.13.1 Storage and Stability ......................................................................
8.13.2 Labeling and Packaging .................................................................
8.13.3 Blinding and Randomization..........................................................
8.13.4 Unblinding/Expectedness...............................................................
8.13.5 Study Drug Accountability.............................................................
9 CONDUCT OF THE TRIAL.........................................................................................
9.1 Ethical and Regulatory Considerations...........................................................
9.2 Informed Consent............................................................................................
9.3 Institutional Review Board / Ethics Committees............................................
9.4 Schedule of Events..........................................................................................
9.5 Study Conduct.................................................................................................
9.5.1 Screening Visit (Study Days -14 to -1) ..........................................
9.5.2 Treatment .........................................................................................
9.5.3 Dose Adjustment: Cycle 1 Week 1 (or Week 2 if dose reduced) ..
9.5.4 Maintenance Dose Cycle..................................................................
9.5.5 Final Visit.........................................................................................
9.5.6 Telephone Follow Up Visit (2 weeks after Final Visit) .................
9.5.7 Unscheduled Visits...........................................................................
9.6 Compliance with Study Procedures ................................................................
9.7 Early Withdrawal from the Study ...................................................................
9.8 Early Termination of the Study.......................................................................
10 ADVERSE EVENT REPORTING..............................................................................
10.1 Classification of Causality ............................................................................
10.2 Classification of Severity ..............................................................................
579
580
582
582
582
582
583
583
584
584
584
584
584
584
585
585
586
586
586
587
587
588
588
589
589
589
590
591
591
591
591
592
593
595
595


10.3 Serious Adverse Event \(SAE\) Reporting
...............................................
10.4 Suspected Unexpected Serious Adverse Reactions (SUSARs) ..................
10.5 Pregnancies....................................................................................................
10.6 Hematologic Adverse Events........................................................................
10.7 Management of Myelosuppression ...............................................................
10.8 Differentiation Syndrome..............................................................................
10.9 Tumor Lysis Syndrome (TLS) ....................................................................
10.10 Infection Prophylaxis ..................................................................................
10.11 Growth Factor Support................................................................................
10.12 Management of Nausea, Vomiting, and Diarrhea.......................................
11 STATISTICAL CONSIDERATIONS.........................................................................
11.1 Study Populations for Analysis.....................................................................
11.2 Safety Analyses.............................................................................................
11.3 Efficacy Analyses..........................................................................................
11.4 Other Endpoints.............................................................................................
11.5 Sample Size Considerations..........................................................................
11.6 Randomization ..............................................................................................
11.7 Pooling of Study Centers ..............................................................................
11.8 Interim Analysis............................................................................................
12 INVESTIGATOR RESPONSIBILITIES ....................................................................
12.1 Investigator's Performance............................................................................
12.2 Confidentiality...............................................................................................
12.3 Source Documentation..................................................................................
12.4 Data Collection..............................................................................................
12.5 Case Report Forms, Investigator's Site File and Record Retention ..............
12.6 Non-Protocol Research .................................................................................
12.7 Publication.....................................................................................................
13 SPONSOR RESPONSIBILITIES................................................................................
13.1 General ..........................................................................................................
13.2  Indemnity .....................................................................................................
13.3  Data Monitoring...........................................................................................
13.4  Audit.............................................................................................................
13.5  Confidentiality..............................................................................................
13.6  Finance .........................................................................................................
14 REFERENCES.............................................................................................................
15 APPENDICES..............................................................................................................
15.1 APPENDIX A:  CCB-01 Schedule of Events...............................................
596
598
598
599
600
600
601
603
603
603
604
604
604
605
608
608
608
608
609
610
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610
611
611
612
612
613
613
613
613
614
614
614
615
616
616


15.2 APPENDIX B: ECOG Performance Status Criteria.....................................
15.3  APPENDIX C: Brequinar/DHO/Flow Cytometry Sampling.......................
15.4  APPENDIX D: Common Terminology Criteria for Adverse Events
(CTCAE) .............................................................................................................
15.5   APPENDIX E:  Sample Subject Consent Form..........................................
15.6 APPENDIX F:  WMA Declaration of Helsinki............................................
15.7 APPENDIX G: Investigator's Statement and Agreement .............................
CCB-01 Protocol v8.0 dated 09Mar2020......................................................................................
STUDY PROTOCOL TITLE PAGE................................................................................
TABLE OF CONTENTS..................................................................................................
LIST OF TABLES ................................................................................................
Table 8-1. Exceptions to Grade 3 Nonhematologic AEs ..........................
Table 8-2. algorithm to Set Twice-Weekly Dose for Chort 3/Expansion
Subjects (Starting Dose 350 mg/m2) ......................................................
Table 8-3. Algorithm to Adjust Twice-Weekly Dose using 84h DHO
for Cohort 3 and Expansion Cohort ..........................................................
Table 11-1. Analysis Sets..........................................................................
Table 11-2. Efficacy Analyses ..................................................................
LIST OF FIGURES...............................................................................................
Figure 8-1. Algorithm to Set Twice-Weekly Dose ...................................
Figure 8-2. Algorithm to Add and Adjust Ribavirin.................................
Figure 8-3. Algorithm to Adjust Dose Using 84h DHO ...........................
Figure 10-1. Monitoring of Tumor Lysis Syndrome.................................
ABBREVIATIONS...........................................................................................................
2 SYNOPSIS.....................................................................................................................
STUDY PERSONNEL .....................................................................................................
SUPPORT SERVICES .....................................................................................................
3 INTRODUCTION..........................................................................................................
3.1 BACKGROUND.............................................................................................
3.2 DIHYDROOROTATE DEHYDROGENASE (DHODH) ...........................
3.3 BREQUINAR..................................................................................................
3.4 RIBAVIRIN ....................................................................................................
3.5 RATIONALE FOR THE PLANNED TRIAL................................................
3.5.1 Brequinar Starting Dose Selection...................................................
3.5.2 Ribavirin Dosing ..............................................................................
3.6 RISK/BENEFIT OF BREQUINAR................................................................
3.7 RISK/BENEFIT OF RIBAVIRIN ..................................................................
619
620
621
622
635
641
642
642
643
648
687
689
692
714
715
649
690
691
692
712
650
652
666
667
668
668
668
669
670
672
672
673
673
674


3.8 RISKS ASSOCIATED WITH PARTICIPATION IN THE CLINICAL
STUDY..................................................................................................................
3.9 POSSIBLE INTERACTIONS WITH CONCOMITANT MEDICAL
TREATMENTS ....................................................................................................
3.9.1 CYP Interactions ..............................................................................
3.10 STEPS TO BE TAKEN TO CONTROL OR MITIGATE RISKS...............
4 TRIAL OBJECTIVES....................................................................................................
4.1 PRIMARY OBJECTIVE ................................................................................
4.2 SECONDARY OBJECTIVES........................................................................
4.3 EXPLORATORY OBJECTIVES...................................................................
5 TRIAL DESIGN ............................................................................................................
6 TRIAL ENDPOINTS.....................................................................................................
6.1 PRIMARY ENDPOINT..................................................................................
6.2 SECONDARY ENDPOINTS .........................................................................
6.3 EXPLORATORY ENDPOINTS ....................................................................
7 TRIAL POPULATION..................................................................................................
7.1 NUMBER OF SUBJECTS .............................................................................
7.2 INCLUSION CRITERIA................................................................................
7.3 EXCLUSION CRITERIA...............................................................................
7.4 INCLUSION OF WOMEN AND MINORITIES...........................................
8 STUDY TREATMENTS...............................................................................................
8.1 DESCRIPTION OF STUDY MEDICATIONS..............................................
8.1.1 Brequinar..........................................................................................
8.1.2 Ribavirin...........................................................................................
8.2 TREATMENT ADMINISTRATION.............................................................
8.3 SAFETY/TOLERABILITY............................................................................
8.3.1 Safety/Tolerability – Subject Level..................................................
8.3.2 Hematologic Toxicity.......................................................................
8.4 COHORT STARTING DOSES......................................................................
8.5 INDIVIDUAL DOSE ADJUSTMENT GUIDELINES..................................
8.5.1 Brequinar Exposure (BRQ PK) and 72h DHO Criteria to Set
Twice-Weekly Dosing...............................................................................
8.5.2 Ribavarin in Combination with Brequinar.......................................
8.5.3 Ribavirin Dose Adjustment..............................................................
8.5.4 Dose Adjustment Using 84h DHO...................................................
8.6 MEDICATION/AE DIARY ...........................................................................
8.7 BONE MARROW BIOPSY ...........................................................................
674
674
675
675
676
676
676
676
677
679
679
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679
680
680
680
681
682
683
684
684
684
684
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686
687
688
688
689
690
690
691
693
693


8.8 EXPANSION COHORT.................................................................................
8.9 STUDY DRUG DISCONTINUATION .........................................................
8.10 BREQUINAR PHARMACOKINETICS (PK)/DIHYDROOROTATE
(DHO) PLASMA LEVELS/FLOW CYTOMETRY ..........................................
8.11 CONCOMITANT MEDICATION/TREATMENT......................................
8.11.1 Gastric pH ......................................................................................
8.12 TREATMENT COMPLIANCE....................................................................
8.13 STORAGE, STABILITY, LABELING AND PACKAGING......................
8.13.1 Storage and Stability ......................................................................
8.13.2 Labeling and Packaging .................................................................
8.13.3 Blinding and Randomization..........................................................
8.13.4 Unblinding/Expectedness...............................................................
8.13.5 Study Drug Accountability.............................................................
8.13.6 Prohibited Medications ..................................................................
9 CONDUCT OF THE TRIAL.........................................................................................
9.1 ETHICAL AND REGULATORY CONSIDERATIONS ..............................
9.2 INFORMED CONSENT.................................................................................
9.3 INSTITUTIONAL REVIEW BOARD / ETHICS COMMITTEES...............
9.4 SCHEDULE OF EVENTS..............................................................................
9.5 STUDY CONDUCT .......................................................................................
9.5.1 Screening Visit (Study Days -14 to -1 ............................................
9.5.2 Treatment .........................................................................................
9.5.3 Dose Adjustment: Cycle 1 Week 1 (or Week 2 if dose reduced) ..
9.5.4 Maintenance Dose Cycle..................................................................
9.5.5 Final Visit.........................................................................................
9.5.6 Telephone Follow Up Visit (2 weeks after Final Visit) .................
9.5.7 Unscheduled Visits...........................................................................
9.6 COMPLIANCE WITH STUDY PROCEDURES..........................................
9.7 EARLY WITHDRAWAL FROM THE STUDY...........................................
9.8 EARLY TERMINATION OF THE STUDY..................................................
10 ADVERSE EVENT REPORTING..............................................................................
10.1 CLASSIFICATION OF CAUSALITY.........................................................
10.2 CLASSIFICATION OF SEVERITY............................................................
10.3 SERIOUS ADVERSE EVENT (SAE) REPORTING ................................
10.4 SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTIONS
(SUSARS) ...........................................................................................................
10.5 PREGNANCIES ...........................................................................................
693
693
694
694
695
695
695
695
695
695
696
696
696
697
697
697
698
698
699
699
700
700
701
702
702
702
702
702
703
704
705
706
706
708
708


10.6 HEMATOLOGIC ADVERSE EVENTS......................................................
10.7 MANAGEMENT OF MYELOSUPPRESSION ..........................................
10.8 DIFFERENTIATION SYNDROME............................................................
10.9 TUMOR LYSIS SYNDROME (TLS) ........................................................
10.10 INFECTION PROPHYLAXIS ...................................................................
10.11 GROWTH FACTOR SUPPORT................................................................
10.12 MANAGEMENT OF NAUSEA, VOMITING, AND DIARRHEA..........
11 STATISTICAL CONSIDERATIONS.........................................................................
11.1 STUDY POPULATIONS FOR ANALYSIS................................................
11.2 SAFETY ANALYSES..................................................................................
11.3 EFFICACY ANALYSES..............................................................................
11.4 OTHER ENDPOINTS ..................................................................................
11.5 SAMPLE SIZE CONSIDERATIONS..........................................................
11.6 RANDOMIZATION.....................................................................................
11.7 POOLING OF STUDY CENTERS..............................................................
11.8 INTERIM ANALYSIS .................................................................................
12 INVESTIGATOR RESPONSIBILITIES ....................................................................
12.1 INVESTIGATOR'S PERFORMANCE........................................................
12.2 CONFIDENTIALITY...................................................................................
12.3 SOURCE DOCUMENTATION...................................................................
12.4 DATA COLLECTION..................................................................................
12.5 CASE REPORT FORMS, INVESTIGATOR'S SITE FILE AND
RECORD RETENTION .......................................................................................
12.6 NON-PROTOCOL RESEARCH..................................................................
12.7 PUBLICATION ............................................................................................
13 SPONSOR RESPONSIBILITIES................................................................................
13.1 GENERAL ....................................................................................................
13.2 INDEMNITY ................................................................................................
13.3 DATA MONITORING.................................................................................
13.4 AUDIT ..........................................................................................................
13.5 CONFIDENTIALITY...................................................................................
13.6 FINANCE......................................................................................................
14 REFERENCES.............................................................................................................
15 APPENDICES..............................................................................................................
15.1 APPENDIX A: CCB-01 SCHEDULE OF EVENTS ...................................
15.2 APPENDIX B: ECOG PERFORMANCE STATUS CRITERIA ................
15.3 APPENDIX C: BREQUINAR/DHO/FLOW CYTOMETRY
709
710
710
711
713
713
713
714
714
714
715
718
719
719
719
719
720
720
720
720
721
721
722
722
723
723
723
723
724
724
724
725
727
727
730


SAMPLING ..........................................................................................................
15.4 APPENDIX D: COMMON TERMINOLOGY CRITERIA FOR
ADVERSE EVENTS (CTCAE) .........................................................................
15.5 APPENDIX E: SAMPLE SUBJECT CONSENT FORM............................
15.6 APPENDIX F: WMA DECLARATION OF HELSINKI.............................
15.7 APPENDIX G: INVESTIGATOR'S STATEMENT AND AGREEMENT.
15.8 APPENDIX H: RIBAVIRIN GENERIC (RIBAVIRIN USP)
CAPSULES, FOR ORAL USE SUMMARY OF PRODUCT
CHARACTERISTICS (SPC) .............................................................................
731
732
733
746
752
753


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Barbara L. Powers, MSN, Ph.D.
04 June 2018
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David P Hesson, PhD
David P Hesson, PhD
June 4, 2018
June 4, 2018
June 4, 2018
Vikram S Kumar, MD
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PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 1 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
STUDY PROTOCOL 
 
 
A Phase 1b/2a open-label, multi-center study to assess the safety, 
efficacy and pharmacokinetics of intrapatient dose-adjusted 
brequinar and inhibition of dihydroorotate dehydrogenase 
(DHODH) in adult subjects with acute myelogenous leukemia 
(AML) 
 
Study No: CCB-01 
 
Version Date: 4 June 2018 
 
Sponsor: 
Clear Creek Bio, Inc. 
585 Massachusetts Avenue, 4th Floor, 
Cambridge MA 02139 
 
Sponsor Telephone: (617) 765-2252 
Sponsor Facsimile: (617) 863-2082 
 
IND Number: 138,335 
 
This confidential document is the property of Clear Creek Bio, Inc.  No unpublished information contained herein 
may be disclosed without the prior written approval of Clear Creek Bio, Inc. This trial will be conducted in 
accordance with the ICH Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95, Jan.97), the Declaration 
of Helsinki (1964, 1975, 1983, 1989, 1996, 2000 (Note for Clarification 2002 & 2004) and 2008), FDA Regulations 
and locally applicable regulations. 
 
 


PROTOCOL NUMBER:  CCB-01  
Page 2 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
TABLE OF CONTENTS 
1 SYNOPSIS .......................................................................................................................... 10 
2 INTRODUCTION .............................................................................................................. 26 
2.1 
Background: Acute Myeloid Leukemia ..................................................................... 26 
2.2 
Dihydroorotate dehydrogenase (DHODH) ................................................................ 26 
2.3 
Brequinar .................................................................................................................... 26 
2.4 
Rationale for the Planned Trial .................................................................................. 28 
2.4.1 Brequinar Starting Dose Selection ................................................................................. 28 
2.5 
Risk/Benefit of Brequinar .......................................................................................... 29 
2.6 
Risks Associated with Participation in the Clinical Study ......................................... 29 
2.7 
Possible Interactions with Concomitant Medical Treatments .................................... 30 
2.7.1 CYP Interactions ............................................................................................................ 30 
2.8 
Steps to be Taken to Control or Mitigate Risks ......................................................... 30 
3 TRIAL OBJECTIVES ........................................................................................................ 31 
3.1 
Primary Objective ...................................................................................................... 31 
3.2 
Secondary Objectives ................................................................................................. 31 
3.3 
Exploratory Objectives ............................................................................................... 31 
4 TRIAL DESIGN ................................................................................................................. 32 
5 TRIAL ENDPOINTS.......................................................................................................... 33 
5.1 
Primary Endpoint ....................................................................................................... 33 
5.2 
Secondary Endpoints .................................................................................................. 33 
5.3 
Exploratory Endpoints................................................................................................ 33 
6 TRIAL POPULATION ....................................................................................................... 34 
6.1 
Number of Subjects .................................................................................................... 34 
6.2 
Inclusion criteria ......................................................................................................... 34 
6.3 
Exclusion Criteria ....................................................................................................... 34 
6.4 
Inclusion of Women and Minorities........................................................................... 35 
7 STUDY TREATMENTS .................................................................................................... 36 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 3 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
7.1 
Description of Brequinar: ........................................................................................... 36 
7.2 
Treatment Administration .......................................................................................... 36 
7.3 
Safety/Tolerability ...................................................................................................... 36 
7.3.1 Safety/Tolerability – Subject Level ............................................................................... 36 
7.3.1.1 
Hematologic Toxicity 
37 
7.3.2 Safety/Tolerability – Cohort Level ................................................................................ 37 
7.4 
Cohort Starting Doses ................................................................................................ 37 
7.5 
Individual Dose Adjustment Guidelines .................................................................... 38 
7.6 
Medication/AE Diary ................................................................................................. 41 
7.7 
Bone Marrow Biopsy ................................................................................................. 41 
7.8 
Flow Cytometry.......................................................................................................... 41 
7.9 
Expansion Cohort ....................................................................................................... 41 
7.10 Study Drug Discontinuation ....................................................................................... 41 
7.11 Brequinar Pharmacokinetics (PK) / Dihydroorotate (DHO) Plasma Levels.............. 42 
7.12 Concomitant Medication/Treatment .......................................................................... 42 
7.12.1 Gastric pH ...................................................................................................................... 42 
7.13 Treatment Compliance ............................................................................................... 42 
7.14 Storage, Stability, Labeling and Packaging ............................................................... 42 
7.14.1 Storage and Stability ...................................................................................................... 42 
7.14.2 Labeling and Packaging ................................................................................................. 43 
7.14.3 Blinding and Randomization ......................................................................................... 43 
7.14.4 Unblinding/Expectedness .............................................................................................. 43 
7.14.5 Study Drug Accountability ............................................................................................ 43 
8 CONDUCT OF THE TRIAL.............................................................................................. 45 
8.1 
Ethical and Regulatory Considerations ...................................................................... 45 
8.2 
Informed Consent ....................................................................................................... 45 
8.3 
Institutional Review Board / Ethics Committees ....................................................... 46 
8.4 
Schedule of Events ..................................................................................................... 46 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 4 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
8.5 
Screening Visit (Study Days -14 to -1) ...................................................................... 47 
8.6 
Compliance with Study Procedures ........................................................................... 50 
8.7 
Early Withdrawal from the Study .............................................................................. 50 
8.8 
Early Termination of the Study .................................................................................. 51 
8.9 
Short Messaging Service (SMS) Medication Reminders ........................................... 51 
9 ADVERSE EVENT REPORTING..................................................................................... 53 
9.1 
Classification of Causality ......................................................................................... 55 
9.2 
Classification of Severity ........................................................................................... 55 
9.3 
Serious Adverse Event (SAE) Reporting ................................................................... 55 
9.4 
Suspected Unexpected Serious Adverse Reactions (SUSARs) ................................. 57 
9.5 
Pregnancies................................................................................................................. 57 
9.6 
Hematologic Adverse Events ..................................................................................... 58 
9.7 
Management of Myelosuppression ............................................................................ 59 
9.8 
Differentiation Syndrome ........................................................................................... 59 
9.9 
Tumor Lysis Syndrome (TLS) ................................................................................... 60 
9.10 Infection Prophylaxis ................................................................................................. 62 
9.11 Growth Factor Support ............................................................................................... 62 
9.12 Management of Nausea, Vomiting, and Diarrhea ...................................................... 62 
10 STATISTICAL CONSIDERATIONS................................................................................ 63 
10.1 Study Populations for Analysis .................................................................................. 63 
10.2 Safety Analyses .......................................................................................................... 63 
10.3 Efficacy Analyses ....................................................................................................... 64 
10.4 Other Endpoints.......................................................................................................... 66 
10.5 Sample Size Considerations ....................................................................................... 67 
10.6 Randomization ........................................................................................................... 67 
10.7 Pooling of Study Centers............................................................................................ 67 
10.8 Interim Analysis ......................................................................................................... 67 
11 INVESTIGATOR RESPONSIBILITIES ........................................................................... 68 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 5 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
11.1 Investigator’s Performance ........................................................................................ 68 
11.2 Confidentiality ............................................................................................................ 68 
11.3 Source Documentation ............................................................................................... 68 
11.4 Data Collection ........................................................................................................... 69 
11.5 Case Report Forms, Investigator’s Site File and Record Retention ........................... 69 
11.6 Non-Protocol Research .............................................................................................. 70 
11.7 Publication .................................................................................................................. 70 
12 SPONSOR RESPONSIBILITIES ...................................................................................... 71 
12.1 General ....................................................................................................................... 71 
12.2 Indemnity ................................................................................................................... 71 
12.3 Data Monitoring ......................................................................................................... 71 
12.4 Audit ........................................................................................................................... 71 
12.5 Confidentiality ............................................................................................................ 72 
12.6 Finance ....................................................................................................................... 72 
13 REFERENCES ................................................................................................................... 73 
14 APPENDICES .................................................................................................................... 75 
14.1 APPENDIX A:  CCB-01 Schedule of Events ............................................................ 75 
14.2 APPENDIX B: ECOG Performance Status Criteria .................................................. 78 
14.3 APPENDIX C: Brequinar/DHO Plasma Sampling .................................................... 79 
14.4 APPENDIX D: Common Terminology Criteria for Adverse Events (CTCAE) ....... 80 
14.5 APPENDIX E:  Sample Subject Consent Form ......................................................... 81 
 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 6 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
LIST OF TABLES 
 
 
Table 1. 
Exceptions to Grade 3 Nonhematologic AEs ............................................................. 37 
Table 2. 
Intra-Subject Dose Adjustment .................................................................................. 38 
Table 3. 
Analysis Sets............................................................................................................... 63 
Table 4. 
Efficacy Analyses ....................................................................................................... 64 
 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 7 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
LIST OF FIGURES 
 
Figure 1. Dose Adjustment – Subject Level .............................................................................. 40 
Figure 2. Monitoring of Tumor Lysis Syndrome ....................................................................... 61 
 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 8 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
ABBREVIATIONS 
Abbreviation 
Definition 
µg 
Microgram 
5-FU 
5-Fluorouracil  
AUC 
Area Under Curve 
BID 
Bis in die (two times a day) 
C6min 
Concentration at 6 minutes 
CHO/HGPRT 
Chinese hamster ovary cell/hypoxanthine-guanine phosphoribosyl-transferase 
CL 
Clearance 
ClR 
Low Renal Clearance 
ClT 
Low Plasma Total Clearance 
CRh 
Partial hematological response 
CRi 
Incomplete hematological response 
CT 
Computerized Tomography 
CYP 
Cytochrome P450 
DHO 
Dihydroorotate 
DHODH 
Dihydroorotate dehydrogenase 
DLT(s) 
Dose-Limiting Toxicity(ies) 
DNA 
Deoxyribonucleic Acid 
ECGs 
Electrocardiograms 
ECOG 
Eastern Cooperative Oncology Group 
ED50 
Median Effective Dose  
EORTC 
European Organisation for the Research and Treatment of Cancer 
ESR 
Erythrocyte Sedimentation Rate 
F 
Bioavailability  
FDA 
United States Food and Drug Administration 
g 
Grams 
GI 
Gastrointestinal 
G-R 
Good Risk Patients 
HPLC 
High-Performance Liquid Chromatography 
HIPAA 
Health Insurance Privacy and Portability Act 
Hr 
Hour 
IB 
Investigator Brochure 
IP 
Intraperitoneal 
IV 
Intravenous 
kg 
Kilograms 
l 
Liters 
LD(10, 50, 90) 
Lethal Dose(10%, 50%, 90%) 
LPS 
Lipopolysaccharide 
M 
Molar 
Mg 
Milligram 
mL 
Milliliters 
MLED10 
Mouse Equivalent Lethal Dose for 10% of population 
mM 
Micromolar 


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Mm 
Millimeters 
MRD 
Minimal Residual Disease 
MRT 
Long Median Residence Time 
MS 
Mucositis/stomatitis 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
NCI 
United States National Cancer Institute 
NMR 
Nuclear Magnetic Resonance Spectroscopy 
NSC 
National Service Center 
ORR 
Overall Response Rate 
PK 
Pharmacokinetic(s) 
PO 
Per Orem 
P-R 
Poor Risk Patients 
PR 
Partial Response 
PS 
Performance Status 
Pts. 
Patients 
QTcF 
Corrected QT interval by Fredericia 
RDP2 
Recommended Dose for Phase II 
RNA 
Ribonucleic Acid 
SC 
Subcutaneous  
SD 
Standard Deviation 
SE 
Standard Error 
SEM 
Standard error of the means 
SI 
Simulation Index 
t½  
Half-Life 
TEAE 
Treatment-emergent adverse event 
USP 
United States Pharmacopeia 
UV 
Ultraviolet 
V 
Volume 
Vd 
Volume of Distribution 
VdSS 
Steady-State Volume of Distribution 
WBC 
White Blood Cell 
WHO 
World Health Organization 
 


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CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
1 
SYNOPSIS 
IND 
138,335 
Title 
A Phase 1b/2a open-label, multi-center study to assess the safety, efficacy 
and pharmacokinetics of intrapatient dose-adjusted brequinar and inhibition 
of dihydroorotate dehydrogenase (DHODH) in adult subjects with acute 
myelogenous leukemia (AML) 
Protocol 
CCB-01 
Investigational 
Medicinal 
Product and 
Dosage 
Brequinar is available as 100 and 250 mg oral capsules to be taken every 
3.5 days with approximately 240 mL of water. Each subject’s mg/m2 dose 
will be calculated based on body surface area at study entry; actual dose 
will be rounded down to the nearest mg based on available oral capsule 
doses.  
Primary 
Objective 
● To determine the safety and tolerability of brequinar and the DHODH 
inhibitory level of brequinar in adult patients with AML. 
Secondary 
Objectives 
 
 
● To determine the overall response rate (ORR) including complete 
remission (CR), CR with incomplete hematologic recovery (CRi), 
morphologic leukemia-free state (MLFS), and partial remission (PR) 
(criteria as defined in the ELN Guidelines, Döhner et al., 2017) and 
complete remission with partial hematological recovery (CRh). 
● To assess the rate of overall survival (OS) and event-free survival 
(EFS). 
● To evaluate duration of response.  
● To characterize the pharmacokinetic (PK) profile of brequinar. 
● To characterize the dihydroorotate (DHO) plasma levels of brequinar 
after oral dosing. 
Exploratory 
Objectives 
● To assess the relationship between DHODH inhibition and the efficacy 
and safety of brequinar.  
● To evaluate molecular and cellular biomarkers that may be predictive of 
antitumor level and/or treatment resistance including cytogenetics, 
molecular profiling, and flow cytometry during and after treatment. 
● To evaluate global gene expression profiles, DNA methylation profiles, 
and other potential prognostic markers to explore predictors of 
antitumor activity and/or resistance to treatment. 


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Design 
This will be a Phase 1b/2a multi-center, open-label, non-randomized 
clinical trial to assess the safety, tolerability and efficacy of dose-adjusted 
brequinar in adult subjects with AML. The study will also assess the 
inhibition of DHODH and the PK profile of brequinar in plasma. Subject 
dosing will be adjusted based on safety/tolerability and DHO level. 
Up to 27 subjects are planned to be entered in this trial: Cohort 1 will have 
6 subjects; two additional cohorts of 3 subjects each may be added if the 
Cohort 1 starting doses require adjustment. Following completion of 
enrollment in the cohort dose-adjustment part of the study, an expansion 
cohort of 15 subjects will be enrolled with a starting dose of the highest 
tolerated starting dose from Cohorts 1 – 3. Safety and tolerability will be 
assessed utilizing physical examination, vital sign measurements, safety 
laboratory testing, 12-lead ECGs and bone marrow sampling, and adverse 
event reporting. Bone marrow sampling (bone marrow aspirate and core 
biopsy) will also be utilized for efficacy. DHO level will be measured using 
a validated assay. PK will be analyzed using standard PK parameters.  
Dosing will continue for up to 12 months in the absence of unacceptable 
toxicity or disease progression.  
Primary 
endpoints: 
● Safety/tolerability and DHO level relationship with safety and 
therapeutic brequinar levels   
Secondary 
endpoints: 
● Rates of treatment-emergent adverse events. 
● Overall Response Rate (ORR) including CR, CRi, CRh, MLFS, or PR. 
● Event free survival (EFS). 
● Duration of response. 
● PK profile of brequinar. 
● DHO plasma profile. 
Exploratory 
endpoints: 
● Relationship between DHODH inhibition and the efficacy and safety of 
brequinar. 
● Antitumor level based on molecular and cellular biomarkers including 
cytogenetics, molecular profiling, and flow cytometry during and after 
treatment. 
● Global gene expression profiles, DNA methylation profiles, and other 
potential prognostic markers to explore predictors of antitumor activity 
and/or resistance to treatment 
Sample Size: 
Up to 27 subjects  


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CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
Number of 
Sites: 
3 – 5 
Study Period: 
An enrollment period of 18 - 24 months is expected. 
Inclusion 
Criteria: 
 
1. Willing and able to provide written informed consent for the trial. 
2. Patients 18 years of age or older, with relapsed/refractory AML by 
World Health Organization classification that have failed prior 
standard therapy and for which no standard therapies are available that 
result in a durable remission. 
3. ECOG Performance Status 0 to 2. 
4. Cardiac ejection fraction ≥ 40% 
5. Adequate hepatic function (unless deemed to be related to underlying 
leukemia). 
a. Direct bilirubin ≤ 2 x ULN 
b. ALT ≤ 3 x ULN 
c. AST ≤ 3 x ULN 
6. Adequate renal function as documented by creatinine clearance ≥ 30 
mL/min based on the Cockcroft-Gault equation. 
7. In the absence of rapidly proliferative disease, the interval from prior 
leukemia-directed therapy to time of study initiation will be at least 7 
days for cytotoxic or non-cytotoxic (immunotherapy) agents. Hydrea 
is allowed up to 48 hours prior to the first dose for patients with 
rapidly proliferative disease.  
8. The effects of brequinar on the developing human fetus are unknown. 
For this reason, women of child-bearing potential and men must agree 
to use adequate contraception (hormonal or barrier method of birth 
control; abstinence) prior to study entry and for the duration of study 
participation. Should a woman become pregnant or suspect she is 
pregnant while she or her partner is participating in this study, she 
should inform her treating physician immediately. Men treated or 
enrolled on this protocol must also agree to use adequate 
contraception prior to the study, for the duration of study 
participation, and for 90 days after completion of brequinar 
administration. 
9. Male subjects must agree to refrain from sperm donation from initial 
study drug administration until 90 days after the last dose of study 
drug. 


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Exclusion 
Criteria: 
1. White blood count > 25 x 109/L (note: hydroxyurea is permitted to 
meet this criterion). 
2. Any concurrent uncontrolled clinically significant medical condition, 
laboratory abnormality, or psychiatric illness that could place the 
participant at unacceptable risk of study treatment. 
3. QTc interval using Fridericia’s formula (QTcF) ≥ 470 msec. 
Participants with a bundle branch block and prolonged QTc interval 
may be eligible after discussion with the medical monitor. 
4. The use of other chemotherapeutic agents or anti-leukemic agents is 
not permitted during study with the following exceptions: 
a. Intrathecal chemotherapy for prophylactic use or maintenance of 
controlled CNS leukemia. 
b. Use of hydroxyurea for the purpose of leukemic cytoreduction may 
be allowed during the first 2 weeks of therapy if in the best interest 
of the participant and is approved by the medical monitor. 
Hydroxyurea can be used to treat leukocytosis if concurrent with 
and thought to be associated with presumed differentiation 
syndrome.  
5. AML relapse less than 6 months following stem cell transplantation.  
6. Presence of graft versus host disease (GVHD) which requires an 
equivalent dose of ≥ 0.5 mg/kg/day of prednisone or therapy beyond 
systemic corticosteroids (e.g. cyclosporine or other calcineurin 
inhibitors or other immunosuppressive agents used for GVHD). 
7. Active cerebrospinal involvement of AML. 
8. Diagnosis of acute promyelocytic leukemia (APL) 
9. Clinically active hepatitis B (HBV) or hepatitis C (HCV) infection. 
10. Severe gastrointestinal or metabolic condition that could interfere with 
the absorption of oral study medication. 
11. Prior malignancy, unless it has not been active or has remained stable 
for at least 3 years. Participants with treated non-melanoma skin 
cancer, in situ carcinoma or cervical intraepithelial neoplasia, 
regardless of the disease-free duration, are eligible if definitive 
treatment for the condition has been completed. Participants with 
organ-confined prostate cancer with no evidence of recurrent or 
progressive disease are eligible if at the active surveillance stage, 
hormonal therapy has been initiated, or the malignancy has been 
surgically removed or treated with definitive radiotherapy. 


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12. Nursing women or women of childbearing potential (WOCBP) with a 
positive urine pregnancy test. 
Treatment 
Subjects will self-administer oral brequinar twice weekly (every 84 hours 
+/- 6 hours). Treatment cycles will be 2 weeks. Visits will take place at 
least every 2 weeks through 3 months; visits thereafter will be every 2 – 4 
weeks at the discretion of the investigator at each site. Inter-cohort and 
intra-subject dose adjustments may occur throughout the study as outlined 
in the sections below. 
Procedures 
Screening Visit (Study Days -14 to -1) 
These procedures must be completed within the 14 days prior to starting 
dosing. Obtain the subject’s written informed consent, then collect baseline 
information: 
- Demographics (height, weight, date of birth, gender, race, ethnicity) 
- Pertinent medical/surgical history (including AML diagnosis and 
laboratory and clinical evidence of progression, previous AML 
treatment, and any available chromosomal and mutational testing 
results per institutional guidelines) 
- Concomitant medications. 
- Physical examination (including weight).  
- Vital signs (heart rate, respiratory rate, blood pressure, body 
temperature).  
- Pregnancy test for women of childbearing potential (WOCBP).  
- ECOG performance assessment.  
- Hematology/chemistry. 
- 12-lead ECG with QTcF and MUGA scan or echocardiogram to 
assess cardiac function. 
- Bone marrow sampling  
- Confirm subject meets all inclusion and no exclusion criteria. 
Treatment 
The treatment period begins with Cycle 1, Day 1 of the first 2-week dosing 
cycle. 
Cycle 1 Day 1: 
- Collect any adverse events or new concomitant medications since 
Screening.  
- Draw samples for baseline (pre-dose) brequinar/DHO, flow 
cytometry, and hematology/chemistry.  
- Conduct physical examination (including weight), vital signs, urine 
pregnancy test for WOCBP, and 12-lead ECG.  
- Review results and confirm subject remains eligible for the study.  


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- Determine subject’s starting dose based on the respective cohort 
mg/m2 starting dose. 
- Dispense study medication.  
- Subject is to take the first dose at the clinic and remain for 
brequinar/DHO sampling. Collect brequinar/DHO samples at 1, 2, 4, 
and 6 hours post dose. 
- Process and store brequinar/DHO samples per the supplied 
laboratory manual. 
- Dispense the subject’s calendar/diary. The diary will collect 
dates/times of study medication administration and AEs/new 
concomitant medications. 
- Enroll subject for text message reminders if the subject consents to 
that service.  
- Ship the flow cytometry sample per the supplied laboratory manual. 
Cycle 1 Day 2:  
- Collect 24h post dose brequinar/DHO and flow cytometry samples. 
Check the diary/elicit information about AEs/new concomitant 
medications since the last visit. 
- Process and store brequinar/DHO samples per the supplied 
laboratory manual. 
- Ship the flow cytometry sample per the supplied laboratory manual. 
Cycle 1 Day 3:  
- Collect 48h post dose brequinar/DHO and flow cytometry samples. 
Check the diary/elicit information about AEs/new concomitant 
medications since the last visit.  
- Process and store brequinar/DHO samples per the supplied 
laboratory manual. 
- Ship the flow cytometry sample per the supplied laboratory manual. 
Cycle 1 Day 4:  
- Collect 72h post dose brequinar/DHO samples. Check the 
diary/elicit information about AEs/new concomitant medications 
since the last visit. 
- Process and store brequinar/DHO samples per the supplied 
laboratory manual. 
Cycle 1 Day 8:  
- Vital signs. 
- Check the diary/elicit information about AEs/new concomitant 
medications since the last visit. 
- Prior to the morning dose, collect brequinar/DHO samples 
(approximately 84h post the second dose of Cycle 1) and 
hematology/chemistry samples, then have subject take study 
medication.  


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- Process and store brequinar/DHO samples per the supplied 
laboratory manual. 
- Notify DHO assay laboratory of incoming shipment and ship Cycle 
1 brequinar/DHO samples (samples from Days 1, 2, 3, 4 and 8). 
 
Cycle 2 (and any Dose Adjustment Cycle) 
Repeat this visit as needed whenever any dose adjustment is required. 
Day 1:  
- Collect unused study medication and check the diary/elicit 
information about AEs/new concomitant medications since the last 
visit.  
- Take vital signs and perform physical examination (including 
weight). 
- Collect pre-dose brequinar/DHO samples (approximately 84h post 
the fourth dose of the previous cycle) and hematology/chemistry 
samples.  
- Process and store brequinar/DHO samples per the supplied 
laboratory manual. 
- Review laboratory results/safety information and determine whether 
the subject should adjust the dose (based on acceptable safety and 
DHO level), continue with the current dose or hold study medication 
(unacceptable safety) per the guidelines below.  
- If dosing will continue, dispense study medication.  
- Dispense calendar/diary. 
- Manage text message reminders as needed (as a default do nothing, 
pause if study medication is put on hold, and restart if study 
medication is restarted) 
Day 8:  
- Collect and check the diary/elicit information about AEs/new 
concomitant medications since the last visit. 
- Vital signs. 
- Collect pre-dose brequinar/DHO and hematology/chemistry samples. 
- Perform bone marrow sampling for flow cytometry (window ±7 
days). 
- If the subject is being dosed (i.e., has acceptable safety), have the 
subject take the morning dose.  
- Process and store brequinar/DHO samples per the supplied 
laboratory manual. 
- If the subject’s medication was held, review safety information and 
determine whether dosing can resume. If dosing can resume, 
determine dose, dispense adequate medication for 4 doses and have 
the subject take the morning dose.  


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- Continue to withhold study drug if safety remains unacceptable. 
- Dispense calendar/diary. 
- Manage text message reminders as needed (as a default do nothing, 
pause if study medication is put on hold, and restart if study 
medication is restarted) 
- Notify DHO assay laboratory of incoming shipment and ship 
brequinar/DHO samples (samples from current cycle's Days 1 and 
8). 
 
Subjects may undergo dose adjustments at any time using the guidelines 
presented above. Subjects with acceptable safety can continue to escalate 
every 2 weeks by 150 mg/m2 increments through 800 mg/m2. Subjects with 
unacceptable safety can continue to undergo dose reductions of 75 mg/m2 
with no lower limit. Re-escalation to a dose previously shown as not 
tolerated for an individual subject is not permitted for these subjects. 
Dose adjustments are permitted throughout the study for an individual 
subject based on safety, DHO level, and clinical response with an upper 
limit of 800 mg/m2. 
Maintenance Dose Cycle (visit every 2 - 4 weeks) 
Once a subject reaches a stable or maintenance dose (see Figure 1), the 
subject will be in the Maintenance Dose Cycle.  
In the first 3 months from starting study drug, the Maintenance Dose Cycle 
procedures will occur every 2 weeks (with the exception of bone marrow 
aspiration as discussed below). After completing 3 months from starting 
study drug, subjects may come to the clinic for a Maintenance Dose Cycle 
visit every 2 - 4 weeks (visit interval at the investigator’s discretion). 
A subject may still move into a Dose Adjustment Cycle after a maintenance 
dose if required for a change in safety, DHO level or clinical response 
(Figure 1).  
Day 1: 
 
- Collect unused study medication and check the diary/elicit 
information about AEs/new concomitant medications since the last 
visit. 
- Collect pre-dose brequinar/DHO and hematology/chemistry samples.  
- Conduct physical examination, vital signs, urine pregnancy test for 
WOCBP, 12-lead ECG and bone marrow sampling (note that bone 
marrow is collected on study Day 22 (C2D8 ± 7 days), at Day 43, 
and then every 12 weeks; only the Day 43 sample will be assessed 
for hematological toxicity).  


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- Review the laboratory results/safety information and determine 
whether the subject should maintain current dose (acceptable safety) 
or hold study medication (unacceptable safety).  
- Dispense study medication. 
- Dispense calendar/diary.  
- Manage text message reminders as needed (as a default do nothing, 
pause if study medication is put on hold, and restart if study 
medication is restarted) 
- Notify DHO assay laboratory of incoming shipment and ship 
brequinar/DHO samples. 
Final Visit 
This visit is to take place when a subject is discontinuing from the study. 
- Collect and check the diary/elicit information about AEs/new 
concomitant medications since the last visit.  
- Collect brequinar/DHO and hematology/chemistry samples.  
- Collect unused study medication. 
- Conduct physical examination, vital signs, urine pregnancy test for 
WOCBP, 12-lead ECG and bone marrow sampling (do not collect 
bone marrow if < 4 weeks since previous bone marrow sample 
obtained).  
- Review the safety information and determine whether the subject has 
acceptable safety or unacceptable safety. 
- Notify DHO assay laboratory of incoming shipment and ship 
brequinar/DHO samples.  
- Stop text message reminders. 
 
Follow Up Visit (2 weeks after Final Visit) 
- Contact subject to elicit information about AEs/new concomitant 
medications since the last visit. 
Survival information will be collected while the study is ongoing. 
Unscheduled Visits 
Unscheduled visits and tests to assess AEs are permitted as needed. 
Safety/ 
Tolerability 
Safety/Tolerability – Subject Level 
Acceptable safety/tolerability for a subject through Day 42 is defined as no 
≥ Grade 3, treatment-emergent, study-drug-related, non-hematologic 
adverse events. Due to the expected hematologic profile associated with 
AML, hematologic AEs of any grade will not be considered dose-limiting 
during the first 42 days of dosing. Exceptions to the non-hematologic 
Grade 3 criterion are provided in the table below.  


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Exceptions to Grade 3 Nonhematologic AEs  
Condition 
Exception Description  
Nausea/ 
Emesis 
Grade 3 nausea and/or emesis resolving to less than or 
equal to Grade 2 or baseline within 1 week after the use 
of an optimal antiemetic regimen based on standard 
practice. 
Diarrhea 
Grade 3 diarrhea resolving to less than or equal to Grade 
1 or baseline within 1 week after receiving the maximal 
supportive therapy based on standard practice. 
Fatigue 
Grade 3 fatigue lasting less than 1 week. 
Laboratory 
abnormalities 
Asymptomatic Grade 3 laboratory abnormalities that are 
not considered to be clinically significant. 
Hematologic Toxicity 
After the subject has completed the first 42 days of treatment, the definition 
of unacceptable safety expands to include hematologic AEs defined as ≥ 
Grade 4 neutropenia and/or thrombocytopenia, with a hypocellular bone 
marrow and no greater than 5% marrow blasts lasting for ≥ 2 weeks. 
Anemia will not be considered a hematologic AE for the definition of 
unacceptable safety. For clinic visits when bone marrow sampling is 
scheduled, the timing of the bone marrow sampling can be adjusted to 
ensure that the results are available at the time of the clinic visit. 
Safety/Tolerability – Cohort Level 
Acceptable safety for a cohort starting dose is defined as having acceptable 
safety for the majority of subjects in that cohort at that starting dose (e.g., 4 
out of a cohort’s 6 subjects have no non-hematologic AEs ≥ Grade 3 with 
exceptions noted in table above). 
Cohort Starting 
Doses 
Cohort 1 will treat 6 subjects at a starting dose of 500 mg/m2 twice weekly.  
If there is unacceptable safety/tolerability and/or inadequate DHO level at a 
starting dose for the majority of subjects in a cohort, up to two additional 
cohort(s) of 3 subjects will be added. The starting doses for each 
subsequent cohort may be increased or decreased by up to 300 mg/m2 up to 
a maximum starting dose of 800 mg/m2 based on both safety/tolerability 
and adequacy of DHO level. Cohort starting doses will be jointly 
determined by the Sponsor and investigators and communicated to the 
study teams.  
See the “Intra-subject dose adjustment” section for individual subject 
dosing adjustment criteria. 
Expansion 
Cohort 
Once a cohort starting dose has been reached that has adequate DHO level 
and acceptable safety/tolerability in a majority of the cohort’s subjects, 15 
subjects will be added at that cohort’s starting dose. Decisions about 


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adequacy of DHO level will be made following review of these data from 
each cohort. These subjects may also undergo individual dose adjustment. 
Individual Dose 
Adjustment 
Guidelines 
Intra-subject dose adjustment will be considered every 2 weeks depending 
on safety and DHO levels. There is a maximum of 2 dose adjustments 
within the first 42 days of initiating treatment. Each subject’s dose can be 
escalated, maintained (stable dose), held then reduced, or discontinued. The 
highest dose planned is 800 mg/m2, however, this upper limit may be 
adjusted depending on safety, DHO level, and clinical response. There is no 
lower limit planned. 
As noted above, safety will be a key part of determining dose adjustments. 
Subjects who resume dosing at a lower dose after experiencing 
unacceptable safety may not undergo later dose escalations beyond the dose 
where the unacceptable safety occurred.  
Each subject will continue dosing twice weekly at the individually adjusted 
dose for up to 12 months in the absence of unacceptable toxicity or disease 
progression. Intra-subject dose adjustment is permitted at any time 
throughout the study based on safety/tolerability and DHO level (Figure 1). 
Subjects who discontinue due to unacceptable safety/tolerability or die 
prior to Day 42 will not be replaced.  
Intra-subject dose adjustment increments and duration of dosing may be 
revised from planned amounts after each preceding cohort’s safety, DHO 
plasma levels and bone marrow results have been reviewed.  
Each subject’s baseline DHO sample will be obtained at C1D1 prior to 
dosing. Dose adjustment decisions based on DHO will be determined by 
DHO trough level (i.e., DHO level obtained pre-dose D8 of the previous 
cycle). The initial target for “adequate” trough DHO level will be set at the 
higher of either 100 ng/mL or 2X the subject’s baseline DHO level (see the 
brequinar Investigator’s Brochure (IB)). This target may be adjusted during 
the study depending on safety or efficacy signals observed during the study. 
As described below, dose adjustments are also based on safety and whether 
the dose has reached the planned upper limit (currently planned to be 800 
mg/m2). 
The intrasubject dose-adjustment criteria are presented below.  
Intrasubject Dose Adjustment Criteria 
Acceptable 
Safety/Tolerability? 
(see safety definition 
above) 
Adequate 
DHO Level? 
Planned Intra-Subject Dose 
Adjustment 
Yes 
Yes 
Maintain; continue at same dose. 


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Yes 
No 
Escalate by 150 mg/m2 for the next 2-
week cycle up to a maximum of 800 
mg/m2. 
No 
Regardless of 
DHO  
Hold two doses (one week), then reassess 
AE; if AE has resolved to ≤ Gr. 2, de-
escalate dose by 75 mg/m2 and resume 
dosing. If AE has not resolved, reassess 
again in one week.  
If AE does not resolve to ≤ Gr. 2 by two 
weeks after dosing held, discontinue 
further dosing. Subject will remain in the 
study for safety follow up for 42 days 
after last dose of study drug or until AEs 
have resolved or become stable. 
 
Brequinar/DHO  Plasma brequinar/DHO samples are to be obtained for each subject for the 
first study dose (Cycle 1 Dose 1 for that subject). Sample scheduling is 0 
hours (prior to dosing), and post dose at 1, 2, 4, 6, 24, 48, and 72 hours. 
Note that this schedule does not apply to subjects in the expansion cohort 
who will have trough sampling only prior to the start of each two-week 
cycle. 
A brequinar/DHO trough sample is to be obtained prior to dosing on Day 8 
(C84, 84 hours after the Cycle 1 Day 4 dose) of Cycle 1, and prior to dosing 
on Days 1 and 8 of Cycles 2 and 3.  
The 84-hour post dose brequinar/DHO sample is to be repeated prior to 
dosing at the beginning of each 2-week cycle and at the Final Visit. This 
sampling schedule also applies for the expansion cohort subjects.  
Statistical 
Analysis 
A separate, detailed statistical analysis plan (SAP) will be finalized prior to 
locking the database. All analyses of safety and anti-leukemic activity for 
this open-label, early Phase study will be descriptive in nature and 
presented by dose group and overall, as appropriate, for the dose-
adjustment phase and the expansion phase. Procedures for accounting for 
missing, unused and spurious data will be described in the SAP.   
Summaries for quantitative variables will include the mean, median, 
quartiles, standard deviation and error, minimum, and maximum. For 
qualitative variables, the summaries will include the number and 
percentage of subjects for each outcome, and the exact 95% CI, when 
appropriate. No hypothesis testing will be performed. Any statistical testing 
will be considered exploratory and descriptive. All computations will be 
performed using SAS® (Version 9.3 or higher). 
Subject disposition, subject demographics and baseline characteristics will 
be summarized. Subject data listings will also be provided.  


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PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 23 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
dose of brequinar. Censoring rules for time-to-event endpoints will be 
described in the SAP. 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 24 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
STUDY PERSONNEL 
SPONSOR CONTACT 
Name: 
Barbara Powers, MSN, Ph.D. 
Title: 
Clinical Operations 
Address: 
Clear Creek Bio, Inc. 
585 Massachusetts Avenue, 4th Floor, 
Cambridge, MA 02139 
Telephone No.: 
484-686-0545 
Fax No.: 
617-863-2082 
E-mail: 
bpowers@clearcreekbio.com 
 
SPONSOR MEDICAL CONTACT 
Name:  
Robert Sims, MD 
Title: 
Senior Medical Director / Medical Monitor  
Address: 
Novella Clinical 
1700 Perimeter Park Drive 
Morrisville, NC 27560   
Telephone No.: 
614-721-2630 
24-hour Safety No.: 
1-866-758-2798 or 919-313-7111 
E-mail: 
robert.sims@novellaclinical.com;  
YYA36071medmon@novellaclinical.com  
Medical Monitor Fax No.: 
206-826-0483 
 
SAE Reporting Fax:     
       919.313.1412 (US Toll-free:  1-866-761-1274) 
SAE Reporting email:  
       safety-inbox@novellaclinical.com 
 
LEAD INVESTIGATOR 
Name: 
Amir Fathi, MD 
Title: 
Assistant Professor of Medicine 
Affiliation: 
Massachusetts General Hospital 
Telephone No.: 
617-724-1124 
E-mail: 
afathi@mgh.harvard.edu 
 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 25 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
SUPPORT SERVICES 
 
CRO Project Manager 
Name: 
Daniel Ferrone 
Company: 
Novella Clinical 
Address: 
1700 Perimeter Park Drive 
Morrisville, NC 27560 
Telephone No.: 
919-972-7158 
Mobile No.: 
704-806-7219 
Fax No.: 
919-710-8769 
E-mail: 
dferrone@novellaclinical.com  
 
Data Management/eCRF PROVIDER 
Name: 
Company: 
Address: 
 
Telephone No.: 
Kari Hayden 
Novella Clinical 
1700 Perimeter Park Drive 
Morrisville, NC 27560  
919-972-2397 
Help Desk: 
1-866-342-0693 
Help Desk E-mail: 
sitesupport@novellaclinical.com 
 
STATISTICAL ANALYSIS 
Name: 
Young Choy 
Title: 
Senior Biostatistician 
Telephone No.: 
919-972 -7423 
Fax No.: 
919-710-8769 
E-mail: 
ychoy@novellaclinical.com 
 
STUDY DRUG HOLDING COMPANY 
Name: 
Almac Clinical Services 
Address: 
25 Fretz Road 
Souderton, PA 18964 
Telephone No.: 
215-660-8500 
Email:  
clinicalservices@almacgroup.com 
 
 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 26 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
2 
INTRODUCTION 
2.1 Background: Acute Myeloid Leukemia 
Acute myeloid leukemia (AML) is a malignant disorder of immature hematopoietic cells, 
characterized by differentiation arrest and rapid proliferation of abnormal myeloid precursors. 
These abnormal cells accumulate in the bone marrow and interfere with the production of normal 
blood cells. More than 20,000 people are diagnosed with AML per year in the United States (US) 
(SEER, 2015). The median age at diagnosis is 67 years. 
Although there have been recent advances including midostaurin, enasidenib, CPX-351, 
gemtuzumab ozogomycin and venetoclax, outcomes for patients with AML remain poor. With 
modern treatment regimens, expected complete remission (CR) rates are 60-70%, but long-term 
cure rates are 15-25%. Younger patients (i.e. those 50 years of age or younger) with diploid 
karyotypes have a CR rate of 70-80% and cure rates of 20-25%, while older patients and/or those 
with adverse cytogenetics have CR rates of 35-50% and cure rates of < 10%.1  It is therefore critical 
to improve both the remission rate and the durability of remission in AML patients of all ages. 
2.2 Dihydroorotate dehydrogenase (DHODH) 
Dihydroorotate dehydrogenase (DHODH) catalyzes the fourth step in pyrimidine synthesis, the 
conversion of dihydroorotate (DHO) to orotate. The enzyme is located on the inner mitochondrial 
membrane and transfers electrons between DHO and complex III of the electron-transport chain 
via the reduction of its ubiquinone (coenzyme Q10) cofactor.  
DHODH is a ubiquitous enzyme, and lack of its level is not compatible with life. The Miller 
syndrome, a rare autosomal recessive disorder in which patients have inherited hypomorphic 
mutations in both alleles of DHODH, results in multi-organ dysfunction (Ng 2010). Two weak 
inhibitors of human DHODH are approved for clinical use. Leflunomide, a pro-drug, is used in the 
treatment of patients with rheumatoid arthritis. Its active form, teriflunomide, is marketed for 
multiple sclerosis. Leflunomide is known to affect erythroid differentiation of K562 cells in vitro, 
via the depletion of uridine triphosphate (UTP) and cytidine triphosphate (CTP) ribonucleotides 
(Huang 2002). Despite the connection between bone marrow level, blood cell differentiation and 
DHODH, leukemia models of leflunomide have not been very promising. Leukemic mice treated 
with leflunomide demonstrated no reduction in leukemic burden and experienced significant 
weight loss and lethargy. 
Recent nonclinical studies have demonstrated that inhibition of DHODH can overcome myeloid 
differentiation arrest (Sykes et al., 2016). The mechanism through which a reduction in de novo 
pyrimidine biosynthesis modulates myeloid differentiation is not clear. The differentiation effect 
of DHODH inhibitors appears to involve a combination of inhibition of nucleic acid synthesis, 
cell-cycle arrest, and changes in the post-translational glycosylation of important protein targets.  
2.3 Brequinar 
It is well known that brequinar is a potent inhibitor of DHODH. Brequinar is one of more than 300 
quinoline-carboxylic acid derivatives prepared in an analog synthesis program in the 1980s, which 
was started after it was found that a compound of this class had antitumor activity. Brequinar was 
selected by DuPont for further development as a potential clinical drug because of its activity 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
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DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
against experimental tumors and because its water solubility made it relatively straightforward to 
formulate. Ultimately, the rationale to use brequinar for the treatment of multiple solid tumors did 
not translate into efficacy after extensive clinical development and the project was terminated by 
DuPont in 1994. Clear Creek Bio exclusively licensed the historic data from Bristol Myers Squibb 
(that acquired DuPont in 2001). 
Sykes et al. showed that brequinar’s pro-myeloid differentiation activity might be useful for the 
treatment of AML. Utilizing a high throughput screening technique, brequinar was identified as a 
compound that overcame arrest of myeloid differentiation. Brequinar triggers myeloid 
differentiation in vitro and in vivo. Brequinar was highly active in vivo, as demonstrated in 
syngeneic murine AML models (HoxA9+Meis1 and MLL/AF9) as well as xenotransplant AML 
models (THP1, HL60, MOLM13, OCI/AML3). In an aggressive MLL/AF9 murine model of 
AML, treatment with brequinar promoted myeloid differentiation, reduced leukemic cell burden, 
and improved overall survival. Brequinar also led to a reduction in the number of leukemia stem 
cells, reduced colony-formation level, and depleted the number of leukemia-initiating cell level.  
In addition, Sykes and colleagues demonstrated that treatment with brequinar was better-tolerated 
and more effective than treatment with cytotoxic chemotherapy in animal models. Brequinar was 
given for many weeks without cumulative toxicity. The effect of brequinar and DHODH inhibition 
on normal cells was also assessed through study of competitive bone marrow transplantation 
assays. Mice were treated with brequinar, 5-fluorouracil (5-FU), or induction chemotherapy, and 
their bone marrow was transplanted in competition (1:1) with normal (untreated) bone marrow to 
gauge the effect of therapy on hematopoietic stem cell (HSC) function. The fitness of HSCs from 
mice treated with brequinar were functionally equivalent to those of untreated mice when 
compared to that of HSCs exposed to 5-FU and induction chemotherapy, which promoted a 
marked decrease in fitness.  
Sykes et al. administered brequinar at a dose and schedule (every 72 hours) that was non-toxic to 
the animals yet led to eradication of the leukemia cells. This schedule of administration was based 
on data demonstrating that the pro-differentiation effect of brequinar required a period of sustained 
DHODH-inhibition of approximately three days. This observation suggests that brequinar’s 
efficacy depends on producing approximately 72-hours “time-above-threshold” to maintain 
sustained DHODH inhibition. The hypothesis is that pyrimidine starvation via inhibition of 
DHODH for approximately 72 hours elicits pro-myeloid differentiation and leads to the anti-
leukemia efficacy of brequinar.  
Sykes et al. also showed that normal cells could tolerate longer periods of pyrimidine starvation 
than their leukemic counterparts. The proposed dosing regimen of brequinar in this clinical trial, 
CCB-01, is intended to take advantage of the different sensitivity of normal and leukemic cells 
and thus spare normal cells while eradicating leukemic cells.  
A pharmacodynamic marker of enzyme inhibition (i.e. target engagement) is required to 
accomplish this type of rational dosing approach. Sykes and colleagues demonstrated how 
DHODH inhibition could be monitored by the accumulation of the substrate DHO. Indeed, 
inhibition of the DHODH enzyme led to the rapid accumulation of intracellular DHO, which was 
reflected by accumulation of DHO in plasma hence the rationale for measuring plasma DHO as 
the pharmacodynamic marker in CCB-01.  


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 28 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
Given this new information, real-time monitoring of target engagement via plasma DHO of 
DHODH inhibition in each patient should permit identification of a brequinar dose that is both 
efficacious and well-tolerated. Maintaining intermittent DHODH inhibition for prolonged 
treatment cycles may be efficacious compared to previous studies using short periods and high 
doses followed by long periods of recovery.  
The prior data on the clinical evaluation of brequinar in patients with multiple solid tumors 
provides valuable safety data that supports the safety of the proposed dosage regimen. Brequinar 
has not been studied clinically in myeloid malignancies in the past. Given encouraging pre-clinical 
results, brequinar was evaluated decades ago in phase 1 and phase 2 trials of more than 800 patients 
with advanced solid tumor malignancies (Arteaga 1989, Burris 1998, Noe 1990, Schwartsmann 
1990). These studies indicated a lack of efficacy for brequinar at the doses and schedules evaluated. 
However, many of these trials studied brequinar administered as a single, high dose infusion given 
weekly or daily x 5 days every 3-4 weeks or every day for 21 days. The lack of efficacy in the 
previous trials may have been due to the narrow therapeutic window with the high doses studied, 
and to the inability, or lack of knowledge, to use a pharmacodynamic marker such as plasma DHO 
to fine-tune a therapeutic window based on differential pyrimidine starvation of myeloid 
precursors versus normal cells.  
 
2.4 Rationale for the Planned Trial 
This study is designed to obtain safety and efficacy data for brequinar in patients with AML. 
Subject Population 
The population for this study is patients 18 years of age or older, with relapsed/refractory AML by 
World Health Organization classification that have failed prior standard therapy and for which no 
standard therapies are available that result in a durable remission. 
Study Treatments 
This is an open label study of oral brequinar using intra-subject dose adjustment. The dose-
adjustment scheme is presented in more detail in Section 7.5.  
2.4.1 Brequinar Starting Dose Selection 
The rationale underlying the proposed dosage regimen for brequinar and the use of plasma DHO 
to guide dosing is the prior demonstration using nonclinical models by Sykes et al. (2016) that 
malignant cells are more sensitive than normal cells to periods of DHODH inhibition. The 
objective is to identify a dose and regimen of brequinar that maintains suppression of DHODH 
adequate to induce differentiation and stop myeloid proliferation but avoid harming normal cells. 
These features have been realized in vivo in animal models. Specifically, intermittent dosing that 
preserved elevated levels of the metabolite DHO markedly reduced AML cells, preserved normal 
hematopoietic stem cells, and improved animal survival. These recent findings and historic  
pharmacokinetic (PK) and safety data from humans support the planned approach.  
Rather than intermittent high doses as were given by DuPont, Clear Creek proposes to use 
relatively low doses and prolonged exposure to brequinar. There will not be a lengthy conventional 


PROTOCOL NUMBER:  CCB-01  
Page 29 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
rest period as is generally required between infrequent high doses. There will instead be twice-a-
week administration of lower doses with a dosing interval that allows enough time for normal cells 
to recover from or avoid pyrimidine starvation in between the periods of DHODH inhibition. 
Based on its average half-life of 10.5 hours and what has been observed in the clinical PK data 
(see the brequinar IB), brequinar plasma levels return to baseline at about 3.5 days or 84 hours 
after an oral dose. For this reason, the proposed clinical study includes a biweekly schedule of 
brequinar dosed approximately every 84 hours, while measuring plasma DHO to fine-tune the 
dosing schedule that ensures sustained DHODH inhibition while avoiding adverse effects to 
normal cells. 
Safety data from previous oncology clinical studies of brequinar (see brequinar IB, Section 5) with 
maximum tolerated doses as high as 2250 mg/m2 repeated every 3 weeks suggest that a starting 
dose for Cohort 1 of 500 mg/m2 p.o. will be safe and well-tolerated in subjects with AML. Each 
subject’s subsequent dosing may be adjusted depending on the safety, tolerability and DHO level 
obtained during the period following dose adjustment. Each of the two planned subsequent cohorts 
may also have an adjusted starting dose, again depending on safety, tolerability and DHO level 
observed in previous cohorts. See Section 7.4. 
2.5 Risk/Benefit of Brequinar 
As presented in the brequinar IB, more than 800 patients have been exposed to this compound for 
treatment of a variety of solid tumors at various treatment regimens, doses, and routes including a 
single dose, once weekly, twice weekly, single dose every 3 weeks, daily times 5 every 4 weeks, 
and daily times 21 days for multiple courses. The maximum intravenous dose given was 2,250 
mg/m2 every 3 weeks, and the maximum oral dose was 100 mg/m2 daily for 21 days. Study results 
have not shown evidence of efficacy in solid tumors at the doses and regimens studied. However, 
the preclinical work of Sykes et al (2016) have demonstrated the efficacy of brequinar in a mouse 
model of leukemia, indicating that brequinar may be effective in patients with this type of 
leukemia. It is for this reason that study CCB-01 will study patients with AML.   
A universal hallmark of AML is the arrest of leukemic myeloblasts at an immature and self-
renewing stage of development. Therapies that can overcome differentiation arrest caused by 
DHODH represent a powerful treatment strategy. A potential benefit of brequinar treatment in 
patients with AML is that brequinar has been identified as a compound that can inhibit DHODH.  
The major risk associated with brequinar is myelosuppression, particularly a decrease in platelet 
count. Patients with AML typically have a low platelet count due to their disease, and there is a 
risk that treatment with brequinar may worsen existing thrombocytopenia. 
2.6 Risks Associated with Participation in the Clinical Study 
In studies utilizing the weekly schedule of administration in patients with refractory solid tumors, 
reversible myelosuppression, in particular thrombocytopenia, and mucositis have been the primary 
dose-limiting toxicities. In addition, skin rash, nausea/vomiting, fatigue, and leukopenia have been 
dose-limiting in trials utilizing other schedules of drug administration. The majority of these 
adverse effects have been less than grade IV in severity and resolve following discontinuation of 
dosing. Symptoms of tumor lysis syndrome have not previously been reported following exposure 
to brequinar, however clinicians will monitor for and treat this condition should it arise per the 
CONFIDENTIAL:  Clear Creek Bio, Inc. 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 30 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
guidelines presented in Section 9.9. An increased risk of infection may occur due to the 
myelosuppressive effects of brequinar (particularly neutropenia); infection prophylaxis and 
treatment are described in Sections 9.10 and 9.11. Differentiation syndrome has been seen in other 
pro-differentiating agents and will be closely followed as described in Section 9.7. 
2.7 Possible Interactions with Concomitant Medical Treatments 
Brequinar has been administered to subjects taking a variety of concomitant medications that are 
typical in cancer patients. No formal interaction studies have been conducted for these 
medications, however, there have not been any reports of interactions with any medications during 
the clinical trials with more than 800 cancer patients.  
2.7.1 CYP Interactions 
No formal drug-drug interaction studies have been performed with medications commonly used 
in treating AML. The nonclinical studies have demonstrated there is no first-pass metabolism, and 
there have been no apparent hepatotoxic effects in the clinical studies performed to date.  
2.8 Steps to be Taken to Control or Mitigate Risks 
Guidelines for the prevention, monitoring and treatment of differentiation syndrome, tumor lysis 
syndrome, infection prophylaxis and growth factor support are provided in Section 9. 


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PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 32 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
4 
TRIAL DESIGN 
This will be a Phase 1b/2a multi-center, open-label, non-randomized clinical trial to assess the 
safety, tolerability and efficacy of dose-adjusted brequinar in adult subjects with AML. The study 
will also assess the inhibition of DHODH and the PK profile of brequinar in plasma. Intra-subject 
dosing may be adjusted based on safety/tolerability and DHO level.  
Up to 27 subjects are planned to be entered in this trial: Cohort 1 will have 6 subjects; two 
additional cohorts of 3 subjects each will be added if adjustments are required to the cohort starting 
dose. Following completion of enrollment in the cohort dose-adjustment part of the study, an 
expansion cohort of 15 subjects will be enrolled with a starting dose of the highest tolerated starting 
dose from Cohorts 1 to 3. Safety will be assessed utilizing physical examination, vital sign 
measurements, safety laboratory testing, 12-lead ECGs and bone marrow sampling. Bone marrow 
sampling will also be utilized for efficacy. Tolerability will be assessed by spontaneously reported 
and elicited adverse events. DHO level will be measured using a validated assay. PK will be 
analyzed using standard PK parameters.  
Dosing will continue for up to 12 months in the absence of unacceptable toxicity or disease 
progression. 
Study procedures are presented in more detail in Section 7. 


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PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 34 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
6 
TRIAL POPULATION 
6.1 Number of Subjects 
Subjects who meet all the inclusion and none of the exclusion criteria will be enrolled in the study 
until approximately 27 subjects have completed the study.     
6.2 Inclusion criteria 
1. Willing and able to provide written informed consent for the trial. 
2. Patients 18 years of age or older, with relapsed/refractory AML by World Health 
Organization (WHO) classification that have failed prior standard therapy and for which 
no standard therapies are available that result in a durable remission. 
3. ECOG Performance Status 0 to 2. 
4. Cardiac ejection fraction ≥ 40% 
5. Adequate hepatic function (unless deemed to be related to underlying leukemia) 
a. Direct bilirubin ≤ 2 x ULN 
b. ALT ≤ 3 x ULN 
c. AST ≤ 3 x ULN 
6. Adequate renal function as documented by creatinine clearance ≥ 30 mL/min based on the 
Cockcroft-Gault equation 
7. In the absence of rapidly proliferative disease, the interval from prior leukemia-directed 
therapy to time of study initiation will be at least 7 days for cytotoxic or non-cytotoxic 
(immunotherapy) agents. Hydrea is allowed up to 48 hours prior to the first dose for 
patients with rapidly proliferative disease.  
8. The effects of brequinar on the developing human fetus are unknown.  For this reason, 
women of child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry and for the 
duration of study participation.  Should a woman become pregnant or suspect she is 
pregnant while she or her partner is participating in this study, she should inform her 
treating physician immediately.  Men treated or enrolled on this protocol must also agree 
to use adequate contraception prior to the study, for the duration of study participation, and 
for 90 days after completion of brequinar administration. 
9. Male subjects must agree to refrain from sperm donation from initial study drug 
administration until 90 days after the last dose of study drug. 
6.3 Exclusion Criteria 
1. White blood count > 25 x 109/L (note: hydroxyurea is permitted to meet this criterion). 
2. Any concurrent uncontrolled clinically significant medical condition, laboratory 
abnormality, or psychiatric illness that could place the participant at unacceptable risk of 
study treatment. 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 35 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
3. QTc interval using Fridericia’s formula (QTcF) ≥ 470 msec. Participants with a bundle 
branch block and prolonged QTc interval may be eligible after discussion with the medical 
monitor. 
4. The use of other chemotherapeutic agents or anti-leukemic agents is not permitted during 
study with the following exceptions: 
a. Intrathecal chemotherapy for prophylactic use or maintenance of controlled CNS 
leukemia. 
b. Use of hydroxyurea for the purpose of leukemic cytoreduction may be allowed 
during the first 2 weeks of therapy if in the best interest of the participant and is 
approved by the medical monitor. Hydroxyurea can be used to treat leukocytosis 
if concurrent with and thought to be associated with presumed differentiation 
syndrome.  
5. AML relapse less than 6 months following stem cell transplantation.  
6. Presence of graft versus host disease (GVHD) which requires an equivalent dose of ≥ 
0.5mg/kg/day of prednisone or therapy beyond systemic corticosteroids (e.g. cyclosporine 
or other calcineurin inhibitors or other immunosuppressive agents used for GVHD). 
7. Active cerebrospinal involvement of AML. 
8. Diagnosis of acute promyelocytic leukemia (APL). 
9. Clinically active hepatitis B (HBV) or hepatitis C (HCV) infection. 
10. Severe gastrointestinal or metabolic condition that could interfere with the absorption of 
oral study medication. 
11. Prior malignancy, unless it has not been active or has remained stable for at least 3 years. 
Participants with treated non-melanoma skin cancer, in situ carcinoma or cervical 
intraepithelial neoplasia, regardless of the disease-free duration, are eligible if definitive 
treatment for the condition has been completed. Participants with organ-confined prostate 
cancer with no evidence of recurrent or progressive disease are eligible if at the active 
surveillance stage, if hormonal therapy has been initiated or the malignancy has been 
surgically removed or treated with definitive radiotherapy. 
12. Nursing women or women of childbearing potential (WOCBP) with a positive urine 
pregnancy test. 
6.4 Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this trial. 
 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 36 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
7 
STUDY TREATMENTS 
Subjects will self-administer oral brequinar twice weekly (approximately every 84 hours). 
Treatment cycles will be 2 weeks. Dose adjustment is to occur as outlined below. Visits will take 
place at least every 2 weeks through 3 months. More frequent visits are permitted to assess and/or 
treat adverse events. Less frequent visits (up to 4-week intervals) are permitted after 3 months 
depending on subject safety/tolerability and response. Inter-cohort and intra-subject dose 
adjustments are permitted depending on safety and plasma DHO levels. Cohort 1 will begin at 500 
mg/m2 twice weekly and will follow the cohort dose-adjustment scheme shown below. Subsequent 
cohorts will have a starting dose that has been adjusted based on the safety/tolerability and DHO 
levels of the previous cohort. The dosing for individual subjects may be adjusted based on the 
safety/tolerability and DHO levels as shown in Section 7.5. 
7.1 Description of Brequinar: 
Brequinar will be supplied as 100 and 250 mg capsules. Dosing will be determined on a mg/m2 
basis based on the starting dose of a subject’s cohort and the tolerability, safety and DHO level 
assessed following each dose. Brequinar capsules should be taken whole; they should not be 
crushed or chewed. If the participant forgets to take the daily dose, he/she should make up the dose 
within 8 hours after the missed dose. If more than 8 hours have elapsed or if the dose was vomited 
or if the subject for any reason is unable to take the scheduled dose within 8 hours, omit that dose, 
and the subject should resume treatment with the next scheduled dose. Any medication remaining 
from extra supplies or missed doses should not be taken beyond the last scheduled day of brequinar 
administration but should be documented in the subject diary and returned by the participant for 
drug accountability purposes.  
7.2 Treatment Administration 
Subjects will take oral brequinar twice weekly (approximately every 3.5 days) e.g., Monday 
morning and Thursday evening. Each dose is to be taken with approximately 240 mL of water. 
The subject does not need to be fasting. The chosen dosing schedule needs to accommodate clinic 
visits as well as shipping and receipt of the brequinar brequinar/DHO samples. Sample processing 
and shipping procedures will be addressed in a separate laboratory manual.  
7.3 Safety/Tolerability 
Safety/tolerability is assessed for each subject at each study visit using the Common Terminology 
Criteria for Adverse Events v4.0 (CTCAE). Safety/tolerability will be used to determine both 
individual cohort starting doses and dosing adjustments. Safety at the subject level is defined in 
Section 7.3.1; hematologic toxicity is defined in Section 7.3.1.1; and safety at the cohort level is 
defined in Section 7.3.1.1. 
7.3.1 Safety/Tolerability – Subject Level 
Acceptable safety/tolerability for a subject through Day 42 is defined as no ≥ Grade 3, treatment-
emergent, study-drug-related, non-hematologic adverse events. Due to the expected hematologic 
profile associated with AML, hematologic AEs of any grade will not be considered dose-limiting 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 37 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
during the first 42 days of dosing. Exceptions to the non-hematologic Grade 3 criterion are 
provided in Table 1.  
Table 1. 
Exceptions to Grade 3 Nonhematologic AEs  
Condition 
Exception Description  
Nausea/ 
Emesis 
Grade 3 nausea and/or emesis resolving to ≤ Grade 2 or baseline within 1 
week after the use of an optimal antiemetic regimen based on standard 
practice. 
Diarrhea 
Grade 3 diarrhea resolving to ≤ Grade 1 or baseline within 1 week after 
receiving the maximal supportive therapy based on standard practice. 
Fatigue 
Grade 3 fatigue lasting less than 1 week. 
Laboratory 
abnormalities 
Asymptomatic Grade 3 laboratory abnormalities that are not considered to 
be clinically significant. 
7.3.1.1 Hematologic Toxicity 
After the subject has completed the first 42 days of treatment, the definition of unacceptable safety 
expands to include hematologic AEs defined as ≥ Grade 4 neutropenia and/or thrombocytopenia, 
with a hypocellular bone marrow and no greater than 5% marrow blasts lasting for 2 weeks or 
more. Anemia will not be considered a hematologic AE for the definition of unacceptable safety. 
For clinic visits when bone marrow sampling is scheduled, the timing of the bone marrow sampling 
can be adjusted to ensure that the results are available at the time of the clinic visit. 
7.3.2 Safety/Tolerability – Cohort Level 
Acceptable safety for a cohort starting dose is defined as having acceptable safety (see Section 
7.3.1) for the majority of subjects in that cohort at that starting dose (e.g., 4 out of a cohort’s 6 
subjects have no non-hematologic AEs ≥ Grade 3 with exceptions noted in Table 1). 
7.4 Cohort Starting Doses 
Cohort 1 will treat 6 subjects at 500 mg/m2 twice weekly.  
If there is unacceptable safety/tolerability and/or inadequate DHO level at a starting dose in the 
majority of subjects in a cohort (see Section 7.3.1), up to two additional cohort(s) of 3 subjects 
will be added with the starting doses adjusted (escalated or de-escalated) based on both 
safety/tolerability and adequacy of DHO level. The starting doses for each subsequent cohort may 
be adjusted by up to 300 mg/m2 based on both safety/tolerability and adequacy of DHO level. 
Cohort starting doses will be determined by the Sponsor and communicated to the study teams. 
The planned upper limit for cohort starting dose is 800 mg/m2. 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 38 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
7.5 Individual Dose Adjustment Guidelines 
Intra-subject dose adjustment will be considered every 2 weeks depending on safety and DHO 
levels. There is a maximum of 2 dose adjustments within the first 42 days of initiating treatment. 
Each subject’s dose can be escalated, maintained (stable dose), held then reduced, or discontinued. 
The highest dose planned is 800 mg/m2, however, this upper limit may be adjusted depending on 
safety, DHO level, and clinical response. There is no lower limit planned. 
As noted above, safety will be a key part of determining dose adjustments. Subjects who resume 
dosing at a lower dose after experiencing unacceptable safety may not undergo later dose 
escalations beyond the dose where the unacceptable safety occurred.  
Each subject will continue dosing twice weekly at the individually adjusted dose for up to 12 
months in the absence of unacceptable toxicity or disease progression. Intra-subject dose 
adjustment is permitted at any time throughout the study based on safety/tolerability and DHO 
levels. Subjects who discontinue due to unacceptable safety/tolerability or die prior to Day 42 will 
not be replaced.  
Intra-subject dose adjustment increments and duration of dosing may be revised from planned 
amounts after each preceding cohort’s safety, DHO plasma levels and bone marrow results have 
been reviewed. 
Each subject’s baseline DHO sample will be obtained at C1D1 prior to dosing. Dose adjustment 
decisions based on DHO will be determined by DHO trough level (i.e., DHO level obtained pre-
dose D8 of the previous cycle). The initial target for “adequate” trough DHO level will be set at 
the higher of either 100 ng/mL or 2X the subject’s baseline DHO level. This target may be 
adjusted during the study depending on safety or efficacy signals observed during the study. As 
described below, dose adjustments are also based on safety and whether the dose has reached the 
planned upper limit (currently planned to be 800 mg/m2). 
Table 2 and Figure 1 present the intra-subject dose-adjustment criteria. 
Table 2. 
Intra-Subject Dose Adjustment 
Acceptable Safety/Tolerability? 
(see safety definition above) 
Adequate DHO 
Level? 
Planned Intra-Subject Dose Adjustment 
Yes 
Yes 
Maintain; continue at same dose. 
Yes 
No 
Escalate by 150 mg/m2 for the next 2-week cycle up 
to a maximum of 800 mg/m2. 
No 
Regardless of DHO  
Hold two doses (one week), then reassess AE; if AE 
has resolved to ≤ Gr. 2, de-escalate dose by 75 mg/m2 
and resume dosing. If AE has not resolved, reassess 
again in one week.  
If AE does not resolve to ≤ Gr. 2 by two weeks after 
dosing held, discontinue further dosing. Subject will 
remain in the study for safety follow up for 42 days 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 39 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
after last dose of study drug or until AEs have 
resolved or become stable. 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 40 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
 
Figure 1. 
Dose Adjustment – Subject Level 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 41 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
7.6 Medication/AE Diary 
The participant will be provided with a study calendar of events and will be required to maintain 
a medication diary of each dose of medication. Subjects will be instructed to record the date and 
time each dose of brequinar is taken, indicating if any doses are missed. Subjects will be instructed 
to record adverse events and changes in concomitant medications in the subject calendars/diaries.  
Subjects will be instructed and reminded to bring the medication diary to each clinic visit for 
review. The diary will be returned to clinic staff at the end of each cycle and a new diary dispensed. 
7.7 Bone Marrow Biopsy 
The participant will have a bone marrow sampling (aspiration and core biopsy) at baseline (prior 
to dosing), one for research purposes at the C2D8 visit ± 7 days, and one at Day 43 ± 7 days; 
thereafter, bone marrow sampling will be done every 12 weeks and at the Final Visit. If a 
participant develops frank evidence of progression of AML during the course of treatment based 
on laboratory or clinical assessment, then he/she will be discontinued from study treatment and 
can proceed with additional management off-study per discretion of the treating oncologist. If the 
results of the bone marrow sampling reveal disease progression at the Day 43 visit, then the 
participant will be taken off treatment. Timing of the bone marrow biopsy procedure may be 
adjusted to ensure that results are available for the Day 43 visit. Bone marrow sampling will 
include analysis of the aspirate on smear, core biopsy by microscopy, flow cytometry, and 
karyotype for cytogenetics. Molecular analysis will be performed on the screening bone marrow 
samples. 
7.8 Flow Cytometry 
Peripheral blood samples are to be obtained for flow cytometry in Cycle 1 at baseline (Day 1 pre-
dose), Day 2, and Day 3. 
7.9 Expansion Cohort 
Once a cohort starting dose has been reached that has adequate DHO level (as mentioned above, 
“adequate” trough DHO may be adjusted after reviewing DHO level, safety and clinical response 
data) and acceptable safety/tolerability in a majority of the cohort’s subjects, 15 subjects will be 
added at that cohort’s starting dose. Subjects in this cohort are eligible for intra-subject dose 
adjustment (see below). 
7.10 Study Drug Discontinuation 
If there is evidence of stable disease, partial response, or complete remission (CR, CRi, or CRh), 
the participant may continue with brequinar treatment until there is evidence of disease 
progression, intolerable toxicity, or for a maximum of one year. Study drug will be discontinued 
if there is evidence of unacceptable safety/tolerability that does not resolve within 2 weeks after 
stopping brequinar dosing.  
After treatment discontinuation, participants will be monitored for a minimum of 30 days after the 
last dose of brequinar or until they receive another treatment for their AML. Participants may 
discontinue treatment to receive a stem cell transplantation upon remission, if indicated. 
The reason for study drug discontinuation will be recorded in the source document and the eCRF.  


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PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 43 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
7.14.2 Labeling and Packaging  
Each bottle for subject use will be labeled with at least the following information: 
For Clinical Trial Use Only 
Study Number: 
CCB-01 
Contents: 100 or 250 mg capsules 
For oral use only. Take with approximately 8 ounces water every 3.5 days. 
Subject Number: XX-XXXX 
 
Treatment Duration: As directed 
IND: 138355             Clinical Batch Number: XXXXXXX  
Expiration Date: 
TBD 
Storage: Store at controlled room temperature  
Study Sponsor:  Clear Creek Bio, Inc., 585 Massachusetts Avenue, 4th 
Floor, Cambridge MA 02139 
Caution: New Drug – Limited by US Federal Law to Investigational Use
Only. To be used by Qualified Investigators only. 
7.14.3 Blinding and Randomization 
The trial will be conducted in an open-label manner. The brequinar capsules will be provided to 
each participating institution. No randomization codes are necessary for this open-label study. 
7.14.4 Unblinding/Expectedness 
It is not necessary to break the blind for this open label study as the treatment is known for each 
subject. 
Expectedness will be determined by establishing whether the adverse event is among those 
identified in the Investigator’s Brochure.   
7.14.5 Study Drug Accountability 
The study drug provided is for use only as directed in this protocol. 
The Investigator must keep a record of all study medication received, used and discarded.  It must 
be clear from the records which subject received which medication. Adequate drug is to be 
dispensed for each dosing period to allow for dosing every 3.5 days during the period until the 
next clinic visit, plus one additional dose to act as a spare in the event medication is unable to be 
used.  
The pharmacist/staff member responsible for drug accountability is to document the date and time 
of dispensing and for what subject the study drug was intended (i.e., record subject initials and 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 44 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
birth date or other unique identifier). A pharmacy manual will be provided by the Sponsor detailing 
how to calculate the mg/m2 dose together with examples of combinations of the 100 and 250 mg 
capsules to provide the most efficient use of the clinical supplies. 
At the end of the study, any unused study drug will be returned to the Sponsor for destruction or 
destroyed locally; disposition of study drug will be documented.   
The Sponsor will be permitted access to the trial supplies at any time within usual business hours 
and with appropriate notice during or after completion of the study to perform drug accountability 
reconciliation. 
 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 45 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
8 
CONDUCT OF THE TRIAL 
8.1 Ethical and Regulatory Considerations 
The trial will be performed in accordance with the Declaration of Helsinki (1964) (Appendix F) 
as revised in Tokyo (1975), Venice (1983), Hong Kong (1989), South Africa (1996), Scotland 
(2000, Note of Clarification 2002 & 2004) and Seoul 2008 (Appendix A), and Fortaleza (Brazil) 
(2013), and with the ICH Tripartite Guideline on Good Clinical Practice (CPMP/ICH/135/95, 
Jan.97) and US FDA Regulations. 
8.2 Informed Consent 
The principles of informed consent in the current edition of the Declaration of Helsinki must be 
implemented in each clinical study before protocol-specified procedures are carried out.  Informed 
consent must be obtained in accordance with US Code of Federal Regulations (21 CFR Part 50) 
as well as local and national regulations. Information should be given in both oral and written form 
whenever possible and deemed appropriate by the Institutional Review Board (IRB). Subjects and 
their relatives, if necessary, must be given ample opportunity to inquire about details of the study. 
The Investigator or qualified designated person will verbally inform subjects as to the nature, 
expected duration and purpose of the trial, the administration of the Investigational Medicinal 
Product (IMP), and the hazards involved, as well as the potential benefits that may come from 
treatment with this IMP. The trial procedures will be explained in lay language and any questions 
will be answered. The subjects will be given an IRB-approved consent form. The subjects will be 
given appropriate time to consider their participation in the trial and have any questions answered 
prior to signing the consent form. If a subject agrees to participate, he/she will sign and date an 
informed consent form and be provided with a copy of the signed consent. All subjects who sign 
an informed consent form are to be recorded on the applicable screening log.   
The subject will be informed that his/her medical records will be subject to review by the Sponsor, 
Sponsor’s representatives, and possibly by a representative of the Food and Drug Administration 
and other relevant regulatory authorities. Subjects will be informed that they are free to refuse 
participation in this clinical investigation, and if they should participate, it will be made clear to 
them that they may withdraw from the trial at any time without prejudicing further medical care 
they may require. The subject will receive a copy of the consent form as well as an information 
sheet about the trial.  
Signed written informed consent must be obtained from every subject prior to any study-specific 
procedures.  Standard procedures carried out prior to signing the informed consent but within the 
time constraints of the protocol may be used for baseline evaluation; they need not be repeated. 
An original signed informed consent form will be filed in the Investigator Site File and will be 
subject to review by the Sponsor; a copy will be given to the subject and a copy will be filed with 
the subject’s medical notes. 
The study should be discussed with the potential participant only after an initial review of his/her 
clinical status and appropriateness for participation have been evaluated to determine if he/she 
meets the subject selection criteria. 


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PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 47 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
Hematology tests include: hemoglobin, hematocrit, complete blood count with differential and 
platelet count.  
8.5 Screening Visit (Study Days -14 to -1) 
These procedures must be completed within the 14 days prior to starting dosing. Obtain the 
subject’s written informed consent, then collect baseline information: 
- Demographics (height, weight, date of birth, gender, race, ethnicity) 
- Pertinent medical/surgical history (including AML diagnosis and laboratory and clinical 
evidence of progression, previous AML treatment, and any available chromosomal and 
mutational testing results per institutional guidelines) and concomitant medications. 
- Physical examination (including weight).  
- Vital signs (heart rate, respiratory rate, seated blood pressure, body temperature).  
- Pregnancy test for women of childbearing potential (WOCBP).  
- ECOG performance assessment.  
- Hematology/chemistry. 
- 12-lead ECG with QTcF and MUGA scan or echocardiogram to assess cardiac function.  
- Bone marrow sampling. 
- Confirm subject meets all inclusion and no exclusion criteria. 
Treatment 
The treatment period begins with Cycle 1, Day 1 of the first 2-week dosing cycle. 
Cycle 1 Day 1: 
- Collect any adverse events or new concomitant medications since Screening.  
- Draw samples for baseline (pre-dose) brequinar/DHO, flow cytometry, and 
hematology/chemistry.  
- Conduct physical examination (including weight), vital signs, urine pregnancy test for 
WOCBP, and 12-lead ECG.  
- Review results and confirm subject remains eligible for the study.  
- Determine subject’s starting dose based on the respective cohort mg/m2 starting dose. 
- Dispense study medication.  
- Subject is to take the first dose at the clinic and remain for brequinar/DHO sampling. Collect 
brequinar/DHO samples at 1, 2, 4, and 6 hours post dose. 
- Process and store brequinar/DHO samples per the supplied laboratory manual. 
- Dispense the subject’s calendar/diary. The diary will collect dates/times of study medication 
administration and AEs/new concomitant medications.  
- Enroll subject for text message reminders if the subject consents to that service.  
- Ship the flow cytometry sample per the supplied laboratory manual. 
Cycle 1 Day 2:  
- Collect 24h post dose brequinar/DHO and flow cytometry samples. Check the diary/elicit 
information about AEs/new concomitant medications since the last visit. 
- Process and store brequinar/DHO samples per the supplied laboratory manual. 
- Ship the flow cytometry sample per the supplied laboratory manual 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 48 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
Cycle 1 Day 3:  
- Collect 48h post dose brequinar/DHO and flow cytometry samples. Check the diary/elicit 
information about AEs/new concomitant medications since the last visit.  
- Process and store brequinar/DHO samples per the supplied laboratory manual. 
- Ship the flow cytometry sample per the supplied laboratory manual. 
Cycle 1 Day 4:  
- Collect 72h post dose brequinar/DHO samples. Check the diary/elicit information about 
AEs/new concomitant medications since the last visit. 
- Process and store brequinar/DHO samples per the supplied laboratory manual. 
Cycle 1 Day 8:  
- Vital signs. 
- Check the diary/elicit information about AEs/new concomitant medications since the last 
visit. 
- Prior to the morning dose, collect brequinar/DHO samples (approximately 84h post the 
second dose of Cycle 1) and hematology/chemistry samples, then have subject take study 
medication.  
- Process and store brequinar/DHO samples per the supplied laboratory manual. 
- Notify DHO assay laboratory of incoming shipment and ship Cycle 1 brequinar/DHO 
samples (samples from Days 1, 2, 3, 4 and 8). 
 
Cycle 2 (and any Dose Adjustment Cycle) 
Repeat this visit as needed when dose adjustment is ongoing. 
● Day 1:   
- Collect unused study medication and check the diary/elicit information about AEs/new 
concomitant medications since the last visit.  
- Take vital signs and perform physical examination (including weight). 
- Collect pre-dose brequinar/DHO samples (approximately 84h post the fourth dose of the 
previous cycle) and hematology/chemistry samples.  
- Process and store brequinar/DHO samples per the supplied laboratory manual. 
- Review laboratory results/safety information and determine whether the subject should 
adjust the dose (based on acceptable safety and DHO level), continue with the current dose 
or hold study medication (unacceptable safety) per the guidelines below.  
- If dosing will continue, dispense study medication.  
- Dispense calendar/diary. 
- Manage text message reminders as needed (as a default do nothing, pause if study 
medication is put on hold, and restart if study medication is restarted)  
● Day 8:  
- Collect and check the diary/elicit information about AEs/new concomitant medications 
since the last visit. 
- Vital signs. 
- Collect pre-dose brequinar/DHO and hematology/chemistry samples. 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 49 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
- Perform bone marrow sampling for flow cytometry (window ±7 days). 
- If the subject is being dosed (i.e., has acceptable safety), have the subject take the morning 
dose.  
- If the subject’s medication was held, review safety information and determine whether 
dosing can resume. If dosing can resume, determine dose, dispense adequate medication for 
4 doses and have the subject take the morning dose.  
- Process and store brequinar/DHO samples per the supplied laboratory manual. 
- Continue to withhold study drug if safety remains unacceptable. 
- Dispense calendar/diary. 
- Manage text message reminders as needed (as a default do nothing, pause if study 
medication is put on hold, and restart if study medication is restarted) 
- Notify DHO assay laboratory of incoming shipment and ship brequinar/DHO samples 
(samples from current cycle's Days 1 and 8). 
 
Subjects may undergo dose adjustments at any time using the guidelines presented above. Subjects 
with acceptable safety can continue to escalate every 2 weeks by 150 mg/m2 increments through 
800 mg/m2. Subjects with unacceptable safety can continue to undergo dose reductions of 75 
mg/m2 with no lower limit. Re-escalation to a dose previously shown as not tolerated for an 
individual subject is not permitted for these subjects. 
Dose adjustments are permitted throughout the study for an individual subject based on safety, 
DHO level, and clinical response with an upper limit of 800 mg/m2. This upper limit may be 
adjusted depending on safety/tolerability/DHO/brequinar PK or other factors during the study. 
Maintenance Dose Cycle (visit every 2 - 4 weeks) 
Once a subject reaches a stable or maintenance dose (see Figure 1), the subject will be in the 
Maintenance Dose Cycle.  
In the first 3 months from starting study drug, the Maintenance Dose Cycle procedures will occur 
every 2 weeks (with the exception of bone marrow sampling as discussed below). After completing 
3 months from starting study drug, subjects may come to the clinic for a Maintenance Dose Cycle 
visit every 2 - 4 weeks per the investigator’s discretion. 
A subject may still move into a Dose Adjustment Cycle after a maintenance dose if required for 
a change in safety, DHO level or clinical response.  
Day 1: 
- Collect unused study medication and check the diary/elicit information about AEs/new 
concomitant medications since the last visit. 
- Collect pre-dose brequinar/DHO and hematology/chemistry samples.  
- Conduct physical examination, vital signs, urine pregnancy test for WOCBP, 12-lead ECG 
and bone marrow sampling (note that bone marrow is collected at the C2D8 visit (window 
±7 days), at Day 43, then every 12 weeks; only the Day 43 sample will be assessed for 
hematological toxicity). 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 50 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
- Review the laboratory results/safety information and determine whether the subject should 
maintain current dose (acceptable safety) or hold study medication (unacceptable safety).  
- Dispense study medication. 
- Dispense calendar/diary.  
- Manage text message reminders as needed (as a default do nothing, pause if study 
medication is put on hold, and restart if study medication is restarted) 
- Notify DHO assay laboratory of incoming shipment and ship brequinar/DHO samples. 
 
Final Visit 
This visit is to take place when a subject is discontinuing from the study. 
- Collect and check the diary/elicit information about AEs/new concomitant medications 
since the last visit.  
- Collect brequinar/DHO and hematology/chemistry samples.  
- Collect unused study medication. 
- Conduct physical examination, vital signs, urine pregnancy test for WOCBP, 12-lead ECG 
and bone marrow sampling (do not collect bone marrow if < 4 weeks since previous bone 
marrow sample obtained).  
- Review the safety information and determine whether the subject has acceptable safety or 
unacceptable safety.  
- Notify DHO assay laboratory of incoming shipment and ship brequinar/DHO samples.  
- Stop text message reminders. 
 
Follow Up Visit (2 weeks after Final Visit) 
- Contact subject to elicit information about AEs/new concomitant medications since the last 
visit. 
Survival information will be collected while the study is ongoing. 
Unscheduled Visits 
Unscheduled visits and tests to assess AEs are permitted as needed providing the AE onset occurs 
within four (4) weeks after the final dose. 
8.6 Compliance with Study Procedures 
The time at which study procedures are conducted should follow the protocol timelines as closely 
as possible.  However, it is recognized in a clinical setting that protocol-specified timings may not 
occur exactly as specified in the protocol. Provided that activities are carried out within the 
identified window, it will not be necessary to file a protocol violation.   
8.7 Early Withdrawal from the Study  
A subject may withdraw from the study at any time for any reason or for one of the reasons listed 
below. The Sponsor or Investigator may also terminate a subject’s study participation after 
discussion with the other party if it is believed it would be unsafe for the subject to continue in the 
study.    


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PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 52 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
For protocol CCB-01, the Sponsor intends to utilize a third-party vendor with a HIPAA-compliant 
platform to send one-way text message reminders to study participants who have a mobile device. 
The SMS/text message will be sent on the days and times he or she is to take his or her study 
medication, e.g., Monday mornings and Thursday evenings. The exact timings of the reminders 
will be customized for each study participant. The PHI the third-party vendor receives will be 
restricted to the participant’s mobile device number and study identification number. The study 
participant is not to reply to the text message except to "opt out" from the service by sending 
"STOP" in the message body. In any other case if he/she sends a text message, the texting service 
will reply with a message indicating that messages sent by participants are not being monitored. 
Study participants must agree to “opt in” for this service and can "opt out" at any time even if they 
initially agreed. Study participants will need to sign an addendum to the informed consent 
document documenting their decision prior to enrollment in the system (see Appendix 14.5).   
The third-party vendor will sign an agreement with the Sponsor to use participant data only for the 
purposes of this study. Data will be purged from the vendor's servers at the conclusion of the trial 
upon written request by the Sponsor. Data will remain in the vendor's encrypted back-up files that 
will be maintained per HIPAA-compliant standards. 
 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 53 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
9 
ADVERSE EVENT REPORTING 
An adverse event is any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal relationship with 
this treatment.  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of the 
medicinal product, whether or not considered related to the medicinal product.  
Events that occur prior to dosing will be entered as medical history; AEs that occur after dosing 
will be entered on the AE form. 
Subjects will be questioned and observed for evidence of AEs, whether or not related to study 
drug. All AEs will be documented in the subject's medical record and CRF.  For any pre-existing 
condition or abnormal laboratory finding that changes in severity after dosing, this change should 
be recorded as an AE. New abnormal laboratory findings that are clinically significant are 
considered AEs. 
AEs will be collected beginning from the time of informed consent through at least 14 days after 
the final dose of study medication. AEs will be specified as pre-treatment or treatment-emergent. 
AE details are to be documented including start and stop date and times, whether continuous or 
intermittent, severity, any intervention utilized to correct the event (e.g., medication, surgery or 
other therapy), outcome and the relationship to the study drug.   
AEs identified in the protocol as critical to the evaluation of safety must be reported to the Sponsor 
by the Investigator according to the reporting requirements within the time periods specified in the 
protocol. 
AEs determined by the Investigator to be related to study drug must be followed until resolution 
or until they are considered stable or for at least 30 days after discontinuation of study drug, or 
until new treatment for AML is initiated, whichever occurs first.   
Any SAEs experienced after 30 days post the last dose of study drug should only be reported to 
the sponsor if the investigator suspects a causal relationship to the study drug.   
Abnormal laboratory values or test results occurring after study enrollment constitute AEs only if 
they induce clinical signs or symptoms, are considered clinically significant, require therapy (e.g., 
hematologic abnormality that requires transfusion or hematological stem cell support), or require 
changes in study drug (e.g., discontinuation of study drug). 
New signs or symptoms or worsening in severity of a cancer symptom that occur in association 
with disease progression should be recorded as AEs. Disease progression should not be reported 
as an AE unless worsening of signs and symptoms occur, or death from disease progression. 
If a death occurs during the SAE reporting period, the cause of death is considered as the AE and 
the death is considered its outcome. Death should be considered an outcome, not an event. The 
event or condition leading to death should be recorded and reported as a single medical concept 
on the Adverse Event eCRF. Generally, only one such event should be reported. “Fatal” will be 
recorded as the outcome of this respective event; death will not be recorded as separate event. If 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 54 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
the primary cause of death is disease progression, the cause of death should be clearly identified 
as progression of cancer under study. 
In cases of surgical or diagnostic procedures, the condition leading to the procedure is considered 
as the AE instead of the procedure itself. Each AE will be coded by the Sponsor from the verbatim 
text to a preferred term using a thesaurus based on the Medical Dictionary for Regulatory Activities 
(MedDRA).  
The following guidelines will be followed for the recording and reporting of adverse and serious 
adverse events. 
1. Baseline events will be recorded in the medical history section of the case report form and 
will include the terminology event name, grade, and start date of the event.  The medical 
history section of the case report form will serve as the source document for baseline events 
once signed and dated by the principal investigator.   
a. Baseline events are any medical condition, symptom, or clinically significant lab 
abnormality present before the informed consent is signed. 
i. Hematologic laboratory abnormalities will not be recorded as baseline events 
for patients with acute leukemia, myelodysplastic syndrome, chronic 
lymphocytic leukemia, or chronic myeloid leukemia in blast phase. 
ii. If exact start date is unknown, month and year or year may be used as the start 
date of the baseline event. 
2. The maximum grade of the adverse event will be captured per course or protocol-defined 
visit date. 
3. These adverse events will be recorded in the case report form: 
a. Any grade adverse event that is possibly, probably, or definitely related to the study 
drug. 
b. All serious adverse events regardless of attribution to the study drug. 
c. Any grade adverse event regardless of attribution to the study drug that results in any 
dose modification. 
4. Hematologic adverse events will not be recorded or reported for studies in patients with acute 
leukemia, myelodysplastic syndrome, chronic lymphocytic leukemia, or chronic myeloid 
leukemia in blast phase except for: 
a. Prolonged myelosuppression as defined by the NCI-CTCAE criteria specific for 
leukemia, e.g. marrow hypocellularity on day 42 or later (6 weeks) from start of 
therapy without evidence of leukemia (< 5% blasts), or that results in dose 
modifications, interruptions or meets the protocol definition of DLT or SAE. 
5. Serious adverse events will be reported according to institutional policy. 
6. Protocol specific language regarding the recording and reporting of adverse and serious 
adverse events will be followed in the event of discordance between the protocol and 
Leukemia-specific adverse event recording and reporting guidelines.  
(MD Anderson Cancer Center Leukemia-specific Adverse Event Recording and Reporting 
Guidelines) 
 


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PROTOCOL NUMBER:  CCB-01  
Page 57 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
MEDICAL MONITOR:  
E-mail:
Robert Sims, MD  
robert.sims@novellaclinical.com;  
YYA36071medmon@novellaclinical.com 
Telephone: 
614-721-2630
24-hour safety line: 1-866-758-2798 or 919-313-7111
Fax: 
 
 
206-826-0483
Sponsor Representative: 
Barbara Powers, MSN, Ph.D. 
E-mail:
bpowers@clearcreekbio.com  
Telephone:
484-686-0545
All SAEs will be reported to the IRB periodically, at the end of the study or per local institutional 
guidelines.   
9.4 Suspected Unexpected Serious Adverse Reactions (SUSARs) 
Suspected, unexpected, serious adverse reactions (SUSARs) are SAEs that are both related to the 
study drug (Relationship = Related) and unexpected (not previously described in the investigator’s 
brochure). All SUSARs will be reported in an expedited manner to the Sponsor or designee and 
IRB by the Investigators and to all relevant regulatory authorities by the Sponsor. Expectedness 
will be judged by the Medical Monitor and site PI. It is critical that all SAEs are reported within 
the 24-hour guideline so that the expectedness determination can be made. SUSARs require 
immediate attention and expedited reporting to relevant regulatory authorities. 
The Sponsor is to ensure that all relevant information about fatal or life-threatening SUSARs are 
appropriately recorded and reported to the concerned Regulatory Authority and to the concerned 
IRB(s) within seven (7) calendar days of the date of first report to the Medical Monitor/Sponsor. 
Follow-up information is to be subsequently communicated to the relevant Regulatory Authority 
within an additional eight calendar days. 
All other SUSARs are to be reported to the Regulatory Authority and to the IRB(s) concerned as 
soon as possible within a maximum of fifteen calendar days of first knowledge by the Medical 
Monitor/Sponsor. 
The Medical Monitor/Sponsor or designee must also inform all Investigators studying the 
investigational medicinal product about SUSARs and ensure that all IRBs have been notified. 
For reported deaths of a subject, the Investigator shall supply the Sponsor and the IRB(s) with 
additional information requested on an expedited basis.   
9.5 Pregnancies 
Pregnancy occurring in a female subject or a subject’s partner during the study period will be 
documented in the subject’s source documents and reported on a Pregnancy Form to the Sponsor 
Contact and to the IRB/IEC by the investigational staff within 1 working day of their knowledge 
of the event. The pregnancy information should be submitted using a Pregnancy Report Form. The 
collection period for a pregnancy occurring in a subject or a subject’s partner will begin at the first 
dose of study drug and will continue through 90 days after the last dose of study drug. Monitoring 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 58 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
of the subject or partner should continue until the conclusion of the pregnancy, if the subject or 
subject’s partner has consented to this. Monitoring of the baby should continue for 3 months after 
birth, if the subject or subject’s partner has consented to this.  
 
Pregnancy itself is not an AE; it should be reported for tracking purposes. The Investigator or 
designee will discontinue the pregnant subject from the treatment aspects of the study, continue to 
follow her per protocol for safety outcomes only, and advise her to seek prenatal care and 
counseling from her primary care provider. Data on fetal outcome and breast-feeding will be 
collected for regulatory reporting and drug safety evaluation. 
  
If the pregnancy is due to a subject’s failure to comply with the contraceptive requirements of this 
protocol, this should also be documented as a protocol deviation.  
 
Complications of pregnancy or congenital abnormalities in the newborn child will be reported 
appropriately as AEs.  
The site clinical staff will request the pregnant subject to notify the site of the outcome of the 
pregnancy (i.e., birth, loss, or termination). To help ensure this, the site clinical staff will follow-
up with the subject until the end of pregnancy, with the subject’s consent. This request and the 
subject’s response will be documented in the subject’s source document. 
9.6 Hematologic Adverse Events 
It is recognized that laboratory value variability is a frequent and expected and may be present at 
Baseline when a subject enrolls in the study. In general, mild day to day fluctuation of laboratory 
values should not be classified as AEs. Fluctuations in laboratory values resulting from adverse 
changes in the patient’s medical condition should be reported as AEs. Laboratory abnormalities 
that constitute an AE in their own right as per CTCAE V4.03 criteria if applicable (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study drug), should be recorded on the AE eCRF. 
Whenever possible, a diagnosis, rather than a symptom should be provided (e.g., anemia instead 
of low hemoglobin). Laboratory abnormalities that meet the criteria for AEs should be followed 
until they have returned to normal or an adequate explanation of the abnormality is found. When 
an abnormal laboratory or test result corresponds to a sign/symptom of an already reported AE, it 
is not necessary to separately record the lab/test result as an additional event.  
Laboratory abnormalities that do not meet the definition of an AE should not be reported as AEs. 
A laboratory abnormality designated a Grade 3 or 4 event (severe) as per CTCAE does not 
automatically indicate a SAE unless it meets the definition of serious as defined below and/or as 
per Investigator’s discretion.  
For laboratory abnormalities and any AEs, it should be noted that the terms serious and severe are 
not symptoms. The term severe describes the intensity of the specific event (e.g., Grade 3 or 4). 
The term serious is based on patient and event outcomes or actions required as described in the 
protocol definition of SAEs and is usually associated with events posing a threat to the subject’s 


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PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 61 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
 
Figure 2. 
Monitoring of Tumor Lysis Syndrome 
 
TLS Treatment 
TLS requires urgent inpatient management including intense nursing care, cardiac monitoring, 
nephrology consultation, and measurements of uric acid, creatinine, and electrolytes every four 
to six hours. Treat any electrolyte abnormalities and any acute renal injury.  
 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 62 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
9.10 Infection Prophylaxis 
Supportive care, including prophylactic antibiotics, antifungal and/or antiviral agents, are 
frequently used in neutropenic patients, and may be used per standard institutional practice and as 
deemed necessary by the investigator. 
9.11 Growth Factor Support 
The use of myeloid growth factors (granulocyte-colony stimulating factor [G-CSF] and 
granulocyte-macrophage colony-stimulating factor [GM-CSF]) may be given to support subjects 
who have developed Grade 4 neutropenia or Grade 3 neutropenia with fever and/or infection, per 
institutional guidelines. 
9.12 Management of Nausea, Vomiting, and Diarrhea 
Recommended management of nausea and vomiting is to administer antiemetics. The 
recommended treatment for managing diarrhea is loperamide antidiarrheal therapy, 4 mg at first 
onset, followed by 2 mg with each loose movement until diarrhea-free for 12 hours (maximum 
dosage: 16 mg/24 hours). Adjunct anti-diarrheal therapy is permitted. 
 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 63 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
10 STATISTICAL CONSIDERATIONS 
A separate, detailed statistical analysis plan (SAP) will be finalized prior to locking the database. 
All analyses of safety and anti-leukemic activity for this open-label early Phase study will be 
descriptive in nature and presented by dose group and overall, as appropriate, for the dose-
adjustment phase and the expansion phase. Procedures for accounting for missing, unused and 
spurious data will be described in the SAP.   
Summaries for quantitative variables will include the mean, median, quartiles, standard deviation 
and error, minimum, and maximum. For qualitative variables, the summaries will include the 
number and percentage of subjects for each outcome, and the exact 95% CI, when appropriate. No 
hypothesis testing will be performed. Any statistical testing will be considered exploratory and 
descriptive. All computations will be performed using SAS® (Version 9.3 or higher). 
Subject disposition, subject demographics and baseline characteristics will be summarized. 
Subject data listings will also be provided. The following sections will briefly summarize of the 
planned statistical analyses and analysis sets for the primary and secondary endpoints. 
10.1 Study Populations for Analysis 
The analysis sets are defined in Table 3. 
Table 3. 
Analysis Sets 
Analysis Set 
Description 
Enrolled Analysis Set 
All subjects who have been enrolled in the study. 
Safety Analysis Set 
All subjects who were administered brequinar. 
Efficacy Analysis Set 
All subjects with AML disease at baseline and who were administered 
brequinar. 
Pharmacokinetic Analysis Set 
All subjects who take at least 1 dose of brequinar and have at least 1 
quantifiable plasma concentration collected post-dose without important 
protocol deviations/violations or events thought to significantly affect the 
PK. 
 
 
The Efficacy Analysis Set will be used for efficacy analyses. The Safety Analysis Set will be used 
for safety analyses.   
10.2 Safety Analyses 
All safety analyses will be performed on the Safety Analysis Set.  Safety and tolerability will be 
assessed in terms of AEs, SAEs, safety laboratory data, physical examinations, vital signs, 12-lead 
ECGs and bone marrow sampling.  
Adverse event data will be descriptively evaluated. All AEs will be listed. The incidence and 
duration of TEAEs, defined as AEs occurring after the first dose of study treatment through 30 
days after the last dose of study treatment, will be tabulated by Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term and system organ class, and by severity and relationship to 
study treatment. All laboratory results, vital sign measurements, ECGs and bone marrow 


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PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 67 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
statistics.  Relationships between brequinar PK parameters and clinical outcomes (e.g., efficacy, 
toxicity) may be explored.  PK analyses will be performed on the PK Analysis Set. 
Blood samples for DHO analysis will be obtained at pre-specified times and will be summarized.  
Relationships between DHO levels and PK and clinical outcomes (e.g., efficacy, toxicity) will be 
explored. 
Changes in myeloid markers per serial flow cytometry will be studied to look for evidence of 
myeloid differentiation. 
10.5 Sample Size Considerations 
Formal sample size calculations are not applicable for this phase 1b/2a, open label study. Up to 27 
subjects are planned to be entered in this trial: Cohort 1 will have 6 subjects; two additional cohorts 
of 3 subjects each will be added if adjustments are required to the cohort starting dose. An 
expansion cohort of 15 subjects will be enrolled with a starting dose of the highest tolerated starting 
dose from Cohorts 1 to 3.   
10.6 Randomization 
No randomization scheme is needed for this open label study. 
10.7 Pooling of Study Centers 
Not applicable to this small, early phase study. 
10.8 Interim Analysis 
No interim analysis is planned for this trial. 


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PROTOCOL NUMBER:  CCB-01  
 
 
 
 
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PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
of documents will be documented in writing.  The new owner will assume responsibility for data 
retention and archiving. 
Should the Investigator retire, relocate, or for other reasons withdraw from the responsibility of 
keeping the trial essential documents, custody must be transferred to a person who will accept that 
responsibility, and the Sponsor must be notified in writing of the name and address of said person. 
11.6 Non-Protocol Research 
No investigational procedures other than those outlined in this protocol may be undertaken on the 
subjects in this trial without the prior written permission of the subject, the Sponsor, the IRB and, 
when appropriate, the regulatory authority. 
11.7 Publication 
The Sponsor acknowledges the benefit of making widely available the results of all clinical trials 
and intends to publish the results of this trial. All publications resulting from the clinical trial must 
be in a form that does not reveal technical information that the Sponsor considers confidential or 
proprietary.  A copy of any abstract, presentation or manuscript proposed for publication must be 
submitted to the Sponsor for review at least 30 days before its submission for any meeting or 
journal. In addition, if deemed necessary by the Sponsor for protection of proprietary information 
prior to patent filing, the Investigator agrees to a further delay of 60 days before any presentation 
or publication is submitted. The Sponsor reserves the right to include the report of this trial in any 
regulatory documentation or submission or in any informational materials prepared for the medical 
profession. 
Authorship determination will be at the discretion of the Sponsor and will include evaluation of 
the following criteria: Investigator must participate in the review of and content of the protocol; 
review and comment on the study results; participate in the writing, reviewing and commenting of 
the manuscript; and approve the final manuscript for submission. 
 
 
 
 
 
 
 
 
 
 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 71 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
12 SPONSOR RESPONSIBILITIES 
12.1 General 
The Sponsor agrees to adhere to the ICH Note for Guidance on Good Clinical Practice 
(CPMP/ICH/135/95, Jan.97) and US FDA Regulations. It is the Sponsor's responsibility to obtain 
appropriate regulatory approval to perform the trial (if applicable). The Sponsor should notify 
promptly all concerned investigator(s), IRB(s) and the Regulatory Authority of findings that could 
adversely affect the health of the patients/ subjects, impact on the conduct of the trial or alter the 
Regulatory Authority’s authorization to continue the trial. If it is necessary to change, or deviate 
from the protocol to eliminate an immediate hazard to the subjects the Sponsor will notify the 
relevant regulatory authority and relevant IRB of the new events, the measures taken and the plan 
for further action as soon as possible.  This will be by telephone in the first instance followed by a 
written report.   
On completion of the trial, the Sponsor will inform the regulatory authority that the trial has ended.  
If the study is terminated for any reason the Sponsor will provide a written statement to the relevant 
regulatory authority and the IRB with the reasons for termination of the trial. This will be 
conducted within 15 days of the decision to terminate the trial.  The Sponsor will report in an 
expeditious manner all suspected unexpected serious adverse reactions (SUSARs) to the relevant 
regulatory authority and IRBs.   
12.2  Indemnity 
The Sponsor will provide compensation insurance against any risk incurred by a subject as a result 
of participation in this trial. The Sponsor will indemnify the Investigators as detailed in a separate 
document. 
12.3  Data Monitoring 
Suitably qualified and trained clinical research personnel of the Sponsor will visit the trial site at 
regular intervals during the trial for monitoring purposes and to assist the research staff with any 
queries. CRFs and source documentation will be available for review during monitoring visits to 
the trial site. The function of this monitoring is to ensure compliance with the protocol, adherence 
to regulatory and Good Clinical Practice obligations, proper maintenance of records including IMP 
accountability records, correct administration of IMP including storage conditions and accurate 
reporting of AEs.   
Once the data from the case report forms have been entered onto the database, they will be 
reviewed and the data verified against the subject’s source data. Any discrepancies will be tracked 
by paper or electronically with an electronic audit trail. 
12.4  Audit 
The Sponsor has an obligation to audit a proportion of studies.  A department other than the clinical 
department will undertake this obligation. Therefore, the Sponsor, an independent auditor or a 
regulatory authority may audit the trial site and trial documentation. These audits may take place 
while the trial is being conducted or up to several years later.   


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
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PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
12.5  Confidentiality 
The Sponsor will not keep any material on file bearing any subject’s name, and subjects’ 
confidentiality will be maintained at all times. 
12.6  Finance 
This will be the subject of a separate agreement between the Investigator/Institution and Sponsor. 


PROTOCOL NUMBER:  CCB-01  
Page 73 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
13 REFERENCES 
Arteaga CL, Brown TD, Kuhn JG, et al. Phase I clinical and pharmacokinetic trial of Brequinar 
sodium (DuP 785: NSC 368390). Cancer Res 1989; 49(16): 4648-4653. 
Cairo MS, Coiffier B, Reiter A, et al. Recommendations for the evaluation of risk and prophylaxis 
of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS 
panel consensus. Br J Haematol 2010; 149:578. 
Coiffer B, Altman A, Pui CH, et al. Guidelines for the management of pediatric and adult tumor 
lysis syndrome: an evidence-based review. J Clin Oncol 2008; 26:2767. 
Burris HA 3rd, Raymond E, Awada A, et al. Pharmaocokinetic and phase I studies of brequinar 
(DUP 785; NSC 368390) in combination with cisplatin in patients with advanced malignancies. 
Invest New Drugs 1998; 16(1): 19-27. 
Döhner H, Estey E, Grimwade D, Amadori S, Applebaum FR, Büchner T, et al. Diagnosis and 
management of AML in adults: 2017 ELN recommendations from an expert international expert 
panel. Blood 2017; 129(4): 424-447. 
Howard SC, Jones, DF, Pui, C-H. The Tumor Lysis Syndrome. N Engl J Med 2011; 364:1844-
1854.  
Huang M, Wang Y, Collins M, et al. A77 1726 induces differentiation of human myeloid leukemia 
K562 cells by depletion of intracellular CTP pools. Mol Pharmacol 2002; 62(3):463-472.  
Kantarjian HM, Stein AS, Bargou RC, Grande Garcia C, Larson RA, Stelljes M, et al. 
Blinatumomab treatment of older adults with relapsed/refractory B-precursor acute lymphoblastic 
leukemia: Results from 2 phase 2 studies. Cancer 2016; 122(4): 2178-2185. 
Ng SB, Buckingham KJ, Lee C, et al. Exome sequencing identifies the cause of a mendelian 
disorder. Nature 2010; 42: 30-35. 
Noe DA, Rowinsky EK, Shen HS, et al. Phase I and pharmacokinetic study of brequinar sodium 
(NSC 368390). Cancer Res 1990; 50(15): 4595 – 4599.  
Savona MR, Malcovati L, Komrokji R, et al. An international consortium proposal of uniform 
response criteria for myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in adults. Blood 
2015;125(12): 1857-1865. 
Schwartsmann G, Dodion P, Vermorken JB, et al. Phase I study of Brequinar sodium (NSC 
368390) in patients with solid malignancies. Cancer Chemother Pharmacol. 1990; 25(5): 345-351. 
Surveillance, Epidemiology, and End Results (SEER) Program, 1973-2015. 
www.seer.cancer.gov.  
CONFIDENTIAL:  Clear Creek Bio, Inc. 


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PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
Sykes DB, Kfoury YS, Mercier FE, et al. Inhibition of dihydroorotate dehydrogenase overcomes 
differentiation blockade in acute myeloid leukemia. Cell 2016; 167(1): 171-186. 
 
 
 


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PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
14 APPENDICES 
14.1 APPENDIX A:  CCB-01 Schedule of Events 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 76 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
CCB-01 Schedule of Events 
 
 
 
 
 
Proceduresa 
Screenb 
Cycle 1 (Study Days 1 – 14) 
Dose 
Adjustment 
Cycle (Cycle 2 
and beyond as 
needed) 
Maintenance 
Dose Cycle  (no 
dose 
adjustment) 
Every 2 weeks 
Final 
Visit 
F/U  
Phone 
Call 
Survival 
D1 
D2 
D3 
D4 
D8 
D1 
D8 
D1 
 
Final 
Visit  
+ 2 wks 
 
Informed Consentb 
X 
 
 
 
 
 
 
 
 
 
 
 
AE/Concomitant Medications  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Medical historyc  
X 
 
 
 
 
 
 
 
 
 
 
 
Demographicsd 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical Examd 
X 
X 
 
 
 
 
X 
 
X 
X 
 
 
Vital Signsd 
X 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
Pregnancy Teste  
X 
 
 
 
 
 
 
 
X 
X 
 
 
ECOG Performance Status 
X 
 
 
 
 
 
 
 
 
 
 
 
Hematology/Chemistry 
X 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
Flow Cytometryf 
X 
 
X 
X 
 
 
 
 
 
 
 
 
Chromosomal/mutational testingg 
X 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
X 
X 
 
 
MUGA/Echocardiogram  
X 
 
 
 
 
 
 
 
 
 
 
 
Bone Marrow Samplingh 
X 
 
 
 
 
 
 
X 
 
X 
 
 
Brequinar/DHO Plasma Samplei 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Biobanking samplesj 
X 
 
 
 
 
 
 
 
X 
X 
 
 
Ship DHO Plasma Samples 
 
 
 
 
 
X 
 
X 
X 
 
 
 
Dispense/Collect Study Medication  
 
X 
 
 
 
 
X 
 
X 
X 
 
 
Dispense/Collect Subject Calendar/Diary 
 
X 
 
 
 
 
X 
 
X 
X 
 
 
Survival Assessment 
 
 
 
 
 
 
 
 
 
 
 
X 
 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 77 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
a. Visit window of ± 1 day for dose escalation cycles; window of ± 3 days for non dose escalation cycles. 
b. Obtain informed consent prior to performing any screening or study-specific procedures. Screening procedures must be 
performed within 14 days prior to initial study drug administration.  Procedures at C1D1 that are repeats of Screening may 
be omitted if <72h since Screening assessment. 
c. Medical history is to include AML diagnosis, previous AML treatment, and standard chromosomal and mutational results 
per institutional guidelines. 
d. Demographic information is to include date of birth, height, weight, race, and ethnic origin. Rectal examination may be 
deferred for Physical Examination. Vital signs include heart rate, respiratory rate, seated blood pressure, respiratory rate, 
oral/aural body temperature. Physical exam is to include weight. 
e. For women of childbearing potential only. 
f. Flow cytometry testing of peripheral blood is to be obtained at 0 (pre-dose C1D1), post dose 48 and 72 hours..  
g. Testing panel is per institutional standard of care; obtain sample at Screening. 
h. Bone marrow sampling local testing will include analysis of the aspirate on smear, core biopsy by microscopy, flow 
cytometry, and karyotype for cytogenetics. Local molecular analysis will be performed on the screening bone marrow 
samples only. All bone marrow samples will be sent for biobanking from where further analysis can be done. Perform bone 
marrow sampling at screening, at study Day 22 (C2D8) with a window ±7 days, at Day 43, and once every 12 weeks after a 
stable dose has been reached. Timing of this procedure may be adjusted to ensure results are available for the next clinic 
visit. 
i. Brequinar/DHO plasma sampling schedule: Cycle 1: 0 (pre-dose), post dose 1, 2, 4, 6, 24, 48, 72 hours and C1D8 pre-dose 
(+84h after C1D4 dose); Cycle 2 and adjustment cycles: pre-dose Days 1 and 8; every 2-week Maintenance Cycle until 3-
months on drug: pre-dose Day 1 and every 2 to 4 week Maintenance Dose Cycle beyond 3-months on drug. Day 1 sample 
window ±15 minutes through 6h draw; window for additional C1 draws ±2h; window for Cycle 2 and beyond plasma 
brequinar/DHO draws ±4h. Ensure trough samples (e.g., C1D1, C2D1, C3D1) are obtained prior to dosing. Plasma 
samples for brequinar/DHO for expansion cohort are to be obtained prior to dosing on Day 1 of each 2-week cycle for the 
first 3 cycles, then every 12 weeks. 
j. Biobanking samples (peripheral blood and bone marrow) are to be collected whenever bone marrow sampling is 
performed. 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 78 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
 
14.2 APPENDIX B: ECOG Performance Status Criteria 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal level.  Fully active, able to 
carry 
on 
all 
pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal level; minor 
signs or symptoms of disease. 
1 
Symptoms, 
but 
ambulatory.  
Restricted in physically strenuous 
level, but ambulatory and able to 
carry out work of a light or 
sedentary 
nature 
(e.g., 
light 
housework, office work). 
80 
Normal level with effort; some signs 
or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal level or to do active work. 
2 
In 
bed 
<50% 
of 
the 
time.  
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities.  Up and about more 
than 50% of waking hours. 
60 
Requires occasional assistance but is 
able to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any self-
care.  Totally confined to bed or 
chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, 
fatal 
processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 79 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
14.3 APPENDIX C: Brequinar/DHO Plasma Sampling 
Information is provided in a separate laboratory manual regarding collection, processing, storing, 
and shipment of samples.  
Brequinar and DHO plasma samples are to be obtained at the following time points (±30 minutes 
through 6h, then ±2h for the 24h, 48h, 72h and 84h samples: 
 
Cycle 1 
Cycle 2* 
Maintenance 
Dose Cycle 
Final 
Visit 
 
D1 
D2 
D 3 
D 4 
D8 
D1 
D8 
D1 
 
Time 
Point 
Pre-
dose 
1h 
2h 
4h 
6h 
24h 
48h 
72h 
84h 
after 
prev. 
dose 
84h 
after 
prev. 
dose 
84h 
after 
prev. 
dose 
84h after prev. 
dose 
84h 
after 
prev. 
dose 
*Or any cycle where the brequinar dose has been adjusted from the previous 2-week dose. 
 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 80 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
14.4 APPENDIX D: Common Terminology Criteria for Adverse Events (CTCAE) 
 
https://evs.nci.nih.gov/ftp1/CTCAE/About.html 
 
 
 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 81 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
14.5  APPENDIX E: 
Sample Subject Consent Form  
 
TITLE:  
A Phase 1b/IIa open-label, multi-center study to assess the safety, efficacy and 
pharmacokinetics of intrapatient dose-adjusted brequinar and inhibition of 
dihydroorotate dehydrogenase (DHODH) in adult subjects with acute myelogenous 
leukemia (AML) 
 
PROTOCOL NO.: 
CCB-01  
SPONSOR: 
 
Clear Creek Bio, Inc.  
 
 
585 Massachusetts Avenue, 4th Floor, 
 
 
Cambridge MA 02139 
 
INVESTIGATOR: 
 
<insert PI name> 
Site(s): 
 
<insert name> 
 
 
<insert address> 
STUDY-RELATED 
PHONE NUMBER(S): <insert name(s)> 
 
<insert number> 
 
<insert alternate number (24-hour contact number)> 
 
VERSION and DATE:  <e.g. CCB-01 Master ICF Version 2.0 04June2018> 
 
You are being asked to take part in a research study. Before you decide to participate, it is important 
for you to understand why the research is being done and what it will involve. Please take time to 
read the following information carefully and discuss it with others, if you wish, before deciding 
whether or not to take part. Ask us if there is anything that is not clear or if you would like more 
information. 
WHAT IS THE PURPOSE OF THE STUDY? 
The purpose of the study is to evaluate the safety, efficacy, pharmacokinetics (PK) (level of study 
medication in the blood) and the inhibition (decrease in level) of an enzyme called “dihydroorotate 
dehydrogenase” (DHODH). DHODH blocks the ability of blood cells formed in the bone marrow 
to differentiate (grow into mature white blood cells that can fight infection and platelets that help 
blood to clot). Brequinar is a drug that has been shown in animals in the laboratory to be able to 
decrease the level of DHODH and decrease leukemic cells in the bone marrow. Reducing DHODH 
level in patients with AML may help treat this type of leukemia by allowing cells in the bone 
marrow to grow into different types of mature cells.  


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PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 84 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
- Before you take your morning dose, you will have blood samples taken for brequinar/DHO 
and hematology/chemistry.  
- If you are not having any side effects that may indicate it is not safe for you to continue 
taking the study medication, you will be given adequate medication for another 2 weeks (4 
doses). Take your next dose of study medication in the clinic. 
● Day 8:  
At this visit, you will: 
- Have your vital signs checked. 
- Have a bone marrow sample taken for flow cytometry (window ±7 days). 
- Before you take your morning dose, you will have blood samples taken for brequinar/DHO 
and hematology/chemistry.  
- Your diary will be checked for any new medical events, new medications or a change in 
dose of any medications since the last visit. 
- If you are not having any side effects that may indicate it is not safe for you to continue 
taking the study medication, you will continue to take the medication dispensed to you. 
 
Maintenance Dose Cycle (visit every 2 - 4 weeks) 
Once you have reached a “stable dose” where no more dose adjustments seem to be needed, you 
will return to the clinic every 2 weeks and have the procedures below. After you've been taking 
the study medication for 3 months, your study doctor may space your visits out to every 4 weeks.  
Day 1: 
At this visit, you will: 
- Be asked about any new medical events or new or changed medications since your last visit.  
- Have blood samples taken for pre-dose brequinar/DHO and hematology/chemistry.  
- Have a physical examination, vital signs, urine pregnancy test for women able to bear 
children, 12-lead ECG. 
- Have a bone marrow sampling (the bone marrow aspiration sampling is performed at study 
Day 22 ±7 days, at study Day 43 and repeated every 12 weeks or more often if there is a 
safety concern).  
- Your study team will review the laboratory results/safety information and determine 
whether you should stay at the same dose or whether you should temporarily stop taking 
the study medication or whether the dose should be changed.  
- If you are not having any side effects that may indicate it is not safe for you to continue 
taking the study medication, you will be given additional medication and continue to take 
the medication dispensed to you as directed by the study team. 
- Your diary/calendar will be collected and a new one provided to you.  
 
Final Visit 
This visit is to take place if you or your study team decide you should stop participation in the 
study or you have reached 12 months of study participation. At this visit, you will: 


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PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 87 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
If a condition of which you were unaware is discovered during the study, a full report will be sent 
to your doctor if you request this.  You will be advised of the appropriate action to take for 
treatment. 
Pregnancy-Related Risks 
Taking part in this study can result in risks to an unborn or breastfeeding baby, so you should not 
become pregnant, breastfeed a baby, or father a child while participating in this study. If you are 
able to become pregnant or father a child, you must use birth control during the study and for at 
least 3 months after your last dose of study drug if you are sexually active. 
Birth control specifications: Female participants who are able to become pregnant must use 2 
methods of birth control while on this study. Male participants must use an effective barrier method 
(such as a condom) while on this study. 
Talk with the study team about acceptable methods of birth control to use while taking part in this 
study. 
Males: Tell the study team right away if your partner becomes pregnant or suspects pregnancy. 
Females: If you are pregnant, you will not be enrolled into this study. If you become pregnant or 
suspect that you are pregnant during the study, you must tell your doctor right away. 
Getting pregnant may result in your removal from this study.  
WHAT ARE THE POSSIBLE BENEFITS? 
The study drug may help to control the disease. Future patients may benefit from what is learned. 
There may be no benefits for you in this study.  
WILL IT COST ANYTHING TO BE IN THE STUDY? 
If you participate in this study, you will not have to pay for the cost of the study drug used in the 
study. 
You or your insurer will be responsible for the cost of your usual ongoing medical care, including 
procedures and non-study medications that the doctor or your regular doctor requires during this 
study as part of your usual medical care. If you have any questions, please ask the doctor and/or a 
member of the study staff about the costs that will or will not be covered by the sponsor. 
IS THERE PAYMENT FOR PARTICIPATION? 
You will not receive any payment for participation in this study. 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 88 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
WHAT ARE THE ALTERNATIVES FOR TREATMENT? 
You do not have to participate in this research study to receive treatment. Instead, you may be 
eligible for recently approved therapies, and may be able to have a bone marrow transplant outside 
of this study. You may choose to receive other investigational therapies, if available. You may 
also choose not to have treatment for cancer at all. Regardless of your choices, you will receive 
appropriate medical care, including treatment for pain and other symptoms of cancer. Please note 
that you will be informed in a timely manner if new information becomes available that is relevant 
during your participation in this study. 
WHAT IF SOMETHING GOES WRONG? 
An important part of this study is to see if the investigational product causes side effects. You must 
inform the staff if you feel unwell or have any unusual symptoms at any time during the study, no 
matter how minor you think they are. If you experience such events, treatment will be made 
available by the doctor. 
You will be provided any reasonably necessary medical treatment for any injuries sustained as a 
result of participating in this study, except to the extent such costs are covered by your medical or 
hospital insurance or by governmental programs providing such coverage. You must follow the 
directions of the doctor to be eligible for this coverage. Neither the sponsor nor the doctor have 
plans to provide other compensation in the event of an injury. You are not giving up any of your 
legal rights by signing this consent form. 
Certain tests, procedures, and/or drugs that you may receive as part of this study may be without 
cost to you because they are for research purposes only. However, your insurance provider and/or 
you may be financially responsible for the cost of care and treatment of any complications resulting 
from the research tests, procedures, and/or drugs. Standard medical care that you receive under 
this research study will be billed to your insurance provider and/or you in the ordinary manner. 
Before taking part in this study, you may ask about which parts of the research-related care may 
be provided without charge, which costs your insurance provider may pay for, and which costs 
may be your responsibility. You may ask that a financial counselor be made available to you to 
talk about the costs of this study. 
WILL ALL THE DOCUMENTS CONCERNING ME REMAIN CONFIDENTIAL? 
Yes. The company that is conducting this study will not keep any document on file that contains 
your name; you will only be identified by your initials and a subject number. It will be necessary 
for the sponsor, its representatives, the regulatory authorities, other institutions participating in the 
study, and possibly the Institutional Review Board (an IRB is a group of people who review the 
risks and benefits of a study) to review your medical records, but these will be treated in the 
strictest confidence permitted by law. If the results of the study are published, you will not be 
identified by name. Your personal health information (PHI) will be kept as confidentially as 
possible according to state and federal laws. However, in some situations, the Food and Drug 
Administration (FDA) could be required to reveal the names of participants. 


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PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 91 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
<Insert IRB name > 
<Insert address> 
<Insert telephone number> 
<Insert email if applicable> 
The IRB will not be able to answer some study-specific questions however, you may contact the 
IRB if the research staff cannot be reached or if you wish to talk to someone other than the research 
staff.  
Do not sign this consent form unless you have had a chance to ask questions and have received 
satisfactory answers to all of your questions. 
You will be given a signed and dated copy of this consent form to keep. 
Thank you for taking the time to read this consent form. 
 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 92 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
Consent Form Signature Page 
 
SUBJECT’S DATE OF BIRTH:  ______/______/______ 
  
mmm /    dd    /  yyyy 
 
Print Name of Investigator: 
 
 
Please initial 
box: 
1. I confirm that I have read this consent form for the above study and have 
had the opportunity to ask questions. 
 
2. I understand my participation is voluntary and I am free to withdraw at any 
time, without giving any reason, without my medical care or legal rights 
being affected. 
 
3. I understand that sections of any of my medical records may be looked at 
by responsible individuals from Clear Creek Bio, Inc. and/or its 
representatives or from regulatory authorities and the IRB where it is 
relevant to my taking part in research. I give permission for these individuals 
to have access to my records. 
 
4. I understand that my data may be transmitted outside the country to 
countries with less strict data protection laws. 
 
5. I agree to take part in the above study. 
 
 
By signing this consent form, I have not given up any of my legal rights. 
 
 
 
 
Printed Name of Subject                       Signature of Subject 
Date   
Time 
 
 
                                                                      
Printed Name of person conducting      Sign  
Date  
 
Time 
informed consent discussion 
 
 
Original with Investigator File 
1 copy for subject 
1 copy for Subject’s Medical Records 
 
 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 93 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
Addendum to Informed Consent for Short Messaging Service (SMS/text) 
Reminders for Protocol CCB-01 
 
 
TITLE:  
A Phase 1b/IIa open-label, multi-center study to assess the safety, efficacy and 
pharmacokinetics of intrapatient dose-adjusted brequinar and inhibition of 
dihydroorotate dehydrogenase (DHODH) in adult subjects with acute myelogenous 
leukemia (AML) 
 
 
PROTOCOL NO.: 
CCB-01  
 
SPONSOR: 
 
Clear Creek Bio, Inc.  
 
 
585 Massachusetts Avenue, 4th Floor, 
 
 
Cambridge MA 02139 
 
INVESTIGATOR: 
 
<insert PI name> 
Site(s): 
 
<insert name> 
 
 
<insert address> 
STUDY-RELATED 
PHONE NUMBER(S): <insert name(s)> 
 
<insert number> 
 
<insert alternate number (24-hour contact number)> 
 
VERSION and DATE:  <e.g. CCB-01 Addendum ICF Version 1.0 31May2018> 
 
WHY AM I BEING ASKED TO SIGN THIS ADDENDUM TO THE CONSENT? 
You are being asked to sign this addendum to the consent because you have agreed to participant 
in study CCB-01 and because it is very important for you to take your study medication at the 
correct times (e.g., Monday mornings and Thursdays evenings). One effective way to help you 
remember to take your medication on time is for you to receive a text reminder on your phone. 
The sponsor of the study (Clear Creek Bio, Inc.) is using an external vendor to generate a text 
message reminder that will be sent to your mobile device when it is time for you to take your study 
medication.  
 
VOLUNTARY NATURE OF THIS SERVICE 
It is entirely optional for you to receive this service. Your decision to receive text message 
reminders for your medications will not in any way affect your ability to enroll in the study. You 
may also "opt out" at any time by responding "STOP" to the messages, or by contacting your study 
team.  
 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 94 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
DESCRIPTION OF THE NATURE OF THE DATA YOU WILL PROVIDE 
You will provide your mobile device number to the study team who will then enter the number 
into the third-party vendor's system for sending out the text reminders.  
 
DESCRIPTION OF HOW THE DATA WILL BE USED 
The only information that will be shared with the third-party vendor is your mobile device number 
and your study participant identification number. The system is set up so that one-way messages 
are sent from the service to you. You should not reply to the messages you receive except to "opt 
out". If you do send a message, the texting service will reply with a message indicating that the 
messages you may send are not being monitored. 
 
WHAT WILL THE MESSAGE SAY? 
On the twice-weekly schedule (i.e., Monday mornings and Thursday evenings), you will receive a 
text with the following information: “It is time for you to take your CCB-01 study medication. 
Thank you for participating in this study.” You may delete this message after reading. 
 
DESCRIPTION OF HOW THIS DATA WILL BE SECURELY MANAGED 
The mobile device number you provide to be used for these reminders will be managed in a manner 
that ensures the best possible security. The mobile device number will not be shared with any other 
third-party vendor or the sponsor of this study (Clear Creek Bio, Inc.). 
 
WHAT IF I DON’T HAVE A PHONE THAT CAN RECEIVE TEXT MESSAGES? 
If you do not have a mobile phone or cannot receive text messages, you cannot participate in 
receiving these text message reminders. 
 
DISCLOSURES OF RISKS AND VULNERABILITIES 
Although unlikely, it is possible that the unencrypted text messages you receive could 
inadvertently be seen by someone else. Because the messages are de-identified (your name will 
not appear), the most information that could be seen would be that you are participating in a study. 
You are not sending any information back to the third-party vendor, so nothing you send could be 
seen by mistake. 
 
The study team members are not responsible for any loss or breach of data that results from 
something beyond their control, e.g., you lose your mobile device containing text messages 
reminders, or a third-party vendor or host experiences a server/data breach.  
 
Standard text/data messaging rates apply to these messages, and because some mobile phone 
providers charge an additional fee for the sending and receiving of text messages, you might be 
charged additionally by your mobile phone provider if you choose to receive the text message 
reminders.  
 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 95 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
PROCESS FOR NOTIFYING PARTICIPANT IN CASE OF AN ACTUAL OR 
POTENTIAL SECURITY BREACH 
If the third-party vendor that has your mobile device number experiences a breach or a potential 
breach, the third-party vendor will notify the sponsor of this study, Clear Creek Bio, Inc. The 
sponsor will notify the study team at each participating institution, and the study team will contact 
you regarding the possible risks associated with the breach/potential breach regarding your mobile 
device number.  
 
 
Consent Form SMS/Text Addendum Signature  
 
SUBJECT’S DATE OF BIRTH:  ______/______/_____ 
       mmm /    dd    /  yyyy 
 
Print Name of Investigator: 
 
 
 
Please initial 
box: 
1. I confirm that I have read this consent form for receiving text message 
medication reminders for the above study and have had the opportunity to 
ask questions. 
 
 
2. I understand my participation is voluntary in this text messaging service and 
I am free to withdraw at any time, without giving any reason, without my 
medical care or legal rights being affected. 
 
 
3. I give permission for the study team and third-party vendor to have access 
to my mobile device number. 
 
 
4. I agree to take part in the mobile device text message reminder for the above 
study. 
 
 
 
By signing this consent form, I have not given up any of my legal rights. 
 
 
 
Printed Name of Subject                       Signature of Subject 
Date   
Time 
 
                                                                      
Printed Name of person conducting      Sign  
Date  
 
Time 
informed consent discussion 
 
 
Original with Investigator File 
1 copy for subject 
1 copy for Subject’s Medical Records 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 96 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
APPENDIX F:  WMA Declaration of Helsinki 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by 
the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000  
53th WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 added) 
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added) 
59th WMA General Assembly, Seoul, October 2008 
A. INTRODUCTION  
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including 
research on identifiable human material and data.  
The Declaration is intended to be read as a whole and each of its constituent paragraphs should 
not be applied without consideration of all other relevant paragraphs. 
2. Although the Declaration is addressed primarily to physicians, the WMA encourages other 
participants in medical research involving human subjects to adopt these principles. 
3. It is the duty of the physician to promote and safeguard the health of patients, including those 
who are involved in medical research. The physician's knowledge and conscience are dedicated 
to the fulfillment of this duty. 
4. The Declaration of Geneva of the WMA binds the physician with the words, "The health of 
my patient will be my first consideration," and the International Code of Medical Ethics 
declares that, "A physician shall act in the patient's best interest when providing medical care." 
5. Medical progress is based on research that ultimately must include studies involving human 
subjects. Populations that are underrepresented in medical research should be provided 
appropriate access to participation in research. 
6. In medical research involving human subjects, the well-being of the individual research subject 
must take precedence over all other interests. 
7. The primary purpose of medical research involving human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic 
interventions (methods, procedures and treatments). Even the best current interventions must 
be evaluated continually through research for their safety, effectiveness, efficiency, 
accessibility and quality. 
8. In medical practice and in medical research, most interventions involve risks and burdens. 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 97 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
9. Medical research is subject to ethical standards that promote respect for all human subjects and 
protect their health and rights. Some research populations are particularly vulnerable and need 
special protection. These include those who cannot give or refuse consent for themselves and 
those who may be vulnerable to coercion or undue influence. 
10. Physicians should consider the ethical, legal and regulatory norms and standards for research 
involving human subjects in their own countries as well as applicable international norms and 
standards. No national or international ethical, legal or regulatory requirement should reduce 
or eliminate any of the protections for research subjects set forth in this Declaration. 
B. BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH  
11. It is the duty of physicians who participate in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal 
information of research subjects. 
12. Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant sources 
of information, and adequate laboratory and, as appropriate, animal experimentation. The 
welfare of animals used for research must be respected.  
13. Appropriate caution must be exercised in the conduct of medical research that may harm the 
environment. 
14. The design and performance of each research study involving human subjects must be clearly 
described in a research protocol. The protocol should contain a statement of the ethical 
considerations involved and should indicate how the principles in this Declaration have been 
addressed. The protocol should include information regarding funding, sponsors, institutional 
affiliations, other potential conflicts of interest, incentives for subjects and provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation in 
the research study. The protocol should describe arrangements for post-study access by study 
subjects to interventions identified as beneficial in the study or access to other appropriate 
care or benefits. 
15. The research protocol must be submitted for consideration, comment, guidance and approval 
to a research ethics committee before the study begins. This committee must be independent 
of the researcher, the sponsor and any other undue influence. It must take into consideration 
the laws and regulations of the country or countries in which the research is to be performed 
as well as applicable international norms and standards but these must not be allowed to reduce 
or eliminate any of the protections for research subjects set forth in this Declaration. The 
committee must have the right to monitor ongoing studies. The researcher must provide 
monitoring information to the committee, especially information about any serious adverse 
events. No change to the protocol may be made without consideration and approval by the 
committee. 
16. Medical research involving human subjects must be conducted only by individuals with the 
appropriate scientific training and qualifications. Research on patients or healthy volunteers 
requires the supervision of a competent and appropriately qualified physician or other health 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 98 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
care professional. The responsibility for the protection of research subjects must always rest 
with the physician or other health care professional and never the research subjects, even 
though they have given consent. 
17. Medical research involving a disadvantaged or vulnerable population or community is only 
justified if the research is responsive to the health needs and priorities of this population or 
community and if there is a reasonable likelihood that this population or community stands to 
benefit from the results of the research. 
18. Every medical research study involving human subjects must be preceded by careful 
assessment of predictable risks and burdens to the individuals and communities involved in 
the research in comparison with foreseeable benefits to them and to other individuals or 
communities affected by the condition under investigation. 
19. Every clinical trial must be registered in a publicly accessible database before recruitment of 
the first subject. 
20. Physicians may not participate in a research study involving human subjects unless they are 
confident that the risks involved have been adequately assessed and can be satisfactorily 
managed. Physicians must immediately stop a study when the risks are found to outweigh the 
potential benefits or when there is conclusive proof of positive and beneficial results. 
21. Medical research involving human subjects may only be conducted if the importance of the 
objective outweighs the inherent risks and burdens to the research subjects. 
22. Participation by competent individuals as subjects in medical research must be voluntary. 
Although it may be appropriate to consult family members or community leaders, no 
competent individual may be enrolled in a research study unless he or she freely agrees. 
23. Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information and to minimize the impact of the study on their 
physical, mental and social integrity. 
24. In medical research involving competent human subjects, each potential subject must be 
adequately informed of the aims, methods, sources of funding, any possible conflicts of 
interest, institutional affiliations of the researcher, the anticipated benefits and potential risks 
of the study and the discomfort it may entail, and any other relevant aspects of the study. The 
potential subject must be informed of the right to refuse to participate in the study or to 
withdraw consent to participate at any time without reprisal. Special attention should be given 
to the specific information needs of individual potential subjects as well as to the methods 
used to deliver the information. After ensuring that the potential subject has understood the 
information, the physician or another appropriately qualified individual must then seek the 
potential subject's freely-given informed consent, preferably in writing. If the consent cannot 
be expressed in writing, the non-written consent must be formally documented and witnessed. 
25. For medical research using identifiable human material or data, physicians must normally seek 
consent for the collection, analysis, storage and/or reuse. There may be situations where 
consent would be impossible or impractical to obtain for such research or would pose a threat 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 99 of 101 
PROTOCOL VERSION: FINAL; 2.0 
DATE:  4 June 2018 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
to the validity of the research. In such situations the research may be done only after 
consideration and approval of a research ethics committee. 
26. When seeking informed consent for participation in a research study the physician should be 
particularly cautious if the potential subject is in a dependent relationship with the physician 
or may consent under duress. In such situations the informed consent should be sought by an 
appropriately qualified individual who is completely independent of this relationship. 
27. For a potential research subject who is incompetent, the physician must seek informed consent 
from the legally authorized representative. These individuals must not be included in a 
research study that has no likelihood of benefit for them unless it is intended to promote the 
health of the population represented by the potential subject, the research cannot instead be 
performed with competent persons, and the research entails only minimal risk and minimal 
burden. 
28. When a potential research subject who is deemed incompetent is able to give assent to 
decisions about participation in research, the physician must seek that assent in addition to the 
consent of the legally authorized representative. The potential subject's dissent should be 
respected. 
29. Research involving subjects who are physically or mentally incapable of giving consent, for 
example, unconscious patients, may be done only if the physical or mental condition that 
prevents giving informed consent is a necessary characteristic of the research population. In 
such circumstances the physician should seek informed consent from the legally authorized 
representative. If no such representative is available and if the research cannot be delayed, the 
study may proceed without informed consent provided that the specific reasons for involving 
subjects with a condition that renders them unable to give informed consent have been stated 
in the research protocol and the study has been approved by a research ethics committee. 
Consent to remain in the research should be obtained as soon as possible from the subject or 
a legally authorized representative. 
30. Authors, editors and publishers all have ethical obligations with regard to the publication of 
the results of research. Authors have a duty to make publicly available the results of their 
research on human subjects and are accountable for the completeness and accuracy of their 
reports. They should adhere to accepted guidelines for ethical reporting. Negative and 
inconclusive as well as positive results should be published or otherwise made publicly 
available. Sources of funding, institutional affiliations and conflicts of interest should be 
declared in the publication. Reports of research not in accordance with the principles of this 
Declaration should not be accepted for publication. 
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE 
31. The physician may combine medical research with medical care only to the extent that the 
research is justified by its potential preventive, diagnostic or therapeutic value and if the 
physician has good reason to believe that participation in the research study will not adversely 
affect the health of the patients who serve as research subjects. 


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PROTOCOL NUMBER:  CCB-01
Page 0 of 101
PROTOCOL VERSION: FINAL v. 3.0
DATE:  04 October 2018
CONFIDENTIAL:  Clear Creek Bio, Inc.
CCB-01 Approvals and Revision History
Protocol agreed by:
Clinical Development
Date:
PRINT NAME:
Research & Development
Date:
PRINT NAME:
Chemistry and Manufacturing/Quality
Date:
PRINT NAME:
Sponsor Representative
Date:
PRINT NAME:
Revision History/Amendments:
Version Number
Date
1.0
31 May 2018
2.0
04 June 2018
3.0
04 October 2018


PROTOCOL NUMBER:  CCB-01
Page 1 of 101
PROTOCOL VERSION: FINAL v. 3.0 
DATE:  04 October 2018 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
STUDY PROTOCOL
A Phase 1b/2a open-label, multi-center study to assess the safety, 
efficacy and pharmacokinetics of intrapatient dose-adjusted 
brequinar and inhibition of dihydroorotate dehydrogenase 
(DHODH) in adult subjects with acute myelogenous leukemia 
(AML)
Study No: CCB-01
Version Date: 04 October 2018
Sponsor:
Clear Creek Bio, Inc.
585 Massachusetts Avenue, 4th Floor,
Cambridge MA 02139
Sponsor Telephone: (617) 765-2252
Sponsor Facsimile: (617) 863-2082
IND Number: 138335
This confidential document is the property of Clear Creek Bio, Inc. No unpublished information contained herein 
may be disclosed without the prior written approval of Clear Creek Bio, Inc. This trial will be conducted in 
accordance with the ICH Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95, Jan.97), the Declaration 
of Helsinki (1964, 1975, 1983, 1989, 1996, 2000 (Note for Clarification 2002 & 2004) and 2008), FDA Regulations 
and locally applicable regulations.


PROTOCOL NUMBER:  CCB-01
Page 2 of 101
PROTOCOL VERSION: FINAL v. 3.0 
DATE:  04 October 2018 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
TABLE OF CONTENTS
1
SYNOPSIS .................................................................................................................11
2
INTRODUCTION ......................................................................................................27
2.1 
Background: Acute Myeloid Leukemia .....................................................................27
2.2
Dihydroorotate dehydrogenase (DHODH) ................................................................27
2.3
Brequinar....................................................................................................................27
2.4 
Rationale for the Planned Trial .................................................................................. 29 
2.4.1 Brequinar Starting Dose Selection ............................................................................. 29 
2.5 
Risk/Benefit of Brequinar .......................................................................................... 30 
2.6 
Risks Associated with Participation in the Clinical Study ......................................... 30 
2.7 
Possible Interactions with Concomitant Medical Treatments .................................... 31 
2.7.1 CYP Interactions ........................................................................................................ 31 
2.8 
Steps to be Taken to Control or Mitigate Risks ......................................................... 31 
3 
TRIAL OBJECTIVES ................................................................................................ 32 
3.1 
Primary Objective ...................................................................................................... 32 
3.2 
Secondary Objectives ................................................................................................. 32 
3.3 
Exploratory Objectives ............................................................................................... 32 
4 
TRIAL DESIGN ........................................................................................................ 33 
5
TRIAL ENDPOINTS.................................................................................................34
5.1
Primary Endpoint .......................................................................................................34
5.2
Secondary Endpoints..................................................................................................34
5.3
Exploratory Endpoints................................................................................................34
6
TRIAL POPULATION..............................................................................................35
6.1
Number of Subjects....................................................................................................35
6.2
Inclusion criteria.........................................................................................................35
6.3
Exclusion Criteria.......................................................................................................35
6.4
Inclusion of Women and Minorities...........................................................................36
7
STUDY TREATMENTS ...........................................................................................37


PROTOCOL NUMBER:  CCB-01
Page 3 of 101
PROTOCOL VERSION: FINAL v. 3.0 
DATE:  04 October 2018 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
7.1
Description of Brequinar: ...........................................................................................37
7.2 
Treatment Administration ..........................................................................................37
7.3
Safety/Tolerability......................................................................................................37
7.3.1 Safety/Tolerability – Subject Level............................................................................37
7.3.1.1
Hematologic Toxicity............................................................................................38
7.3.2 Safety/Tolerability – Cohort Level ............................................................................38
7.3.3 Safety/Tolerability – Expansion Cohort.....................................................................39
7.4 
Cohort Starting Doses ................................................................................................39
7.5 
Individual Dose Adjustment Guidelines ....................................................................39
7.5.1 DHO Threshold ..........................................................................................................40
7.6 
Medication/AE Diary .................................................................................................42
7.7 
Bone Marrow Biopsy .................................................................................................42
7.8 
Flow Cytometry..........................................................................................................42
7.9 
Expansion Cohort .......................................................................................................42
7.10 Study Drug Discontinuation .......................................................................................42
7.11 Brequinar Pharmacokinetics (PK) / Dihydroorotate (DHO) Plasma Levels..............43
7.12 Concomitant Medication/Treatment ..........................................................................43
7.12.1 
Gastric pH ..............................................................................................................43
7.13 Treatment Compliance...............................................................................................43
7.14 Storage, Stability, Labeling and Packaging ...............................................................44
7.14.1
Storage and Stability..............................................................................................44
7.14.2 
Labeling and Packaging ........................................................................................44
7.14.3
Blinding and Randomization.................................................................................44
7.14.4
Unblinding/Expectedness......................................................................................44
7.14.5
Study Drug Accountability....................................................................................44
8
CONDUCT OF THE TRIAL.....................................................................................46
8.1
Ethical and Regulatory Considerations......................................................................46
8.2
Informed Consent.......................................................................................................46


PROTOCOL NUMBER:  CCB-01
Page 4 of 101
PROTOCOL VERSION: FINAL v. 3.0 
DATE:  04 October 2018 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
8.3
Institutional Review Board / Ethics Committees.......................................................47
8.4 
Schedule of Events .....................................................................................................47
8.5
Study Conduct............................................................................................................48
8.5.1 Screening Visit (Study Days -14 to -1)......................................................................48
8.5.2 Cycle 1........................................................................................................................48
8.5.3 Cycle 2 (and any Dose Adjustment Cycle) ................................................................ 49 
8.5.4 Maintenance Dose Cycle (visit every 2 - 4 weeks) .................................................... 50 
8.5.5 Final Visit ................................................................................................................... 51 
8.5.6 Follow Up Visit (2 weeks after Final Visit) ............................................................... 51 
8.5.7 Unscheduled Visits ..................................................................................................... 51 
8.6 
Compliance with Study Procedures ........................................................................... 52 
8.7 
Early Withdrawal from the Study .............................................................................. 52 
8.8 
Early Termination of the Study .................................................................................. 52 
8.9 
Short Messaging Service (SMS) Medication Reminders ........................................... 52 
9 
ADVERSE EVENT REPORTING ............................................................................ 54 
9.1 
Classification of Causality ......................................................................................... 56 
9.2 
Classification of Severity ........................................................................................... 56 
9.3 
Serious Adverse Event (SAE) Reporting ................................................................... 56 
9.4
Suspected Unexpected Serious Adverse Reactions (SUSARs) .................................58
9.5
Pregnancies.................................................................................................................58
9.6
Hematologic Adverse Events.....................................................................................59
9.7 
Management of Myelosuppression ............................................................................ 60 
9.8
Differentiation Syndrome...........................................................................................60
9.9
Tumor Lysis Syndrome (TLS)...................................................................................61
9.10 Infection Prophylaxis .................................................................................................63
9.11 Growth Factor Support...............................................................................................63
9.12 Management of Nausea, Vomiting, and Diarrhea......................................................63
10
STATISTICAL CONSIDERATIONS.......................................................................64


PROTOCOL NUMBER:  CCB-01
Page 5 of 101
PROTOCOL VERSION: FINAL v. 3.0 
DATE:  04 October 2018 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
10.1 Study Populations for Analysis ..................................................................................64
10.2 Safety Analyses ..........................................................................................................64
10.3 Efficacy Analyses.......................................................................................................65
10.4 Other Endpoints..........................................................................................................67
10.5 Sample Size Considerations.......................................................................................68
10.6 Randomization ...........................................................................................................68
10.7 Pooling of Study Centers............................................................................................68
10.8 Interim Analysis .........................................................................................................68
11
INVESTIGATOR RESPONSIBILITIES ..................................................................69
11.1 Investigator’s Performance ........................................................................................69
11.2 Confidentiality ............................................................................................................69
11.3 Source Documentation ...............................................................................................69
11.4 Data Collection ...........................................................................................................70
11.5 Case Report Forms, Investigator’s Site File and Record Retention ........................... 70 
11.6 Non-Protocol Research .............................................................................................. 71 
11.7 Publication .................................................................................................................. 71 
12 
SPONSOR RESPONSIBILITIES .............................................................................. 72 
12.1 General ....................................................................................................................... 72 
12.2 Indemnity ...................................................................................................................72
12.3 Data Monitoring.........................................................................................................72
12.4 Audit...........................................................................................................................72
12.5 Confidentiality ............................................................................................................ 73 
12.6 Finance .......................................................................................................................73
13
REFERENCES...........................................................................................................74
14
APPENDICES............................................................................................................75
14.1 APPENDIX A:  CCB-01 Schedule of Events............................................................75
14.2 APPENDIX B: ECOG Performance Status Criteria..................................................78
14.3 APPENDIX C: Brequinar/DHO Plasma Sampling....................................................79


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14.4 APPENDIX D: Common Terminology Criteria for Adverse Events (CTCAE) .......80 
14.5 APPENDIX E:  Sample Subject Consent Form ......................................................... 81 
14.6 Appendix F: WMA Declaration of Helsinki...............................................................96


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LIST OF TABLES
Table 1.
Exceptions to Grade 3 Nonhematologic AEs............................................................. 38
Table 2.
Intra-Subject Dose Adjustment .................................................................................. 40
Table 3.
Analysis Sets............................................................................................................... 64
Table 4.
Efficacy Analyses ....................................................................................................... 65


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LIST OF FIGURES
Figure 1.
Dose Adjustment – Subject Level .............................................................................. 41
Figure 2.
Monitoring of Tumor Lysis Syndrome....................................................................... 62


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ABBREVIATIONS
Abbreviation
Definition 
µg
Microgram 
5-FU
5-Fluorouracil  
AUC
Area Under Curve
BID
Bis in die (two times a day)
C6min
Concentration at 6 minutes
CHO/HGPRT
Chinese hamster ovary cell/hypoxanthine-guanine phosphoribosyl-transferase
CL
Clearance
ClR
Low Renal Clearance 
ClT 
Low Plasma Total Clearance
CRh
Partial hematological response
CRi
Incomplete hematological response
CT
Computerized Tomography
CYP
Cytochrome P450
DHO
Dihydroorotate 
DHODH
Dihydroorotate dehydrogenase
DLT(s) 
Dose-Limiting Toxicity(ies)
DNA
Deoxyribonucleic Acid
ECGs 
Electrocardiograms 
ECOG 
Eastern Cooperative Oncology Group
ED50
Median Effective Dose  
EORTC
European Organisation for the Research and Treatment of Cancer 
ESR
Erythrocyte Sedimentation Rate 
F 
Bioavailability 
FDA
United States Food and Drug Administration
g
Grams 
GI 
Gastrointestinal 
G-R 
Good Risk Patients 
HPLC 
High-Performance Liquid Chromatography
HIPAA 
Health Insurance Privacy and Portability Act
Hr 
Hour 
IB 
Investigator Brochure
IP 
Intraperitoneal
IV 
Intravenous 
kg 
Kilograms 
l
Liters 
LD(10, 50, 90) 
Lethal Dose(10%, 50%, 90%) 
LPS 
Lipopolysaccharide
M 
Molar
Mg 
Milligram
mL 
Milliliters
MLED10
Mouse Equivalent Lethal Dose for 10% of population 
mM
Micromolar


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Mm
Millimeters
MRD
Minimal Residual Disease
MRT
Long Median Residence Time
MS
Mucositis/stomatitis
MTD 
Maximum Tolerated Dose
NCI
National Cancer Institute
NCI
United States National Cancer Institute
NMR
Nuclear Magnetic Resonance Spectroscopy
NSC
National Service Center 
ORR 
Overall Response Rate 
PK 
Pharmacokinetic(s)
PO 
Per Orem 
P-R
Poor Risk Patients
PR 
Partial Response 
PS
Performance Status 
Pts.
Patients
QTcF 
Corrected QT interval by Fredericia
RDP2
Recommended Dose for Phase II 
RNA
Ribonucleic Acid 
SC 
Subcutaneous  
SD 
Standard Deviation 
SE 
Standard Error 
SEM 
Standard error of the means 
SI 
Simulation Index
t½ 
Half-Life 
TEAE 
Treatment-emergent adverse event 
USP
United States Pharmacopeia
UV
Ultraviolet
V 
Volume 
Vd 
Volume of Distribution 
VdSS 
Steady-State Volume of Distribution
WBC
White Blood Cell
WHO 
World Health Organization


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1
SYNOPSIS
IND 
138,335 
Title
A Phase 1b/2a open-label, multi-center study to assess the safety, efficacy 
and pharmacokinetics of intrapatient dose-adjusted brequinar and inhibition 
of dihydroorotate dehydrogenase (DHODH) in adult subjects with acute 
myelogenous leukemia (AML) 
Protocol 
CCB-01
Investigational 
Medicinal 
Product and 
Dosage 
Brequinar is available as 100 and 250 mg oral capsules to be taken every 3.5 
days with approximately 240 mL of water. Each subject’s mg/m2 dose will 
be calculated based on body surface area at study entry; actual dose will be 
rounded down to the nearest mg based on available oral capsule doses.  
Primary 
Objective 
To determine the safety and tolerability of brequinar and the DHODH 
inhibitory level of brequinar in adult patients with AML. 
Secondary 
Objectives 
 
 
To determine the overall response rate (ORR) including complete 
remission (CR), CR with incomplete hematologic recovery (CRi),
morphologic leukemia-free state (MLFS), and partial remission (PR) 
(criteria as defined in the ELN Guidelines, Döhner et al., 2017) and 
complete remission with partial hematological recovery (CRh). 
To assess the rate of overall survival (OS) and event-free survival (EFS). 
To evaluate duration of response.  
To characterize the pharmacokinetic (PK) profile of brequinar.
To characterize the dihydroorotate (DHO) plasma levels of brequinar 
after oral dosing.
Exploratory 
Objectives 
To assess the relationship between DHODH inhibition and the efficacy 
and safety of brequinar. 
To evaluate molecular and cellular biomarkers that may be predictive of 
antitumor level and/or treatment resistance including cytogenetics, 
molecular profiling, and flow cytometry during and after treatment.
To evaluate global gene expression profiles, DNA methylation profiles, 
and other potential prognostic markers to explore predictors of antitumor 
activity and/or resistance to treatment. 
Design 
This will be a Phase 1b/2a multi-center, open-label, non-randomized clinical 
trial to assess the safety, tolerability and efficacy of dose-adjusted brequinar 
in adult subjects with AML. The study will also assess the inhibition of 


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DHODH and the PK profile of brequinar in plasma. Subject dosing will be 
adjusted based on safety/tolerability and DHO level. 
Up to 27 subjects are planned to be entered in this trial: Cohort 1 will have 6 
subjects; two additional cohorts of 3 subjects each may be added if the 
Cohort 1 starting dose requires adjustment. Cohorts 2 and 3 may be 
expanded to 6 subjects using a 3 + 3 design if required by safety assessments 
as described in Section 7.3.2.  Following completion of enrollment in the 
starting dose-adjustment part of the study, an expansion cohort of 
approximately 15 subjects will be enrolled with a starting dose of the highest 
tolerated dose from Cohorts 1 – 3. Safety and tolerability will be assessed 
utilizing physical examination, vital sign measurements, safety laboratory 
testing, 12-lead ECGs, bone marrow sampling, and adverse event reporting. 
Bone marrow sampling (bone marrow aspirate and core biopsy) will also be 
utilized for efficacy. DHO level will be measured using a validated assay. 
PK will be analyzed using standard PK parameters.  
Dosing will continue for up to 12 months in the absence of unacceptable 
toxicity or disease progression.  
Primary 
endpoints: 
Safety/tolerability and DHO level relationship with safety and 
therapeutic brequinar levels   
Secondary 
endpoints: 
Rates of treatment-emergent adverse events. 
Overall Response Rate (ORR) including CR, CRi, CRh, MLFS, or PR. 
Event free survival (EFS). 
Duration of response. 
PK profile of brequinar. 
DHO plasma profile. 
Exploratory 
endpoints: 
Relationship between DHODH inhibition and the efficacy and safety of 
brequinar. 
Antitumor level based on molecular and cellular biomarkers including 
cytogenetics, molecular profiling, and flow cytometry during and after 
treatment. 
Global gene expression profiles, DNA methylation profiles, and other 
potential prognostic markers to explore predictors of antitumor activity 
and/or resistance to treatment. 
Sample Size: 
Up to 27 subjects  
Number of 
3 – 5 


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Sites: 
Study Period:
An enrollment period of 18 - 24 months is expected.
Inclusion 
Criteria: 
 
1. Willing and able to provide written informed consent for the trial. 
2. Patients 18 years of age or older, with relapsed/refractory AML by 
World Health Organization classification who have exhausted 
available therapy. 
3. ECOG Performance Status 0 to 2. 
4.
5. Adequate hepatic function (unless deemed to be related to underlying 
leukemia).
1.
 
2.
 
3.
 
6. Adequate renal function as documented by 
mL/min based on the Cockcroft-Gault equation. 
7. In the absence of rapidly proliferative disease, the interval from prior 
leukemia-directed therapy to time of study initiation will be at least 7 
days for cytotoxic or non-cytotoxic (immunotherapy) agents. Hydrea 
is allowed up to 48 hours prior to the first dose for patients with 
rapidly proliferative disease.  
8. The effects of brequinar on the developing human fetus are unknown. 
For this reason, women of child-bearing potential and men must 
agree to use adequate contraception (hormonal or barrier method of 
birth control; abstinence) prior to study entry and for the duration of 
study participation. Should a woman become pregnant or suspect she 
is pregnant while she or her partner is participating in this study, she 
should inform her treating physician immediately. Men treated or 
enrolled on this protocol must also agree to use adequate 
contraception prior to the study, for the duration of study 
participation, and for 90 days after completion of brequinar 
administration.
9. Male subjects must agree to refrain from sperm donation from initial 
study drug administration until 90 days after the last dose of study 
drug.
Exclusion 
Criteria: 
1. Patients in need of immediate leukapheresis. 
2. White blood count > 25 x 109/L (note: hydroxyurea is permitted to 


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meet this criterion). 
3. Any concurrent uncontrolled clinically significant medical condition, 
laboratory abnormality, or psychiatric illness that could place the 
participant at unacceptable risk of study treatment.
4.
Participants with a bundle branch block and prolonged QTc interval 
may be eligible after discussion with the medical monitor.
5. The use of other chemotherapeutic agents or anti-leukemic agents is 
not permitted during study with the following exceptions:
a.
Intrathecal chemotherapy for prophylactic use or maintenance of 
controlled CNS leukemia. 
6. Use of hydroxyurea for the purpose of leukemic cytoreduction may 
be allowed during the first 2 weeks of therapy if in the best interest of 
the participant and is approved by the medical monitor. Hydroxyurea 
can be used to treat leukocytosis if concurrent with and thought to be 
associated with presumed differentiation syndrome.
7. AML relapse less than 6 months following stem cell transplantation.  
8. Presence of graft versus host disease (GVHD) which requires an 
systemic corticosteroids (e.g. cyclosporine or other calcineurin 
inhibitors or other immunosuppressive agents used for GVHD).
9. Active cerebrospinal involvement of AML.
10. Diagnosis of acute promyelocytic leukemia (APL) 
11. Clinically active hepatitis B (HBV) or hepatitis C (HCV) infection.
12. Severe gastrointestinal or metabolic condition that could interfere 
with the absorption of oral study medication. 
13. Prior malignancy, unless it has not been active or has remained stable 
for at least 3 years. Participants with treated non-melanoma skin 
cancer, in situ carcinoma or cervical intraepithelial neoplasia, 
regardless of the disease-free duration, are eligible if definitive 
treatment for the condition has been completed. Participants with 
organ-confined prostate cancer with no evidence of recurrent or 
progressive disease are eligible if at the active surveillance stage, 
hormonal therapy has been initiated, or the malignancy has been 
surgically removed or treated with definitive radiotherapy. 
14. Nursing women or women of childbearing potential (WOCBP) with a 
positive urine pregnancy test. 


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Treatment 
Subjects will self-administer oral brequinar twice weekly (every 84 hours +/-
6 hours). Treatment cycles will be 2 weeks. Visits will take place at least 
every 2 weeks through 3 months; visits thereafter will be every 2 – 4 weeks 
at the discretion of the investigator at each site. Inter-cohort and intra-subject 
dose adjustments may occur throughout the study as outlined in the sections 
below. Subjects in Cohort 1 may not escalate above the initial 500 mg/m2 
starting dose. 
Procedures
Screening Visit (Study Days -14 to -1)
These procedures must be completed within the 14 days prior to starting 
dosing. Obtain the subject’s written informed consent, then collect baseline 
information:
-
Demographics (height, weight, date of birth, gender, race, ethnicity)
-
Pertinent medical/surgical history (including AML diagnosis and 
laboratory and clinical evidence of progression, previous AML 
treatment, and any available chromosomal and mutational testing 
results per institutional guidelines) 
-
Concomitant medications. 
-
Physical examination (including weight).  
-
Vital signs (heart rate, respiratory rate, blood pressure, body 
temperature).  
-
Pregnancy test for women of childbearing potential (WOCBP)  
-
ECOG performance assessment.  
-
Hematology/chemistry. 
-
12-lead ECG with QTcF and MUGA scan or echocardiogram to 
assess cardiac function. 
-
Bone marrow sampling
-
Confirm subject meets all inclusion and no exclusion criteria. 
Treatment
The treatment period begins with Cycle 1, Day 1 of the first 2-week dosing 
cycle. 
Cycle 1 Day 1:
-
Collect any adverse events or new concomitant medications since 
Screening.  
-
Draw samples for baseline (pre-dose) brequinar/DHO, flow 
cytometry, and hematology/chemistry. 
-
Conduct physical examination (including weight), vital signs, urine 
pregnancy test for WOCBP and 12-lead ECG.
-
Review results and confirm subject remains eligible for the study.  
-
Determine subject’s starting dose based on the respective cohort 
mg/m2 starting dose. 
-
Dispense study medication.  


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-
Subject is to take the first dose at the clinic and remain for 
brequinar/DHO sampling. Collect brequinar/DHO samples at 1, 2, 4, 
and 6 hours post dose.
-
Process and store brequinar/DHO samples per the supplied laboratory 
manual.
-
Dispense the subject’s calendar/diary. The diary will collect 
dates/times of study medication administration and AEs/new 
concomitant medications.
-
Enroll subject for text message reminders if the subject consents to 
that service.  
-
Ship the flow cytometry sample per the supplied laboratory manual. 
Cycle 1 Day 2:  
-
Collect 24h post dose brequinar/DHO and flow cytometry samples. 
Check the diary/elicit information about AEs/new concomitant 
medications since the last visit. 
-
Process and store brequinar/DHO samples per the supplied laboratory 
manual. 
-
Ship the flow cytometry sample per the supplied laboratory manual. 
Cycle 1 Day 3:  
-
Collect 48h post dose brequinar/DHO and flow cytometry samples. 
Check the diary/elicit information about AEs/new concomitant 
medications since the last visit.  
-
Process and store brequinar/DHO samples per the supplied laboratory 
manual. 
-
Ship the flow cytometry sample per the supplied laboratory manual. 
Cycle 1 Day 4:  
-
Collect 72h post dose brequinar/DHO samples. Check the diary/elicit 
information about AEs/new concomitant medications since the last 
visit. 
-
Process and store brequinar/DHO samples per the supplied laboratory 
manual. 
Cycle 1 Day 8:  
-
Vital signs. 
-
Check the diary/elicit information about AEs/new concomitant 
medications since the last visit. 
-
Prior to the morning dose, collect brequinar/DHO samples 
(approximately 84h post the second dose of Cycle 1) and 
hematology/chemistry samples, then have subject take study 
medication.  
-
Process and store brequinar/DHO samples per the supplied laboratory 
manual. 
-
Notify DHO assay laboratory of incoming shipment and ship Cycle 1 


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brequinar/DHO samples (samples from Days 1, 2, 3, 4 and 8).
Cycle 2 (and any Dose Adjustment Cycle) 
Repeat this visit as needed whenever any dose adjustment is required.
Day 1: 
-
Collect unused study medication and check the diary/elicit 
information about AEs/new concomitant medications since the last 
visit.  
-
Take vital signs and perform physical examination (including weight).
-
Collect pre-dose brequinar/DHO samples (approximately 84h post the 
fourth dose of the previous cycle) and hematology/chemistry samples. 
-
Process and store brequinar/DHO samples per the supplied laboratory 
manual.
-
Review laboratory results/safety information and determine whether 
the subject should adjust the dose (based on acceptable safety and 
DHO level), continue with the current dose or hold study medication 
(unacceptable safety) per the guidelines below.  
-
If dosing will continue, dispense study medication.  
-
Dispense calendar/diary. 
-
Manage text message reminders as needed (as a default do nothing, 
pause if study medication is put on hold, and restart if study 
medication is restarted) 
Day 8: 
-
Collect and check the diary/elicit information about AEs/new 
concomitant medications since the last visit. 
-
Vital signs. 
-
Collect pre-dose brequinar/DHO and hematology/chemistry samples. 
-
Perform bone marrow sampling for flow cytometry (window ±7 days).
-
If the subject is being dosed (i.e., has acceptable safety), have the 
subject take the morning dose.  
-
Process and store brequinar/DHO samples per the supplied laboratory 
manual.
-
If the subject’s medication was held, review safety information and 
determine whether dosing can resume. If dosing can resume, 
determine dose, dispense adequate medication for 4 doses and have 
the subject take the morning dose. 
-
Continue to withhold study drug if safety remains unacceptable.
-
Dispense calendar/diary. 
-
Manage text message reminders as needed (as a default do nothing, 
pause if study medication is put on hold, and restart if study 
medication is restarted) 
-
Notify DHO assay laboratory of incoming shipment and ship 


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brequinar/DHO samples (samples from current cycle's Days 1 and 8).
 
Subjects may undergo dose adjustments at any time using the guidelines 
presented in Section 7 of the protocol. Subjects with acceptable safety can 
continue to escalate every 2 weeks by 150 mg/m2 increments through 800 
mg/m2, with the exception of Cohort 1 subjects who may not escalate above 
the 500 mg/m2 starting dose. Subjects with unacceptable safety can continue 
to undergo dose reductions of 75 mg/m2 with no lower limit. Re-escalation to 
a dose previously shown as not tolerated for an individual subject is not 
permitted for these subjects.
Dose adjustments are permitted throughout the study (except for the 
restriction of no escalation in Cohort 1) for an individual subject based on 
safety, DHO level, and clinical response with an upper limit of 800 mg/m2.
Maintenance Dose Cycle (visit every 2 - 4 weeks)
Once a subject reaches a stable or maintenance dose (see Figure 1), the 
subject will be in the Maintenance Dose Cycle. 
In the first 3 months from starting study drug, the Maintenance Dose Cycle 
procedures will occur every 2 weeks (with the exception of bone marrow 
aspiration as discussed below). After completing 3 months from starting 
study drug, subjects may come to the clinic for a Maintenance Dose Cycle 
visit every 2 - 4 weeks (visit interval at the investigator’s discretion).
A subject may still move into a Dose Adjustment Cycle after a maintenance 
dose if required for a change in safety, DHO level or clinical response
(Figure 1).  
Day 1:
-
Collect unused study medication and check the diary/elicit 
information about AEs/new concomitant medications since the last 
visit. 
-
Collect pre-dose brequinar/DHO and hematology/chemistry samples.  
-
Conduct physical examination, vital signs, urine pregnancy test for 
WOCBP 12-lead ECG and bone marrow sampling (note that bone 
marrow is collected on study Day 22 (C2D8 ± 7 days), at Day 43, and 
then every 12 weeks; the Day 43 sample will be assessed for 
hematological toxicity).  
-
Review the laboratory results/safety information and determine 
whether the subject should maintain current dose (acceptable safety) 
or hold study medication (unacceptable safety).  
-
Dispense study medication. 
-
Dispense calendar/diary.  
-
Manage text message reminders as needed (as a default do nothing, 
pause if study medication is put on hold, and restart if study 


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medication is restarted)
-
Notify DHO assay laboratory of incoming shipment and ship 
brequinar/DHO samples. 
Final Visit
This visit is to take place when a subject is discontinuing from the study.
-
Collect and check the diary/elicit information about AEs/new 
concomitant medications since the last visit.  
-
Collect brequinar/DHO and hematology/chemistry samples.  
-
Collect unused study medication. 
-
Conduct physical examination, vital signs, urine pregnancy test for 
WOCBP
, 12-lead ECG
since previous), and bone marrow sampling (if > 12 weeks since 
previous bone marrow sample obtained). 
-
Review the safety information and determine whether the subject has 
acceptable safety or unacceptable safety. 
-
Notify DHO assay laboratory of incoming shipment and ship 
brequinar/DHO samples.  
-
Stop text message reminders. 
Follow Up Visit (2 weeks after Final Visit)
-
Contact subject to elicit information about AEs/new concomitant 
medications since the last visit.
Survival information will be collected while the study is ongoing. 
Unscheduled Visits
Unscheduled visits and tests to assess AEs are permitted as needed. 
Safety/
Tolerability 
Safety/Tolerability – Subject Level
Grade 3, treatment-emergent, study-drug-related, non-hematologic adverse 
events. Due to the expected hematologic profile associated with AML, 
hematologic AEs of any grade will not be considered dose-limiting during 
the first 42 days of dosing. Exceptions to the non-hematologic Grade 3 
criterion are provided in the table below.  
Exceptions to Grade 3 Nonhematologic AEs 
Condition
Exception Description 
Nausea/
Emesis 
Grade 3 nausea and/or emesis resolving to less than or equal 
to Grade 2 or baseline within 1 week after the use of an 
optimal antiemetic regimen based on standard practice.
Diarrhea 
Grade 3 diarrhea resolving to less than or equal to Grade 1 or 
baseline within 1 week after receiving the maximal 
supportive therapy based on standard practice.


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Fatigue 
Grade 3 fatigue lasting less than 1 week.
Laboratory 
abnormalities
Asymptomatic Grade 3 laboratory abnormalities that are not 
considered to be clinically significant.
Hematologic Toxicity
After the subject has completed the first 42 days of treatment, the definition 
of unacceptable safety expands to include hematologic AEs defined as 
prolonged neutropenia with ANC < 500 from the start of therapy in the 
absence of disease, 
 and/or 
Grade 4 
thrombocytopenia, with a hypocellular bone marrow and no greater than 5% 
hematologic AE for the definition of unacceptable safety. Febrile 
neutropenia is also excluded from the DLT definition for this population. For 
clinic visits when bone marrow sampling is scheduled, the timing of the bone 
marrow sampling can be adjusted to ensure that the results are available at 
the time of the clinic visit. 
Safety/Tolerability – Cohort Level
Acceptable safety/tolerability at the cohort level is defined below: 
a)
safety/tolerability 
leading 
to 
dose 
reduction 
or 
treatment 
discontinuation (a dose limiting toxicity or DLT), then that dose is 
considered to have unacceptable safety/tolerability and the previous
dose which was safe/tolerated must be considered as the highest 
safe/tolerated dose.  
b) If 1 out of 3 subjects at a dose level experiences a DLT, then 3 
additional subjects will be added to the cohort and treated at the same 
dose that led to the DLT. Upon cohort expansion to 6 subjects, if a 
total of 
out of 6 subjects has a DLT at that dose, then this dose is 
considered a safe/tolerated dose. However, if >2 out of 6 subjects at a 
dose level experience a DLT, then that dose is considered to have 
unacceptable safety/tolerability and the previous dose which was 
safe/tolerated must be considered as the highest safe/tolerated dose.
Cohort Starting 
Doses 
Cohort 1 will treat 6 subjects at 500 mg/m2 twice weekly. No dose escalation 
is permitted for Cohort 1 subjects, but the dose may be reduced for an 
individual subject in this cohort if the subject experiences unacceptable 
safety. 
After all subjects in Cohort 1 have completed a 42-day treatment period, up 
to two additional cohort(s) of 3 subjects each will be added with the starting 
doses adjusted (escalated or de-escalated) based on both safety/tolerability 
and adequacy of DHO level results in Cohort 1.  
If all subjects in a cohort have acceptable safety at a dose level, the next 
cohort’s starting dose may be escalated by 150 mg/m2. If the safety rules are 


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not met at a cohort’s starting dose, the next cohort’s starting dose will be 
reduced to the highest dose found to be safe/tolerated in the previous cohort. 
The planned upper limit for cohort starting dose is 800 mg/m2. There is no 
lower limit.
See the “Intra-subject dose adjustment” section for individual subject dosing 
adjustment criteria.
Expansion 
Cohort 
Once a dose has been reached that has adequate DHO level and acceptable 
safety/tolerability, approximately 15 subjects will be added starting at the 
highest safe/tolerated dose identified in the earlier cohorts. Decisions about 
adequacy of DHO threshold level will be made following review of these 
data from each cohort. These subjects may also undergo individual dose 
adjustment. See Section 7.3.3 for the expansion cohort safety rules. 
Individual Dose 
Adjustment 
Guidelines
With the exception of subjects in Cohort 1 whose dose may not be escalated 
above the 500 mg/m2 starting dose, intra-subject dose adjustment will be 
considered every 2 weeks depending on safety and DHO levels. There is a 
maximum of 2 dose adjustments for each subject within the first 42 days of 
initiating treatment. Each subject’s dose can be escalated, maintained (stable 
dose), held then reduced, or discontinued. The highest dose planned is 800 
mg/m2, however, this upper limit may be adjusted depending on safety, DHO 
level, and clinical response. There is no lower limit planned. 
As noted above, safety will be a key part of determining dose adjustments. 
Subjects who resume dosing at a lower dose after experiencing unacceptable 
safety may not undergo later dose escalations beyond the dose where the 
unacceptable safety occurred. 
Each subject will continue dosing twice weekly at the individually adjusted 
dose for up to 12 months in the absence of unacceptable toxicity or disease 
progression. Intra-subject dose adjustment is permitted at any time 
throughout the study based on safety/tolerability and DHO level (with the 
exception of no escalation for Cohort 1 subjects). Subjects who discontinue 
due to unacceptable safety/tolerability or die prior to Day 42 will not be 
replaced. 
Intra-subject dose adjustment increments and duration of dosing may be 
revised from planned amounts after each preceding cohort’s safety, DHO 
plasma levels and bone marrow results have been reviewed.  
Each subject’s baseline DHO sample will be obtained at C1D1 prior to 
dosing. Dose adjustment decisions based on DHO will be determined by 
DHO trough level (i.e., DHO level obtained pre-dose D8 of the previous 
cycle). The initial target for “adequate” trough DHO level will be set at 100 
ng/mL. This target may be adjusted during the study depending on safety or 
efficacy signals observed during the study. As described below, dose 


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adjustments are also based on safety and whether the dose has reached the 
planned upper limit (currently planned to be 800 mg/m2). 
The intrasubject dose-adjustment criteria are presented below.  
Intra-subject Dose Adjustment Criteria*
Acceptable 
Safety/Tolerability?
(see safety definition 
above)
Adequate 
DHO Level?
Planned Intra-Subject Dose 
Adjustment
Yes
Yes
Maintain; continue at same dose. 
Yes
No 
Escalate by 150 mg/m2 for the next 2-
week cycle up to a maximum of 800 
mg/m2. 
No 
Regardless of 
DHO 
Hold two doses (one week), then reassess 
-
escalate dose by 75 mg/m2 and resume 
dosing. If AE has not resolved, reassess 
again in one week.  
weeks after dosing held, discontinue 
further dosing. Subject will remain in the 
study for safety follow up for 42 days 
after last dose of study drug or until AEs 
have resolved or become stable. 
*Subjects in Cohort 1 may not escalate above the initial 500 mg/m2 starting dose
and may have dose reductions based on safety only.
Brequinar/DHO  Plasma brequinar/DHO samples are to be obtained for each subject for the 
first study dose (Cycle 1 Dose 1 for that subject). Sample scheduling is 0 
hours (prior to dosing), and post dose at 1, 2, 4, 6, 24, 48, and 72 hours. Note 
that this schedule does not apply to subjects in the expansion cohort who will 
have trough sampling only prior to the start of each two-week cycle.
A brequinar/DHO trough sample is to be obtained prior to dosing on Day 8 
(C84, 84 hours after the Cycle 1 Day 4 dose) of Cycle 1, and prior to dosing 
on Days 1 and 8 of Cycles 2 and 3.  
The 84-hour post dose brequinar/DHO sample is to be repeated prior to 
dosing at the beginning of each 2-week cycle and at the Final Visit. This 
sampling schedule also applies for the expansion cohort subjects.  
Statistical 
Analysis 
A separate, detailed statistical analysis plan (SAP) will be finalized prior to 
locking the database. All analyses of safety and anti-leukemic activity for 
this open-label, early Phase study will be descriptive in nature and presented 
by dose group and overall, as appropriate, for the dose-adjustment phase and 
the expansion phase. Procedures for accounting for missing, unused and 
spurious data will be described in the SAP.
Summaries for quantitative variables will include the mean, median, 
quartiles, standard deviation and error, minimum, and maximum. For 


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qualitative variables, the summaries will include the number and percentage 
of subjects for each outcome, and the exact 95% CI, when appropriate. No 
hypothesis testing will be performed. Any statistical testing will be 
considered exploratory and descriptive. All computations will be performed 
using SAS® (Version 9.3 or higher). 
Subject disposition, subject demographics and baseline characteristics will be 
summarized. Subject data listings will also be provided.  
All safety analyses will be performed on the Safety Analysis Set.  Safety and 
tolerability will be assessed in terms of AEs, SAEs, safety laboratory data, 
physical examinations, vital signs, 12-lead ECGs and bone marrow 
sampling.  
Adverse event data will be descriptively evaluated. All AEs will be listed. 
The incidence and duration of treatment-emergent adverse events (TEAEs), 
defined as AEs occurring after the first dose of study treatment through 30 
days after the last dose of study treatment will be tabulated by Medical 
Dictionary for Regulatory Activities (MedDRA) preferred term and system 
organ class, and by severity and relationship to study treatment. All 
laboratory results, vital sign measurements, ECGs and bone marrow 
assessments will be summarized using appropriate descriptive statistics. 
Efficacy analysis is described below. 
Assess anti-leukemic activity by ELN Guidelines including CRh, as follows:  

Overall Response rate (ORR) – the proportion of subjects in the 
Efficacy Analysis Set with a best overall response of CR, CRi, CRh, 
MLFS and PR  

Complete Remission (CR) rate – the proportion of subjects in the 
Efficacy Analysis Set with a best overall response of CR 

Complete Remission with Incomplete Hematologic Recovery (CRi) 
rate – the proportion of subjects in the Efficacy Analysis Set with a 
best overall response of CRi 

Complete remission with partial hematological recovery (CRh) – 
the proportion of subjects in the Efficacy Analysis Set with a best 
overall response of CRh 

Morphologic Leukemia Free State (MLFS) rate – the proportion of 
subjects in the Efficacy Analysis Set with a best overall response of 
MLFS 

Partial Remission (PR) rate – the proportion of subjects in the 
Efficacy Analysis Set with a best overall response of PR 

Event-free survival (EFS) – the interval between first brequinar 
 reappearance of blasts 
in blood, or development of extramedullary disease), disease 
progression, or death


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
Overall survival (OS) – the time from first dose of brequinar to date 
of death or last known alive date
For ORR and other endpoints defined as proportions, estimated response 
rates and two-sided exact binomial 95% CIs will be provided. The 
distributions of EFS and other time-to-event endpoints will be summarized 
using the Kaplan-Meier method. Time to event analyses will be from first 
dose of brequinar. Censoring rules for time-to-event endpoints will be 
described in the SAP. 


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STUDY PERSONNEL
SPONSOR CONTACT
Name:
Title:
Address:
Telephone No.:
Fax No.: 
E-mail:
Barbara Powers, MSN, Ph.D. 
Clinical Operations
Clear Creek Bio, Inc.
585 Massachusetts Avenue, 4th Floor, 
Cambridge, MA 02139
484-686-0545
617-863-2082
bpowers@clearcreekbio.com
SPONSOR MEDICAL CONTACT
Name: 
Title:
Address:
Telephone No.:
24-hour Safety No.:
E-mail:
Medical Monitor Fax No.:
SAE Reporting Fax:
SAE Reporting email: 
Robert Sims, MD 
Senior Medical Director / Medical Monitor 
Novella Clinical 
614-721-2630
1-866-758-2798 or 919-313-7111
robert.sims@novellaclinical.com; 
YYA36071medmon@novellaclinical.com 
206-826-0483
 919.313.1412 (US Toll-free:  
1-866-761-1274) safety-
inbox@novellaclinical.com 
LEAD INVESTIGATOR
Name:
Amir Fathi, MD
Title:
Assistant Professor of Medicine 
Affiliation:
Massachusetts General Hospital
Telephone No.:
E-mail:
617-724-1124
afathi@mgh.harvard.edu


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SUPPORT SERVICES
CRO Project Manager
Name:
Company: 
Address:
Telephone No.:
Mobile No.: 
Fax No.: 
E-mail:
Daniel Ferrone
Novella Clinical
1700 Perimeter Park Drive 
Morrisville, NC 27560
919-972-7158
704-806-7219
919-710-8769
dferrone@novellaclinical.com
Data Management/eCRF PROVIDER
Name:
Company: 
Address:
Telephone No.:
Help Desk:
Help Desk E-mail:
Kari Hayden
Novella Clinical 
1700 Perimeter Park Drive 
Morrisville, NC 27560 
919-972-2397
1-866-342-0693
sitesupport@novellaclinical.com
STATISTICAL ANALYSIS
Name:
Title:
Telephone No.:
Fax No.: 
E-mail:
Young Choy
Senior Biostatistician 
919-972 -7423
919-710-8769
ychoy@novellaclinical.com
STUDY DRUG HOLDING COMPANY
Name:
Address:
Telephone No.:
Email: 
Almac Clinical Services
25 Fretz Road
Souderton, PA 18964
215-660-8500
clinicalservices@almacgroup.com


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2
INTRODUCTION
2.1 Background: Acute Myeloid Leukemia
Acute myeloid leukemia (AML) is a malignant disorder of immature hematopoietic cells, 
characterized by differentiation arrest and rapid proliferation of abnormal myeloid precursors. 
These abnormal cells accumulate in the bone marrow and interfere with the production of normal 
blood cells. More than 20,000 people are diagnosed with AML per year in the United States (US) 
(SEER, 2015 [1]). The median age at diagnosis is 67 years. 
Although there have been recent advances including midostaurin, enasidenib, CPX-351, 
gemtuzumab ozogomycin and venetoclax, outcomes for patients with AML remain poor. With 
modern treatment regimens, expected complete remission (CR) rates are 60-70%, but long-term 
cure rates are 15-25%. Younger patients (i.e. those 50 years of age or younger) with diploid 
karyotypes have a CR rate of 70-80% and cure rates of 20-25%, while older patients and/or those 
with adverse cytogenetics have CR rates of 35-50% and cure rates of < 10%.1  It is therefore 
critical to improve both the remission rate and the durability of remission in AML patients of all 
ages.
2.2 Dihydroorotate dehydrogenase (DHODH)
Dihydroorotate dehydrogenase (DHODH) catalyzes the fourth step in pyrimidine synthesis, the 
conversion of dihydroorotate (DHO) to orotate. The enzyme is located on the inner 
mitochondrial membrane and transfers electrons between DHO and complex III of the electron-
transport chain via the reduction of its ubiquinone (coenzyme Q10) cofactor.  
DHODH is a ubiquitous enzyme, and lack of its level is not compatible with life. The Miller 
syndrome, a rare autosomal recessive disorder in which patients have inherited hypomorphic 
mutations in both alleles of DHODH, results in multi-organ dysfunction (Ng et al., 2010 [2]). 
Two weak inhibitors of human DHODH are approved for clinical use. Leflunomide, a pro-drug, 
is used in the treatment of patients with rheumatoid arthritis. Its active form, teriflunomide, is 
marketed for multiple sclerosis. Leflunomide is known to affect erythroid differentiation of K562 
cells in vitro, via the depletion of uridine triphosphate (UTP) and cytidine triphosphate (CTP) 
ribonucleotides (Huang et al., 2002 [3]). Despite the connection between bone marrow level, 
blood cell differentiation and DHODH, leukemia models of leflunomide have not been very 
promising. Leukemic mice treated with leflunomide demonstrated no reduction in leukemic 
burden and experienced significant weight loss and lethargy. 
Recent nonclinical studies have demonstrated that inhibition of DHODH can overcome myeloid 
differentiation arrest (Sykes et al., 2016 [4]). The mechanism through which a reduction in de 
novo pyrimidine biosynthesis modulates myeloid differentiation is not clear. The differentiation 
effect of DHODH inhibitors appears to involve a combination of inhibition of nucleic acid 
synthesis, cell-cycle arrest, and changes in the post-translational glycosylation of important 
protein targets.  
2.3 Brequinar
It is well known that brequinar is a potent inhibitor of DHODH. Brequinar is one of more than 
300 quinoline-carboxylic acid derivatives prepared in an analog synthesis program in the 1980s, 


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which was started after it was found that a compound of this class had antitumor activity. 
Brequinar was selected by DuPont for further development as a potential clinical drug because of 
its activity against experimental tumors and because its water solubility made it relatively 
straightforward to formulate. Ultimately, the rationale to use brequinar for the treatment of 
multiple solid tumors did not translate into efficacy after extensive clinical development and the 
project was terminated by DuPont in 1994. Clear Creek Bio exclusively licensed the historic data 
from Bristol Myers Squibb (that acquired DuPont in 2001). 
Sykes et al. showed that brequinar’s pro-myeloid differentiation activity might be useful for the 
treatment of AML. Utilizing a high throughput screening technique, brequinar was identified as a 
compound that overcame arrest of myeloid differentiation. Brequinar triggers myeloid
differentiation in vitro and in vivo. Brequinar was highly active in vivo, as demonstrated in 
syngeneic murine AML models (HoxA9+Meis1 and MLL/AF9) as well as xenotransplant AML 
models (THP1, HL60, MOLM13, OCI/AML3). In an aggressive MLL/AF9 murine model of 
AML, treatment with brequinar promoted myeloid differentiation, reduced leukemic cell burden, 
and improved overall survival. Brequinar also led to a reduction in the number of leukemia stem 
cells, reduced colony-formation level, and depleted the number of leukemia-initiating cell level.  
In addition, Sykes and colleagues demonstrated that treatment with brequinar was better-
tolerated and more effective than treatment with cytotoxic chemotherapy in animal models. 
Brequinar was given for many weeks without cumulative toxicity. The effect of brequinar and 
DHODH inhibition on normal cells was also assessed through study of competitive bone marrow 
transplantation assays. Mice were treated with brequinar, 5-fluorouracil (5-FU), or induction 
chemotherapy, and their bone marrow was transplanted in competition (1:1) with normal 
(untreated) bone marrow to gauge the effect of therapy on hematopoietic stem cell (HSC) 
function. The fitness of HSCs from mice treated with brequinar were functionally equivalent to 
those of untreated mice when compared to that of HSCs exposed to 5-FU and induction 
chemotherapy, which promoted a marked decrease in fitness.  
Sykes et al. administered brequinar at a dose and schedule (every 72 hours) that was non-toxic to 
the animals yet led to eradication of the leukemia cells. This schedule of administration was 
based on data demonstrating that the pro-differentiation effect of brequinar required a period of 
sustained DHODH-inhibition of approximately three days. This observation suggests that 
brequinar’s efficacy depends on producing approximately 72-hours “time-above-threshold” to 
maintain sustained DHODH inhibition. The hypothesis is that pyrimidine starvation via 
inhibition of DHODH for approximately 72 hours elicits pro-myeloid differentiation and leads to 
the anti-leukemia efficacy of brequinar. 
Sykes et al. also showed that normal cells could tolerate longer periods of pyrimidine starvation 
than their leukemic counterparts. The proposed dosing regimen of brequinar in this clinical trial, 
CCB-01, is intended to take advantage of the different sensitivity of normal and leukemic cells 
and thus spare normal cells while eradicating leukemic cells.  
A pharmacodynamic marker of enzyme inhibition (i.e. target engagement) is required to 
accomplish this type of rational dosing approach. Sykes and colleagues demonstrated how 
DHODH inhibition could be monitored by the accumulation of the substrate DHO. Indeed, 
inhibition of the DHODH enzyme led to the rapid accumulation of intracellular DHO, which was 


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reflected by accumulation of DHO in plasma hence the rationale for measuring plasma DHO as 
the pharmacodynamic marker in CCB-01. 
Given this new information, real-time monitoring of target engagement via plasma DHO of 
DHODH inhibition in each patient should permit identification of a brequinar dose that is both 
efficacious and well-tolerated. Maintaining intermittent DHODH inhibition for prolonged 
treatment cycles may be efficacious compared to previous studies using short periods and high 
doses followed by long periods of recovery. 
The prior data on the clinical evaluation of brequinar in patients with multiple solid tumors 
provides valuable safety data that supports the safety of the proposed dosage regimen. Brequinar 
has not been studied clinically in myeloid malignancies in the past. Given encouraging pre-
clinical results, brequinar has been evaluated in phase 1 and phase 2 trials of more than 800 
patients with advanced solid tumor malignancies (Arteaga 1989 [5], Burris 1998 [6], Noe 1990 
[7], Schwartsmann 1990 [8]). These studies indicated a lack of efficacy for brequinar at the doses 
and schedules evaluated. However, many of these trials studied brequinar administered as a 
single, high dose infusion given weekly or daily x 5 days every 3-4 weeks or every day for 21 
days. The lack of efficacy in the previous trials may have been due to the narrow therapeutic 
window with the high doses studied, and to the inability, or lack of knowledge, to use a 
pharmacodynamic marker such as plasma DHO to fine-tune a therapeutic window based on 
differential pyrimidine starvation of myeloid precursors versus normal cells.  
2.4 Rationale for the Planned Trial
This study is designed to obtain safety and efficacy data for brequinar in patients with AML. 
Subject Population 
The population for this study is patients 18 years of age or older, with relapsed/refractory AML 
by World Health Organization classification that have failed prior standard therapy and for 
which no standard therapies are available that result in a durable remission.
Study Treatments 
This is an open label study of oral brequinar using intra-subject dose adjustment. The dose-
adjustment scheme is presented in more detail in Section 7.5.  
2.4.1
Brequinar Starting Dose Selection
The rationale underlying the proposed dosage regimen for brequinar and the use of plasma DHO 
to guide dosing is the prior demonstration using nonclinical models by Sykes et al. (2016) [4] 
that malignant cells are more sensitive than normal cells to periods of DHODH inhibition. The 
objective is to identify a dose and regimen of brequinar that maintains suppression of DHODH 
adequate to induce differentiation and stop myeloid proliferation but avoid harming normal cells. 
These features have been realized in vivo in animal models. Specifically, intermittent dosing that 
preserved elevated levels of the metabolite DHO markedly reduced AML cells, preserved normal 
hematopoietic stem cells, and improved animal survival. These recent findings and historic 
pharmacokinetic (PK) and safety data from humans support the planned approach.  


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Rather than intermittent high doses as were given by DuPont, Clear Creek will use relatively low 
doses and prolonged exposure to brequinar. There will not be a lengthy conventional rest period 
as is generally required between infrequent high doses. There will instead be twice-a-week 
administration of lower doses with a dosing interval that allows enough time for normal cells to 
recover from or avoid pyrimidine starvation in between the periods of DHODH inhibition. Based 
on its average half-life of 10.5 hours and what has been observed in the clinical PK data (see the 
Brequinar IB [9]), brequinar plasma levels return to baseline at about 3.5 days or 84 hours after 
an oral dose. For this reason, the proposed clinical study includes a biweekly schedule of 
brequinar dosed approximately every 84 hours, while measuring plasma DHO to fine-tune the 
dosing schedule that ensures sustained DHODH inhibition while avoiding adverse effects to 
normal cells. 
Safety data from previous oncology clinical studies of brequinar (see Brequinar IB, Section 5)
with maximum tolerated doses as high as 2250 mg/m2 repeated every 3 weeks suggest that a 
starting dose for Cohort 1 of 500 mg/m2 p.o. will be safe and well-tolerated in subjects with 
AML. Each subject’s subsequent dosing may be adjusted depending on the safety, tolerability 
and DHO level obtained during the period following dose adjustment. Each of the two planned 
subsequent cohorts may also have an adjusted starting dose, again depending on safety, 
tolerability and DHO level observed in previous cohorts. See Section 7.4. 
2.5 Risk/Benefit of Brequinar
As presented in the brequinar IB, more than 800 patients have been exposed to this compound 
for treatment of a variety of solid tumors at various treatment regimens, doses, and routes 
including a single dose, once weekly, twice weekly, single dose every 3 weeks, daily times 5 
every 4 weeks, and daily times 21 days for multiple courses. The maximum intravenous dose 
given was 2,250 mg/m2 every 3 weeks, and the maximum oral dose was 100 mg/m2 daily for 21 
days. Study results have not shown evidence of efficacy in solid tumors at the doses and 
regimens studied. However, the preclinical work of Sykes et al (2016) [4] have demonstrated the 
efficacy of brequinar in a mouse model of leukemia, indicating that brequinar may be effective in 
patients with this type of leukemia. It is for this reason that study CCB-01 will study patients 
with AML.   
A universal hallmark of AML is the arrest of leukemic myeloblasts at an immature and self-
renewing stage of development. Therapies that can overcome differentiation arrest caused by 
DHODH represent a powerful treatment strategy. A potential benefit of brequinar treatment in 
patients with AML is that brequinar has been identified as a compound that can inhibit DHODH.  
The major risk associated with brequinar is myelosuppression, particularly a decrease in platelet 
count. Patients with AML typically have a low platelet count due to their disease, and there is a 
risk that treatment with brequinar may worsen existing thrombocytopenia. 
2.6 Risks Associated with Participation in the Clinical Study
In studies utilizing the weekly schedule of administration in patients with refractory solid tumors, 
reversible myelosuppression, in particular thrombocytopenia, and mucositis have been the 
primary dose-limiting toxicities. In addition, skin rash, nausea/vomiting, fatigue, and leukopenia 
have been dose-limiting in trials utilizing other schedules of drug administration. The majority of 


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these adverse effects have been less than grade IV in severity and resolve following 
discontinuation of dosing. Symptoms of tumor lysis syndrome have not previously been reported 
following exposure to brequinar, however clinicians will monitor for and treat this condition 
should it arise per the guidelines presented in Section 9.9. An increased risk of infection may 
occur due to the myelosuppressive effects of brequinar (particularly neutropenia); infection 
prophylaxis and treatment are described in Sections 9.10 and 9.11. Differentiation syndrome has 
been seen in other pro-differentiating agents and will be closely followed as described in Section 
9.7. 
2.7 Possible Interactions with Concomitant Medical Treatments
Brequinar has been administered to subjects taking a variety of concomitant medications that are 
typical in cancer patients. No formal interaction studies have been conducted for these 
medications, however, there have not been any reports of interactions with any medications 
during the clinical trials with more than 800 cancer patients.  
2.7.1
CYP Interactions
No formal drug-drug interaction studies have been performed with medications commonly used 
in treating AML. The nonclinical studies have demonstrated there is no first-pass metabolism, 
and there have been no apparent hepatotoxic effects in the clinical studies performed to date.  
2.8 Steps to be Taken to Control or Mitigate Risks
Guidelines for the prevention, monitoring and treatment of differentiation syndrome, tumor lysis 
syndrome, infection prophylaxis and growth factor support are provided in Section 9. 


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3
TRIAL OBJECTIVES
3.1 Primary Objective
The primary objective of this study is to determine the safety and tolerability of brequinar and 
the dihydroorotate dehydrogenase (DHODH) inhibitory activity of brequinar in adult patients 
with AML. 
3.2 Secondary Objectives
The secondary objectives of this study are: 

To determine the overall response rate (ORR) including complete remission (CR), CR with 
incomplete hematologic recovery (CRi), morphologic leukemia-free state (MLFS), partial 
remission (PR) (criteria as defined in the ELN Guidelines, by Döhner et al., 2017 [10]) and 
complete remission with partial hematological recovery (CRh). 

To assess the rate of overall survival (OS) and event-free survival (EFS)  

To evaluate duration of response  

To characterize the pharmacokinetic (PK) profile of brequinar. 

To characterize the DHO plasma levels after oral dosing with brequinar. 
3.3 Exploratory Objectives
The exploratory objectives of this study are: 

To assess the relationship between DHODH inhibition and the efficacy and safety of 
brequinar.  

To evaluate molecular and cellular biomarkers that may be predictive of antitumor level 
and/or treatment resistance including cytogenetics, molecular profiling, and flow cytometry 
during and after treatment. 

To evaluate global gene expression profiles, DNA methylation profiles, and other potential 
prognostic markers to explore predictors of antitumor activity and/or resistance to treatment. 


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4
TRIAL DESIGN
This will be a Phase 1b/2a multi-center, open-label, non-randomized clinical trial to assess the 
safety, tolerability and efficacy of dose-adjusted brequinar in adult subjects with AML. The 
study will also assess the inhibition of DHODH and the PK profile of brequinar in plasma. Intra-
subject dosing may be adjusted based on safety/tolerability and DHO level.  
Up to 27 subjects are planned to be entered in this trial: Cohort 1 will have 6 subjects; two 
additional cohorts of 3 subjects each will be added if adjustments are required to the cohort 
starting doses. Cohorts 2 and 3 may be expanded to 6 subjects if required by safety assessments 
as described in Section 7.3.2. Following completion of enrollment in the cohort dose-adjustment 
part of the study, an expansion cohort of 15 subjects will be enrolled with a starting dose of the 
highest tolerated starting dose from Cohorts 1 to 3. Safety will be assessed utilizing physical 
examination, vital sign measurements, safety laboratory testing, 12-lead ECGs and bone marrow 
sampling. Bone marrow sampling will also be utilized for efficacy. Tolerability will be assessed 
by spontaneously reported and elicited adverse events. DHO level will be measured using a 
validated assay. PK will be analyzed using standard PK parameters.  
Dosing will continue for up to 12 months in the absence of unacceptable toxicity or disease 
progression. 
Study procedures are presented in more detail in Section 7. 


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5
TRIAL ENDPOINTS
5.1 Primary Endpoint

Safety/tolerability and DHO level relationship with safety and therapeutic brequinar levels  
5.2 Secondary Endpoints

Rates of treatment-emergent adverse events.

Overall Response Rate (ORR) including CR, CRh, CRi, MLFS, or PR

Event-free survival (EFS).

Duration of response

PK profile of brequinar.

DHO plasma profile.
5.3 Exploratory Endpoints

Relationship between DHODH inhibition and the efficacy and safety of brequinar.  

Antitumor level based on molecular and cellular biomarkers including cytogenetics, 
molecular profiling, and flow cytometry during and after treatment.

Global gene expression profiles, DNA methylation profiles, and other potential prognostic 
markers to explore predictors of antitumor activity and/or resistance to treatment 


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6
TRIAL POPULATION
6.1 Number of Subjects
Subjects who meet all the inclusion and none of the exclusion criteria will be enrolled in the 
study until approximately 27 subjects have completed the study.     
6.2 Inclusion criteria
1. Willing and able to provide written informed consent for the trial. 
2. Patients 18 years of age or older, with relapsed/refractory AML by World Health 
Organization (WHO) classification who have exhausted available therapy. 
3. ECOG Performance Status 0 to 2.
4.
 
5. Adequate hepatic function (unless deemed to be related to underlying leukemia)
a.
b.
c.
6.
the Cockcroft-Gault equation.
7. In the absence of rapidly proliferative disease, the interval from prior leukemia-directed 
therapy to time of study initiation will be at least 7 days for cytotoxic or non-cytotoxic 
(immunotherapy) agents. Hydrea is allowed up to 48 hours prior to the first dose for 
patients with rapidly proliferative disease.  
8. The effects of brequinar on the developing human fetus are unknown.  For this reason, 
women of child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry and for the 
duration of study participation.  Should a woman become pregnant or suspect she is 
pregnant while she or her partner is participating in this study, she should inform her 
treating physician immediately.  Men treated or enrolled on this protocol must also agree 
to use adequate contraception prior to the study, for the duration of study participation, 
and for 90 days after completion of brequinar administration.
9. Male subjects must agree to refrain from sperm donation from initial study drug 
administration until 90 days after the last dose of study drug. 
6.3 Exclusion Criteria
1. Patients in need of immediate leukapheresis are excluded. 
2. White blood count > 25 x 109/L (note: hydroxyurea is permitted to meet this criterion).


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3. Any concurrent uncontrolled clinically significant medical condition, laboratory 
abnormality, or psychiatric illness that could place the participant at unacceptable risk of 
study treatment. 
4.
branch block and prolonged QTc interval may be eligible after discussion with the 
medical monitor. 
5. The use of other chemotherapeutic agents or anti-leukemic agents is not permitted during 
study with the following exceptions: 
a.
Intrathecal chemotherapy for prophylactic use or maintenance of controlled CNS 
leukemia. 
b. Use of hydroxyurea for the purpose of leukemic cytoreduction may be allowed 
during the first 2 weeks of therapy if in the best interest of the participant and is 
approved by the medical monitor. Hydroxyurea can be used to treat leukocytosis 
if concurrent with and thought to be associated with presumed differentiation 
syndrome.  
6. AML relapse less than 6 months following stem cell transplantation.  
7.
0.5mg/kg/day of prednisone or therapy beyond systemic corticosteroids (e.g. 
cyclosporine or other calcineurin inhibitors or other immunosuppressive agents used for 
GVHD).
8. Active cerebrospinal involvement of AML.
9. Diagnosis of acute promyelocytic leukemia (APL).
10. Clinically active hepatitis B (HBV) or hepatitis C (HCV) infection.
11. Severe gastrointestinal or metabolic condition that could interfere with the absorption of 
oral study medication. 
12. Prior malignancy, unless it has not been active or has remained stable for at least 3 years. 
Participants with treated non-melanoma skin cancer, in situ carcinoma or cervical 
intraepithelial neoplasia, regardless of the disease-free duration, are eligible if definitive 
treatment for the condition has been completed. Participants with organ-confined prostate 
cancer with no evidence of recurrent or progressive disease are eligible if at the active 
surveillance stage, if hormonal therapy has been initiated or the malignancy has been 
surgically removed or treated with definitive radiotherapy. 
13. Nursing women or women of childbearing potential (WOCBP) with a positive urine 
pregnancy test. 
6.4 Inclusion of Women and Minorities
Both men and women of all races and ethnic groups are eligible for this trial. 
 


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7
STUDY TREATMENTS
Subjects will self-administer oral brequinar twice weekly (approximately every 84 hours). 
Treatment cycles will be 2 weeks. Dose adjustment is to occur as outlined below. Visits will take 
place at least every 2 weeks through 3 months. More frequent visits are permitted to assess 
and/or treat adverse events. Less frequent visits (up to 4-week intervals) are permitted after 3 
months depending on subject safety/tolerability and response. Cohort 1 will begin at 500 mg/m2
twice weekly. Subjects in Cohort 1 may not escalate above the initial 500 mg/m2 starting dose, 
but the intra-subject dose may be reduced if unacceptable safety occurs. Subsequent cohorts will 
have a starting dose that may be adjusted based on the safety/tolerability (Section 7.3.1, Section 
7.3.2) and DHO levels of the previous cohort. The dosing for individual subjects may be adjusted 
based on the safety/tolerability and DHO levels as shown in Section 7.5. 
7.1 Description of Brequinar:
Brequinar will be supplied as 100 and 250 mg capsules. Dosing will be determined on a mg/m2
basis based on the starting dose of a subject’s cohort and the tolerability, safety and DHO level
assessed following each dose. Brequinar capsules should be taken whole; they should not be 
crushed or chewed. If the participant forgets to take the daily dose, he/she should make up the 
dose within 8 hours after the missed dose. If more than 8 hours have elapsed or if the dose was 
vomited or if the subject for any reason is unable to take the scheduled dose within 8 hours, omit
that dose, and the subject should resume treatment with the next scheduled dose. Any medication 
remaining from extra supplies or missed doses should not be taken beyond the last scheduled day 
of brequinar administration but should be documented in the subject diary and returned by the 
participant for drug accountability purposes.  
7.2 Treatment Administration
Subjects will take oral brequinar twice weekly (approximately every 3.5 days) e.g., Monday 
morning and Thursday evening. Each dose is to be taken with approximately 240 mL of water. 
The subject does not need to be fasting. The chosen dosing schedule needs to accommodate 
clinic visits as well as shipping and receipt of the brequinar brequinar/DHO samples. Sample 
processing and shipping procedures will be addressed in a separate laboratory manual.  
7.3 Safety/Tolerability
Safety/tolerability is assessed for each subject at each study visit using the Common 
Terminology Criteria for Adverse Events v4.0 (CTCAE). After completion of Cohort 1 (which 
will have a fixed starting dose of 500 mg/m2 with no dose escalation permitted), 
safety/tolerability will be used to determine both cohort starting doses for subsequent cohorts and 
individual dosing adjustments. Safety at the subject level is defined in Section 7.3.1; hematologic 
toxicity is defined in Section 7.3.1.1; and safety at the cohort level is defined in Section 7.4. 
7.3.1
Safety/Tolerability – Subject Level
Acceptable safety/tolerability for a subject through Day 42 is defined as no 
Grade 3, treatment-
emergent, study-drug-related, non-hematologic adverse events. Due to the expected hematologic 
profile associated with AML, hematologic AEs of any grade will not be considered dose-limiting 


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during the first 42 days of dosing. Exceptions to the non-hematologic Grade 3 criterion are 
provided in Table 1. 
Table 1.
Exceptions to Grade 3 Nonhematologic AEs 
Condition
Exception Description 
Nausea/ 
Emesis 
within 1 
week after the use of an optimal antiemetic regimen based on standard 
practice.
Diarrhea 
receiving the maximal supportive therapy based on standard practice.
Fatigue
Grade 3 fatigue lasting less than 1 week.
Laboratory 
abnormalities
Asymptomatic Grade 3 laboratory abnormalities that are not considered 
to be clinically significant. 
7.3.1.1
Hematologic Toxicity
After the subject has completed the first 42 days of treatment, the definition of unacceptable 
safety expands to include hematologic AEs defined as prolonged neutropenia with ANC < 500 
from the start of therapy in the absence of disease, 
 and/or
thrombocytopenia, with a hypocellular bone marrow and no greater than 5% marrow blasts 
lasting for 2 weeks or more. Anemia will not be considered a hematologic AE for the definition 
of unacceptable safety. Febrile neutropenia is also excluded from the DLT definition for this 
population. For clinic visits when bone marrow sampling is scheduled, the timing of the bone 
marrow sampling can be adjusted to ensure that the results are available at the time of the clinic 
visit. 
7.3.2
Safety/Tolerability – Cohort Level
Acceptable safety/tolerability at the cohort level is defined below: 
a)
to dose reduction or treatment discontinuation (a dose limiting toxicity or DLT), then that 
dose is considered to have unacceptable safety/tolerability and the previous dose which 
was safe/tolerated must be considered as the highest safe/tolerated dose.  
b) If 1 out of 3 subjects at a dose level experiences a DLT, then 3 additional subjects will be 
added to the cohort and treated at the same dose that led to the DLT. I
6 subjects has a DLT at that dose, then this dose is considered a safe/tolerated dose. 
However, if >2 out of 6 subjects at a dose level experience a DLT, then that dose is 
considered to have unacceptable safety/tolerability and the previous dose which was 
safe/tolerated must be considered as the highest safe/tolerated dose. 


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7.3.3
Safety/Tolerability – Expansion Cohort
The safety and tolerability of the starting dose for the Expansion Cohort will have been 
determined during the Cohort Level adjustments defined in the preceding section. If >1 of the 
first 5 subjects in the Expansion Cohort cannot tolerate this starting dose based on the rules for 
safety and tolerability at the subject level (Section 7.3.1), the starting dose for the next cohort 
will be reduced by 75 mg/m2. If >1 of the second 5 subjects cannot tolerate the reduced starting 
dose, the starting dose will be again reduced by 75 mg/m2 for the final 5 subjects planned for this 
cohort. All of these subjects are eligible for intra-subject dose adjustment and will follow the 
same individual subject safety rules for either stopping dosing or dose adjustment as presented in 
Section 7.3.1 and Section 7.5. 
7.4 Cohort Starting Doses
Cohort 1 will treat 6 subjects at 500 mg/m2 twice weekly. No dose escalation is permitted for 
Cohort 1 subjects, but the dose may be reduced for an individual subject in this cohort if the 
subject experiences unacceptable safety.   
After all subjects in Cohort 1 have completed a 42-day treatment period, up to two additional 
cohort(s) of 3 subjects each will be added with the starting doses adjusted (escalated or de-
escalated) based on both safety/tolerability and adequacy of DHO level results in Cohort 1. 
If all subjects in a cohort have acceptable safety at a dose level, the next cohort’s starting dose 
may be escalated by 150 mg/m2. If the safety rules are not met at a cohort’s starting dose, the 
next cohort’s starting dose will be reduced to the highest dose found to be safe/tolerated in the 
previous cohort. The planned upper limit for cohort starting dose is 800 mg/m2. There is no 
lower limit.
See the “Intra-subject dose adjustment” section for individual subject dosing adjustment criteria.
7.5 Individual Dose Adjustment Guidelines
With the exception of subjects in Cohort 1 whose dose may not be escalated above the 500 
mg/m2 starting dose, intra-subject dose adjustment will be considered every 2 weeks depending 
on safety and DHO levels. There is a maximum of 2 dose adjustments for each subject within the 
first 42 days of initiating treatment. Each subject’s dose can be adjusted from the starting dose by 
being escalated, maintained (stable dose), held then reduced, or discontinued (except in Cohort 1 
where subjects’ doses may not be escalated beyond the 500 mg/m2 starting dose). The highest 
dose planned is 800 mg/m2, however, this upper limit may be adjusted depending on safety, 
DHO level, and clinical response. There is no lower limit planned. As noted above, safety will be 
a key part of determining dose adjustments. Subjects who resume dosing at a lower dose after 
experiencing unacceptable safety may not undergo later dose escalations beyond the dose where 
the unacceptable safety occurred. 
Each subject will continue dosing twice weekly at the individually adjusted dose for up to 12 
months in the absence of unacceptable toxicity or disease progression. Intra-subject dose 
adjustment is permitted at any time throughout the study based on safety/tolerability and DHO 
levels (except in Cohort 1). Subjects who discontinue due to unacceptable safety/tolerability or 
die prior to Day 42 will not be replaced. 


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Intra-subject dose adjustment increments and duration of dosing may be revised from planned 
amounts after each preceding cohort’s safety, DHO plasma levels, and bone marrow results have 
been reviewed.
7.5.1
DHO Threshold
Each subject’s baseline DHO sample will be obtained at C1D1 prior to dosing. Dose adjustment 
decisions based on DHO will be determined by DHO trough level (i.e., DHO level obtained pre-
dose D8 of the previous cycle). The initial target for “adequate” trough DHO level will be set at 
100 ng/mL. This target may be adjusted during the study depending on safety or efficacy signals 
observed during the study. As described below, dose adjustments are also based on safety and 
whether the dose has reached the planned upper limit (currently planned to be 800 mg/m2). 
Table 2 and Figure 1 present the intra-subject dose-adjustment criteria. Note that there is no dose 
escalation in Cohort 1. 
Table 2. 
Intra-Subject Dose Adjustment* 
Acceptable Safety/Tolerability?
(see safety definition above)
Adequate 
DHO Level?
Planned Intra-Subject Dose Adjustment
Yes
Yes
Maintain; continue at same dose.
Yes
No
Escalate by 150 mg/m2 for the next 2-week cycle up to a 
maximum of 800 mg/m2.
No 
Regardless of 
DHO  
Hold two doses (one week), then reassess AE; if AE has 
-escalate dose by 75 mg/m2 and 
resume dosing. If AE has not resolved, reassess again in one 
week.  
held, discontinue further dosing. Subject will remain in the 
study for safety follow up for 42 days after last dose of study 
drug or until AEs have resolved or become stable.
* Subjects in Cohort 1 may not escalate above the initial 500 mg/m2 starting dose and may have dose reductions 
based on safety only. 


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Figure 1.
Dose Adjustment – Subject Level


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7.6 Medication/AE Diary
The participant will be provided with a study calendar of events and will be required to maintain 
a medication diary of each dose of medication. Subjects will be instructed to record the date and 
time each dose of brequinar is taken, indicating if any doses are missed. Subjects will be 
instructed to record adverse events and changes in concomitant medications in the subject 
calendars/diaries. 
Subjects will be instructed and reminded to bring the medication diary to each clinic visit for 
review. The diary will be returned to clinic staff at the end of each cycle and a new diary 
dispensed. 
7.7 Bone Marrow Biopsy
The participant will have a bone marrow sampling (aspiration and core biopsy) at baseline (prior 
to dosing), one for research purposes at the C2D8 visit ± 7 days, and one at Day 43 ± 7 days; 
thereafter, bone marrow sampling will be every 12 weeks and at the Final Visit. If a participant 
develops frank evidence of progression of AML during the course of treatment based on 
laboratory or clinical assessment, then he/she will be discontinued from study treatment and can 
proceed with additional management off-study per discretion of the treating oncologist. If the 
results of the bone marrow sampling reveal disease progression at the Day 43 visit, then the 
participant will be taken off treatment. Timing of the bone marrow biopsy procedure may be 
adjusted to ensure that results are available for the Day 43 visit. Bone marrow sampling will 
include analysis of the aspirate on smear, core biopsy by microscopy, flow cytometry, and 
karyotype for cytogenetics. Molecular analysis will be performed on the screening bone marrow 
samples. 
7.8 Flow Cytometry
Peripheral blood samples are to be obtained for flow cytometry in Cycle 1 at baseline (Day 1 
pre-dose), Day 2, and Day 3 
7.9 Expansion Cohort
Once a dose has been reached that has adequate DHO level (as mentioned above, “adequate” 
trough DHO may be adjusted after reviewing DHO level, safety and clinical response data), and 
acceptable safety/tolerability, approximately 15 subjects will be added starting at the highest 
safe/tolerated dose identified in the earlier cohorts. Decisions regarding adequacy of DHO 
threshold level will be made following review of these data from each cohort. These subjects are 
eligible for intra-subject dose adjustment (see Section 7.3.1 and Section 7.5). 
The expansion cohort will follow the same visit procedures as the Maintenance Dose cohort and 
visit frequency may vary from 2 to 4 weeks.  
7.10 Study Drug Discontinuation
If there is evidence of stable disease, partial response, or complete remission (CR, CRi, or CRh), 
the participant may continue with brequinar treatment until there is evidence of disease 
progression, intolerable toxicity, or for a maximum of one year. Study drug will be discontinued 


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if there is evidence of unacceptable safety/tolerability that does not resolve within 2 weeks after 
stopping brequinar dosing. 
After treatment discontinuation, participants will be monitored for a minimum of 30 days after 
the last dose of brequinar or until they receive another treatment for their AML. Participants may 
discontinue treatment to receive a stem cell transplantation upon remission, if indicated.
The reason for study drug discontinuation will be recorded in the source document and the 
eCRF.  
7.11 Brequinar Pharmacokinetics (PK) / Dihydroorotate (DHO) Plasma Levels
Plasma samples for brequinar/DHO levels are to be obtained for each subject for the subject’s 
first study dose (Cycle 1 Dose 1 for that subject). Sample scheduling is baseline at 0 hours (prior 
to dosing), and post dose at 1, 2, 4, 6, 24, 48, and 72 hours. Note that this schedule does not 
apply to Cycle 1 for subjects in the expansion cohort, see below. 
A brequinar/DHO trough sample is to be obtained prior to dosing on Day 8 (C84h, 84 hours after 
the Cycle 1 Day 4 dose) of Cycle 1, and prior to dosing on Days 1 and 8 of Cycles 2 and 3. 
The 84-hour brequinar/DHO sample is to be repeated prior to dosing at the beginning of each 2-
week cycle and at the Final Visit. This sampling schedule also applies for the expansion cohort 
subjects. 
Directions regarding sample processing are presented in a separate laboratory manual.
7.12 Concomitant Medication/Treatment
The name, start date (if known), indication for use and whether ongoing or stopped for 
medications/treatments taken within two weeks prior to study entry as well as any medications 
taken during the study are to be recorded. The use of other chemotherapeutic agents or anti-
leukemic agents is not permitted during study with the following exceptions: 

Intrathecal chemotherapy for prophylactic use or maintenance of controlled CNS 
leukemia; 

Use of hydroxyurea for the purpose of leukemic cytoreduction may be allowed during the 
first 2 weeks of therapy if in the best interest of the participant and is approved by the 
medical monitor. Hydroxyurea can be used to treat leukocytosis if concurrent with and 
thought to be associated with presumed differentiation syndrome.  
7.12.1 Gastric pH
Whenever possible, participants should discontinue proton pump inhibitors, antacids, and H2-
receptor antagonists which increase the gastric pH and may reduce absorption of oral 
medications including brequinar resulting in decreased systemic exposure. Discontinuation of 
these medications is not required but is strongly recommended. 
7.13 Treatment Compliance
Compliance will be assessed by reviewing the subject’s medication diary and accounting of 
returned clinical supplies.  


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7.14 Storage, Stability, Labeling and Packaging
7.14.1 Storage and Stability
The study drug is stored at room temperature. Stability testing is ongoing. 
7.14.2 Labeling and Packaging 
Each bottle for subject use will be labeled with at least the following information: 
For Clinical Trial Use Only
Study Number: 
CCB-01
Contents: 100 or 250 mg capsules 
For oral use only. Take with approximately 8 ounces water every 3.5 days. 
Subject Number: XX-XXXX
Treatment Duration: As directed
IND: 138355             Clinical Batch Number: XXXXXXX
Expiration Date: 
TBD 
Storage: Store at controlled room temperature  
Study Sponsor:  Clear Creek Bio, Inc., 585 Massachusetts Avenue, 4th 
Floor, Cambridge MA 02139 
Caution: New Drug – Limited by US Federal Law to Investigational Use
Only. To be used by Qualified Investigators only.
7.14.3 Blinding and Randomization
The trial will be conducted in an open-label manner. The brequinar capsules will be provided to 
each participating institution. No randomization codes are necessary for this open-label study.
7.14.4 Unblinding/Expectedness
It is not necessary to break the blind for this open label study as the treatment is known for each 
subject. 
Expectedness will be determined by establishing whether the adverse event is among those 
identified in the Investigator’s Brochure.   
7.14.5 Study Drug Accountability
The study drug provided is for use only as directed in this protocol. 
The Investigator must keep a record of all study medication received, used and discarded.  It 
must be clear from the records which subject received which medication. Adequate drug is to be 
dispensed for each dosing period to allow for dosing every 3.5 days during the period until the 


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next clinic visit, plus one additional dose to act as a spare in the event medication is unable to be 
used.
The pharmacist/staff member responsible for drug accountability is to document the date and 
time of dispensing and for what subject the study drug was intended (i.e., record subject initials 
and birth date or other unique identifier). A pharmacy manual will be provided by the Sponsor 
detailing how to calculate the mg/m2 dose together with examples of combinations of the 100 
and 250 mg capsules to provide the most efficient use of the clinical supplies.
At the end of the study, any unused study drug will be returned to the Sponsor for destruction or 
destroyed locally; disposition of study drug will be documented.   
The Sponsor will be permitted access to the trial supplies at any time within usual business hours 
and with appropriate notice during or after completion of the study to perform drug 
accountability reconciliation. 
 


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8
CONDUCT OF THE TRIAL
8.1 Ethical and Regulatory Considerations
The trial will be performed in accordance with the Declaration of Helsinki (1964) (Appendix F) 
as revised in Tokyo (1975), Venice (1983), Hong Kong (1989), South Africa (1996), Scotland 
(2000, Note of Clarification 2002 & 2004) and Seoul 2008 (Appendix A), and Fortaleza (Brazil) 
(2013), and with the ICH Tripartite Guideline on Good Clinical Practice (CPMP/ICH/135/95, 
Jan.97) and US FDA Regulations. 
8.2 Informed Consent
The principles of informed consent in the current edition of the Declaration of Helsinki must be 
implemented in each clinical study before protocol-specified procedures are carried out.  
Informed consent must be obtained in accordance with US Code of Federal Regulations (21 CFR 
Part 50) as well as local and national regulations. Information should be given in both oral and 
written form whenever possible and deemed appropriate by the Institutional Review Board 
(IRB). Subjects and their relatives, if necessary, must be given ample opportunity to inquire 
about details of the study. 
The Investigator or qualified designated person will verbally inform subjects as to the nature, 
expected duration and purpose of the trial, the administration of the Investigational Medicinal 
Product (IMP), and the hazards involved, as well as the potential benefits that may come from 
treatment with this IMP. The trial procedures will be explained in lay language and any questions 
will be answered. The subjects will be given an IRB-approved consent form. The subjects will be 
given appropriate time to consider their participation in the trial and have any questions 
answered prior to signing the consent form. If a subject agrees to participate, he/she will sign and 
date an informed consent form and be provided with a copy of the signed consent. All subjects 
who sign an informed consent form are to be recorded on the applicable screening log.   
The subject will be informed that his/her medical records will be subject to review by the 
Sponsor, Sponsor’s representatives, and possibly by a representative of the Food and Drug 
Administration and other relevant regulatory authorities. Subjects will be informed that they are 
free to refuse participation in this clinical investigation, and if they should participate, it will be 
made clear to them that they may withdraw from the trial at any time without prejudicing further 
medical care they may require. The subject will receive a copy of the consent form as well as an 
information sheet about the trial.  
Signed written informed consent must be obtained from every subject prior to any study-specific 
procedures.  Standard procedures carried out prior to signing the informed consent but within the 
time constraints of the protocol may be used for baseline evaluation; they need not be repeated. 
An original signed informed consent form will be filed in the Investigator Site File and will be 
subject to review by the Sponsor; a copy will be given to the subject and a copy will be filed with 
the subject’s medical notes. 
The study should be discussed with the potential participant only after an initial review of his/her 
clinical status and appropriateness for participation have been evaluated to determine if he/she 
meets the subject selection criteria. 


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A sample subject information sheet and consent form is attached to this protocol as Appendix E.
The final version at each institution may differ depending on institutional requirements and 
standard formats. This protocol will not be amended for site specific changes to the sample.
8.3 Institutional Review Board / Ethics Committees
It is the responsibility of the Investigator to submit the protocol, consent form and information 
sheet to the IRB. An Investigator’s brochure will be available for review by the IRB. The 
protocol and consent form must be approved by the IRB prior to the recruitment of the first 
subject. The template consent form may be revised in accordance with site-specific requirements 
with Sponsor review and approval. A copy of the IRB written approval must be provided to the 
Sponsor and investigator before the trial may start at that institution. Written approval from the 
IRB is also required for substantial protocol amendments prior to their implementation.    
A substantial amendment may arise from changes to the protocol or from new information 
relating to the scientific documents in support of the trial.  Amendments are “substantial” when 
they are likely to have an impact on: 

the safety or physical or mental integrity of the subjects; 

the scientific value of the trial; 

the conduct or management of the trial; or

the quality or safety of any IMP used in the trial. 
If it is necessary to change or deviate from the protocol to eliminate an immediate hazard to the 
subjects, the Investigator will notify the Sponsor and the IRB of the new events and the measures 
taken as soon as possible.   
The Investigator will report promptly to the Sponsor and IRB any new information that may 
adversely affect the safety of the subjects or the conduct of the trial. On completion of the trial, 
the Investigator will inform the applicable IRB as per local IRB requirements that the trial has 
ended. If the study is terminated for any reason, the investigator will return all clinical supplies 
and study-related equipment supplied by the Sponsor to the Sponsor unless otherwise specified. 
8.4 Schedule of Events
Physical examinations, vital signs, ECG, laboratory assessments, bone marrow sampling and 
other observations will be undertaken by experienced personnel throughout the study based on 
the Schedule of Events. Standard chromosomal and mutational testing will be performed per 
institutional guidelines. 
See 14.1 Schedule of Events in Appendix A for the full list of study assessments and timings.  
Blood chemistry tests include: blood urea nitrogen (BUN), creatinine, alkaline phosphatase 
(ALP), alanine amino transferase (ALT), aspartate amino transferase (AST), bilirubin, total 
protein, albumin, glucose, serum electrolytes (sodium, potassium, chloride, carbon 
dioxide/bicarbonate, and calcium).  


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Hematology tests include: hemoglobin, hematocrit, complete blood count with differential and 
platelet count. 
8.5 Study Conduct
8.5.1
Screening Visit (Study Days -14 to -1)
These procedures must be completed within the 14 days prior to starting dosing. Obtain the 
subject’s written informed consent, then collect baseline information:
-
Demographics (height, weight, date of birth, gender, race, ethnicity).
-
Pertinent medical/surgical history (including AML diagnosis and laboratory and clinical 
evidence of progression, previous AML treatment, and any available chromosomal and 
mutational testing results per institutional guidelines) and concomitant medications.
-
Physical examination (including weight). 
-
Vital signs (heart rate, respiratory rate, seated blood pressure, body temperature).  
-
Pregnancy test for women of childbearing potential (WOCBP).  
-
ECOG performance assessment.  
-
Hematology/chemistry. 
-
12-lead ECG with QTcF and MUGA scan or echocardiogram to assess cardiac function.  
-
Bone marrow sampling. 
-
Confirm subject meets all inclusion and no exclusion criteria. 
Treatment
The treatment period begins with Cycle 1, Day 1 of the first 2-week dosing cycle. 
8.5.2
Cycle 1
Cycle 1 Day 1: 
-
Collect any adverse events or new concomitant medications since Screening.  
-
Draw samples for baseline (pre-dose) brequinar/DHO, flow cytometry, and 
hematology/chemistry.  
-
Conduct physical examination (including weight), vital signs, urine pregnancy test for 
WOCBP, and 12-lead ECG.  
-
Review results and confirm subject remains eligible for the study.  
-
Determine subject’s starting dose based on the respective cohort mg/m2 starting dose.
-
Dispense study medication.  
-
Subject is to take the first dose at the clinic and remain for brequinar/DHO sampling. 
Collect brequinar/DHO samples at 1, 2, 4, and 6 hours post dose. 
-
Process and store brequinar/DHO samples per the supplied laboratory manual. 
-
Dispense the subject’s calendar/diary. The diary will collect dates/times of study 
medication administration and AEs/new concomitant medications. 
-
Enroll subject for text message reminders if the subject consents to that service. 
-
Ship the flow cytometry sample per the supplied laboratory manual.


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Cycle 1 Day 2: 
-
Collect 24h post dose brequinar/DHO and flow cytometry samples. Check the diary/elicit 
information about AEs/new concomitant medications since the last visit. 
-
Process and store brequinar/DHO samples per the supplied laboratory manual. 
-
Ship the flow cytometry sample per the supplied laboratory manual 
Cycle 1 Day 3:  
-
Collect 48h post dose brequinar/DHO and flow cytometry samples. Check the diary/elicit 
information about AEs/new concomitant medications since the last visit.  
-
Process and store brequinar/DHO samples per the supplied laboratory manual. 
-
Ship the flow cytometry sample per the supplied laboratory manual. 
Cycle 1 Day 4:  
-
Collect 72h post dose brequinar/DHO samples. Check the diary/elicit information about 
AEs/new concomitant medications since the last visit. 
-
Process and store brequinar/DHO samples per the supplied laboratory manual. 
Cycle 1 Day 8:  
-
Vital signs. 
-
Check the diary/elicit information about AEs/new concomitant medications since the last 
visit. 
-
Prior to the morning dose, collect brequinar/DHO samples (approximately 84h post the 
second dose of Cycle 1) and hematology/chemistry samples, then have subject take study 
medication.  
-
Process and store brequinar/DHO samples per the supplied laboratory manual. 
-
Notify DHO assay laboratory of incoming shipment and ship Cycle 1 brequinar/DHO 
samples (samples from Days 1, 2, 3, 4 and 8). 
8.5.3
Cycle 2 (and any Dose Adjustment Cycle)
Repeat this visit as needed when dose adjustment is ongoing. 
Day 1:   
-
Collect unused study medication and check the diary/elicit information about AEs/new 
concomitant medications since the last visit.  
-
Take vital signs and perform physical examination (including weight). 
-
Collect pre-dose brequinar/DHO samples (approximately 84h post the fourth dose of the 
previous cycle) and hematology/chemistry samples.  
-
Process and store brequinar/DHO samples per the supplied laboratory manual. 
-
Review laboratory results/safety information and determine whether the subject should 
adjust the dose (based on acceptable safety and DHO level), continue with the current 
dose or hold study medication (unacceptable safety) per the guidelines below.  
-
If dosing will continue, dispense study medication.  
-
Dispense calendar/diary. 


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-
Manage text message reminders as needed (as a default do nothing, pause if study 
medication is put on hold, and restart if study medication is restarted)
Day 8:  
-
Collect and check the diary/elicit information about AEs/new concomitant medications 
since the last visit. 
-
Vital signs. 
-
Collect pre-dose brequinar/DHO and hematology/chemistry samples. 
-
Perform bone marrow sampling (window ±7 days). 
-
If the subject is being dosed (i.e., has acceptable safety), have the subject take the morning 
dose.  
-
If the subject’s medication was held, review safety information and determine whether 
dosing can resume. If dosing can resume, determine dose, dispense adequate medication 
for 4 doses and have the subject take the morning dose.  
-
Process and store brequinar/DHO samples per the supplied laboratory manual. 
-
Continue to withhold study drug if safety remains unacceptable. 
-
Dispense calendar/diary.
-
Manage text message reminders as needed (as a default do nothing, pause if study 
medication is put on hold, and restart if study medication is restarted)
-
Notify DHO assay laboratory of incoming shipment and ship brequinar/DHO samples 
(samples from current cycle's Days 1 and 8). 
 
Subjects may undergo dose adjustments at any time using the guidelines presented above. 
Subjects with acceptable safety can continue to escalate every 2 weeks by 150 mg/m2 increments 
through 800 mg/m2. Subjects with unacceptable safety can continue to undergo dose reductions 
of 75 mg/m2 with no lower limit. Re-escalation to a dose previously shown as not tolerated for an 
individual subject is not permitted for these subjects.
Dose adjustments are permitted throughout the study for an individual subject based on safety, 
DHO level, and clinical response with an upper limit of 800 mg/m2. This upper limit may be 
adjusted depending on safety/tolerability/DHO/brequinar PK or other factors during the study.
8.5.4
Maintenance Dose Cycle (visit every 2 - 4 weeks)
Once a subject reaches a stable or maintenance dose (see Figure 1), the subject will be in the 
Maintenance Dose Cycle.  
In the first 3 months from starting study drug, the Maintenance Dose Cycle procedures will occur 
every 2 weeks (with the exception of bone marrow sampling as discussed below). After 
completing 3 months from starting study drug, subjects may come to the clinic for a Maintenance 
Dose Cycle visit every 2 - 4 weeks per the investigator’s discretion.
A subject may still move into a Dose Adjustment Cycle after a maintenance dose if required for 
a change in safety, DHO level or clinical response. 


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Day 1:
-
Collect unused study medication and check the diary/elicit information about AEs/new 
concomitant medications since the last visit.
-
Collect pre-dose brequinar/DHO and hematology/chemistry samples. 
-
Conduct physical examination vital signs, urine pregnancy test for WOCBP, 12-lead ECG 
and bone marrow sampling (note that bone marrow is collected at the C2D8 visit (window 
±7 days), at Day 43, then every 12 weeks; the Day 43 sample will be assessed for 
hematological toxicity). 
-
Review the laboratory results/safety information and determine whether the subject should 
maintain current dose (acceptable safety) or hold study medication (unacceptable safety).  
-
Dispense study medication. 
-
Dispense calendar/diary.  
-
Manage text message reminders as needed (as a default do nothing, pause if study 
medication is put on hold, and restart if study medication is restarted) 
-
Notify DHO assay laboratory of incoming shipment and ship brequinar/DHO samples. 
8.5.5
Final Visit
This visit is to take place when a subject is discontinuing from the study. 
-
Collect and check the diary/elicit information about AEs/new concomitant medications 
since the last visit.  
-
Collect brequinar/DHO and hematology/chemistry samples.  
-
Collect unused study medication. 
-
Conduct physical examination, vital signs, urine pregnancy test for WOCBP, 12-lead 
ECG and bone marrow sampling (do not collect bone marrow if < 4 weeks since previous 
bone marrow sample obtained).  
-
Review the safety information and determine whether the subject has acceptable safety or 
unacceptable safety.  
-
Notify DHO assay laboratory of incoming shipment and ship brequinar/DHO samples.  
-
Stop text message reminders. 
8.5.6
Follow Up Visit (2 weeks after Final Visit)
-
Contact subject to elicit information about AEs/new concomitant medications since the 
last visit. Survival information will be collected while the study is ongoing. 
8.5.7
Unscheduled Visits
Unscheduled visits and tests to assess AEs are permitted as needed providing the AE onset 
occurs within four (4) weeks after the final dose.


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8.6 Compliance with Study Procedures
The time at which study procedures are conducted should follow the protocol timelines as 
closely as possible.  However, it is recognized in a clinical setting that protocol-specified timings 
may not occur exactly as specified in the protocol. Provided that activities are carried out within 
the identified window, it will not be necessary to file a protocol violation.   
8.7 Early Withdrawal from the Study 
A subject may withdraw from the study at any time for any reason or for one of the reasons listed 
below. The Sponsor or Investigator may also terminate a subject’s study participation after 
discussion with the other party if it is believed it would be unsafe for the subject to continue in 
the study.    
Subjects must be withdrawn from the study if any of the following events occur: 

Significant protocol violation or non-compliance, either on the part of the subject or the 
investigator or other site personnel; 

Decision of the Investigator or Sponsor that removal is in the subject's best interest; 

Severe unrelated medical illness or complication; 

Safety reasons/ significant adverse event; 

Subject request (withdrawal of consent); 

Sponsor decision. 
Collect/conduct all evaluations for subjects who withdraw from the study prior to completing the 
treatment period, unless consent is withdrawn.     
8.8 Early Termination of the Study
If the Sponsor or an Investigator believes it would be unsafe to continue the study, or for any 
reason at the Sponsor’s request, the study may be terminated at that site or the entire study 
terminated after discussion with the other parties. 
The Sponsor will provide a written statement to the IRB and the relevant regulatory authority 
with the reasons for termination of the study. This will be conducted within 15 days of the 
decision to terminate the study.  
If the study is terminated, a close out monitoring visit will be performed and applicable 
procedures will be carried out to close the trial site(s). 
8.9 Short Messaging Service (SMS) Medication Reminders
The Health Insurance Portability and Accountability Act of 1996 (HIPAA) was enacted in part to 
protect the security and privacy of protected health information (PHI). Covered entities (e.g., 
health care providers engaged in certain electronic transactions, health plans, and health care 
clearinghouses) that create, maintain, transmit, use, and disclose an individual’s PHI are required 
to meet HIPAA requirements. 


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HIPAA’s Privacy Rule restricts uses and disclosures of PHI, creates individual rights with 
respect to their PHI, and mandates administrative requirements. Among other requirements, the 
privacy rule requires a covered entity to reasonably safeguard PHI from any intentional or 
unintentional use or disclosure that is in violation of the requirements of HIPAA. 
HIPAA’s Security Rule requires covered entities to ensure confidentiality, integrity, and 
availability of its electronic PHI, to protect against reasonably anticipated threats or hazards to 
the security or integrity of its electronic PHI, to protect against reasonably anticipated 
impermissible uses and disclosure of its electronic PHI, and to ensure compliance by their 
workforce. Additionally, the Security Rule requires covered entities to put in place detailed 
administrative, physical, and technical safeguards to protect electronic PHI. To do this, covered 
entities are required to implement access controls and set up backup and audit controls for 
electronic PHI in a manner commensurate with the associated risk. 
For protocol CCB-01, the Sponsor intends to utilize a third-party vendor with a HIPAA-
compliant platform to send one-way text message reminders to study participants who have a 
mobile device. The SMS/text message will be sent on the days and times he or she is to take his 
or her study medication, e.g., Monday mornings and Thursday evenings. The exact timings of 
the reminders will be customized for each study participant. The PHI the third-party vendor 
receives will be restricted to the participant’s mobile device number and study identification 
number. The study participant is not to reply to the text message except to "opt out" from the 
service by sending "STOP" in the message body. In any other case if he/she sends a text
message, the texting service will reply with a message indicating that messages sent by 
participants are not being monitored. Study participants must agree to “opt in” for this service 
and can "opt out" at any time even if they initially agreed. Study participants will need to sign an 
addendum to the informed consent document documenting their decision prior to enrollment in 
the system (see Appendix 14.5).   
The third-party vendor will sign an agreement with the Sponsor to use participant data only for 
the purposes of this study. Data will be purged from the vendor's servers at the conclusion of the 
trial upon written request by the Sponsor. Data will remain in the vendor's encrypted back-up 
files that will be maintained per HIPAA-compliant standards. 
 


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9
ADVERSE EVENT REPORTING
An adverse event is any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal relationship with 
this treatment.  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of the 
medicinal product, whether or not considered related to the medicinal product.
Events that occur prior to dosing will be entered as medical history; AEs that occur after dosing 
will be entered on the AE form. 
Subjects will be questioned and observed for evidence of AEs, whether or not related to study 
drug. All AEs will be documented in the subject's medical record and CRF.  For any pre-existing 
condition or abnormal laboratory finding that changes in severity after dosing, this change should 
be recorded as an AE. New abnormal laboratory findings that are clinically significant are 
considered AEs. 
AEs will be collected beginning from the time of informed consent through at least 14 days after 
the final dose of study medication. AEs will be specified as pre-treatment or treatment-emergent. 
AE details are to be documented including start and stop date and times, whether continuous or 
intermittent, severity, any intervention utilized to correct the event (e.g., medication, surgery or 
other therapy), outcome and the relationship to the study drug.   
AEs identified in the protocol as critical to the evaluation of safety must be reported to the 
Sponsor by the Investigator according to the reporting requirements within the time periods 
specified in the protocol. 
AEs determined by the Investigator to be related to study drug must be followed until resolution 
or until they are considered stable or for at least 30 days after discontinuation of study drug, or 
until new treatment for AML is initiated, whichever occurs first.   
Any SAEs experienced after 30 days post the last dose of study drug should only be reported to 
the sponsor if the investigator suspects a causal relationship to the study drug.   
Abnormal laboratory values or test results occurring after study enrollment constitute AEs only if 
they induce clinical signs or symptoms, are considered clinically significant, require therapy 
(e.g., hematologic abnormality that requires transfusion or hematological stem cell support), or 
require changes in study drug (e.g., discontinuation of study drug). 
New signs or symptoms or worsening in severity of a cancer symptom that occur in association 
with disease progression should be recorded as AEs. Disease progression should not be reported 
as an AE unless worsening of signs and symptoms occur, or death from disease progression.
If a death occurs during the SAE reporting period, the cause of death is considered as the AE and 
the death is considered its outcome. Death should be considered an outcome, not an event. The 
event or condition leading to death should be recorded and reported as a single medical concept 
on the Adverse Event eCRF. Generally, only one such event should be reported. “Fatal” will be 
recorded as the outcome of this respective event; death will not be recorded as separate event. If 


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the primary cause of death is disease progression, the cause of death should be clearly identified 
as progression of cancer under study.
In cases of surgical or diagnostic procedures, the condition leading to the procedure is considered 
as the AE instead of the procedure itself. Each AE will be coded by the Sponsor from the 
verbatim text to a preferred term using a thesaurus based on the Medical Dictionary for 
Regulatory Activities (MedDRA).  
The following guidelines will be followed for the recording and reporting of adverse and serious 
adverse events. 
1. Baseline events will be recorded in the medical history section of the case report form and 
will include the terminology event name, grade, and start date of the event.  The medical 
history section of the case report form will serve as the source document for baseline events 
once signed and dated by the principal investigator.  
a.
Baseline events are any medical condition, symptom, or clinically significant lab 
abnormality present before the informed consent is signed. 
i. Hematologic laboratory abnormalities will not be recorded as baseline events 
for patients with acute leukemia, myelodysplastic syndrome, chronic 
lymphocytic leukemia, or chronic myeloid leukemia in blast phase. 
ii. If exact start date is unknown, month and year or year may be used as the start 
date of the baseline event. 
2. The maximum grade of the adverse event will be captured per course or protocol-defined 
visit date. 
3. These adverse events will be recorded in the case report form: 
a.
Any grade adverse event that is possibly, probably, or definitely related to the study 
drug. 
b. All serious adverse events regardless of attribution to the study drug. 
c.
Any grade adverse event regardless of attribution to the study drug that results in any 
dose modification. 
4. Hematologic adverse events will not be recorded or reported for studies in patients with acute 
leukemia, myelodysplastic syndrome, chronic lymphocytic leukemia, or chronic myeloid 
leukemia in blast phase except for: 
a.
Prolonged myelosuppression as defined by the NCI-CTCAE criteria specific for 
leukemia, e.g. marrow hypocellularity on day 42 or later (6 weeks) from start of 
therapy without evidence of leukemia (< 5% blasts), or that results in dose 
modifications, interruptions or meets the protocol definition of DLT or SAE. 
5. Serious adverse events will be reported according to institutional policy. 
6. Protocol specific language regarding the recording and reporting of adverse and serious 
adverse events will be followed in the event of discordance between the protocol and 
Leukemia-specific adverse event recording and reporting guidelines.  
(MD Anderson Cancer Center Leukemia-specific Adverse Event Recording and Reporting 
Guidelines) 
 


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The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html).  
9.1 Classification of Causality
Attribution is the relationship between an adverse event or serious adverse event
and the study treatment. Attribution will be assigned as follows:

Definite – The AE is clearly related to the study treatment.

Probable – The AE is likely related to the study treatment

Possible – The AE may be related to the study treatment.

Unlikely - The AE is doubtfully related to the study treatment.

Unrelated - The AE is clearly NOT related to the study treatment
Guidance for assessing causality:
The Investigator will need to determine whether an AE is considered related to (“caused by”’) 
the study drug rather than some underlying condition, for example, AML.   
For the purposes of this study, ‘drug related’ shall mean ‘Definite’, ‘Probable’ and ‘Possible’ 
relationship to drug as determined by the PI.
9.2 Classification of Severity
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All appropriate treatment 
areas should have access to a copy of the criteria. The CTCAE version 4.0. A copy of the 
CTCAE version 4.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm and in Appendix D.
AEs that are expected are subject to expedited reporting only if the adverse event varies in 
nature, intensity or frequency from the expected toxicity information that is provided in the 
Investigator Brochure.
9.3 Serious Adverse Event (SAE) Reporting
The regulatory definition of a Serious Adverse Event (SAE) is any untoward medical occurrence 
or effect that at any dose: 

results in death;

is life threatening (at the time of the event);

requires in-patient hospitalization or prolongation of existing hospitalization;

results in persistent or significant disability / incapacity, or

is a congenital anomaly / birth defect;

all other events that are considered medically serious by the Investigator.


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Disability is defined as a substantial disruption of a person’s ability to conduct normal life 
functions. 
A life-threatening adverse event is one that places the patient/subject, in the view of the 
Investigator, at immediate risk of death from the event as it occurred.  It does not include an 
event that, had it occurred in a more severe form, might have caused death.   
An unexpected adverse event is any adverse drug event, the nature or severity of which is not 
consistent with the applicable product information (e.g. Investigator’s brochure for an 
unauthorized investigational product or summary of product characteristics for an authorized 
product). 
Enter only one event as the reason for the SAE on the SAE form.  Other non-serious events 
which did not directly result in the SAE should be detailed in the description section on the SAE 
form and listed separately as AEs if necessary. For fatal SAEs, report the cause of death as an 
SAE with a fatal outcome rather than reporting death as the SAE term. 
Note that hospitalizations for the following reasons should not be reported as SAEs: 

Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition;  

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent;  

Social reasons and respite care in the absence of any deterioration in the subject’s general 
condition ; 

Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of an SAE given 
above is not an SAE.  
 
ANY SERIOUS ADVERSE EVENT MUST BE REPORTED IMMEDIATELY (WITHIN 
24 HOURS) BY EMAIL OR FAX TO THE SPONSOR CONTACT USING THE FORM 
PROVIDED.
ENTER THE SUBJECT’S AVAILABLE INFORMATION INTO THE
ECRF WITHIN 48 HOURS.
The subjects are to be identified in the immediate and follow-up reports by unique code numbers 
supplied by the sponsor.  The email address and fax telephone number for reporting SAEs can be 
found below and at the front of this protocol.   
Reports relating to the subject’s subsequent medical course following a SAE must be submitted 
to the Sponsor contact until the event has subsided or, in case of permanent impairment, it 
stabilizes and the overall clinical outcome has been ascertained. 
SAE REPORTING FAX:     919-313-1412 (US Toll-free:  1-866-761-1274)
SAE REPORTING EMAIL: safety-inbox@novellaclinical.com 


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MEDICAL MONITOR:
E-mail:
Robert Sims, MD
robert.sims@novellaclinical.com; 
YYA36071medmon@novellaclinical.com 
Telephone:
614-721-2630
24-hour safety line: 1-866-758-2798 or 919-313-7111
Fax:
206-826-0483
Sponsor Representative: 
Barbara Powers, MSN, Ph.D.
E-mail:
bpowers@clearcreekbio.com  
Telephone:
484-686-0545
All SAEs will be reported to the IRB periodically, at the end of the study or per local 
institutional guidelines.   
9.4 Suspected Unexpected Serious Adverse Reactions (SUSARs)
Suspected, unexpected, serious adverse reactions (SUSARs) are SAEs that are both related to the 
study drug (Relationship = Related) and unexpected (not previously described in the 
investigator’s brochure). All SUSARs will be reported in an expedited manner to the Sponsor or 
designee and IRB by the Investigators and to all relevant regulatory authorities by the Sponsor. 
Expectedness will be judged by the Medical Monitor and site PI. It is critical that all SAEs are 
reported within the 24-hour guideline so that the expectedness determination can be made. 
SUSARs require immediate attention and expedited reporting to relevant regulatory authorities.
The Sponsor is to ensure that all relevant information about fatal or life-threatening SUSARs 
are appropriately recorded and reported to the concerned Regulatory Authority and to the 
concerned IRB(s) within seven (7) calendar days of the date of first report to the Medical 
Monitor/Sponsor. Follow-up information is to be subsequently communicated to the relevant 
Regulatory Authority within an additional eight calendar days. 
All other SUSARs are to be reported to the Regulatory Authority and to the IRB(s) concerned as 
soon as possible within a maximum of fifteen calendar days of first knowledge by the Medical 
Monitor/Sponsor. 
The Medical Monitor/Sponsor or designee must also inform all Investigators studying the 
investigational medicinal product about SUSARs and ensure that all IRBs have been notified. 
For reported deaths of a subject, the Investigator shall supply the Sponsor and the IRB(s) with 
additional information requested on an expedited basis.   
9.5 Pregnancies
Pregnancy occurring in a female subject or a subject’s partner during the study period will be 
documented in the subject’s source documents and reported on a Pregnancy Form to the Sponsor 
Contact and to the IRB/IEC by the investigational staff within 1 working day of their knowledge 
of the event. The pregnancy information should be submitted using a Pregnancy Report Form. 
The collection period for a pregnancy occurring in a subject or a subject’s partner will begin at 
the first dose of study drug and will continue through 90 days after the last dose of study drug. 


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Monitoring of the subject or partner should continue until the conclusion of the pregnancy, if the 
subject or subject’s partner has consented to this. Monitoring of the baby should continue for 3 
months after birth, if the subject or subject’s partner has consented to this. 
Pregnancy itself is not an AE; it should be reported for tracking purposes. The Investigator or 
designee will discontinue the pregnant subject from the treatment aspects of the study, continue 
to follow her per protocol for safety outcomes only, and advise her to seek prenatal care and 
counseling from her primary care provider. Data on fetal outcome and breast-feeding will be 
collected for regulatory reporting and drug safety evaluation.
  
If the pregnancy is due to a subject’s failure to comply with the contraceptive requirements of 
this protocol, this should also be documented as a protocol deviation.  
 
Complications of pregnancy or congenital abnormalities in the newborn child will be reported 
appropriately as AEs.  
The site clinical staff will request the pregnant subject to notify the site of the outcome of the 
pregnancy (i.e., birth, loss, or termination). To help ensure this, the site clinical staff will follow-
up with the subject until the end of pregnancy, with the subject’s consent. This request and the 
subject’s response will be documented in the subject’s source document. 
9.6 Hematologic Adverse Events
It is recognized that laboratory value variability is a frequent and expected and may be present at 
Baseline when a subject enrolls in the study. In general, mild day to day fluctuation of laboratory 
values should not be classified as AEs. Fluctuations in laboratory values resulting from adverse 
changes in the patient’s medical condition should be reported as AEs. Laboratory abnormalities 
that constitute an AE in their own right as per CTCAE V4.03 criteria if applicable (are 
considered clinically significant, induce clinical signs or symptoms, require concomitant therapy 
or require changes in study drug), should be recorded on the AE eCRF. 
Whenever possible, a diagnosis, rather than a symptom should be provided (e.g., anemia instead 
of low hemoglobin). Laboratory abnormalities that meet the criteria for AEs should be followed 
until they have returned to normal or an adequate explanation of the abnormality is found. When 
an abnormal laboratory or test result corresponds to a sign/symptom of an already reported AE, it 
is not necessary to separately record the lab/test result as an additional event.  
Laboratory abnormalities that do not meet the definition of an AE should not be reported as AEs. 
A laboratory abnormality designated a Grade 3 or 4 event (severe) as per CTCAE does not 
automatically indicate a SAE unless it meets the definition of serious as defined below and/or as 
per Investigator’s discretion.  
For laboratory abnormalities and any AEs, it should be noted that the terms serious and severe 
are not symptoms. The term severe describes the intensity of the specific event (e.g., Grade 3 or 
4). The term serious is based on patient and event outcomes or actions required as described in 
the protocol definition of SAEs and is usually associated with events posing a threat to the 
subject’s life or ability to function. A severe AE (Grade 3 or 4) does not necessarily need to be 


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considered serious; laboratory abnormalities (such as WBC or platelet count) may be severe but 
not serious.
After the subject has completed the first 42 days of treatment, hematologic dose-limiting toxicity 
(DLT) is defined as prolonged neutropenia with ANC < 500 from the start of therapy in the 
absence of disease, 
, and/or 
thrombocytopenia, with a 
hypocellular bone marrow and no greater than 5% marrow blasts lasting for 2 weeks or more. 
Anemia will not be considered a hematologic AE for the definition of unacceptable safety. The 
timing of the bone marrow sampling can be adjusted to ensure that the results are available for 
the visit on Day 43 (Day 1 of Cycle 4).
Participants with neutropenia or thrombocytopenia because of disease prior to the start of therapy 
do not require treatment interruption for myelosuppression. Dose reductions of brequinar in these 
participants should be considered on an individual case basis and discussed with the Sponsor. 
9.7 Management of Myelosuppression
Myelosuppression and the related adverse events (thrombocytopenia, anemia, neutropenia, 
febrile neutropenia) are common in both treated and untreated patients with AML. Based on 
clinical observations with DHODH inhibition and with historical evidence from previous studies 
with brequinar, participants treated with brequinar may experience thrombocytopenia and 
neutropenia.  
If a participant achieves a clinical response including CR, CRi, CRh, or MLFS while on study 
and they have not recovered absolute neutrophil count (ANC) > 500/uL within 14 days of study 
drug interruption, brequinar dosing may be further interrupted until ANC recovers to > 500/uL,
unless the low ANC is thought to be due to the underlying disease. Brequinar may be reinitiated 
at an adjusted dose per discussion with the Sponsor. Granulocyte colony-stimulating factor 
(GCSF) may be administered if in the best interest of the participant. 
9.8 Differentiation Syndrome
Based on its proposed pro-differentiating mechanism of action, it is possible that participants 
receiving treatment with brequinar may develop signs and symptoms of differentiation syndrome 
(DS). Clinical features may include some or all of the following: unexplained fever, skin rash, 
hypoxia, respiratory compromise, interstitial pulmonary infiltrates, pleural and/or pericardial 
effusion, weight gain, and clinical deterioration. Laboratory features may include an increase in 
ANC and/or platelets. An increase in mature leukocytes may be observed in the bone marrow 
aspirate differential if a bone marrow biopsy is conducted during this time. However, no single 
sign or symptom may be considered per se as diagnostic of the syndrome, and other causes 
should be sought and excluded. 
It is recommended that the prophylactic and therapeutic measures indicated below be undertaken 
at the earliest manifestations of suspected differentiation syndrome: 

Temporary hold of brequinar if clinical features cannot be medically managed with the 
following: 
-
Control of leukocytosis with hydroxyurea;  


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-
Prompt administration of corticosteroids at a suggested dose of 10 mg of 
dexamethasone IV every 12 hours until disappearance of symptoms and signs, 
continued for a minimum of 3 days;
-
Initiation of furosemide, if clinically required; 
-
Prompt initiation of leukapheresis, if required. 
If brequinar dosing is held, brequinar may be reinitiated without dose reduction once the 
participant’s clinical condition improves, upon discussion with the Sponsor. 
9.9 Tumor Lysis Syndrome (TLS)
Tumor lysis syndrome (TLS) is characterized by nausea, vomiting, diarrhea, anorexia, lethargy, 
irregular heart rhythms, heart failure, hematuria, seizures, muscle cramps, syncope, tetany and 
possible sudden death due to the acute metabolic irregularities of hyperkalemia, 
hyperphosphatemia and hypocalemia associated with the breakdown of tumor cells secondary to 
cytotoxic therapy. 
While TLS was not observed in the previous extensive clinical experience with brequinar, the 
experience with brequinar in hematologic malignancies is limited. Signs and symptoms of TLS 
will therefore be carefully monitored particularly in the period that tumor lysis is most likely to 
occur (24-48 hours after first dose). The risk stratification in AML for TLS from the international 
guidelines by Cairo et al., 2010 [11] is as follows:

Low risk disease: WBC < 25 x 109 /L and LDH < 2 x upper limit of normal (ULN);

Intermediate risk disease (IRD): WBC 25 to 100 x 109 /L or WBC < 25 x 109 /L and LDH 
 2 x ULN;  

High risk disease (HRD): WBC  100 x 109 /L.
The guidelines for the prevention, monitoring and treatment of TLS are described below: 
TLS Prevention [Recommended]:  

IV hydration: aggressive hydration is recommended for patients at intermediate to high 
risk for TLS with a goal of initially 2 to 3 L/m2 per day of IV fluid per the international 
guidelines (Coiffer et al., 2008 [12]). 

Hypouricemic agents: allopurinol for intermediate risk disease (IRD). 
TLS Monitoring: (Howard et al., 2011 [13]) 

Figure 2 provides a flow chart for TLS monitoring. 


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Figure 2.
Monitoring of Tumor Lysis Syndrome
TLS Treatment
TLS requires urgent inpatient management including intense nursing care, cardiac monitoring, 
nephrology consultation, and measurements of uric acid, creatinine, and electrolytes every four 
to six hours. Treat any electrolyte abnormalities and any acute renal injury. 


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9.10 Infection Prophylaxis
Supportive care, including prophylactic antibiotics, antifungal and/or antiviral agents, are 
frequently used in neutropenic patients, and may be used per standard institutional practice and 
as deemed necessary by the investigator. 
9.11 Growth Factor Support
The use of myeloid growth factors (granulocyte-colony stimulating factor [G-CSF] and 
granulocyte-macrophage colony-stimulating factor [GM-CSF]) may be given to support subjects 
who have developed Grade 4 neutropenia or Grade 3 neutropenia with fever and/or infection, per 
institutional guidelines. 
9.12 Management of Nausea, Vomiting, and Diarrhea
Recommended management of nausea and vomiting is to administer antiemetics. The 
recommended treatment for managing diarrhea is loperamide antidiarrheal therapy, 4 mg at first 
onset, followed by 2 mg with each loose movement until diarrhea-free for 12 hours (maximum 
dosage: 16 mg/24 hours). Adjunct anti-diarrheal therapy is permitted. 
 


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10
STATISTICAL CONSIDERATIONS
A separate, detailed statistical analysis plan (SAP) will be finalized prior to locking the database. 
All analyses of safety and anti-leukemic activity for this open-label early Phase study will be 
descriptive in nature and presented by dose group and overall, as appropriate, for the dose-
adjustment phase and the expansion phase. Procedures for accounting for missing, unused and 
spurious data will be described in the SAP.   
Summaries for quantitative variables will include the mean, median, quartiles, standard deviation 
and error, minimum, and maximum. For qualitative variables, the summaries will include the 
number and percentage of subjects for each outcome, and the exact 95% CI, when appropriate. 
No hypothesis testing will be performed. Any statistical testing will be considered exploratory 
and descriptive. All computations will be performed using SAS® (Version 9.3 or higher). 
Subject disposition, subject demographics and baseline characteristics will be summarized. 
Subject data listings will also be provided. The following sections will briefly summarize of the 
planned statistical analyses and analysis sets for the primary and secondary endpoints. 
10.1 Study Populations for Analysis
The analysis sets are defined in Table 3. 
Table 3. 
Analysis Sets 
Analysis Set
Description
Enrolled Analysis Set 
All subjects who have been enrolled in the study. 
Safety Analysis Set 
All subjects who were administered brequinar. 
Efficacy Analysis Set 
All subjects with AML disease at baseline and who were administered 
brequinar. 
Pharmacokinetic Analysis Set 
All subjects who take at least 1 dose of brequinar and have at least 1 
quantifiable plasma concentration collected post-dose without important 
protocol deviations/violations or events thought to significantly affect the PK. 
The Efficacy Analysis Set will be used for efficacy analyses. The Safety Analysis Set will be 
used for safety analyses.   
10.2 Safety Analyses
All safety analyses will be performed on the Safety Analysis Set.  Safety and tolerability will be 
assessed in terms of AEs, SAEs, safety laboratory data, physical examinations, vital signs, 12-
lead ECGs and bone marrow sampling.  
Adverse event data will be descriptively evaluated. All AEs will be listed. The incidence and 
duration of TEAEs, defined as AEs occurring after the first dose of study treatment through 30 
days after the last dose of study treatment, will be tabulated by Medical Dictionary for 
Regulatory Activities (MedDRA) preferred term and system organ class, and by severity and 
relationship to study treatment. All laboratory results, vital sign measurements, ECGs and bone 
marrow assessments will be summarized using appropriate descriptive statistics. 


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10.3 Efficacy Analyses
Efficacy analyses will be performed using the Efficacy Analysis Set.  Table 4 summarizes the 
planned analysis of primary and secondary efficacy endpoints. 
Table 4.
Efficacy Analyses
Endpoint
Statistical Analysis Methods
Primary 
There is no primary efficacy endpoint for this study. 
Secondary

Assess anti-leukemic activity as follows: 
o
Overall Response rate (ORR) – the proportion of subjects
in the Efficacy Analysis Set with a best overall response 
of CR, CRi, CRh, MLFS and PR  
o
Complete Remission (CR) rate – the proportion of 
subjects in the Efficacy Analysis Set with a best overall 
response of CR
o
Complete Remission with Incomplete Hematologic 
Recovery (CRi) rate – the proportion of subjects in the 
Efficacy Analysis Set with a best overall response of CRi 
o
Complete remission with partial hematological recovery 
(CRh) – the proportion of subjects in the Efficacy 
Analysis Set with a best overall response of CRh 
o
Morphologic Leukemia Free State (MLFS) rate – the 
proportion of subjects in the Efficacy Analysis Set with a 
best overall response of MLFS 
o
Partial Remission (PR) rate – the proportion of subjects in 
the Efficacy Analysis Set with a best overall response of 
PR 
o
Event-free survival (EFS) – the interval between first 
brequinar 
blasts, reappearance of blasts in blood, or development of 
extramedullary disease), disease progression, or death 
o
Overall survival (OS) – the time from first dose of 
brequinar to date of death or last known alive date
For ORR and other endpoints defined as proportions, estimated 
response rates and two-sided exact binomial 95% CIs will be 
provided.  The distributions of EFS and other time-to-event endpoints 
will be summarized using the Kaplan-Meier method.  Time to event 
analyses will be from first dose of brequinar.  Censoring rules for 


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time-to-event endpoints will be described in the SAP. 
Exploratory
Will be described in the SAP finalized before database lock. 
Disease response for participants with AML will be assessed based on Döhner et al, 2017 [10]. 
Complete remission (CR):  

Bone marrow showing less than 5% myeloblasts with normal maturation of all cell lines, 

ANC of at least 1000/µL  

Platelet count of 100,000/µL

Absence of blasts in peripheral blood

Absence of identifiable leukemic cells in the bone marrow

Absence of extramedullary disease. 
Complete Remission with Incomplete Blood Count Recovery (CRi): 

Same as for CR but without achievement of ANC at least 1000/uL (CRi) and/or platelet 
count of 100,000/uL (CRp). 
Complete Remission with Partial Hematological Recovery (CRh)

Complete remission with partial hematological recovery defined as <5% of blasts in the 
bone marrow, no evidence of disease, and partial recovery of peripheral blood counts 
(platelets >50,000/microliter and ANC >500/microliter) (Kantarjian HM et al, 2016 [14]). 
Partial Remission: 

All hematologic criteria of CR are fulfilled, and 

A decrease of bone marrow blast percentage to 5% to 25%, and 

Decrease of pretreatment bone marrow blast percentage by at least 50%.
Morphologic Leukemia Free State:

Bone marrow blasts <5%; 

Absence of blasts with Auer rods; 

Absence of extramedullary disease;

No hematologic recovery required
Stable Disease:

Failure to achieve a response

Not meeting criteria for Progressive Disease


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Progressive Disease
Evidence for an increase in bone marrow blast percentage and/or increase of absolute blast 
counts in the blood:

>50% increase in marrow blasts over baseline (a minimum 15% point increase is required 
in cases with <30% blasts at baseline; or persistent marrow blast percentage of >70% 
over at least 3 months; without at least a 100% improvement in absolute neutrophil count 
(ANC) to an absolute level 
platelet count to >50 x 109/L
-transfused]; or

>50% increase in peripheral blasts (WBC x % blasts) to >25 x 109/L 
absence of differentiation syndrome); or

New extramedullary disease 
Duration of Response  

The duration of response is defined as the number of days from the time response criteria 
are initially met for CR, CRi, CRh, PR, or MLFS (whichever is first recorded) until the 
first date that recurrent or progressive disease is objectively documented, or death due to 
any cause. Participants without events reported are censored at the last disease evaluation.
Clinical Benefit
Requires one of the following in the absence of progression or CR/partial response and 
independent of marrow response to be considered a clinical benefit: 

Erythroid response 
o
Transfusion Independence
units 
of packed red blood cell transfusions in the previous 8 weeks. Only red blood cell 
g/dL will count in the red blood cell TI response evaluation. 

Platelet response 
o
Transfusion independence when previously requiring platelet transfusions of at 
least a rate of 4 platelet transfusions in the previous 8 weeks.
 
10.4 Other Endpoints
Brequinar Pharmacokinetics (PK)
Blood samples for PK analysis will be obtained at pre-specified times. Plasma PK parameters of 
brequinar including steady-state plasma concentration (Css); elimination half-life (T1/2); Area 
under the concentration curve (AUC); systemic clearance (CL) and volume of distribution at 
steady state (Vss) will be estimated by compartmental and non-compartmental analysis 
(WinNonlin or similar).
Concentration data and PK parameters will be tabulated and summarized using descriptive 


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statistics.  Relationships between brequinar PK parameters and clinical outcomes (e.g., efficacy, 
toxicity) may be explored.  PK analyses will be performed on the PK Analysis Set.
Blood samples for DHO analysis will be obtained at pre-specified times and will be summarized.  
Relationships between DHO levels and PK and clinical outcomes (e.g., efficacy, toxicity) will be 
explored. 
Changes in myeloid markers per serial flow cytometry will be studied to look for evidence of 
myeloid differentiation. 
10.5 Sample Size Considerations
Formal sample size calculations are not applicable for this phase 1b/2a, open label study. Up to 
27 subjects are planned to be entered in this trial: Cohort 1 will have 6 subjects; two additional 
cohorts of 3 subjects each will be added if adjustments are required to the cohort starting dose. 
The cohorts with 3 subjects may be expanded to 6 subjects depending on safety outcomes within 
the cohort. An expansion cohort of approximately 15 subjects will be enrolled with a starting 
dose of the highest tolerated starting dose from Cohorts 1 to 3.   
10.6 Randomization
No randomization scheme is needed for this open label study. 
10.7 Pooling of Study Centers
Not applicable to this small, early phase study. 
10.8 Interim Analysis
No interim analysis is planned for this trial. 


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11
INVESTIGATOR RESPONSIBILITIES
11.1 Investigator’s Performance
The Investigator will ensure that all those concerned with conducting the trial are:
provided with copies of the protocol and all safety information prior to the start of the
trial;
trained regarding the conduct of the study and the training has been documented.
The Investigator will sign the Investigator’s Statement and Agreement (Appendix 14.6) to 
indicate commitment to comply with the contents. 
11.2 Confidentiality
The Investigator shall assure the subject that his/her identity will be protected and confidentiality 
will be maintained during all audits and inspections of the trial site and documentation. A unique 
number will be assigned to each subject at the start of the trial and this, with the subject’s initials, 
will be used to identify the subject. In some cases, a further step may be taken to assign “fake 
initials” to the subject, per individual site requirements. The subject’s number will be the site 
number followed by the number of this subject at this site and will be used as the unique 
identifier in the source records and on the CRF, on all trial correspondence and in the trial 
database. The Investigator will keep a list of identification codes or initials used for each subject 
along with the unique number assigned. 
All information provided to the Investigator relevant to the investigational medicinal product 
(IMP), as well as information obtained during the course of the trial will be regarded as 
confidential. The Investigator and members of his/her research team agree not to disclose or 
publish such information in any way to any third-party without prior written permission from the 
Sponsor which will not be unreasonably withheld, except as required by law, or as permitted by 
the Publications section of this protocol, Section 11.7. 
The Investigator will take all measures to ensure subject’s confidentiality will be maintained at 
all times. 
11.3 Source Documentation
Investigators are to maintain adequate source documentation of the original study data, for 
example medication records, laboratory reports and pharmacy records as appropriate. The 
Investigator will allow inspections of the trial site and documentation by clinical research and 
audit personnel from the Sponsor, external auditors or representatives of regulatory authorities. 
The purpose of these inspections is to verify and corroborate the data collected on the CRFs. In 
order to do this, direct access to the subjects' medical or clinic records is necessary. The 
Investigator will ensure that certain information is contained in the medical or clinic records of 
the subject and that the entries are signed and dated, as follows: 

sufficient data to allow verification of the entry criteria in terms of past and present medical
and medication histories;

a note on the day the subject entered the trial describing the trial number, the IMP being


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evaluated, the trial number assigned to that subject and a statement that consent was 
obtained;

a note of each subsequent trial visit including any concerns about AEs and their resolution;

notes of all concomitant medication taken by the subject, including start and stop dates;

a note of when the subject terminated from the trial, the reason for termination and the 
subject’s general condition at termination;

a copy of the signed informed consent form should be kept in the medical records of each 
subject during the clinical phase of the study. A signed copy should also be filed in the 
investigator file.
11.4 Data Collection
Suitably qualified and trained personnel at the trial site will ensure compliance with the protocol, 
adherence to ICH GCP obligations, proper maintenance of trial records including IMP 
accountability records, correct administration of IMP including storage conditions and accurate 
reporting of AEs. In addition, suitably qualified and trained clinical research personnel of the 
Sponsor will visit the trial site at regular intervals during the trial for monitoring purposes and to 
assist the research staff with any queries. All queries and discrepancies relating to the data 
collection are to be resolved at the completion of the trial. 
11.5 Case Report Forms, Investigator’s Site File and Record Retention
The Sponsor may provide the CRFs in paper, electronic (eCRF), or other media. The forms will 
be reviewed against source documentation at each monitoring visit. All CRFs and supporting 
source documentation must be completed and available to the Sponsor in a timely manner. 
Changes or corrections due to data clarification and resolutions will be tracked by paper or 
electronically with an audit trail. 
Prior to review of the case report forms by the Sponsor’s representative, they should be reviewed 
for completeness and accuracy by the Investigator or a member of the research team.
The Investigator must maintain an Investigator Site File which includes, but is not limited to, the 
Investigator’s Brochure, the protocol plus any amendments, all correspondence with the IRB 
including the approval for the trial to proceed, Regulatory Authority approval/ notification (if 
applicable) including a sample of an approved informed consent, IMP accountability, Source 
Documents, investigator and staff curricula vitae (CVs,) trial documentation, and all trial 
correspondence. The original signed informed consent forms and the final report will be kept in 
the Investigator Site File. 
The Investigator will archive all essential documents. The medical files of trial subjects shall be 
retained in accordance with national legislation and in accordance with the maximum period of 
time permitted by the hospital, institution or private practice. The Investigator has a 
responsibility to retain essential documents for as long as is required by the Sponsor and 
applicable regulatory authorities.  It is the responsibility of the Sponsor to inform the Investigator 
as to when these documents no longer need to be retained. Investigators will be asked to contact 
the Sponsor prior to the destruction of any data or removal to another site if this occurs prior to 


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the Sponsor notification that the documentation is no longer required. Any transfer of ownership 
of the data or of documents will be documented in writing.  The new owner will assume 
responsibility for data retention and archiving. 
Should the Investigator retire, relocate, or for other reasons withdraw from the responsibility of 
keeping the trial essential documents, custody must be transferred to a person who will accept 
that responsibility, and the Sponsor must be notified in writing of the name and address of said 
person.
11.6 Non-Protocol Research
No investigational procedures other than those outlined in this protocol may be undertaken on 
the subjects in this trial without the prior written permission of the subject, the Sponsor, the IRB 
and, when appropriate, the regulatory authority.
11.7 Publication
The Sponsor acknowledges the benefit of making widely available the results of all clinical trials 
and intends to publish the results of this trial. All publications resulting from the clinical trial 
must be in a form that does not reveal technical information that the Sponsor considers 
confidential or proprietary.  A copy of any abstract, presentation or manuscript proposed for 
publication must be submitted to the Sponsor for review at least 30 days before its submission 
for any meeting or journal. In addition, if deemed necessary by the Sponsor for protection of 
proprietary information prior to patent filing, the Investigator agrees to a further delay of 60 days 
before any presentation or publication is submitted. The Sponsor reserves the right to include the 
report of this trial in any regulatory documentation or submission or in any informational 
materials prepared for the medical profession. 
Authorship determination will be at the discretion of the Sponsor and will include evaluation of 
the following criteria: Investigator must participate in the review of and content of the protocol; 
review and comment on the study results; participate in the writing, reviewing and commenting 
of the manuscript; and approve the final manuscript for submission. 


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12
SPONSOR RESPONSIBILITIES
12.1 General
The Sponsor agrees to adhere to the ICH Note for Guidance on Good Clinical Practice 
(CPMP/ICH/135/95, Jan.97) and US FDA Regulations. It is the Sponsor's responsibility to 
obtain appropriate regulatory approval to perform the trial (if applicable). The Sponsor should 
notify promptly all concerned investigator(s), IRB(s) and the Regulatory Authority of findings 
that could adversely affect the health of the patients/ subjects, impact on the conduct of the trial 
or alter the Regulatory Authority’s authorization to continue the trial. If it is necessary to change 
or deviate from the protocol to eliminate an immediate hazard to the subjects the Sponsor will 
notify the relevant regulatory authority and relevant IRB of the new events, the measures taken 
and the plan for further action as soon as possible.  This will be by telephone in the first instance 
followed by a written report.   
On completion of the trial, the Sponsor will inform the regulatory authority that the trial has 
ended.  If the study is terminated for any reason the Sponsor will provide a written statement to 
the relevant regulatory authority and the IRB with the reasons for termination of the trial. This 
will be conducted within 15 days of the decision to terminate the trial.  The Sponsor will report 
in an expeditious manner all suspected unexpected serious adverse reactions (SUSARs) to the 
relevant regulatory authority and IRBs.   
12.2
Indemnity
The Sponsor will provide compensation insurance against any risk incurred by a subject as a 
result of participation in this trial. The Sponsor will indemnify the Investigators as detailed in a 
separate document. 
12.3
Data Monitoring
Suitably qualified and trained clinical research personnel of the Sponsor will visit the trial site at 
regular intervals during the trial for monitoring purposes and to assist the research staff with any 
queries. CRFs and source documentation will be available for review during monitoring visits to 
the trial site. The function of this monitoring is to ensure compliance with the protocol, 
adherence to regulatory and Good Clinical Practice obligations, proper maintenance of records 
including IMP accountability records, correct administration of IMP including storage conditions 
and accurate reporting of AEs.   
Once the data from the case report forms have been entered onto the database, they will be 
reviewed and the data verified against the subject’s source data. Any discrepancies will be 
tracked by paper or electronically with an electronic audit trail. 
12.4
Audit
The Sponsor has an obligation to audit a proportion of studies.  A department other than the 
clinical department will undertake this obligation. Therefore, the Sponsor, an independent 
auditor or a regulatory authority may audit the trial site and trial documentation. These audits 
may take place while the trial is being conducted or up to several years later.   


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12.5
Confidentiality
The Sponsor will not keep any material on file bearing any subject’s name, and subjects’
confidentiality will be maintained at all times. 
12.6
Finance
This will be the subject of a separate agreement between the Investigator/Institution and Sponsor.


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13
REFERENCES
1. Surveillance, Epidemiology, and End Results (SEER) Program, 1973-2015.
www.seer.cancer.gov.
2. Ng SB, Buckingham KJ, Lee C, et al. Exome sequencing identifies the cause of a 
mendelian disorder. Nature 2010; 42: 30-35.
3. Huang M, Wang Y, Collins M, et al. A77 1726 induces differentiation of human myeloid 
leukemia K562 cells by depletion of intracellular CTP pools. Mol Pharmacol 2002; 
62(3):463-472.
4. Sykes DB, Kfoury YS, Mercier FE, et al. Inhibition of dihydroorotate dehydrogenase 
overcomes differentiation blockade in acute myeloid leukemia. Cell 2016; 167(1): 
171-186.
5. Arteaga CL, Brown TD, Kuhn JG, et al. Phase I clinical and pharmacokinetic trial of 
Brequinar sodium (DuP 785: NSC 368390). Cancer Res 1989; 49(16): 4648-4653.
6. Burris HA 3rd, Raymond E, Awada A, et al. Pharmaocokinetic and phase I studies of 
brequinar (DUP 785; NSC 368390) in combination with cisplatin in patients with 
advanced malignancies. Invest New Drugs 1998; 16(1): 19-27.
7. Noe DA, Rowinsky EK, Shen HS, et al. Phase I and pharmacokinetic study of brequinar 
sodium (NSC 368390). Cancer Res 1990; 50(15): 4595 – 4599.
8. Schwartsmann G, Dodion P, Vermorken JB, et al. Phase I study of Brequinar sodium 
(NSC 368390) in patients with solid malignancies. Cancer Chemother Pharmacol. 1990; 
25(5): 345-351.
9. Brequinar Investigator’s Brochure
10. Döhner H, Estey E, Grimwade D, Amadori S, Applebaum FR, Büchner T, et al. 
Diagnosis and management of AML in adults: 2017 ELN recommendations from an 
expert international expert panel. Blood 2017; 129(4): 424-447.
11. Cairo MS, Coiffier B, Reiter A, et al. Recommendations for the evaluation of risk and 
prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant 
diseases: an expert TLS panel consensus. Br J Haematol 2010; 149:578.
12. Coiffer B, Altman A, Pui CH, et al. Guidelines for the management of pediatric and adult 
tumor lysis syndrome: an evidence-based review. J Clin Oncol 2008; 26:2767.
13. Howard SC, Jones, DF, Pui, C-H. The Tumor Lysis Syndrome. N Engl J Med 2011; 
364:1844-1854.
14. Kantarjian HM, Stein AS, Bargou RC, Grande Garcia C, Larson RA, Stelljes M, et al. 
Blinatumomab treatment of older adults with relapsed/refractory B-precursor acute 
lymphoblastic leukemia: Results from 2 phase 2 studies. Cancer 2016; 122(4): 
2178-2185.


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14
APPENDICES
14.1 APPENDIX A:  CCB-01 Schedule of Events


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CCB-01 Schedule of Events
Proceduresa
Screenb
Cycle 1 (Study Days 1 – 14)
Dose 
Adjustment
Cycle (Cycle 2 
and beyond as 
needed)
Maintenance 
Dose Cycle (no 
dose 
adjustment)
Every 2 weeks
Final 
Visit
F/U 
Phone
Call
Survival
D1
D2
D3
D4
D8
D1
D8
D1
Final 
Visit 
+ 2 wks
Informed Consentb 
X 
 
 
 
 
 
 
 
 
 
 
 
AE/Concomitant Medications  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Medical historyc  
X 
 
 
 
 
 
 
 
 
 
 
 
Demographicsd 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical Examd 
X 
X 
 
 
 
 
X 
 
X 
X 
 
 
Vital Signsd
X
X
X
X
X
X
X
Pregnancy Teste
X
X
X
ECOG Performance Status
X
Hematology/Chemistry
X
X
X
X
X
X
X
Flow Cytometryf 
 
 
X 
X 
 
 
 
 
 
 
 
 
Chromosomal/mutational testingg 
X 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG
X
X
X
MUGA/Echocardiogram 
X
Bone Marrow Samplingh
X
X
X
Brequinar/DHO Plasma Samplei
X
X
X
X
X
X
X
X
X
Biobanking samplesj
X
X
X
Ship DHO Plasma Samples
X
X
X
Dispense/Collect Study Medication 
X
X
X
X
Dispense/Collect Subject Calendar/Diary
X
X
X
X
Survival Assessment
X


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 77 of 101 
PROTOCOL VERSION: FINAL v. 3.0 
DATE:  04 October 2018 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
a.
Visit window of ± 1 day for dose escalation cycles; window of ± 3 days for non dose escalation cycles.
b.
Obtain informed consent prior to performing any screening or study-specific procedures. Screening procedures must be performed 
within 14 days prior to initial study drug administration.  Procedures at C1D1 that are repeats of Screening may be omitted if <72h 
since Screening assessment. 
c.
Medical history is to include AML diagnosis, previous AML treatment, and standard chromosomal and mutational results per 
institutional guidelines. 
d.
Demographic information is to include date of birth, height, weight, race, and ethnic origin. Rectal examination may be deferred for 
Physical Examination. Vital signs include heart rate, respiratory rate, seated blood pressure, respiratory rate, oral/aural body 
temperature. Physical exam is to include weight. 
e.
For women of childbearing potential only. 
f.
Flow cytometry testing of peripheral blood is to be obtained at 0 (pre-dose C1D1), post dose 48  and 72 hours.  
g.
Testing panel is per institutional standard of care; obtain sample at Screening. 
h.
Bone marrow sampling local testing will include analysis of the aspirate on smear, core biopsy by microscopy, flow cytometry, and 
karyotype for cytogenetics. Local molecular analysis will be performed on the screening bone marrow samples only. Bone marrow 
samples will be sent for biobanking  further analysis. Perform bone marrow sampling at screening, at study Day 22 (C2D8), at Day 43, 
and once every 12 weeks after a stable dose has been reachedTiming of this procedure may be adjusted to ensure results are available 
for the next clinic visit. 
i.
Brequinar/DHO plasma sampling schedule: Cycle 1: 0 (pre-dose), post dose 1, 2, 4, 6, 24, 48, 72 hours and C1D8 pre-dose (+84h after 
C1D4 dose); Cycle 2 and adjustment cycles: pre-dose Days 1 and 8; every 2-week Maintenance Cycle until 3-months on drug: pre-
dose Day 1 and every 2 to 4 week Maintenance Dose Cycle beyond 3-months on drug. Day 1 sample window ±15 minutes through 6h 
draw; window for additional C1 draws ±2h; window for Cycle 2 and beyond plasma brequinar/DHO draws ±4h. Ensure trough 
samples (e.g., C1D1, C2D1, C3D1) are obtained prior to dosing. Plasma samples for brequinar/DHO for expansion cohort are to be 
obtained prior to dosing on Day 1 of each 2-week cycle for the first 3 cycles, then every 12 weeks. 
j.
Biobanking samples (bone marrow) are to be collected whenever bone marrow sampling is performed. 


PROTOCOL NUMBER:  CCB-01
Page 78 of 101
PROTOCOL VERSION: FINAL v. 3.0 
DATE:  04 October 2018 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
14.2 APPENDIX B: ECOG Performance Status Criteria
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade 
Descriptions
Percent 
Description
0
Normal level.  Fully active, able to 
carry 
on 
all 
pre-disease 
performance without restriction.
100 
Normal, no complaints, no evidence 
of disease.
90 
Able to carry on normal level; minor 
signs or symptoms of disease.
1 
Symptoms, 
but 
ambulatory.  
Restricted in physically strenuous 
level, but ambulatory and able to 
carry out work of a light or 
sedentary 
nature 
(e.g., 
light 
housework, office work).
80 
Normal level with effort; some signs 
or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal level or to do active work.
2 
In 
bed 
<50% 
of 
the 
time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours.
60 
Requires occasional assistance but is 
able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.
40 
Disabled, requires special care and 
assistance. 
30
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, 
fatal 
processes 
progressing rapidly. 
5 
Dead.
0 
Dead. 
 


PROTOCOL NUMBER:  CCB-01
Page 79 of 101
PROTOCOL VERSION: FINAL v. 3.0 
DATE:  04 October 2018 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
14.3 APPENDIX C: Brequinar/DHO Plasma Sampling
Information is provided in a separate laboratory manual regarding collection, processing, storing, 
and shipment of samples.  
Brequinar and DHO plasma samples are to be obtained at the following time points (±30 minutes 
through 6h, then ±2h for the 24h, 48h, 72h and 84h samples:
Cycle 1
Cycle 2*
Maintenance 
Dose Cycle 
Final 
Visit 
D1 
D2 
D 3 
D 4 
D8 
D1 
D8 
D1 
 
Time 
Point 
Pre-
dose 
1h 
2h 
4h 
6h 
24h 
48h 
72h 
84h 
after 
prev. 
dose 
84h 
after 
prev. 
dose 
84h 
after 
prev. 
dose 
84h after prev. 
dose 
84h 
after 
prev. 
dose 
*Or any cycle where the brequinar dose has been adjusted from the previous 2-week dose.


PROTOCOL NUMBER:  CCB-01
Page 80 of 101
PROTOCOL VERSION: FINAL v. 3.0 
DATE:  04 October 2018 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
14.4 APPENDIX D: Common Terminology Criteria for Adverse Events (CTCAE)
https://evs.nci.nih.gov/ftp1/CTCAE/About.html


PROTOCOL NUMBER:  CCB-01
Page 81 of 101
PROTOCOL VERSION: FINAL v. 3.0 
DATE:  04 October 2018 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
14.5
APPENDIX E:
Sample Subject Consent Form 
TITLE:
A Phase 1b/IIa open-label, multi-center study to assess the safety, efficacy and 
pharmacokinetics of intrapatient dose-adjusted brequinar and inhibition of 
dihydroorotate dehydrogenase (DHODH) in adult subjects with acute myelogenous 
leukemia (AML)
PROTOCOL NO.:
CCB-01
SPONSOR: 
 
Clear Creek Bio, Inc. 
 
585 Massachusetts Avenue, 4th Floor, 
 
 
Cambridge MA 02139 
 
INVESTIGATOR: 
 
<insert PI name> 
Site(s):
<insert name> 
 
 
<insert address> 
STUDY-RELATED
PHONE NUMBER(S): <insert name(s)>
 
<insert number>
<insert alternate number (24-hour contact number)> 
VERSION and DATE: <e.g. CCB-01 Master ICF Version 2.0 04June2018>
 
You are being asked to take part in a research study. Before you decide to participate, it is 
important for you to understand why the research is being done and what it will involve. Please 
take time to read the following information carefully and discuss it with others, if you wish, 
before deciding whether or not to take part. Ask us if there is anything that is not clear or if you 
would like more information. 
WHAT IS THE PURPOSE OF THE STUDY?
The purpose of the study is to evaluate the safety, efficacy, pharmacokinetics (PK) (level of 
study medication in the blood) and the inhibition (decrease in level) of an enzyme called 
“dihydroorotate dehydrogenase” (DHODH). DHODH blocks the ability of blood cells formed in 
the bone marrow to differentiate (grow into mature white blood cells that can fight infection and 
platelets that help blood to clot). Brequinar is a drug that has been shown in animals in the 
laboratory to be able to decrease the level of DHODH and decrease leukemic cells in the bone 
marrow. Reducing DHODH level in patients with AML may help treat this type of leukemia by 
allowing cells in the bone marrow to grow into different types of mature cells.  


PROTOCOL NUMBER:  CCB-01
Page 82 of 101
PROTOCOL VERSION: FINAL v. 3.0 
DATE:  04 October 2018 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
WHY HAVE I BEEN ASKED TO PARTICIPATE?
You have been asked to consider participating in this study because you because you have AML 
that has not responded to treatment (refractory), or the leukemia has recurred (relapsed).
HOW LONG WILL I BE IN THE STUDY?
Your participation in this study will last approximately 7 months and approximately 27 subjects 
will be participating in this study. If you respond (your leukemia improves) due to the effects of 
the study medication, you may be able to continue being treated for up to one year. You will take 
the study medication about every three-and-one-half (3.5) days, for example on Monday 
mornings and Thursday evenings. You and your study team can decide on the exact schedule for 
you to take your medication.
WHAT WILL HAPPEN TO ME IF I TAKE PART?
If you decide to take part in the study, you will have the following procedures: 
Screening Assessment
The Screening period is defined as the period prior to the administration of study drug. During 
this period, the investigator or designee will obtain/perform the following: 

Written, informed consent;

Demographic details (height, weight, date of birth, race, ethnicity). 

Pertinent medical/surgical history, medications you are currently taking or have taken 
recently.

Physical examination.  

Vital signs (heart rate, respiratory rate, blood pressure, body temperature).  

Pregnancy test for women of childbearing potential (WOCBP).  

ECOG performance assessment (a measure of your ability to perform activities of 
daily living).  

Blood samples for hematology/chemistry. 

Standard chromosomal and mutational testing (blood samples) if not already done. 

Bone marrow sampling (aspiration and biopsy). 

12-lead ECG with QTcF and MUGA scan or echocardiogram to assess cardiac 
function.  
If you qualify for the study, the treatment period begins with Cycle 1, Day 1 of the first 2-week 
dosing cycle. 
Cycle 1 Day 1:
At this visit you will: 

Be asked about any new medical events or new or changed medications since your 
last visit.

Have blood samples taken for baseline brequinar/DHO, flow cytometry, and 
hematology/chemistry.  


PROTOCOL NUMBER:  CCB-01
Page 83 of 101
PROTOCOL VERSION: FINAL v. 3.0 
DATE:  04 October 2018 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 

Have a physical examination (including weight) (unless within one week of 
Screening), vital signs, urine pregnancy test for women able to bear children, and 12-
lead ECG. 

If you qualify for the study and still choose to participate, you will be given adequate 
study medication for 2 weeks (4 doses). 

You will take the first dose at the clinic and remain at the clinic for pharmacokinetic 
(PK) and dihydroorotate (DHO) blood sampling at 1, 2, 4, and 6 hours after this first
dose. Each dose of study medication will be made up of several capsules, depending 
on what dose you will be taking. Take the medication with about 8 ounces of plain 
water. You can take more water than 8 ounces if needed. 

Be given a calendar/diary you will use to write down the dates/times of study 
medication administration and any new medical events, new medications or a change 
in dose of any medications. Please bring your study medication and diary to every 
visit.
Cycle 1 Day 2: You will come back to the clinic approximately 24 hours (the next day) after 
your first dose to have blood samples taken for brequinar/DHO. Your diary will be checked 
for any new medical events, new medications or a change in dose of any medications since 
the last visit. 
Cycle 1 Day 3: You will come back to the clinic approximately 48 hours (2 days) after your 
first dose to have blood samples taken for brequinar/DHO and flow cytometry. Your diary 
will be checked for any new medical events, new medications or a change in dose of any 
medications since the last visit. 
Cycle 1 Day 4: You will come back to the clinic approximately 72 hours (3 days) after your 
first dose to have blood samples taken for brequinar/DHO and flow cytometry. Your diary 
will be checked for any new medical events, new medications or a change in dose of any 
medications since the last visit. You will take your second dose of study medication this 
evening. 
Cycle 1 Day 8:  
At this visit, you will: 
-
Have your vital signs checked. 
-
Before you take your morning dose, you will have blood samples taken for
brequinar/DHO and hematology/chemistry.
-
Take your next dose of study medication in the clinic. 
-
Your diary will be checked for any new medical events, new medications or a change in 
dose of any medications since the last visit.
Cycle 2 
You will return to the clinic 2 weeks after starting the study medication. The study team may 
adjust your dose of study medication (you may be given more or less of the drug) depending on 
your safety results, laboratory, and DHO levels. This visit may be repeated as needed if your
dose adjustment continues.
Day 1:  


PROTOCOL NUMBER:  CCB-01
Page 84 of 101
PROTOCOL VERSION: FINAL v. 3.0 
DATE:  04 October 2018 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
-
Your unused study medication will be collected (if you have any), and your diary will be 
checked for any new medical events, new medications or a change in dose of any 
medications since the last visit. 
-
Your vital signs will be checked and a physical examination performed. 
-
Before you take your morning dose, you will have blood samples taken for 
brequinar/DHO and hematology/chemistry.  
-
If you are not having any side effects that may indicate it is not safe for you to continue 
taking the study medication, you will be given adequate medication for another 2 weeks (4 
doses). Take your next dose of study medication in the clinic. 
Day 8: 
At this visit, you will: 
-
Have your vital signs checked. 
-
Have a bone marrow sample taken for flow cytometry (window ±7 days). 
-
Before you take your morning dose, you will have blood samples taken for 
brequinar/DHO and hematology/chemistry.  
-
Your diary will be checked for any new medical events, new medications or a change in 
dose of any medications since the last visit. 
-
If you are not having any side effects that may indicate it is not safe for you to continue 
taking the study medication, you will continue to take the medication dispensed to you. 
 
Maintenance Dose Cycle (visit every 2 - 4 weeks)
Once you have reached a “stable dose” where no more dose adjustments seem to be needed, you 
will return to the clinic every 2 weeks and have the procedures below. After you've been taking 
the study medication for 3 months, your study doctor may space your visits out to every 4 weeks.
Day 1:
At this visit, you will: 
-
Be asked about any new medical events or new or changed medications since your last 
visit.  
-
Have blood samples taken for pre-dose brequinar/DHO and hematology/chemistry.  
-
Have a physical examination, vital signs, urine pregnancy test for women able to bear 
children, 12-lead ECG. 
-
Have a bone marrow sampling (the bone marrow aspiration sampling is performed at 
study Day 22 ±7 days, at study Day 43 and repeated every 12 weeks or more often if there 
is a safety concern).  
-
Your study team will review the laboratory results/safety information and determine 
whether you should stay at the same dose or whether you should temporarily stop taking 
the study medication or whether the dose should be changed.  
-
If you are not having any side effects that may indicate it is not safe for you to continue 
taking the study medication, you will be given additional medication and continue to take 
the medication dispensed to you as directed by the study team. 
-
Your diary/calendar will be collected and a new one provided to you.  


PROTOCOL NUMBER:  CCB-01
Page 85 of 101
PROTOCOL VERSION: FINAL v. 3.0 
DATE:  04 October 2018 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
Final Visit
This visit is to take place if you or your study team decide you should stop participation in the 
study or you have reached 12 months of study participation. At this visit, you will: 
-
Be asked about any new medical events or new or changed medications since your last 
visit.  
-
Have blood samples taken for brequinar/DHO, flow cytometry and hematology/chemistry. 
-
Have a physical examination (including weight), vital signs, urine pregnancy test for 
women able to bear children, 12-lead ECG and bone marrow sampling (unless it has been 
less than 4 weeks since the previous bone marrow sampling).  
-
Turn in any unused study medication. 
-
Turn in your calendar/diary. 
Follow Up Visit (2 weeks after Final Visit)
-
You will be contacted by phone to be asked about any new medical events or new or 
changed medications since your last clinic visit.  
WHAT ARE THE POSSIBLE DISADVANTAGES AND RISKS OF TAKING PART IN 
THIS RESEARCH?
Risks from brequinar:
While participating in this study, you are at risk for side effects. These side effects will vary from 
person to person. The more commonly occurring side effects are listed in this form, as are rare 
but serious side effects. You should discuss these with the study doctor. You may also want to 
ask about uncommon side effects that have been observed in small numbers of patients but are 
not listed in this form.  
Brequinar has been given to more than 800 patients with various forms of cancer in more than 20 
clinical trials and has also been tested in patient with psoriasis (a skin condition) and those who 
have had a kidney or liver transplant. The most common side effects have been:

Thrombocytopenia (low platelet count, platelets are a part of the blood that help your 
blood clot, they may need to be replaced)

Stomatitis/mucositis (the inside of your mouth and intestines may develop ulcers which 
make eating and drinking difficult)

Skin rash

Nausea

Vomiting 

Diarrhea

Neutropenia (low white blood cell count, which may reduce the body’s ability to fight 
infections) 

Anemia (low red blood cell count, red cells carry oxygen) 

Fatigue  


PROTOCOL NUMBER:  CCB-01
Page 86 of 101
PROTOCOL VERSION: FINAL v. 3.0 
DATE:  04 October 2018 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
In most cases, these side effects went away within about 2 weeks after patients stopped taking 
brequinar, but that cannot be guaranteed as the drug may work differently for you. If you develop 
these side effects during the study, your study team may decide to have you temporarily stop 
taking brequinar to see if the side effects get better. You and your study team may also decide to 
either stop your study participation or reduce the dose of the study medication to see if you can 
tolerate a lower dose.
Brequinar may cause differentiation syndrome. This is a condition that affects your blood cells 
which may be life-threatening or lead to death if not treated. Differentiation syndrome has not 
been previously seen with brequinar. Call your healthcare provider or go to the nearest hospital 
emergency room right away if you develop any of the following symptoms of differentiation 
syndrome: 

Fever

Cough

Shortness of breath

Swelling of arms and legs, around the neck, groin, or underarm area

Fast weight gain (more than 10 pounds within a week)

Bone pain 
If you develop differentiation syndrome, your healthcare provider may start you on 
corticosteroids which you will either take by mouth or receive by vein. You may be monitored in 
the hospital. 
You may also develop Tumor Lysis Syndrome (TLS). TLS is characterized by nausea, vomiting, 
diarrhea, anorexia, lethargy, irregular heart rhythms, heart failure, hematuria, seizures, muscle 
cramps, syncope, tetany and possible sudden death due to the acute metabolic irregularities of 
low blood levels of potassium, phosphorous, and calcium associated with the breakdown of 
tumor cells secondary to cytotoxic therapy.  
While TLS was not observed in the previous subjects who took brequinar in a clinical trial, the 
experience with brequinar in AML is limited. Signs and symptoms of TLS will therefore be 
carefully monitored particularly in the period that tumor lysis is most likely to occur (24-48 
hours after first dose). If you develop this condition, you will be carefully monitored and may 
need to be treated in the hospital.
Risks from Study Procedures: 
Blood draws may cause pain, bleeding, and/or bruising. You may faint and/or develop an 
infection with redness and irritation of the vein at the site where blood is drawn. Frequent blood 
collection may cause anemia (low red blood cell count), which may create a need for blood 
transfusions. 
Having bone marrow sampling (biopsies and aspirations) performed may cause pain, bruising, 
bleeding, redness, low blood pressure, swelling, and/or infection at the site of the biopsies. An 
allergic reaction to the anesthetic may occur. A scar may form at the biopsy site. 


PROTOCOL NUMBER:  CCB-01
Page 87 of 101
PROTOCOL VERSION: FINAL v. 3.0 
DATE:  04 October 2018 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
Bone marrow sampling will include analysis of the aspirate on smear, core biopsy by 
microscopy, flow cytometry, and karyotype for cytogenetics. You can talk with the study team 
about this testing. The type of genetic testing being performed for this study will not provide you 
or your doctor information about diseases that are passed down in families. It will not tell the 
study researchers anything that will prevent you from getting health insurance, and it will not tell 
the study researchers anything about any diseases or conditions you may get in the future. 
There may be risks or side effects that are unknown at this time. 
If a condition of which you were unaware is discovered during the study, a full report will be 
sent to your doctor if you request this.  You will be advised of the appropriate action to take for 
treatment. 
Pregnancy-Related Risks
Taking part in this study can result in risks to an unborn or breastfeeding baby, so you should not 
become pregnant, breastfeed a baby, or father a child while participating in this study. If you are 
able to become pregnant or father a child, you must use birth control during the study and for at 
least 3 months after your last dose of study drug if you are sexually active. 
Birth control specifications: Female participants who are able to become pregnant must use 2 
methods of birth control while on this study. Male participants must use an effective barrier 
method (such as a condom) while on this study.
Talk with the study team about acceptable methods of birth control to use while taking part in 
this study. 
Males: Tell the study team right away if your partner becomes pregnant or suspects pregnancy. 
Females: If you are pregnant, you will not be enrolled into this study. If you become pregnant or 
suspect that you are pregnant during the study, you must tell your doctor right away.
Getting pregnant may result in your removal from this study.
WHAT ARE THE POSSIBLE BENEFITS?
The study drug may help to control the disease. Future patients may benefit from what is learned. 
There may be no benefits for you in this study. 
WILL IT COST ANYTHING TO BE IN THE STUDY?
If you participate in this study, you will not have to pay for the cost of the study drug used in the 
study. 
You or your insurer will be responsible for the cost of your usual ongoing medical care, 
including procedures and non-study medications that the doctor or your regular doctor requires 
during this study as part of your usual medical care. If you have any questions, please ask the 
doctor and/or a member of the study staff about the costs that will or will not be covered by the 
sponsor. 
IS THERE PAYMENT FOR PARTICIPATION?
You will not receive any payment for participation in this study. 


PROTOCOL NUMBER:  CCB-01
Page 88 of 101
PROTOCOL VERSION: FINAL v. 3.0 
DATE:  04 October 2018 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
WHAT ARE THE ALTERNATIVES FOR TREATMENT?
You do not have to participate in this research study to receive treatment. Instead, you may be 
eligible for recently approved therapies, and may be able to have a bone marrow transplant
outside of this study. You may choose to receive other investigational therapies, if available. You 
may also choose not to have treatment for cancer at all. Regardless of your choices, you will 
receive appropriate medical care, including treatment for pain and other symptoms of cancer. 
Please note that you will be informed in a timely manner if new information becomes available 
that is relevant during your participation in this study.
WHAT IF SOMETHING GOES WRONG?
An important part of this study is to see if the investigational product causes side effects. You 
must inform the staff if you feel unwell or have any unusual symptoms at any time during the 
study, no matter how minor you think they are. If you experience such events, treatment will be 
made available by the doctor. 
You will be provided any reasonably necessary medical treatment for any injuries sustained as a 
result of participating in this study, except to the extent such costs are covered by your medical 
or hospital insurance or by governmental programs providing such coverage. You must follow 
the directions of the doctor to be eligible for this coverage. Neither the sponsor nor the doctor
have plans to provide other compensation in the event of an injury. You are not giving up any of 
your legal rights by signing this consent form. 
Certain tests, procedures, and/or drugs that you may receive as part of this study may be without 
cost to you because they are for research purposes only. However, your insurance provider 
and/or you may be financially responsible for the cost of care and treatment of any complications 
resulting from the research tests, procedures, and/or drugs. Standard medical care that you 
receive under this research study will be billed to your insurance provider and/or you in the 
ordinary manner. Before taking part in this study, you may ask about which parts of the research-
related care may be provided without charge, which costs your insurance provider may pay for, 
and which costs may be your responsibility. You may ask that a financial counselor be made 
available to you to talk about the costs of this study. 
WILL ALL THE DOCUMENTS CONCERNING ME REMAIN CONFIDENTIAL?
Yes. The company that is conducting this study will not keep any document on file that contains 
your name; you will only be identified by your initials and a subject number. It will be necessary 
for the sponsor, its representatives, the regulatory authorities, other institutions participating in 
the study, and possibly the Institutional Review Board (an IRB is a group of people who review 
the risks and benefits of a study) to review your medical records, but these will be treated in the 
strictest confidence permitted by law. If the results of the study are published, you will not be 
identified by name. Your personal health information (PHI) will be kept as confidentially as 
possible according to state and federal laws. However, in some situations, the Food and Drug 
Administration (FDA) could be required to reveal the names of participants. 


PROTOCOL NUMBER:  CCB-01
Page 89 of 101
PROTOCOL VERSION: FINAL v. 3.0 
DATE:  04 October 2018 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
The permission to use your PHI will continue indefinitely unless you withdraw your 
authorization in writing. 
WILL INFORMATION ABOUT ME BEING IN THIS STUDY BE USED AND 
SHARED?
This section explains how your medical and health records might be used and shared if you agree 
to participate in this study. If you do not sign this consent form, you cannot participate in 
the study. 
During the study, the doctor and/or a member of the study staff will record health information 
about you (your “records”).  Your records include the data collected or reviewed during the 
study, including data about the physical examination, tests, and other procedures described 
above. Your records also will include identifying information, such as your name and address.
By signing this consent form, you:

Allow the doctor and/or a member of the study staff to use your records to carry out this 
study.

Allow the doctor and/or a member of the study staff to share your records with the 
company paying for this study, Clear Creek Bio, Inc., their representatives, and other 
researchers involved in this study. These people will use these records to review the study 
and to check the safety of the study.

Allow the doctor or sponsor to publish results of the study in medical journals or to 
present results at meetings. If this happens, your name will not be used. The doctor also 
may share all of your records and this signed consent form with government agencies, 
including the U.S. Food and Drug Administration (FDA), and government agencies in 
other countries. They may also share your records with regulatory agencies. These 
agencies may use these records to check the information collected in this study, to check 
how the study is carried out, and to check subjects’ safety. 
There are national and state laws that state that the doctor must protect the privacy of your 
records.  However, you do not have a guarantee of absolute privacy because of the need to share 
your information as described above. After the doctor shares your records with the sponsor and 
others, the laws may no longer protect the privacy of your records. These records might be 
shared with other people who do not have to protect the privacy of your records. 
If you get hurt or sick possibly because of being in the study, and you seek medical treatment:

The doctor and sponsor may obtain study-related records from your or other health care 
providers to learn more about the effects of the study and your condition. 

Information about this study might be given to your insurance company or health care 
payer for the purpose of resolving your claim. 

The sponsor might give information that identifies you to its insurance carrier for the 
purpose of resolving your insurance claim. 


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CONFIDENTIAL:  Clear Creek Bio, Inc. 
You have the right to see and copy your records in the doctor’s possession. However, by signing 
this consent form, you agree that you might not be able to review some of these records related 
to the study until after the study is complete. At that time, your right to see these records will be 
restored. 
This consent form has no expiration date.  If you do not cancel this consent form, then it will 
remain valid indefinitely. 
You will receive a signed and dated copy of this consent for your records.
WHAT WILL HAPPEN TO THE RESULTS OF THE RESEARCH STUDY?
The results of the study will be reported in a Clinical Study Report and may be published in 
scientific journals or presented in scientific meetings. The results of this study may also be used 
to support regulatory filings by the sponsor in support of the use of this medication for treating
AML or other blood cancers or diseases. A description of this clinical trial will be available on 
http://www.ClinicalTrials.gov, as required by U.S. law. This web site will not include 
information that can identify you. At most, the web site will include a summary of the results. 
You can search this web site at any time. 
WHO IS ORGANIZING AND FUNDING THE RESEARCH?
The study has been organized and funded by Clear Creek Bio, Inc. The investigational medicinal 
product (study drug) is being provided by Clear Creek Bio, Inc. 
DO I HAVE TO TAKE PART?
Your participation in this study is voluntary. You may decide not to participate, or you may leave 
the study at any time. Your decision will not result in any penalty or loss of benefits to which 
you are entitled. If you decide to take part, you will be asked to sign and date this consent form 
and given a copy to keep.   
Your participation in this study may be ended by the doctor, sponsor, the regulatory agencies or 
the Institutional Review Board (an IRB is a group of people who review the risks and benefits of 
a study).  They can end your participation for any of the following reasons without your consent:

if it is in your best interest;

you do not later consent to any future changes that may be made in the study plan; or

for any other reason. 
If this is the case, you will be given further instructions by the doctor for any final evaluations 
that may be needed. 
CONTACT FOR FURTHER INFORMATION
Any questions, concerns, or complaints about this study or if you feel you have had a 
research-related injury or reaction to the study drug should be directed to <insert PI name and 
contact information [24-hour contact]>.


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DATE:  04 October 2018 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
If you have questions about your rights as a research subject or for questions, concerns or 
complaints about the research, you may contact:
<Insert IRB name > 
<Insert address> 
<Insert telephone number> 
<Insert email if applicable> 
The IRB will not be able to answer some study-specific questions however, you may contact the 
IRB if the research staff cannot be reached or if you wish to talk to someone other than the 
research staff.  
Do not sign this consent form unless you have had a chance to ask questions and have received 
satisfactory answers to all of your questions. 
You will be given a signed and dated copy of this consent form to keep. 
Thank you for taking the time to read this consent form. 
 


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DATE:  04 October 2018 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
Consent Form Signature Page
SUBJECT’S DATE OF BIRTH:  ______/______/______ 
mmm / dd
/ yyyy
Print Name of Investigator:
Please initial 
box:
1.
I confirm that I have read this consent form for the above study and have had 
the opportunity to ask questions. 
 
2.
I understand my participation is voluntary and I am free to withdraw at any 
time, without giving any reason, without my medical care or legal rights 
being affected. 
 
3.
I understand that sections of any of my medical records may be looked at by 
responsible individuals from Clear Creek Bio, Inc. and/or its representatives 
or from regulatory authorities and the IRB where it is relevant to my taking 
part in research. I give permission for these individuals to have access to my 
records. 
4.
I understand that my data may be transmitted outside the country to 
countries with less strict data protection laws.
 
5.
I agree to take part in the above study.
 
By signing this consent form, I have not given up any of my legal rights. 
Printed Name of Subject                       Signature of Subject 
Date 
Time
 
 
                                                                      
Printed Name of person conducting      Sign  
Date 
Time
informed consent discussion 
Original with Investigator File
1 copy for subject
1 copy for Subject’s Medical Records
 
 


PROTOCOL NUMBER:  CCB-01
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DATE:  04 October 2018 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
Addendum to Informed Consent for Short Messaging Service (SMS/text)
Reminders for Protocol CCB-01
 
 
TITLE:
A Phase 1b/IIa open-label, multi-center study to assess the safety, efficacy and 
pharmacokinetics of intrapatient dose-adjusted brequinar and inhibition of 
dihydroorotate dehydrogenase (DHODH) in adult subjects with acute 
myelogenous leukemia (AML)
PROTOCOL NO.: 
CCB-01  
SPONSOR: 
 
Clear Creek Bio, Inc. 
 
585 Massachusetts Avenue, 4th Floor, 
 
 
Cambridge MA 02139 
 
INVESTIGATOR: 
 
<insert PI name> 
Site(s):
<insert name> 
 
 
<insert address> 
STUDY-RELATED
PHONE NUMBER(S): <insert name(s)>
 
<insert number>
<insert alternate number (24-hour contact number)> 
VERSION and DATE: <e.g. CCB-01 Addendum ICF Version 1.0 31May2018> 
 
WHY AM I BEING ASKED TO SIGN THIS ADDENDUM TO THE CONSENT?
You are being asked to sign this addendum to the consent because you have agreed to participant 
in study CCB-01 and because it is very important for you to take your study medication at the 
correct times (e.g., Monday mornings and Thursdays evenings). One effective way to help you 
remember to take your medication on time is for you to receive a text reminder on your phone. 
The sponsor of the study (Clear Creek Bio, Inc.) is using an external vendor to generate a text 
message reminder that will be sent to your mobile device when it is time for you to take your 
study medication.  
 
VOLUNTARY NATURE OF THIS SERVICE
It is entirely optional for you to receive this service. Your decision to receive text message 
reminders for your medications will not in any way affect your ability to enroll in the study. You 
may also "opt out" at any time by responding "STOP" to the messages, or by contacting your 
study team. 


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CONFIDENTIAL:  Clear Creek Bio, Inc. 
DESCRIPTION OF THE NATURE OF THE DATA YOU WILL PROVIDE
You will provide your mobile device number to the study team who will then enter the number 
into the third-party vendor's system for sending out the text reminders.  
 
DESCRIPTION OF HOW THE DATA WILL BE USED
The only information that will be shared with the third-party vendor is your mobile device 
number and your study participant identification number. The system is set up so that one-way 
messages are sent from the service to you. You should not reply to the messages you receive 
except to "opt out". If you do send a message, the texting service will reply with a message 
indicating that the messages you may send are not being monitored. 
 
WHAT WILL THE MESSAGE SAY?
On the twice-weekly schedule (i.e., Monday mornings and Thursday evenings), you will receive 
a text with the following information: “It is time for you to take your CCB-01 study medication. 
Thank you for participating in this study.” You may delete this message after reading. 
 
DESCRIPTION OF HOW THIS DATA WILL BE SECURELY MANAGED
The mobile device number you provide to be used for these reminders will be managed in a 
manner that ensures the best possible security. The mobile device number will not be shared with 
any other third-party vendor or the sponsor of this study (Clear Creek Bio, Inc.). 
 
WHAT IF I DON’T HAVE A PHONE THAT CAN RECEIVE TEXT MESSAGES?
If you do not have a mobile phone or cannot receive text messages, you cannot participate in 
receiving these text message reminders. 
DISCLOSURES OF RISKS AND VULNERABILITIES
Although unlikely, it is possible that the unencrypted text messages you receive could 
inadvertently be seen by someone else. Because the messages are de-identified (your name will 
not appear), the most information that could be seen would be that you are participating in a 
study. You are not sending any information back to the third-party vendor, so nothing you send 
could be seen by mistake. 
The study team members are not responsible for any loss or breach of data that results from 
something beyond their control, e.g., you lose your mobile device containing text messages 
reminders, or a third-party vendor or host experiences a server/data breach.  
 
Standard text/data messaging rates apply to these messages, and because some mobile phone 
providers charge an additional fee for the sending and receiving of text messages, you might be 
charged additionally by your mobile phone provider if you choose to receive the text message 
reminders.  
 


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CONFIDENTIAL:  Clear Creek Bio, Inc. 
PROCESS FOR NOTIFYING PARTICIPANT IN CASE OF AN ACTUAL OR 
POTENTIAL SECURITY BREACH
If the third-party vendor that has your mobile device number experiences a breach or a potential 
breach, the third-party vendor will notify the sponsor of this study, Clear Creek Bio, Inc. The 
sponsor will notify the study team at each participating institution, and the study team will 
contact you regarding the possible risks associated with the breach/potential breach regarding 
your mobile device number.  
 
Consent Form SMS/Text Addendum Signature 
SUBJECT’S DATE OF BIRTH:  ______/______/_____
mmm / dd
/ yyyy
Print Name of Investigator: 
Please initial 
box:
1. I confirm that I have read this consent form for receiving text message 
medication reminders for the above study and have had the opportunity to 
ask questions. 
2. I understand my participation is voluntary in this text messaging service 
and I am free to withdraw at any time, without giving any reason, without 
my medical care or legal rights being affected.
3. I give permission for the study team and third-party vendor to have access 
to my mobile device number. 
4. I agree to take part in the mobile device text message reminder for the 
above study.
By signing this consent form, I have not given up any of my legal rights. 
Printed Name of Subject                       Signature of Subject 
Date 
Time
 
                                                                      
Printed Name of person conducting      Sign 
Date 
Time
informed consent discussion
Original with Investigator File
1 copy for subject
1 copy for Subject’s Medical Records


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PROTOCOL VERSION: FINAL v. 3.0 
DATE:  04 October 2018 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
APPENDIX F:  WMA Declaration of Helsinki
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by 
the:
29th WMA General Assembly, Tokyo, Japan, October 1975
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996
52nd WMA General Assembly, Edinburgh, Scotland, October 2000  
53th WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 added)
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added)
59th WMA General Assembly, Seoul, October 2008 
A. INTRODUCTION 
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including 
research on identifiable human material and data.  
The Declaration is intended to be read as a whole and each of its constituent paragraphs 
should not be applied without consideration of all other relevant paragraphs. 
2. Although the Declaration is addressed primarily to physicians, the WMA encourages other 
participants in medical research involving human subjects to adopt these principles. 
3. It is the duty of the physician to promote and safeguard the health of patients, including those 
who are involved in medical research. The physician's knowledge and conscience are 
dedicated to the fulfillment of this duty. 
4. The Declaration of Geneva of the WMA binds the physician with the words, "The health of 
my patient will be my first consideration," and the International Code of Medical Ethics 
declares that, "A physician shall act in the patient's best interest when providing medical 
care." 
5. Medical progress is based on research that ultimately must include studies involving human 
subjects. Populations that are underrepresented in medical research should be provided 
appropriate access to participation in research. 
6. In medical research involving human subjects, the well-being of the individual research 
subject must take precedence over all other interests. 
7. The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and 
therapeutic interventions (methods, procedures and treatments). Even the best current 
interventions must be evaluated continually through research for their safety, effectiveness, 
efficiency, accessibility and quality. 


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


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


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


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32. The benefits, risks, burdens and effectiveness of a new intervention must be tested against 
those of the best current proven intervention, except in the following circumstances:
The use of placebo, or no treatment, is acceptable in studies where no current proven 
intervention exists; or 
Where for compelling and scientifically sound methodological reasons the use of placebo 
is necessary to determine the efficacy or safety of an intervention and the patients who 
receive placebo or no treatment will not be subject to any risk of serious or irreversible 
harm. Extreme care must be taken to avoid abuse of this option. 
33. At the conclusion of the study, patients entered into the study are entitled to be informed 
about the outcome of the study and to share any benefits that result from it, for example, 
access to interventions identified as beneficial in the study or to other appropriate care or 
benefits. 
34. The physician must fully inform the patient which aspects of the care are related to the 
research. The refusal of a patient to participate in a study or the patient's decision to 
withdraw from the study must never interfere with the patient-physician relationship. 
35. In the treatment of a patient, where proven interventions do not exist or have been 
ineffective, the physician, after seeking expert advice, with informed consent from the 
patient or a legally authorized representative, may use an unproven intervention if in the 
physician's judgment it offers hope of saving life, re-establishing health or alleviating 
suffering. Where possible, this intervention should be made the object of research, designed 
to evaluate its safety and efficacy. In all cases, new information should be recorded and, 
where appropriate, made publicly available. 
22.10.2008 


PROTOCOL NUMBER:  CCB-01
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DATE:  11 October 2018
CONFIDENTIAL:  Clear Creek Bio, Inc.
CCB-01 Approvals and Revision History
Protocol agreed by:
Clinical Development
Date:
PRINT NAME:
Research & Development
Date:
PRINT NAME:
Chemistry and Manufacturing/Quality
Date:
PRINT NAME:
Sponsor Representative
Date:
PRINT NAME:
Revision History/Amendments:
Version Number
Date
1.0
31 May 2018
2.0
04 June 2018
3.0
04 October 2018
4.0
11 October 2018


PROTOCOL NUMBER:  CCB-01
Page 1 of 101
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DATE:  11 October 2018 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
STUDY PROTOCOL
A Phase 1b/2a open-label, multi-center study to assess the safety, 
efficacy and pharmacokinetics of intrapatient dose-adjusted 
brequinar and inhibition of dihydroorotate dehydrogenase 
(DHODH) in adult subjects with acute myelogenous leukemia 
(AML)
Study No: CCB-01
Version Date: 11 October 2018
Sponsor:
Clear Creek Bio, Inc.
585 Massachusetts Avenue, 4th Floor,
Cambridge MA 02139
Sponsor Telephone: (617) 765-2252
Sponsor Facsimile: (617) 863-2082
IND Number: 138335
This confidential document is the property of Clear Creek Bio, Inc. No unpublished information contained herein 
may be disclosed without the prior written approval of Clear Creek Bio, Inc. This trial will be conducted in 
accordance with the ICH Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95, Jan.97), the Declaration 
of Helsinki (1964, 1975, 1983, 1989, 1996, 2000 (Note for Clarification 2002 & 2004) and 2008), FDA Regulations 
and locally applicable regulations.


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CONFIDENTIAL:  Clear Creek Bio, Inc. 
TABLE OF CONTENTS
1
SYNOPSIS..........................................................................................................................11
2
INTRODUCTION ..............................................................................................................27
2.1
Background: Acute Myeloid Leukemia .....................................................................27
2.2
Dihydroorotate dehydrogenase (DHODH) ................................................................27
2.3
Brequinar....................................................................................................................27
2.4
Rationale for the Planned Trial ..................................................................................29
2.4.1 
Brequinar Starting Dose Selection ......................................................................29
2.5
Risk/Benefit of Brequinar ..........................................................................................30
2.6
Risks Associated with Participation in the Clinical Study.........................................30
2.7
Possible Interactions with Concomitant Medical Treatments ....................................31
2.7.1 
CYP Interactions .................................................................................................31
2.8
Steps to be Taken to Control or Mitigate Risks .........................................................31
3
TRIAL OBJECTIVES ........................................................................................................32
3.1
Primary Objective ......................................................................................................32
3.2
Secondary Objectives.................................................................................................32
3.3
Exploratory Objectives...............................................................................................32
4
TRIAL DESIGN.................................................................................................................33
5
TRIAL ENDPOINTS..........................................................................................................34
5.1
Primary Endpoint .......................................................................................................34
5.2
Secondary Endpoints ..................................................................................................34
5.3
Exploratory Endpoints................................................................................................34
6
TRIAL POPULATION .......................................................................................................35
6.1
Number of Subjects....................................................................................................35
6.2
Inclusion criteria.........................................................................................................35
6.3
Exclusion Criteria .......................................................................................................35
6.4
Inclusion of Women and Minorities...........................................................................36
7
STUDY TREATMENTS ....................................................................................................37


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CONFIDENTIAL:  Clear Creek Bio, Inc. 
7.1
Description of Brequinar:...........................................................................................37
7.2
Treatment Administration ..........................................................................................37
7.3
Safety/Tolerability......................................................................................................37
7.3.1 
Safety/Tolerability – Subject Level ....................................................................37 
7.3.1.1 Hematologic Toxicity ......................................................................................... 38 
7.3.2
Safety/Tolerability – Cohort Level .....................................................................38
7.3.3
Safety/Tolerability – Expansion Cohort .............................................................39
7.4
Cohort Starting Doses ................................................................................................39
7.5
Individual Dose Adjustment Guidelines ....................................................................39
7.5.1 
DHO Threshold...................................................................................................40
7.6
Medication/AE Diary.................................................................................................42
7.7
Bone Marrow Biopsy .................................................................................................42
7.8
Flow Cytometry..........................................................................................................42
7.9
Expansion Cohort.......................................................................................................42
7.10 Study Drug Discontinuation .......................................................................................42
7.11 Brequinar Pharmacokinetics (PK) / Dihydroorotate (DHO) Plasma Levels..............43
7.12 Concomitant Medication/Treatment ..........................................................................43
7.12.1
Gastric pH ...........................................................................................................43
7.13 Treatment Compliance...............................................................................................43
7.14 Storage, Stability, Labeling and Packaging ...............................................................44
7.14.1
Storage and Stability...........................................................................................44
7.14.2 
Labeling and Packaging ......................................................................................44 
7.14.3 
Blinding and Randomization .............................................................................. 44 
7.14.4 
Unblinding/Expectedness .................................................................................... 44 
7.14.5 
Study Drug Accountability ................................................................................. 44 
8
CONDUCT OF THE TRIAL..............................................................................................46
8.1
Ethical and Regulatory Considerations ......................................................................46
8.2
Informed Consent.......................................................................................................46


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8.3
Institutional Review Board / Ethics Committees.......................................................47
8.4
Schedule of Events .....................................................................................................47
8.5
Study Conduct............................................................................................................48
8.5.1 
Screening Visit (Study Days -14 to -1) ...............................................................48
8.5.2 
Cycle 1 ................................................................................................................48
8.5.3
Cycle 2 (and any Dose Adjustment Cycle).........................................................49
8.5.4
Maintenance Dose Cycle (visit every 2 - 4 weeks).............................................50
8.5.5 
Final Visit ............................................................................................................ 51 
8.5.6 
Follow Up Visit (2 weeks after Final Visit) ........................................................ 51 
8.5.7 
Unscheduled Visits ............................................................................................. 51 
8.6
Compliance with Study Procedures ...........................................................................52
8.7
Early Withdrawal from the Study ..............................................................................52
8.8
Early Termination of the Study..................................................................................52
8.9
Short Messaging Service (SMS) Medication Reminders...........................................52
9
ADVERSE EVENT REPORTING.....................................................................................54
9.1
Classification of Causality .........................................................................................56
9.2
Classification of Severity ...........................................................................................56
9.3
Serious Adverse Event (SAE) Reporting ...................................................................56
9.4
Suspected Unexpected Serious Adverse Reactions (SUSARs) .................................58
9.5
Pregnancies.................................................................................................................58
9.6
Hematologic Adverse Events.....................................................................................59
9.7
Management of Myelosuppression ............................................................................60
9.8
Differentiation Syndrome...........................................................................................60
9.9
Tumor Lysis Syndrome (TLS)...................................................................................61
9.10 Infection Prophylaxis .................................................................................................63
9.11 Growth Factor Support ...............................................................................................63
9.12 Management of Nausea, Vomiting, and Diarrhea......................................................63
10 STATISTICAL CONSIDERATIONS................................................................................64


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10.1 Study Populations for Analysis..................................................................................64
10.2 Safety Analyses ..........................................................................................................64
10.3 Efficacy Analyses.......................................................................................................65
10.4 Other Endpoints..........................................................................................................67
10.5 Sample Size Considerations .......................................................................................68
10.6 Randomization ...........................................................................................................68
10.7 Pooling of Study Centers............................................................................................68
10.8 Interim Analysis.........................................................................................................68
11 INVESTIGATOR RESPONSIBILITIES ...........................................................................69
11.1 Investigator’s Performance ........................................................................................69
11.2 Confidentiality............................................................................................................69
11.3 Source Documentation ...............................................................................................69
11.4 Data Collection ...........................................................................................................70
11.5 Case Report Forms, Investigator’s Site File and Record Retention ...........................70
11.6 Non-Protocol Research ..............................................................................................71
11.7 Publication..................................................................................................................71
12 SPONSOR RESPONSIBILITIES ......................................................................................72
12.1 General .......................................................................................................................72
12.2 Indemnity ...................................................................................................................72
12.3 Data Monitoring.........................................................................................................72
12.4 Audit...........................................................................................................................72
12.5 Confidentiality............................................................................................................73
12.6 Finance .......................................................................................................................73
13 REFERENCES ...................................................................................................................74
14 APPENDICES ....................................................................................................................75
14.1 APPENDIX A:  CCB-01 Schedule of Events............................................................75
14.2 APPENDIX B: ECOG Performance Status Criteria ..................................................78
14.3 APPENDIX C: Brequinar/DHO Plasma Sampling....................................................79


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14.4 APPENDIX D: Common Terminology Criteria for Adverse Events (CTCAE) .......80
14.5 APPENDIX E:  Sample Subject Consent Form.........................................................81


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CONFIDENTIAL:  Clear Creek Bio, Inc. 
LIST OF TABLES
Table 1.
Exceptions to Grade 3 Nonhematologic AEs ............................................................. 38
Table 2.
Intra-Subject Dose Adjustment .................................................................................. 40
Table 3.
Analysis Sets............................................................................................................... 64
Table 4.
Efficacy Analyses....................................................................................................... 65


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LIST OF FIGURES
Figure 1.
Dose Adjustment – Subject Level .............................................................................. 41
Figure 2.
Monitoring of Tumor Lysis Syndrome....................................................................... 62


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ABBREVIATIONS
Abbreviation
Definition 
µg
Microgram 
5-FU
5-Fluorouracil  
AUC
Area Under Curve
BID
Bis in die (two times a day)
C6min
Concentration at 6 minutes
CHO/HGPRT
Chinese hamster ovary cell/hypoxanthine-guanine phosphoribosyl-transferase
CL
Clearance 
ClR
Low Renal Clearance 
ClT 
Low Plasma Total Clearance 
CRh
Partial hematological response 
CRi
Incomplete hematological response
CT
Computerized Tomography
CYP
Cytochrome P450
DHO
Dihydroorotate 
DHODH
Dihydroorotate dehydrogenase
DLT(s) 
Dose-Limiting Toxicity(ies) 
DNA
Deoxyribonucleic Acid
ECGs 
Electrocardiograms 
ECOG 
Eastern Cooperative Oncology Group 
ED50
Median Effective Dose 
EORTC
European Organisation for the Research and Treatment of Cancer
ESR
Erythrocyte Sedimentation Rate
F
Bioavailability 
FDA
United States Food and Drug Administration 
g
Grams 
GI 
Gastrointestinal 
G-R 
Good Risk Patients
HPLC 
High-Performance Liquid Chromatography
HIPAA 
Health Insurance Privacy and Portability Act 
Hr 
Hour 
IB 
Investigator Brochure 
IP 
Intraperitoneal
IV 
Intravenous 
kg 
Kilograms 
l
Liters
LD(10, 50, 90) 
Lethal Dose(10%, 50%, 90%) 
LPS 
Lipopolysaccharide
M 
Molar
Mg 
Milligram
mL 
Milliliters 
MLED10
Mouse Equivalent Lethal Dose for 10% of population
mM 
Micromolar


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Mm
Millimeters
MRD
Minimal Residual Disease
MRT
Long Median Residence Time 
MS
Mucositis/stomatitis
MTD 
Maximum Tolerated Dose 
NCI
National Cancer Institute
NCI
United States National Cancer Institute
NMR
Nuclear Magnetic Resonance Spectroscopy
NSC
National Service Center
ORR
Overall Response Rate
PK
Pharmacokinetic(s)
PO
Per Orem 
P-R
Poor Risk Patients
PR 
Partial Response 
PS
Performance Status 
Pts.
Patients
QTcF 
Corrected QT interval by Fredericia
RDP2
Recommended Dose for Phase II
RNA
Ribonucleic Acid 
SC 
Subcutaneous  
SD
Standard Deviation
SE 
Standard Error 
SEM
Standard error of the means
SI 
Simulation Index
t½ 
Half-Life 
TEAE 
Treatment-emergent adverse event
USP
United States Pharmacopeia
UV
Ultraviolet 
V 
Volume 
Vd 
Volume of Distribution
VdSS 
Steady-State Volume of Distribution
WBC
White Blood Cell
WHO 
World Health Organization


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1
SYNOPSIS
IND 
138,335 
Title
A Phase 1b/2a open-label, multi-center study to assess the safety, efficacy 
and pharmacokinetics of intrapatient dose-adjusted brequinar and inhibition 
of dihydroorotate dehydrogenase (DHODH) in adult subjects with acute 
myelogenous leukemia (AML) 
Protocol 
CCB-01
Investigational 
Medicinal 
Product and 
Dosage 
Brequinar is available as 100 and 250 mg oral capsules to be taken every 3.5 
days with approximately 240 mL of water. Each subject’s mg/m2 dose will 
be calculated based on body surface area at study entry; actual dose will be 
rounded down to the nearest mg based on available oral capsule doses.  
Primary 
Objective 
To determine the safety and tolerability of brequinar and the DHODH 
inhibitory level of brequinar in adult patients with AML. 
Secondary 
Objectives 
 
 
To determine the overall response rate (ORR) including complete 
remission (CR), CR with incomplete hematologic recovery (CRi),
morphologic leukemia-free state (MLFS), and partial remission (PR) 
(criteria as defined in the ELN Guidelines, Döhner et al., 2017) and 
complete remission with partial hematological recovery (CRh). 
To assess the rate of overall survival (OS) and event-free survival (EFS). 
To evaluate duration of response.  
To characterize the pharmacokinetic (PK) profile of brequinar. 
To characterize the dihydroorotate (DHO) plasma levels of brequinar 
after oral dosing. 
Exploratory 
Objectives 
To assess the relationship between DHODH inhibition and the efficacy 
and safety of brequinar. 
To evaluate molecular and cellular biomarkers that may be predictive of 
antitumor level and/or treatment resistance including cytogenetics, 
molecular profiling, and flow cytometry during and after treatment.
To evaluate global gene expression profiles, DNA methylation profiles, 
and other potential prognostic markers to explore predictors of antitumor 
activity and/or resistance to treatment. 
Design 
This will be a Phase 1b/2a multi-center, open-label, non-randomized clinical 
trial to assess the safety, tolerability and efficacy of dose-adjusted brequinar 
in adult subjects with AML. The study will also assess the inhibition of 


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DHODH and the PK profile of brequinar in plasma. Subject dosing will be 
adjusted based on safety/tolerability and DHO level. 
Up to 27 subjects are planned to be entered in this trial: Cohort 1 will have 6 
subjects; two additional cohorts of 3 subjects each may be added if the 
Cohort 1 starting dose requires adjustment. Cohorts 2 and 3 may be 
expanded to 6 subjects using a 3 + 3 design if required by safety assessments 
as described in Section 7.3.2.  Following completion of enrollment in the 
starting dose-adjustment part of the study, an expansion cohort of 
approximately 15 subjects will be enrolled with a starting dose of the highest 
tolerated dose from Cohorts 1 – 3. Safety and tolerability will be assessed 
utilizing physical examination, vital sign measurements, safety laboratory 
testing, 12-lead ECGs, bone marrow sampling, and adverse event reporting. 
Bone marrow sampling (bone marrow aspirate and core biopsy) will also be 
utilized for efficacy. DHO level will be measured using a validated assay. 
PK will be analyzed using standard PK parameters.  
Dosing will continue for up to 12 months in the absence of unacceptable 
toxicity or disease progression.  
Primary 
endpoints: 
Safety/tolerability and DHO level relationship with safety and 
therapeutic brequinar levels   
Secondary 
endpoints: 
Rates of treatment-emergent adverse events. 
Overall Response Rate (ORR) including CR, CRi, CRh, MLFS, or PR. 
Event free survival (EFS). 
Duration of response. 
PK profile of brequinar. 
DHO plasma profile. 
Exploratory 
endpoints: 
Relationship between DHODH inhibition and the efficacy and safety of 
brequinar. 
Antitumor level based on molecular and cellular biomarkers including 
cytogenetics, molecular profiling, and flow cytometry during and after 
treatment. 
Global gene expression profiles, DNA methylation profiles, and other 
potential prognostic markers to explore predictors of antitumor activity 
and/or resistance to treatment. 
Sample Size: 
Up to 27 subjects  


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Number of 
Sites: 
3 – 5 
Study Period:
An enrollment period of 18 - 24 months is expected.
Inclusion 
Criteria: 
 
1. Willing and able to provide written informed consent for the trial. 
2. Patients 18 years of age or older, with relapsed/refractory AML by 
World Health Organization classification who have exhausted 
available therapy. 
3. ECOG Performance Status 0 to 2. 
4.
5. Adequate hepatic function (unless deemed to be related to underlying 
leukemia).
1.
 
2.
 
3.
3 x ULN 
6.
mL/min based on the Cockcroft-Gault equation. 
7. In the absence of rapidly proliferative disease, the interval from prior 
leukemia-directed therapy to time of study initiation will be at least 7 
days for cytotoxic or non-cytotoxic (immunotherapy) agents. Hydrea 
is allowed up to 48 hours prior to the first dose for patients with 
rapidly proliferative disease.  
8. The effects of brequinar on the developing human fetus are unknown. 
For this reason, women of child-bearing potential and men must 
agree to use adequate contraception (hormonal or barrier method of 
birth control; abstinence) prior to study entry and for the duration of 
study participation. Should a woman become pregnant or suspect she 
is pregnant while she or her partner is participating in this study, she 
should inform her treating physician immediately. Men treated or 
enrolled on this protocol must also agree to use adequate 
contraception prior to the study, for the duration of study 
participation, and for 90 days after completion of brequinar 
administration.
9. Male subjects must agree to refrain from sperm donation from initial 
study drug administration until 90 days after the last dose of study 
drug.


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Exclusion 
Criteria: 
1. Patients in need of immediate leukapheresis.
2. White blood count > 25 x 109/L (note: hydroxyurea is permitted to 
meet this criterion). 
3. Any concurrent uncontrolled clinically significant medical condition, 
laboratory abnormality, or psychiatric illness that could place the 
participant at unacceptable risk of study treatment.
4. Pre-existing liver disease.
5.
Participants with a bundle branch block and prolonged QTc interval 
may be eligible after discussion with the medical monitor.
6. The use of other chemotherapeutic agents or anti-leukemic agents is 
not permitted during study with the following exceptions: 
a.
Intrathecal chemotherapy for prophylactic use or maintenance of 
controlled CNS leukemia. 
7. Use of hydroxyurea for the purpose of leukemic cytoreduction may 
be allowed during the first 2 weeks of therapy if in the best interest of 
the participant and is approved by the medical monitor. Hydroxyurea 
can be used to treat leukocytosis if concurrent with and thought to be 
associated with presumed differentiation syndrome.  
8. AML relapse less than 6 months following stem cell transplantation.  
9. Presence of graft versus host disease (GVHD) which requires an 
systemic corticosteroids (e.g. cyclosporine or other calcineurin 
inhibitors or other immunosuppressive agents used for GVHD).
10. Active cerebrospinal involvement of AML.
11. Diagnosis of acute promyelocytic leukemia (APL) 
12. Clinically active hepatitis B (HBV) or hepatitis C (HCV) infection.
13. Severe gastrointestinal or metabolic condition that could interfere 
with the absorption of oral study medication. 
14. Prior malignancy, unless it has not been active or has remained stable 
for at least 3 years. Participants with treated non-melanoma skin 
cancer, in situ carcinoma or cervical intraepithelial neoplasia, 
regardless of the disease-free duration, are eligible if definitive 
treatment for the condition has been completed. Participants with 
organ-confined prostate cancer with no evidence of recurrent or 
progressive disease are eligible if at the active surveillance stage, 


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hormonal therapy has been initiated, or the malignancy has been 
surgically removed or treated with definitive radiotherapy.
15. Nursing women or women of childbearing potential (WOCBP) with a 
positive urine pregnancy test.
Treatment 
Subjects will self-administer oral brequinar twice weekly (every 84 hours +/- 
6 hours). Treatment cycles will be 2 weeks. Visits will take place at least 
every 2 weeks through 3 months; visits thereafter will be every 2 – 4 weeks 
at the discretion of the investigator at each site. Inter-cohort and intra-subject 
dose adjustments may occur throughout the study as outlined in the sections 
below. Subjects in Cohort 1 may not escalate above the initial 500 mg/m2 
starting dose. 
Procedures
Screening Visit (Study Days -14 to -1)
These procedures must be completed within the 14 days prior to starting 
dosing. Obtain the subject’s written informed consent, then collect baseline 
information:
-
Demographics (height, weight, date of birth, gender, race, ethnicity)
-
Pertinent medical/surgical history (including AML diagnosis and 
laboratory and clinical evidence of progression, previous AML 
treatment, and any available chromosomal and mutational testing 
results per institutional guidelines) 
-
Concomitant medications. 
-
Physical examination (including weight).  
-
Vital signs (heart rate, respiratory rate, blood pressure, body 
temperature).  
-
Pregnancy test for women of childbearing potential (WOCBP)  
-
ECOG performance assessment.  
-
Hematology/chemistry. 
-
12-lead ECG with QTcF and MUGA scan or echocardiogram to 
assess cardiac function. 
-
Bone marrow sampling
-
Confirm subject meets all inclusion and no exclusion criteria. 
Treatment
The treatment period begins with Cycle 1, Day 1 of the first 2-week dosing 
cycle. 
Cycle 1 Day 1:
-
Collect any adverse events or new concomitant medications since 
Screening.  
-
Draw samples for baseline (pre-dose) brequinar/DHO, flow 
cytometry, and hematology/chemistry. 


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-
Conduct physical examination (including weight), vital signs, urine 
pregnancy test for WOCBP and 12-lead ECG.
-
Review results and confirm subject remains eligible for the study. 
-
Determine subject’s starting dose based on the respective cohort 
mg/m2 starting dose.
-
Dispense study medication.  
-
Subject is to take the first dose at the clinic and remain for 
brequinar/DHO sampling. Collect brequinar/DHO samples at 1, 2, 4, 
and 6 hours post dose. 
-
Process and store brequinar/DHO samples per the supplied laboratory 
manual. 
-
Dispense the subject’s calendar/diary. The diary will collect 
dates/times of study medication administration and AEs/new 
concomitant medications. 
-
Enroll subject for text message reminders if the subject consents to 
that service.  
-
Ship the flow cytometry sample per the supplied laboratory manual. 
Cycle 1 Day 2:  
-
Collect 24h post dose brequinar/DHO and flow cytometry samples. 
Check the diary/elicit information about AEs/new concomitant 
medications since the last visit. 
-
Process and store brequinar/DHO samples per the supplied laboratory 
manual. 
-
Ship the flow cytometry sample per the supplied laboratory manual. 
Cycle 1 Day 3:  
-
Collect 48h post dose brequinar/DHO and flow cytometry samples. 
Check the diary/elicit information about AEs/new concomitant 
medications since the last visit.  
-
Process and store brequinar/DHO samples per the supplied laboratory 
manual. 
-
Ship the flow cytometry sample per the supplied laboratory manual. 
Cycle 1 Day 4:  
-
Collect 72h post dose brequinar/DHO samples. Check the diary/elicit 
information about AEs/new concomitant medications since the last 
visit. 
-
Process and store brequinar/DHO samples per the supplied laboratory 
manual. 
Cycle 1 Day 8:  
-
Vital signs. 
-
Check the diary/elicit information about AEs/new concomitant 
medications since the last visit. 


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-
Prior to the morning dose, collect brequinar/DHO samples 
(approximately 84h post the second dose of Cycle 1) and 
hematology/chemistry samples, then have subject take study 
medication. 
-
Process and store brequinar/DHO samples per the supplied laboratory 
manual. 
-
Notify DHO assay laboratory of incoming shipment and ship Cycle 1 
brequinar/DHO samples (samples from Days 1, 2, 3, 4 and 8).
Cycle 2 (and any Dose Adjustment Cycle)
Repeat this visit as needed whenever any dose adjustment is required.
Day 1: 
-
Collect unused study medication and check the diary/elicit 
information about AEs/new concomitant medications since the last 
visit.  
-
Take vital signs and perform physical examination (including weight).
-
Collect pre-dose brequinar/DHO samples (approximately 84h post the 
fourth dose of the previous cycle) and hematology/chemistry samples. 
-
Process and store brequinar/DHO samples per the supplied laboratory 
manual.
-
Review laboratory results/safety information and determine whether 
the subject should adjust the dose (based on acceptable safety and 
DHO level), continue with the current dose or hold study medication 
(unacceptable safety) per the guidelines below.  
-
If dosing will continue, dispense study medication.  
-
Dispense calendar/diary. 
-
Manage text message reminders as needed (as a default do nothing, 
pause if study medication is put on hold, and restart if study 
medication is restarted)
Day 8: 
-
Collect and check the diary/elicit information about AEs/new 
concomitant medications since the last visit.
-
Vital signs.
-
Collect pre-dose brequinar/DHO and hematology/chemistry samples. 
-
Perform bone marrow sampling for flow cytometry (window ±7 days).
-
If the subject is being dosed (i.e., has acceptable safety), have the 
subject take the morning dose.  
-
Process and store brequinar/DHO samples per the supplied laboratory 
manual.
-
If the subject’s medication was held, review safety information and 
determine whether dosing can resume. If dosing can resume, 


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determine dose, dispense adequate medication for 4 doses and have 
the subject take the morning dose. 
-
Continue to withhold study drug if safety remains unacceptable.
-
Dispense calendar/diary. 
-
Manage text message reminders as needed (as a default do nothing,
pause if study medication is put on hold, and restart if study 
medication is restarted) 
-
Notify DHO assay laboratory of incoming shipment and ship 
brequinar/DHO samples (samples from current cycle's Days 1 and 8). 
 
Subjects may undergo dose adjustments at any time using the guidelines 
presented in Section 7 of the protocol. Subjects with acceptable safety can 
continue to escalate every 2 weeks by 150 mg/m2 increments through 800 
mg/m2, with the exception of Cohort 1 subjects who may not escalate above 
the 500 mg/m2 starting dose. Subjects with unacceptable safety can continue 
to undergo dose reductions of 75 mg/m2 with no lower limit. Re-escalation to 
a dose previously shown as not tolerated for an individual subject is not 
permitted for these subjects.
Dose adjustments are permitted throughout the study (except for the 
restriction of no escalation in Cohort 1) for an individual subject based on 
safety, DHO level, and clinical response with an upper limit of 800 mg/m2.
Maintenance Dose Cycle (visit every 2 - 4 weeks)
Once a subject reaches a stable or maintenance dose (see Figure 1), the 
subject will be in the Maintenance Dose Cycle. 
In the first 3 months from starting study drug, the Maintenance Dose Cycle 
procedures will occur every 2 weeks (with the exception of bone marrow 
aspiration as discussed below). After completing 3 months from starting 
study drug, subjects may come to the clinic for a Maintenance Dose Cycle 
visit every 2 - 4 weeks (visit interval at the investigator’s discretion).
A subject may still move into a Dose Adjustment Cycle after a maintenance 
dose if required for a change in safety, DHO level or clinical response
(Figure 1).  
Day 1:
-
Collect unused study medication and check the diary/elicit 
information about AEs/new concomitant medications since the last 
visit. 
-
Collect pre-dose brequinar/DHO and hematology/chemistry samples.  
-
Conduct physical examination, vital signs, urine pregnancy test for 
WOCBP 12-lead ECG and bone marrow sampling (note that bone 
marrow is collected on study Day 22 (C2D8 ± 7 days), at Day 43, and 


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then every 12 weeks; the Day 43 sample will be assessed for 
hematological toxicity). 
-
Review the laboratory results/safety information and determine 
whether the subject should maintain current dose (acceptable safety) 
or hold study medication (unacceptable safety). 
-
Dispense study medication. 
-
Dispense calendar/diary.  
-
Manage text message reminders as needed (as a default do nothing, 
pause if study medication is put on hold, and restart if study 
medication is restarted) 
-
Notify DHO assay laboratory of incoming shipment and ship 
brequinar/DHO samples. 
Final Visit
This visit is to take place when a subject is discontinuing from the study.
-
Collect and check the diary/elicit information about AEs/new 
concomitant medications since the last visit.  
-
Collect brequinar/DHO and hematology/chemistry samples.  
-
Collect unused study medication. 
-
Conduct physical examination, vital signs, urine pregnancy test for 
WOCBP
, 12-lead ECG 
previous), and bone marrow sampling (if > 12 weeks since previous 
bone marrow sample obtained). 
-
Review the safety information and determine whether the subject has 
acceptable safety or unacceptable safety. 
-
Notify DHO assay laboratory of incoming shipment and ship 
brequinar/DHO samples.  
-
Stop text message reminders. 
Follow Up Visit (2 weeks after Final Visit)
-
Contact subject to elicit information about AEs/new concomitant 
medications since the last visit.
Survival information will be collected while the study is ongoing. 
Unscheduled Visits
Unscheduled visits and tests to assess AEs are permitted as needed.


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Safety/ 
Tolerability 
Safety/Tolerability – Subject Level
Grade 3, treatment-emergent, study-drug-related, non-hematologic adverse 
events. Due to the expected hematologic profile associated with AML, 
hematologic AEs of any grade will not be considered dose-limiting during 
the first 42 days of dosing. Exceptions to the non-hematologic Grade 3 
criterion are provided in the table below.  
Exceptions to Grade 3 Nonhematologic AEs 
Condition
Exception Description 
Nausea/
Emesis 
Grade 3 nausea and/or emesis resolving to less than or equal 
to Grade 2 or baseline within 1 week after the use of an 
optimal antiemetic regimen based on standard practice.
Diarrhea 
Grade 3 diarrhea resolving to less than or equal to Grade 1 or 
baseline within 1 week after receiving the maximal 
supportive therapy based on standard practice.
Fatigue 
Grade 3 fatigue lasting less than 1 week.
Laboratory 
abnormalities 
Asymptomatic Grade 3 laboratory abnormalities that are not 
considered to be clinically significant.
For the expansion cohort, the definition of unacceptable safety is expanded 
Dosing is to be held for subjects who experience hepatotoxicity; dosing may 
hepatotoxicity after resuming dosing, dosing is to be discontinued for that 
subject.
Hematologic Toxicity
After the subject has completed the first 42 days of treatment, the definition 
of unacceptable safety expands to include hematologic AEs defined as 
prolonged neutropenia with ANC < 500 from the start of therapy in the 
absence of disease, 
 and/or 
Grade 4 
thrombocytopenia, with a hypocellular bone marrow and no greater than 5% 
hematologic AE for the definition of unacceptable safety. Febrile 
neutropenia is also excluded from the DLT definition for this population. For 
clinic visits when bone marrow sampling is scheduled, the timing of the bone 
marrow sampling can be adjusted to ensure that the results are available at 
the time of the clinic visit. 
Safety/Tolerability – Cohort Level
Acceptable safety/tolerability at the cohort level is defined below:


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a)
safety/tolerability 
leading 
to 
dose 
reduction 
or 
treatment 
discontinuation (a dose limiting toxicity or DLT), then that dose is 
considered to have unacceptable safety/tolerability and the previous
dose which was safe/tolerated must be considered as the highest 
safe/tolerated dose.  
b) If 1 out of 3 subjects at a dose level experiences a DLT, then 3 
additional subjects will be added to the cohort and treated at the same 
dose that led to the DLT. Upon cohort expansion to 6 subjects, if a total 
of 
out of 6 subjects has a DLT at that dose, then this dose is 
considered a safe/tolerated dose. However, if >2 out of 6 subjects at a 
dose level experience a DLT, then that dose is considered to have 
unacceptable safety/tolerability and the previous dose which was 
safe/tolerated must be considered as the highest safe/tolerated dose.
Cohort Starting 
Doses 
Cohort 1 will treat 6 subjects at 500 mg/m2 twice weekly. No dose escalation 
is permitted for Cohort 1 subjects, but the dose may be reduced for an 
individual subject in this cohort if the subject experiences unacceptable safety. 
After all subjects in Cohort 1 have completed a 42-day treatment period, up to 
two additional cohort(s) of 3 subjects each will be added with the starting doses 
adjusted (escalated or de-escalated) based on both safety/tolerability and 
adequacy of DHO level results in Cohort 1. As noted above, additional 
subjects may be added to each of these cohorts if safety needs to be further 
explored.
If all subjects in a cohort have acceptable safety at a dose level, the next 
cohort’s starting dose may be escalated by 150 mg/m2. If the safety rules are 
not met at a cohort’s starting dose, the next cohort’s starting dose will be 
reduced to the highest dose found to be safe/tolerated in the previous cohort. 
The planned upper limit for cohort starting dose is 800 mg/m2. There is no 
lower limit.
See the “Intra-subject dose adjustment” section for individual subject dosing 
adjustment criteria.
Expansion 
Cohort 
Once a dose has been reached that has adequate DHO level and acceptable 
safety/tolerability, approximately 15 subjects will be added starting at the 
highest safe/tolerated dose identified in the earlier cohorts. Decisions about 
adequacy of DHO threshold level will be made following review of these 
data from each cohort. These subjects may also undergo individual dose 
adjustment. See Section 7.3.3 for the expansion cohort safety rules. 
Individual Dose 
Adjustment 
Guidelines
With the exception of subjects in Cohort 1 whose dose may not be escalated 
above the 500 mg/m2 starting dose, intra-subject dose adjustment will be 
considered every 2 weeks depending on safety and DHO levels. There is a 


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maximum of 2 dose adjustments for each subject within the first 42 days of 
initiating treatment. Each subject’s dose can be escalated, maintained (stable 
dose), held then reduced, or discontinued. The highest dose planned is 800 
mg/m2, however, this upper limit may be adjusted depending on safety, DHO 
level, and clinical response. There is no lower limit planned.
As noted above, safety will be a key part of determining dose adjustments. 
Subjects who resume dosing at a lower dose after experiencing unacceptable 
safety may not undergo later dose escalations beyond the dose where the 
unacceptable safety occurred. 
Each subject will continue dosing twice weekly at the individually adjusted 
dose for up to 12 months in the absence of unacceptable toxicity or disease 
progression. Intra-subject dose adjustment is permitted at any time 
throughout the study based on safety/tolerability and DHO level (with the 
exception of no escalation for Cohort 1 subjects). Subjects who discontinue 
due to unacceptable safety/tolerability or die prior to Day 42 will not be 
replaced. 
Intra-subject dose adjustment increments and duration of dosing may be 
revised from planned amounts after each preceding cohort’s safety, DHO 
plasma levels and bone marrow results have been reviewed.  
Each subject’s baseline DHO sample will be obtained at C1D1 prior to 
dosing. Dose adjustment decisions based on DHO will be determined by 
DHO trough level (i.e., DHO level obtained pre-dose D8 of the previous 
cycle). The initial target for “adequate” trough DHO level will be set at 100 
ng/mL. This target may be adjusted during the study depending on safety or 
efficacy signals observed during the study. As described below, dose 
adjustments are also based on safety and whether the dose has reached the 
planned upper limit (currently planned to be 800 mg/m2). 
The intrasubject dose-adjustment criteria are presented below.  
Intra-subject Dose Adjustment Criteria*
Acceptable 
Safety/Tolerability?
(see safety definition 
above)
Adequate 
DHO Level?
Planned Intra-Subject Dose 
Adjustment
Yes
Yes
Maintain; continue at same dose. 
Yes
No 
Escalate by 150 mg/m2 for the next 2-
week cycle up to a maximum of 800 
mg/m2. 
No 
Regardless of 
DHO 
Hold two doses (one week), then reassess 
-
escalate dose by 75 mg/m2 and resume 
dosing. If AE has not resolved, reassess 
again in one week.  
weeks after dosing held, discontinue 


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further dosing. Subject will remain in the 
study for safety follow up for 42 days 
after last dose of study drug or until AEs 
have resolved or become stable. 
*Subjects in Cohort 1 may not escalate above the initial 500 mg/m2 starting dose
and may have dose reductions based on safety only.
Brequinar/DHO  Plasma brequinar/DHO samples are to be obtained for each subject for the 
first study dose (Cycle 1 Dose 1 for that subject). Sample scheduling is 0 
hours (prior to dosing), and post dose at 1, 2, 4, 6, 24, 48, and 72 hours. Note 
that this schedule does not apply to subjects in the expansion cohort who will 
have trough sampling only prior to the start of each two-week cycle.
A brequinar/DHO trough sample is to be obtained prior to dosing on Day 8 
(C84, 84 hours after the Cycle 1 Day 4 dose) of Cycle 1, and prior to dosing 
on Days 1 and 8 of Cycles 2 and 3.  
The 84-hour post dose brequinar/DHO sample is to be repeated prior to 
dosing at the beginning of each 2-week cycle and at the Final Visit. This 
sampling schedule also applies for the expansion cohort subjects.  
Statistical 
Analysis 
A separate, detailed statistical analysis plan (SAP) will be finalized prior to 
locking the database. All analyses of safety and anti-leukemic activity for 
this open-label, early Phase study will be descriptive in nature and presented 
by dose group and overall, as appropriate, for the dose-adjustment phase and 
the expansion phase. Procedures for accounting for missing, unused and 
spurious data will be described in the SAP.   
Summaries for quantitative variables will include the mean, median, 
quartiles, standard deviation and error, minimum, and maximum. For 
qualitative variables, the summaries will include the number and percentage 
of subjects for each outcome, and the exact 95% CI, when appropriate. No 
hypothesis testing will be performed. Any statistical testing will be 
considered exploratory and descriptive. All computations will be performed 
using SAS® (Version 9.3 or higher). 
Subject disposition, subject demographics and baseline characteristics will be 
summarized. Subject data listings will also be provided.  
All safety analyses will be performed on the Safety Analysis Set.  Safety and 
tolerability will be assessed in terms of AEs, SAEs, safety laboratory data, 
physical examinations, vital signs, 12-lead ECGs and bone marrow 
sampling.  
Adverse event data will be descriptively evaluated. All AEs will be listed. 
The incidence and duration of treatment-emergent adverse events (TEAEs), 
defined as AEs occurring after the first dose of study treatment through 30 
days after the last dose of study treatment will be tabulated by Medical 
Dictionary for Regulatory Activities (MedDRA) preferred term and system 


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organ class, and by severity and relationship to study treatment. All 
laboratory results, vital sign measurements, ECGs and bone marrow 
assessments will be summarized using appropriate descriptive statistics.
Efficacy analysis is described below.
Assess anti-leukemic activity by ELN Guidelines including CRh, as follows: 

Overall Response rate (ORR) – the proportion of subjects in the 
Efficacy Analysis Set with a best overall response of CR, CRi, CRh, 
MLFS and PR  

Complete Remission (CR) rate – the proportion of subjects in the 
Efficacy Analysis Set with a best overall response of CR 

Complete Remission with Incomplete Hematologic Recovery (CRi) 
rate – the proportion of subjects in the Efficacy Analysis Set with a 
best overall response of CRi 

Complete remission with partial hematological recovery (CRh) – 
the proportion of subjects in the Efficacy Analysis Set with a best 
overall response of CRh 

Morphologic Leukemia Free State (MLFS) rate – the proportion of 
subjects in the Efficacy Analysis Set with a best overall response of 
MLFS

Partial Remission (PR) rate – the proportion of subjects in the 
Efficacy Analysis Set with a best overall response of PR 

Event-free survival (EFS) – the interval between first brequinar 
 reappearance of blasts 
in blood, or development of extramedullary disease), disease 
progression, or death

Overall survival (OS) – the time from first dose of brequinar to date 
of death or last known alive date
For ORR and other endpoints defined as proportions, estimated response 
rates and two-sided exact binomial 95% CIs will be provided. The 
distributions of EFS and other time-to-event endpoints will be summarized 
using the Kaplan-Meier method. Time to event analyses will be from first 
dose of brequinar. Censoring rules for time-to-event endpoints will be 
described in the SAP. 


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STUDY PERSONNEL
SPONSOR CONTACT
Name:
Barbara Powers, MSN, Ph.D. 
Title:
Clinical Operations 
Address:
Clear Creek Bio, Inc.
585 Massachusetts Avenue, 4th Floor,
Cambridge, MA 02139
Telephone No.: 
484-686-0545 
Fax No.:
617-863-2082 
E-mail:
bpowers@clearcreekbio.com
SPONSOR MEDICAL CONTACT
Name: 
Robert Sims, MD
Title:
Senior Medical Director / Medical Monitor  
Address:
Novella Clinical
Telephone No.: 
614-721-2630
24-hour Safety No.: 
1-866-758-2798 or 919-313-7111 
E-mail:
robert.sims@novellaclinical.com; 
YYA36071medmon@novellaclinical.com 
Medical Monitor Fax No.: 
206-826-0483
SAE Reporting Fax:
 
       919.313.1412 (US Toll-free:  1-866-761-1274)
SAE Reporting email: 
safety-inbox@novellaclinical.com 
 
LEAD INVESTIGATOR
Name:
Amir Fathi, MD
Title:
Assistant Professor of Medicine 
Affiliation: 
Massachusetts General Hospital
Telephone No.: 
617-724-1124 
E-mail:
afathi@mgh.harvard.edu


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CONFIDENTIAL:  Clear Creek Bio, Inc. 
SUPPORT SERVICES
CRO Project Manager
Name:
Daniel Ferrone
Company:
Novella Clinical 
Address:
1700 Perimeter Park Drive
Morrisville, NC 27560
Telephone No.: 
919-972-7158
Mobile No.:
704-806-7219
Fax No.:
919-710-8769
E-mail:
dferrone@novellaclinical.com
Data Management/eCRF PROVIDER
Name:
Company:
Address:
Telephone No.: 
Kari Hayden
Novella Clinical 
1700 Perimeter Park Drive
Morrisville, NC 27560  
919-972-2397
Help Desk: 
1-866-342-0693
Help Desk E-mail: 
sitesupport@novellaclinical.com
STATISTICAL ANALYSIS
Name:
Young Choy 
Title:
Senior Biostatistician 
Telephone No.: 
919-972 -7423
Fax No.:
919-710-8769
E-mail:
ychoy@novellaclinical.com
 
STUDY DRUG HOLDING COMPANY
Name:
Almac Clinical Services 
Address:
25 Fretz Road
Souderton, PA 18964 
Telephone No.: 
215-660-8500
Email: 
clinicalservices@almacgroup.com 


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2
INTRODUCTION
2.1 Background: Acute Myeloid Leukemia
Acute myeloid leukemia (AML) is a malignant disorder of immature hematopoietic cells, 
characterized by differentiation arrest and rapid proliferation of abnormal myeloid precursors. 
These abnormal cells accumulate in the bone marrow and interfere with the production of normal 
blood cells. More than 20,000 people are diagnosed with AML per year in the United States (US) 
(SEER, 2015 [1]). The median age at diagnosis is 67 years. 
Although there have been recent advances including midostaurin, enasidenib, CPX-351, 
gemtuzumab ozogomycin and venetoclax, outcomes for patients with AML remain poor. With 
modern treatment regimens, expected complete remission (CR) rates are 60-70%, but long-term 
cure rates are 15-25%. Younger patients (i.e. those 50 years of age or younger) with diploid 
karyotypes have a CR rate of 70-80% and cure rates of 20-25%, while older patients and/or those 
with adverse cytogenetics have CR rates of 35-50% and cure rates of < 10%.1 It is therefore critical
to improve both the remission rate and the durability of remission in AML patients of all ages.
2.2 Dihydroorotate dehydrogenase (DHODH)
Dihydroorotate dehydrogenase (DHODH) catalyzes the fourth step in pyrimidine synthesis, the 
conversion of dihydroorotate (DHO) to orotate. The enzyme is located on the inner mitochondrial 
membrane and transfers electrons between DHO and complex III of the electron-transport chain 
via the reduction of its ubiquinone (coenzyme Q10) cofactor.  
DHODH is a ubiquitous enzyme, and lack of its level is not compatible with life. The Miller 
syndrome, a rare autosomal recessive disorder in which patients have inherited hypomorphic 
mutations in both alleles of DHODH, results in multi-organ dysfunction (Ng et al., 2010 [2]). Two 
weak inhibitors of human DHODH are approved for clinical use. Leflunomide, a pro-drug, is used 
in the treatment of patients with rheumatoid arthritis. Its active form, teriflunomide, is marketed 
for multiple sclerosis. Leflunomide is known to affect erythroid differentiation of K562 cells in 
vitro, via the depletion of uridine triphosphate (UTP) and cytidine triphosphate (CTP) 
ribonucleotides (Huang et al., 2002 [3]). Despite the connection between bone marrow level, blood 
cell differentiation and DHODH, leukemia models of leflunomide have not been very promising. 
Leukemic mice treated with leflunomide demonstrated no reduction in leukemic burden and 
experienced significant weight loss and lethargy. 
Recent nonclinical studies have demonstrated that inhibition of DHODH can overcome myeloid 
differentiation arrest (Sykes et al., 2016 [4]). The mechanism through which a reduction in de novo 
pyrimidine biosynthesis modulates myeloid differentiation is not clear. The differentiation effect 
of DHODH inhibitors appears to involve a combination of inhibition of nucleic acid synthesis, 
cell-cycle arrest, and changes in the post-translational glycosylation of important protein targets.  
2.3 Brequinar
It is well known that brequinar is a potent inhibitor of DHODH. Brequinar is one of more than 300 
quinoline-carboxylic acid derivatives prepared in an analog synthesis program in the 1980s, which 
was started after it was found that a compound of this class had antitumor activity. Brequinar was 
selected by DuPont for further development as a potential clinical drug because of its activity 


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against experimental tumors and because its water solubility made it relatively straightforward to 
formulate. Ultimately, the rationale to use brequinar for the treatment of multiple solid tumors did 
not translate into efficacy after extensive clinical development and the project was terminated by 
DuPont in 1994. Clear Creek Bio exclusively licensed the historic data from Bristol Myers Squibb 
(that acquired DuPont in 2001). 
Sykes et al. showed that brequinar’s pro-myeloid differentiation activity might be useful for the 
treatment of AML. Utilizing a high throughput screening technique, brequinar was identified as a 
compound that overcame arrest of myeloid differentiation. Brequinar triggers myeloid 
differentiation in vitro and in vivo. Brequinar was highly active in vivo, as demonstrated in 
syngeneic murine AML models (HoxA9+Meis1 and MLL/AF9) as well as xenotransplant AML 
models (THP1, HL60, MOLM13, OCI/AML3). In an aggressive MLL/AF9 murine model of 
AML, treatment with brequinar promoted myeloid differentiation, reduced leukemic cell burden, 
and improved overall survival. Brequinar also led to a reduction in the number of leukemia stem 
cells, reduced colony-formation level, and depleted the number of leukemia-initiating cell level. 
In addition, Sykes and colleagues demonstrated that treatment with brequinar was better-tolerated 
and more effective than treatment with cytotoxic chemotherapy in animal models. Brequinar was 
given for many weeks without cumulative toxicity. The effect of brequinar and DHODH inhibition 
on normal cells was also assessed through study of competitive bone marrow transplantation 
assays. Mice were treated with brequinar, 5-fluorouracil (5-FU), or induction chemotherapy, and 
their bone marrow was transplanted in competition (1:1) with normal (untreated) bone marrow to 
gauge the effect of therapy on hematopoietic stem cell (HSC) function. The fitness of HSCs from 
mice treated with brequinar were functionally equivalent to those of untreated mice when 
compared to that of HSCs exposed to 5-FU and induction chemotherapy, which promoted a 
marked decrease in fitness.  
Sykes et al. administered brequinar at a dose and schedule (every 72 hours) that was non-toxic to 
the animals yet led to eradication of the leukemia cells. This schedule of administration was based 
on data demonstrating that the pro-differentiation effect of brequinar required a period of sustained 
DHODH-inhibition of approximately three days. This observation suggests that brequinar’s 
efficacy depends on producing approximately 72-hours “time-above-threshold” to maintain 
sustained DHODH inhibition. The hypothesis is that pyrimidine starvation via inhibition of 
DHODH for approximately 72 hours elicits pro-myeloid differentiation and leads to the anti-
leukemia efficacy of brequinar.  
Sykes et al. also showed that normal cells could tolerate longer periods of pyrimidine starvation 
than their leukemic counterparts. The proposed dosing regimen of brequinar in this clinical trial, 
CCB-01, is intended to take advantage of the different sensitivity of normal and leukemic cells 
and thus spare normal cells while eradicating leukemic cells.  
A pharmacodynamic marker of enzyme inhibition (i.e. target engagement) is required to 
accomplish this type of rational dosing approach. Sykes and colleagues demonstrated how 
DHODH inhibition could be monitored by the accumulation of the substrate DHO. Indeed, 
inhibition of the DHODH enzyme led to the rapid accumulation of intracellular DHO, which was 
reflected by accumulation of DHO in plasma hence the rationale for measuring plasma DHO as 
the pharmacodynamic marker in CCB-01.  


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Given this new information, real-time monitoring of target engagement via plasma DHO of 
DHODH inhibition in each patient should permit identification of a brequinar dose that is both 
efficacious and well-tolerated. Maintaining intermittent DHODH inhibition for prolonged 
treatment cycles may be efficacious compared to previous studies using short periods and high 
doses followed by long periods of recovery.  
The prior data on the clinical evaluation of brequinar in patients with multiple solid tumors 
provides valuable safety data that supports the safety of the proposed dosage regimen. Brequinar 
has not been studied clinically in myeloid malignancies in the past. Given encouraging pre-clinical 
results, brequinar has been evaluated in phase 1 and phase 2 trials of more than 800 patients with 
advanced solid tumor malignancies (Arteaga 1989 [5], Burris 1998 [6], Noe 1990 [7], 
Schwartsmann 1990 [8]). These studies indicated a lack of efficacy for brequinar at the doses and 
schedules evaluated. However, many of these trials studied brequinar administered as a single, 
high dose infusion given weekly or daily x 5 days every 3-4 weeks or every day for 21 days. The 
lack of efficacy in the previous trials may have been due to the narrow therapeutic window with 
the high doses studied, and to the inability, or lack of knowledge, to use a pharmacodynamic 
marker such as plasma DHO to fine-tune a therapeutic window based on differential pyrimidine 
starvation of myeloid precursors versus normal cells.  
2.4 Rationale for the Planned Trial
This study is designed to obtain safety and efficacy data for brequinar in patients with AML. 
Subject Population 
The population for this study is patients 18 years of age or older, with relapsed/refractory AML by 
World Health Organization classification that have failed prior standard therapy and for which no 
standard therapies are available that result in a durable remission. 
Study Treatments 
This is an open label study of oral brequinar using intra-subject dose adjustment. The dose-
adjustment scheme is presented in more detail in Section 7.5.  
2.4.1
Brequinar Starting Dose Selection
The rationale underlying the proposed dosage regimen for brequinar and the use of plasma DHO 
to guide dosing is the prior demonstration using nonclinical models by Sykes et al. (2016) [4] that 
malignant cells are more sensitive than normal cells to periods of DHODH inhibition. The 
objective is to identify a dose and regimen of brequinar that maintains suppression of DHODH 
adequate to induce differentiation and stop myeloid proliferation but avoid harming normal cells. 
These features have been realized in vivo in animal models. Specifically, intermittent dosing that 
preserved elevated levels of the metabolite DHO markedly reduced AML cells, preserved normal 
hematopoietic stem cells, and improved animal survival. These recent findings and historic 
pharmacokinetic (PK) and safety data from humans support the planned approach.  
Rather than intermittent high doses as were given by DuPont, Clear Creek will use relatively low 
doses and prolonged exposure to brequinar. There will not be a lengthy conventional rest period 
as is generally required between infrequent high doses. There will instead be twice-a-week 


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administration of lower doses with a dosing interval that allows enough time for normal cells to 
recover from or avoid pyrimidine starvation in between the periods of DHODH inhibition. Based 
on its average half-life of 10.5 hours and what has been observed in the clinical PK data (see the 
Brequinar IB [9]), brequinar plasma levels return to baseline at about 3.5 days or 84 hours after an 
oral dose. For this reason, the proposed clinical study includes a biweekly schedule of brequinar 
dosed approximately every 84 hours, while measuring plasma DHO to fine-tune the dosing 
schedule that ensures sustained DHODH inhibition while avoiding adverse effects to normal cells. 
Safety data from previous oncology clinical studies of brequinar (see Brequinar IB, Section 5) with 
maximum tolerated doses as high as 2250 mg/m2 repeated every 3 weeks suggest that a starting 
dose for Cohort 1 of 500 mg/m2 p.o. will be safe and well-tolerated in subjects with AML. Each 
subject’s subsequent dosing may be adjusted depending on the safety, tolerability and DHO level
obtained during the period following dose adjustment. Each of the two planned subsequent cohorts 
may also have an adjusted starting dose, again depending on safety, tolerability and DHO level 
observed in previous cohorts. See Section 7.4. 
2.5 Risk/Benefit of Brequinar
As presented in the brequinar IB, more than 800 patients have been exposed to this compound for 
treatment of a variety of solid tumors at various treatment regimens, doses, and routes including a 
single dose, once weekly, twice weekly, single dose every 3 weeks, daily times 5 every 4 weeks, 
and daily times 21 days for multiple courses. The maximum intravenous dose given was 2,250 
mg/m2 every 3 weeks, and the maximum oral dose was 100 mg/m2 daily for 21 days. Study results 
have not shown evidence of efficacy in solid tumors at the doses and regimens studied. However, 
the preclinical work of Sykes et al (2016) [4] have demonstrated the efficacy of brequinar in a 
mouse model of leukemia, indicating that brequinar may be effective in patients with this type of 
leukemia. It is for this reason that study CCB-01 will study patients with AML.   
A universal hallmark of AML is the arrest of leukemic myeloblasts at an immature and self-
renewing stage of development. Therapies that can overcome differentiation arrest caused by 
DHODH represent a powerful treatment strategy. A potential benefit of brequinar treatment in 
patients with AML is that brequinar has been identified as a compound that can inhibit DHODH.  
The major risk associated with brequinar is myelosuppression, particularly a decrease in platelet 
count. Patients with AML typically have a low platelet count due to their disease, and there is a 
risk that treatment with brequinar may worsen existing thrombocytopenia. 
2.6 Risks Associated with Participation in the Clinical Study
In studies utilizing the weekly schedule of administration in patients with refractory solid tumors, 
reversible myelosuppression, in particular thrombocytopenia, and mucositis have been the primary 
dose-limiting toxicities. In addition, skin rash, nausea/vomiting, fatigue, and leukopenia have been 
dose-limiting in trials utilizing other schedules of drug administration. The majority of these 
adverse effects have been less than grade IV in severity and resolve following discontinuation of 
dosing. Symptoms of tumor lysis syndrome have not previously been reported following exposure 
to brequinar, however clinicians will monitor for and treat this condition should it arise per the 
guidelines presented in Section 9.9. An increased risk of infection may occur due to the 
myelosuppressive effects of brequinar (particularly neutropenia); infection prophylaxis and 


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treatment are described in Sections 9.10 and 9.11. Differentiation syndrome has been seen in other 
pro-differentiating agents and will be closely followed as described in Section 9.7. 
2.7 Possible Interactions with Concomitant Medical Treatments
Brequinar has been administered to subjects taking a variety of concomitant medications that are 
typical in cancer patients. No formal interaction studies have been conducted for these 
medications, however, there have not been any reports of interactions with any medications during 
the clinical trials with more than 800 cancer patients.  
2.7.1
CYP Interactions
No formal drug-drug interaction studies have been performed with medications commonly used 
in treating AML. The nonclinical studies have demonstrated there is no first-pass metabolism, and 
there have been no apparent hepatotoxic effects in the clinical studies performed to date. 
2.8 Steps to be Taken to Control or Mitigate Risks
Guidelines for the prevention, monitoring and treatment of differentiation syndrome, tumor lysis 
syndrome, infection prophylaxis and growth factor support are provided in Section 9. 


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3
TRIAL OBJECTIVES
3.1 Primary Objective
The primary objective of this study is to determine the safety and tolerability of brequinar and the 
dihydroorotate dehydrogenase (DHODH) inhibitory activity of brequinar in adult patients with 
AML. 
3.2 Secondary Objectives
The secondary objectives of this study are:

To determine the overall response rate (ORR) including complete remission (CR), CR with 
incomplete hematologic recovery (CRi), morphologic leukemia-free state (MLFS), partial 
remission (PR) (criteria as defined in the ELN Guidelines, by Döhner et al., 2017 [10]) and 
complete remission with partial hematological recovery (CRh).

To assess the rate of overall survival (OS) and event-free survival (EFS)  

To evaluate duration of response 

To characterize the pharmacokinetic (PK) profile of brequinar. 

To characterize the DHO plasma levels after oral dosing with brequinar.
3.3 Exploratory Objectives
The exploratory objectives of this study are: 

To assess the relationship between DHODH inhibition and the efficacy and safety of brequinar. 

To evaluate molecular and cellular biomarkers that may be predictive of antitumor level and/or 
treatment resistance including cytogenetics, molecular profiling, and flow cytometry during 
and after treatment. 

To evaluate global gene expression profiles, DNA methylation profiles, and other potential 
prognostic markers to explore predictors of antitumor activity and/or resistance to treatment.


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4
TRIAL DESIGN
This will be a Phase 1b/2a multi-center, open-label, non-randomized clinical trial to assess the 
safety, tolerability and efficacy of dose-adjusted brequinar in adult subjects with AML. The study 
will also assess the inhibition of DHODH and the PK profile of brequinar in plasma. Intra-subject 
dosing may be adjusted based on safety/tolerability and DHO level.  
Up to 27 subjects are planned to be entered in this trial: Cohort 1 will have 6 subjects; two 
additional cohorts of 3 subjects each will be added if adjustments are required to the cohort starting 
doses. Cohorts 2 and 3 may be expanded to 6 subjects if required by safety assessments as 
described in Section 7.3.2. Following completion of enrollment in the cohort dose-adjustment part 
of the study, an expansion cohort of 15 subjects will be enrolled with a starting dose of the highest 
tolerated starting dose from Cohorts 1 to 3. Safety will be assessed utilizing physical examination, 
vital sign measurements, safety laboratory testing, 12-lead ECGs and bone marrow sampling. Bone 
marrow sampling will also be utilized for efficacy. Tolerability will be assessed by spontaneously 
reported and elicited adverse events. DHO level will be measured using a validated assay. PK will 
be analyzed using standard PK parameters.  
Dosing will continue for up to 12 months in the absence of unacceptable toxicity or disease 
progression. 
Study procedures are presented in more detail in Section 7. 


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5
TRIAL ENDPOINTS
5.1 Primary Endpoint

Safety/tolerability and DHO level relationship with safety and therapeutic brequinar levels  
5.2 Secondary Endpoints

Rates of treatment-emergent adverse events.

Overall Response Rate (ORR) including CR, CRh, CRi, MLFS, or PR

Event-free survival (EFS).

Duration of response

PK profile of brequinar.

DHO plasma profile.
5.3 Exploratory Endpoints

Relationship between DHODH inhibition and the efficacy and safety of brequinar.  

Antitumor level based on molecular and cellular biomarkers including cytogenetics, molecular 
profiling, and flow cytometry during and after treatment.

Global gene expression profiles, DNA methylation profiles, and other potential prognostic 
markers to explore predictors of antitumor activity and/or resistance to treatment 


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6
TRIAL POPULATION
6.1 Number of Subjects
Subjects who meet all the inclusion and none of the exclusion criteria will be enrolled in the study
until approximately 27 subjects have completed the study.     
6.2 Inclusion criteria
1. Willing and able to provide written informed consent for the trial. 
2. Patients 18 years of age or older, with relapsed/refractory AML by World Health 
Organization (WHO) classification who have exhausted available therapy. 
3. ECOG Performance Status 0 to 2.
4.
 
5. Adequate hepatic function (unless deemed to be related to underlying leukemia)
a.
b.
x ULN
c.
6.
Cockcroft-Gault equation. 
7. In the absence of rapidly proliferative disease, the interval from prior leukemia-directed 
therapy to time of study initiation will be at least 7 days for cytotoxic or non-cytotoxic 
(immunotherapy) agents. Hydrea is allowed up to 48 hours prior to the first dose for 
patients with rapidly proliferative disease.  
8. The effects of brequinar on the developing human fetus are unknown.  For this reason, 
women of child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry and for the 
duration of study participation.  Should a woman become pregnant or suspect she is 
pregnant while she or her partner is participating in this study, she should inform her 
treating physician immediately.  Men treated or enrolled on this protocol must also agree 
to use adequate contraception prior to the study, for the duration of study participation, and 
for 90 days after completion of brequinar administration. 
9. Male subjects must agree to refrain from sperm donation from initial study drug 
administration until 90 days after the last dose of study drug. 
6.3 Exclusion Criteria
1. Patients in need of immediate leukapheresis are excluded. 
2. White blood count > 25 x 109/L (note: hydroxyurea is permitted to meet this criterion).


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3. Any concurrent uncontrolled clinically significant medical condition, laboratory 
abnormality, or psychiatric illness that could place the participant at unacceptable risk of 
study treatment.
4. Pre-existing liver disease. 
5.
branch block and prolonged QTc interval may be eligible after discussion with the medical 
monitor. 
6. The use of other chemotherapeutic agents or anti-leukemic agents is not permitted during 
study with the following exceptions: 
a.
Intrathecal chemotherapy for prophylactic use or maintenance of controlled CNS 
leukemia. 
b. Use of hydroxyurea for the purpose of leukemic cytoreduction may be allowed 
during the first 2 weeks of therapy if in the best interest of the participant and is 
approved by the medical monitor. Hydroxyurea can be used to treat leukocytosis 
if concurrent with and thought to be associated with presumed differentiation 
syndrome.  
7. AML relapse less than 6 months following stem cell transplantation.  
8.
0.5mg/kg/day of prednisone or therapy beyond systemic corticosteroids (e.g. cyclosporine 
or other calcineurin inhibitors or other immunosuppressive agents used for GVHD).
9. Active cerebrospinal involvement of AML.
10. Diagnosis of acute promyelocytic leukemia (APL).
11. Clinically active hepatitis B (HBV) or hepatitis C (HCV) infection. 
12. Severe gastrointestinal or metabolic condition that could interfere with the absorption of 
oral study medication. 
13. Prior malignancy, unless it has not been active or has remained stable for at least 3 years. 
Participants with treated non-melanoma skin cancer, in situ carcinoma or cervical 
intraepithelial neoplasia, regardless of the disease-free duration, are eligible if definitive 
treatment for the condition has been completed. Participants with organ-confined prostate 
cancer with no evidence of recurrent or progressive disease are eligible if at the active 
surveillance stage, if hormonal therapy has been initiated or the malignancy has been 
surgically removed or treated with definitive radiotherapy. 
14. Nursing women or women of childbearing potential (WOCBP) with a positive urine 
pregnancy test. 
6.4 Inclusion of Women and Minorities
Both men and women of all races and ethnic groups are eligible for this trial. 
 


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7
STUDY TREATMENTS
Subjects will self-administer oral brequinar twice weekly (approximately every 84 hours). 
Treatment cycles will be 2 weeks. Dose adjustment is to occur as outlined below. Visits will take 
place at least every 2 weeks through 3 months. More frequent visits are permitted to assess and/or 
treat adverse events. Less frequent visits (up to 4-week intervals) are permitted after 3 months 
depending on subject safety/tolerability and response. Cohort 1 will begin at 500 mg/m2 twice 
weekly. Subjects in Cohort 1 may not escalate above the initial 500 mg/m2 starting dose, but the 
intra-subject dose may be reduced if unacceptable safety occurs. Subsequent cohorts will have a 
starting dose that may be adjusted based on the safety/tolerability (Section 7.3.1, Section 7.3.2) 
and DHO levels of the previous cohort. The dosing for individual subjects may be adjusted based 
on the safety/tolerability and DHO levels as shown in Section 7.5. 
7.1 Description of Brequinar:
Brequinar will be supplied as 100 and 250 mg capsules. Dosing will be determined on a mg/m2
basis based on the starting dose of a subject’s cohort and the tolerability, safety and DHO level
assessed following each dose. Brequinar capsules should be taken whole; they should not be 
crushed or chewed. If the participant forgets to take the daily dose, he/she should make up the dose 
within 8 hours after the missed dose. If more than 8 hours have elapsed or if the dose was vomited
or if the subject for any reason is unable to take the scheduled dose within 8 hours, omit that dose, 
and the subject should resume treatment with the next scheduled dose. Any medication remaining 
from extra supplies or missed doses should not be taken beyond the last scheduled day of brequinar 
administration but should be documented in the subject diary and returned by the participant for 
drug accountability purposes.  
7.2 Treatment Administration
Subjects will take oral brequinar twice weekly (approximately every 3.5 days) e.g., Monday 
morning and Thursday evening. Each dose is to be taken with approximately 240 mL of water. 
The subject does not need to be fasting. The chosen dosing schedule needs to accommodate clinic 
visits as well as shipping and receipt of the brequinar brequinar/DHO samples. Sample processing 
and shipping procedures will be addressed in a separate laboratory manual. 
7.3 Safety/Tolerability
Safety/tolerability is assessed for each subject at each study visit using the Common Terminology 
Criteria for Adverse Events v4.0 (CTCAE). After completion of Cohort 1 (which will have a fixed 
starting dose of 500 mg/m2 with no dose escalation permitted), safety/tolerability will be used to 
determine both cohort starting doses for subsequent cohorts and individual dosing adjustments. 
Safety at the subject level is defined in Section 7.3.1; hematologic toxicity is defined in Section 
7.3.1.1; and safety at the cohort level is defined in Section 7.4.
7.3.1
Safety/Tolerability – Subject Level
Acceptable safety/tolerability for a subject through Day 42 is defined as no  Grade 3, treatment-
emergent, study-drug-related, non-hematologic adverse events. Due to the expected hematologic 
profile associated with AML, hematologic AEs of any grade will not be considered dose-limiting 


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during the first 42 days of dosing. Exceptions to the non-hematologic Grade 3 criterion are 
provided in Table 1. 
Table 1.
Exceptions to Grade 3 Nonhematologic AEs 
Condition
Exception Description 
Nausea/ 
Emesis 
week after the use of an optimal antiemetic regimen based on standard 
practice.
Diarrhea 
Grade 
receiving the maximal supportive therapy based on standard practice.
Fatigue
Grade 3 fatigue lasting less than 1 week.
Laboratory 
abnormalities
Asymptomatic Grade 3 laboratory abnormalities that are not considered to 
be clinically significant.
For the expansion cohort, the definition of unacceptable safety is expanded to include signs of 
resuming dosing, dosing is to be discontinued for that subject. 
7.3.1.1
Hematologic Toxicity
After the subject has completed the first 42 days of treatment, the definition of unacceptable safety 
expands to include hematologic AEs defined as prolonged neutropenia with ANC < 500 from the 
start of therapy in the absence of disease,
 and/or
thrombocytopenia, with a hypocellular bone marrow and no greater than 5% marrow blasts lasting 
for 2 weeks or more. Anemia will not be considered a hematologic AE for the definition of 
unacceptable safety. Febrile neutropenia is also excluded from the DLT definition for this 
population. For clinic visits when bone marrow sampling is scheduled, the timing of the bone 
marrow sampling can be adjusted to ensure that the results are available at the time of the clinic 
visit. 
7.3.2
Safety/Tolerability – Cohort Level
Acceptable safety/tolerability at the cohort level is defined below: 
a)
dose reduction or treatment discontinuation (a dose limiting toxicity or DLT), then that 
dose is considered to have unacceptable safety/tolerability and the previous dose which 
was safe/tolerated must be considered as the highest safe/tolerated dose. 
b) If 1 out of 3 subjects at a dose level experiences a DLT, then 3 additional subjects will be 
added to the cohort and treated at the same dose that led to the DLT. I


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6 subjects has a DLT at that dose, then this dose is considered a safe/tolerated dose. 
However, if >2 out of 6 subjects at a dose level experience a DLT, then that dose is 
considered to have unacceptable safety/tolerability and the previous dose which was 
safe/tolerated must be considered as the highest safe/tolerated dose. 
7.3.3
Safety/Tolerability – Expansion Cohort
The safety and tolerability of the starting dose for the Expansion Cohort will have been determined 
during the Cohort Level adjustments defined in the preceding section. If >1 of the first 5 subjects 
in the Expansion Cohort cannot tolerate this starting dose based on the rules for safety and 
tolerability at the subject level (Section 7.3.1), the starting dose for the next 5 subjects in this cohort
will be reduced by 75 mg/m2. If >1 of the second 5 subjects cannot tolerate the reduced starting 
dose, the starting dose will be again reduced by 75 mg/m2 for the final 5 subjects planned for this 
cohort. All of these subjects are eligible for intra-subject dose adjustment and will follow the same 
individual subject safety rules for either stopping dosing or dose adjustment as presented in Section 
7.3.1 and Section 7.5. 
7.4 Cohort Starting Doses
Cohort 1 will treat 6 subjects at 500 mg/m2 twice weekly. No dose escalation is permitted for 
Cohort 1 subjects, but the dose may be reduced for an individual subject in this cohort if the subject 
experiences unacceptable safety.   
After all subjects in Cohort 1 have completed a 42-day treatment period, up to two additional 
cohort(s) of 3 subjects each will be added with the starting doses adjusted (escalated or de-
escalated) based on both safety/tolerability and adequacy of DHO level results in Cohort 1. As 
noted in Section 7.3.2, additional subjects may be added to Cohorts 2 and 3 to further explore 
safety, if needed. 
If all subjects in a cohort have acceptable safety at a dose level, the next cohort’s starting dose may 
be escalated by 150 mg/m2. If the safety rules are not met at a cohort’s starting dose, the next 
cohort’s starting dose will be reduced to the highest dose found to be safe/tolerated in the previous 
cohort. The planned upper limit for cohort starting dose is 800 mg/m2. There is no lower limit.
See the “Intra-subject dose adjustment” section for individual subject dosing adjustment criteria. 
7.5 Individual Dose Adjustment Guidelines
With the exception of subjects in Cohort 1 whose dose may not be escalated above the 500 mg/m2
starting dose, intra-subject dose adjustment will be considered every 2 weeks depending on safety 
and DHO levels. There is a maximum of 2 dose adjustments for each subject within the first 42 
days of initiating treatment. Each subject’s dose can be adjusted from the starting dose by being 
escalated, maintained (stable dose), held then reduced, or discontinued (except in Cohort 1 where 
subjects’ doses may not be escalated beyond the 500 mg/m2 starting dose). The highest dose 
planned is 800 mg/m2, however, this upper limit may be adjusted depending on safety, DHO level, 
and clinical response. There is no lower limit planned. As noted above, safety will be a key part of 
determining dose adjustments. Subjects who resume dosing at a lower dose after experiencing 


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unacceptable safety may not undergo later dose escalations beyond the dose where the 
unacceptable safety occurred. 
Each subject will continue dosing twice weekly at the individually adjusted dose for up to 12 
months in the absence of unacceptable toxicity or disease progression. Intra-subject dose 
adjustment is permitted at any time throughout the study based on safety/tolerability and DHO 
levels (except in Cohort 1). Subjects who discontinue due to unacceptable safety/tolerability or die 
prior to Day 42 will not be replaced.  
Intra-subject dose adjustment increments and duration of dosing may be revised from planned 
amounts after each preceding cohort’s safety, DHO plasma levels, and bone marrow results have 
been reviewed. 
7.5.1
DHO Threshold
Each subject’s baseline DHO sample will be obtained at C1D1 prior to dosing. Dose adjustment 
decisions based on DHO will be determined by DHO trough level (i.e., DHO level obtained pre-
dose D8 of the previous cycle). The initial target for “adequate” trough DHO level will be set at 
100 ng/mL. This target may be adjusted during the study depending on safety or efficacy signals 
observed during the study. As described below, dose adjustments are also based on safety and 
whether the dose has reached the planned upper limit (currently planned to be 800 mg/m2). 
Table 2 and Figure 1 present the intra-subject dose-adjustment criteria. Note that there is no dose 
escalation in Cohort 1. 
Table 2. 
Intra-Subject Dose Adjustment* 
Acceptable Safety/Tolerability?
(see safety definition above)
Adequate 
DHO Level?
Planned Intra-Subject Dose Adjustment
Yes
Yes 
Maintain; continue at same dose. 
Yes
No
Escalate by 150 mg/m2 for the next 2-week cycle up to a 
maximum of 800 mg/m2. 
No 
Regardless of 
DHO  
Hold two doses (one week), then reassess AE; if AE has 
-escalate dose by 75 mg/m2 and resume 
dosing. If AE has not resolved, reassess again in one week.  
held, discontinue further dosing. Subject will remain in the 
study for safety follow up for 42 days after last dose of study 
drug or until AEs have resolved or become stable.
* Subjects in Cohort 1 may not escalate above the initial 500 mg/m2 starting dose and may have dose reductions 
based on safety only. 


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Figure 1.
Dose Adjustment – Subject Level


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7.6 Medication/AE Diary
The participant will be provided with a study calendar of events and will be required to maintain 
a medication diary of each dose of medication. Subjects will be instructed to record the date and 
time each dose of brequinar is taken, indicating if any doses are missed. Subjects will be instructed 
to record adverse events and changes in concomitant medications in the subject calendars/diaries. 
Subjects will be instructed and reminded to bring the medication diary to each clinic visit for 
review. The diary will be returned to clinic staff at the end of each cycle and a new diary dispensed.
7.7 Bone Marrow Biopsy
The participant will have a bone marrow sampling (aspiration and core biopsy) at baseline (prior 
to dosing), one for research purposes at the C2D8 visit ± 7 days, and one at Day 43 ± 7 days; 
thereafter, bone marrow sampling will be every 12 weeks and at the Final Visit. If a participant 
develops frank evidence of progression of AML during the course of treatment based on laboratory 
or clinical assessment, then he/she will be discontinued from study treatment and can proceed with 
additional management off-study per discretion of the treating oncologist. If the results of the bone 
marrow sampling reveal disease progression at the Day 43 visit, then the participant will be taken 
off treatment. Timing of the bone marrow biopsy procedure may be adjusted to ensure that results 
are available for the Day 43 visit. Bone marrow sampling will include analysis of the aspirate on 
smear, core biopsy by microscopy, flow cytometry, and karyotype for cytogenetics. Molecular 
analysis will be performed on the screening bone marrow samples. 
7.8 Flow Cytometry
Peripheral blood samples are to be obtained for flow cytometry in Cycle 1 at baseline (Day 1 pre-
dose), Day 2, and Day 3 
7.9 Expansion Cohort
Once a dose has been reached that has adequate DHO level (as mentioned above, “adequate” 
trough DHO may be adjusted after reviewing DHO level, safety and clinical response data), and 
acceptable safety/tolerability, approximately 15 subjects will be added starting at the highest 
safe/tolerated dose identified in the earlier cohorts. Decisions regarding adequacy of DHO 
threshold level will be made following review of these data from each cohort. These subjects are 
eligible for intra-subject dose adjustment (see Section 7.3.1 and Section 7.5). 
The expansion cohort will follow the same visit procedures as the Maintenance Dose cohort and 
visit frequency may vary from 2 to 4 weeks.  
7.10 Study Drug Discontinuation
If there is evidence of stable disease, partial response, or complete remission (CR, CRi, or CRh), 
the participant may continue with brequinar treatment until there is evidence of disease 
progression, intolerable toxicity, or for a maximum of one year. Study drug will be discontinued 
if there is evidence of unacceptable safety/tolerability that does not resolve within 2 weeks after 
stopping brequinar dosing.  


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After treatment discontinuation, participants will be monitored for a minimum of 30 days after the 
last dose of brequinar or until they receive another treatment for their AML. Participants may 
discontinue treatment to receive a stem cell transplantation upon remission, if indicated. 
The reason for study drug discontinuation will be recorded in the source document and the eCRF.  
7.11 Brequinar Pharmacokinetics (PK) / Dihydroorotate (DHO) Plasma Levels
Plasma samples for brequinar/DHO levels are to be obtained for each subject for the subject’s first 
study dose (Cycle 1 Dose 1 for that subject). Sample scheduling is baseline at 0 hours (prior to 
dosing), and post dose at 1, 2, 4, 6, 24, 48, and 72 hours. Note that this schedule does not apply to 
Cycle 1 for subjects in the expansion cohort, see below. 
A brequinar/DHO trough sample is to be obtained prior to dosing on Day 8 (C84h, 84 hours after 
the Cycle 1 Day 4 dose) of Cycle 1, and prior to dosing on Days 1 and 8 of Cycles 2 and 3. 
The 84-hour brequinar/DHO sample is to be repeated prior to dosing at the beginning of each 2-
week cycle and at the Final Visit. This sampling schedule also applies for the expansion cohort 
subjects. 
Directions regarding sample processing are presented in a separate laboratory manual.
7.12 Concomitant Medication/Treatment
The name, start date (if known), indication for use and whether ongoing or stopped for
medications/treatments taken within two weeks prior to study entry as well as any medications 
taken during the study are to be recorded. The use of other chemotherapeutic agents or anti-
leukemic agents is not permitted during study with the following exceptions: 

Intrathecal chemotherapy for prophylactic use or maintenance of controlled CNS leukemia; 

Use of hydroxyurea for the purpose of leukemic cytoreduction may be allowed during the 
first 2 weeks of therapy if in the best interest of the participant and is approved by the 
medical monitor. Hydroxyurea can be used to treat leukocytosis if concurrent with and 
thought to be associated with presumed differentiation syndrome.  
7.12.1 Gastric pH
Whenever possible, participants should discontinue proton pump inhibitors, antacids, and H2-
receptor antagonists which increase the gastric pH and may reduce absorption of oral medications 
including brequinar resulting in decreased systemic exposure. Discontinuation of these 
medications is not required but is strongly recommended. 
7.13 Treatment Compliance
Compliance will be assessed by reviewing the subject’s medication diary and accounting of 
returned clinical supplies. 


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7.14 Storage, Stability, Labeling and Packaging
7.14.1 Storage and Stability
The study drug is stored at room temperature. Stability testing is ongoing. 
7.14.2 Labeling and Packaging 
Each bottle for subject use will be labeled with at least the following information: 
For Clinical Trial Use Only
Study Number: 
CCB-01
Contents: 100 or 250 mg capsules 
For oral use only. Take with approximately 8 ounces water every 3.5 days. 
Subject Number: XX-XXXX
Treatment Duration: As directed
IND: 138355             Clinical Batch Number: XXXXXXX
Expiration Date: 
TBD 
Storage: Store at controlled room temperature  
Study Sponsor:  Clear Creek Bio, Inc., 585 Massachusetts Avenue, 4th 
Floor, Cambridge MA 02139 
Caution: New Drug – Limited by US Federal Law to Investigational Use
Only. To be used by Qualified Investigators only.
7.14.3 Blinding and Randomization
The trial will be conducted in an open-label manner. The brequinar capsules will be provided to 
each participating institution. No randomization codes are necessary for this open-label study.
7.14.4 Unblinding/Expectedness
It is not necessary to break the blind for this open label study as the treatment is known for each 
subject. 
Expectedness will be determined by establishing whether the adverse event is among those 
identified in the Investigator’s Brochure.   
7.14.5 Study Drug Accountability
The study drug provided is for use only as directed in this protocol. 
The Investigator must keep a record of all study medication received, used and discarded.  It must 
be clear from the records which subject received which medication. Adequate drug is to be 
dispensed for each dosing period to allow for dosing every 3.5 days during the period until the 


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next clinic visit, plus one additional dose to act as a spare in the event medication is unable to be 
used.
The pharmacist/staff member responsible for drug accountability is to document the date and time 
of dispensing and for what subject the study drug was intended (i.e., record subject initials and 
birth date or other unique identifier). A pharmacy manual will be provided by the Sponsor detailing 
how to calculate the mg/m2 dose together with examples of combinations of the 100 and 250 mg 
capsules to provide the most efficient use of the clinical supplies.
At the end of the study, any unused study drug will be returned to the Sponsor for destruction or 
destroyed locally; disposition of study drug will be documented.   
The Sponsor will be permitted access to the trial supplies at any time within usual business hours 
and with appropriate notice during or after completion of the study to perform drug accountability 
reconciliation.


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8
CONDUCT OF THE TRIAL
8.1 Ethical and Regulatory Considerations
The trial will be performed in accordance with the Declaration of Helsinki (1964) (Appendix F) 
as revised in Tokyo (1975), Venice (1983), Hong Kong (1989), South Africa (1996), Scotland 
(2000, Note of Clarification 2002 & 2004) and Seoul 2008 (Appendix A), and Fortaleza (Brazil) 
(2013), and with the ICH Tripartite Guideline on Good Clinical Practice (CPMP/ICH/135/95, 
Jan.97) and US FDA Regulations. 
8.2 Informed Consent
The principles of informed consent in the current edition of the Declaration of Helsinki must be 
implemented in each clinical study before protocol-specified procedures are carried out.  Informed 
consent must be obtained in accordance with US Code of Federal Regulations (21 CFR Part 50) 
as well as local and national regulations. Information should be given in both oral and written form 
whenever possible and deemed appropriate by the Institutional Review Board (IRB). Subjects and 
their relatives, if necessary, must be given ample opportunity to inquire about details of the study. 
The Investigator or qualified designated person will verbally inform subjects as to the nature, 
expected duration and purpose of the trial, the administration of the Investigational Medicinal 
Product (IMP), and the hazards involved, as well as the potential benefits that may come from 
treatment with this IMP. The trial procedures will be explained in lay language and any questions 
will be answered. The subjects will be given an IRB-approved consent form. The subjects will be 
given appropriate time to consider their participation in the trial and have any questions answered 
prior to signing the consent form. If a subject agrees to participate, he/she will sign and date an 
informed consent form and be provided with a copy of the signed consent. All subjects who sign 
an informed consent form are to be recorded on the applicable screening log.   
The subject will be informed that his/her medical records will be subject to review by the Sponsor, 
Sponsor’s representatives, and possibly by a representative of the Food and Drug Administration 
and other relevant regulatory authorities. Subjects will be informed that they are free to refuse 
participation in this clinical investigation, and if they should participate, it will be made clear to 
them that they may withdraw from the trial at any time without prejudicing further medical care
they may require. The subject will receive a copy of the consent form as well as an information 
sheet about the trial.  
Signed written informed consent must be obtained from every subject prior to any study-specific 
procedures.  Standard procedures carried out prior to signing the informed consent but within the 
time constraints of the protocol may be used for baseline evaluation; they need not be repeated. 
An original signed informed consent form will be filed in the Investigator Site File and will be 
subject to review by the Sponsor; a copy will be given to the subject and a copy will be filed with
the subject’s medical notes.
The study should be discussed with the potential participant only after an initial review of his/her 
clinical status and appropriateness for participation have been evaluated to determine if he/she
meets the subject selection criteria.


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A sample subject information sheet and consent form is attached to this protocol as Appendix E.
The final version at each institution may differ depending on institutional requirements and 
standard formats. This protocol will not be amended for site specific changes to the sample.
8.3 Institutional Review Board / Ethics Committees
It is the responsibility of the Investigator to submit the protocol, consent form and information 
sheet to the IRB. An Investigator’s brochure will be available for review by the IRB. The protocol 
and consent form must be approved by the IRB prior to the recruitment of the first subject. The 
template consent form may be revised in accordance with site-specific requirements with Sponsor 
review and approval. A copy of the IRB written approval must be provided to the Sponsor and 
investigator before the trial may start at that institution. Written approval from the IRB is also 
required for substantial protocol amendments prior to their implementation.    
A substantial amendment may arise from changes to the protocol or from new information relating 
to the scientific documents in support of the trial.  Amendments are “substantial” when they are 
likely to have an impact on:

the safety or physical or mental integrity of the subjects; 

the scientific value of the trial; 

the conduct or management of the trial; or

the quality or safety of any IMP used in the trial. 
If it is necessary to change or deviate from the protocol to eliminate an immediate hazard to the 
subjects, the Investigator will notify the Sponsor and the IRB of the new events and the measures 
taken as soon as possible.   
The Investigator will report promptly to the Sponsor and IRB any new information that may 
adversely affect the safety of the subjects or the conduct of the trial. On completion of the trial, the 
Investigator will inform the applicable IRB as per local IRB requirements that the trial has ended. 
If the study is terminated for any reason, the investigator will return all clinical supplies and study-
related equipment supplied by the Sponsor to the Sponsor unless otherwise specified. 
8.4 Schedule of Events
Physical examinations, vital signs, ECG, laboratory assessments, bone marrow sampling and other 
observations will be undertaken by experienced personnel throughout the study based on the 
Schedule of Events. Standard chromosomal and mutational testing will be performed per 
institutional guidelines.
See 14.1 Schedule of Events in Appendix A for the full list of study assessments and timings.
Blood chemistry tests include: blood urea nitrogen (BUN), creatinine, alkaline phosphatase (ALP), 
alanine amino transferase (ALT), aspartate amino transferase (AST), bilirubin, total protein, 
albumin, glucose, serum electrolytes (sodium, potassium, chloride, carbon dioxide/bicarbonate, 
and calcium). 


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Hematology tests include: hemoglobin, hematocrit, complete blood count with differential and 
platelet count. 
In addition to the already scheduled weekly chemistry assessment during Cycles 1 and 2 for each 
subject, subjects taking potentially hepatotoxic drugs are permitted to have more frequent 
monitoring than indicated in the schedule of events, if ordered by the study team. 
8.5 Study Conduct
8.5.1
Screening Visit (Study Days -14 to -1)
These procedures must be completed within the 14 days prior to starting dosing. Obtain the 
subject’s written informed consent, then collect baseline information:
-
Demographics (height, weight, date of birth, gender, race, ethnicity).
-
Pertinent medical/surgical history (including AML diagnosis and laboratory and clinical 
evidence of progression, previous AML treatment, and any available chromosomal and 
mutational testing results per institutional guidelines) and concomitant medications.
-
Physical examination (including weight). 
-
Vital signs (heart rate, respiratory rate, seated blood pressure, body temperature).  
-
Pregnancy test for women of childbearing potential (WOCBP).  
-
ECOG performance assessment.  
-
Hematology/chemistry. 
-
12-lead ECG with QTcF and MUGA scan or echocardiogram to assess cardiac function.  
-
Bone marrow sampling. 
-
Confirm subject meets all inclusion and no exclusion criteria. 
Treatment
The treatment period begins with Cycle 1, Day 1 of the first 2-week dosing cycle. 
8.5.2
Cycle 1
Cycle 1 Day 1:
-
Collect any adverse events or new concomitant medications since Screening.  
-
Draw samples for baseline (pre-dose) brequinar/DHO, flow cytometry, and 
hematology/chemistry.  
-
Conduct physical examination (including weight), vital signs, urine pregnancy test for 
WOCBP, and 12-lead ECG.  
-
Review results and confirm subject remains eligible for the study.  
-
Determine subject’s starting dose based on the respective cohort mg/m2 starting dose.
-
Dispense study medication.  
-
Subject is to take the first dose at the clinic and remain for brequinar/DHO sampling. Collect 
brequinar/DHO samples at 1, 2, 4, and 6 hours post dose. 
-
Process and store brequinar/DHO samples per the supplied laboratory manual. 
-
Dispense the subject’s calendar/diary. The diary will collect dates/times of study medication 
administration and AEs/new concomitant medications.  
-
Enroll subject for text message reminders if the subject consents to that service.  


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-
Ship the flow cytometry sample per the supplied laboratory manual.
Cycle 1 Day 2: 
-
Collect 24h post dose brequinar/DHO and flow cytometry samples. Check the diary/elicit 
information about AEs/new concomitant medications since the last visit. 
-
Process and store brequinar/DHO samples per the supplied laboratory manual. 
-
Ship the flow cytometry sample per the supplied laboratory manual 
Cycle 1 Day 3:  
-
Collect 48h post dose brequinar/DHO and flow cytometry samples. Check the diary/elicit 
information about AEs/new concomitant medications since the last visit.  
-
Process and store brequinar/DHO samples per the supplied laboratory manual. 
-
Ship the flow cytometry sample per the supplied laboratory manual. 
Cycle 1 Day 4:  
-
Collect 72h post dose brequinar/DHO samples. Check the diary/elicit information about 
AEs/new concomitant medications since the last visit. 
-
Process and store brequinar/DHO samples per the supplied laboratory manual. 
Cycle 1 Day 8:  
-
Vital signs. 
-
Check the diary/elicit information about AEs/new concomitant medications since the last 
visit. 
-
Prior to the morning dose, collect brequinar/DHO samples (approximately 84h post the 
second dose of Cycle 1) and hematology/chemistry samples, then have subject take study 
medication.  
-
Process and store brequinar/DHO samples per the supplied laboratory manual. 
-
Notify DHO assay laboratory of incoming shipment and ship Cycle 1 brequinar/DHO 
samples (samples from Days 1, 2, 3, 4 and 8). 
8.5.3
Cycle 2 (and any Dose Adjustment Cycle)
Repeat this visit as needed when dose adjustment is ongoing. 
Day 1:   
-
Collect unused study medication and check the diary/elicit information about AEs/new 
concomitant medications since the last visit.  
-
Take vital signs and perform physical examination (including weight). 
-
Collect pre-dose brequinar/DHO samples (approximately 84h post the fourth dose of the 
previous cycle) and hematology/chemistry samples.  
-
Process and store brequinar/DHO samples per the supplied laboratory manual. 
-
Review laboratory results/safety information and determine whether the subject should 
adjust the dose (based on acceptable safety and DHO level), continue with the current dose 
or hold study medication (unacceptable safety) per the guidelines below.  
-
If dosing will continue, dispense study medication.  
-
Dispense calendar/diary. 


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-
Manage text message reminders as needed (as a default do nothing, pause if study 
medication is put on hold, and restart if study medication is restarted)
Day 8:  
-
Collect and check the diary/elicit information about AEs/new concomitant medications 
since the last visit. 
-
Vital signs. 
-
Collect pre-dose brequinar/DHO and hematology/chemistry samples. 
-
Perform bone marrow sampling (window ±7 days). 
-
If the subject is being dosed (i.e., has acceptable safety), have the subject take the morning 
dose.  
-
If the subject’s medication was held, review safety information and determine whether 
dosing can resume. If dosing can resume, determine dose, dispense adequate medication for 
4 doses and have the subject take the morning dose.  
-
Process and store brequinar/DHO samples per the supplied laboratory manual. 
-
Continue to withhold study drug if safety remains unacceptable. 
-
Dispense calendar/diary.
-
Manage text message reminders as needed (as a default do nothing, pause if study 
medication is put on hold, and restart if study medication is restarted)
-
Notify DHO assay laboratory of incoming shipment and ship brequinar/DHO samples 
(samples from current cycle's Days 1 and 8). 
 
Subjects may undergo dose adjustments at any time using the guidelines presented above. Subjects 
with acceptable safety can continue to escalate every 2 weeks by 150 mg/m2 increments through 
800 mg/m2. Subjects with unacceptable safety can continue to undergo dose reductions of 75 
mg/m2 with no lower limit. Re-escalation to a dose previously shown as not tolerated for an 
individual subject is not permitted for these subjects.
Dose adjustments are permitted throughout the study for an individual subject based on safety, 
DHO level, and clinical response with an upper limit of 800 mg/m2. This upper limit may be 
adjusted depending on safety/tolerability/DHO/brequinar PK or other factors during the study.
8.5.4
Maintenance Dose Cycle (visit every 2 - 4 weeks)
Once a subject reaches a stable or maintenance dose (see Figure 1), the subject will be in the 
Maintenance Dose Cycle.  
In the first 3 months from starting study drug, the Maintenance Dose Cycle procedures will occur 
every 2 weeks (with the exception of bone marrow sampling as discussed below). After completing 
3 months from starting study drug, subjects may come to the clinic for a Maintenance Dose Cycle 
visit every 2 - 4 weeks per the investigator’s discretion.
A subject may still move into a Dose Adjustment Cycle after a maintenance dose if required for 
a change in safety, DHO level or clinical response. 


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Day 1:
-
Collect unused study medication and check the diary/elicit information about AEs/new 
concomitant medications since the last visit.
-
Collect pre-dose brequinar/DHO and hematology/chemistry samples. 
-
Conduct physical examination vital signs, urine pregnancy test for WOCBP, 12-lead ECG 
and bone marrow sampling (note that bone marrow is collected at the C2D8 visit (window 
±7 days), at Day 43, then every 12 weeks; the Day 43 sample will be assessed for 
hematological toxicity). 
-
Review the laboratory results/safety information and determine whether the subject should 
maintain current dose (acceptable safety) or hold study medication (unacceptable safety).  
-
Dispense study medication. 
-
Dispense calendar/diary.  
-
Manage text message reminders as needed (as a default do nothing, pause if study 
medication is put on hold, and restart if study medication is restarted) 
-
Notify DHO assay laboratory of incoming shipment and ship brequinar/DHO samples. 
8.5.5
Final Visit
This visit is to take place when a subject is discontinuing from the study. 
-
Collect and check the diary/elicit information about AEs/new concomitant medications 
since the last visit.  
-
Collect brequinar/DHO and hematology/chemistry samples.  
-
Collect unused study medication. 
-
Conduct physical examination, vital signs, urine pregnancy test for WOCBP, 12-lead ECG 
and bone marrow sampling (do not collect bone marrow if < 4 weeks since previous bone 
marrow sample obtained).  
-
Review the safety information and determine whether the subject has acceptable safety or 
unacceptable safety.  
-
Notify DHO assay laboratory of incoming shipment and ship brequinar/DHO samples.  
-
Stop text message reminders. 
8.5.6
Follow Up Visit (2 weeks after Final Visit)
-
Contact subject to elicit information about AEs/new concomitant medications since the last 
visit. Survival information will be collected while the study is ongoing. 
8.5.7
Unscheduled Visits
Unscheduled visits and tests to assess AEs are permitted as needed providing the AE onset occurs 
within four (4) weeks after the final dose. 


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8.6 Compliance with Study Procedures
The time at which study procedures are conducted should follow the protocol timelines as closely 
as possible.  However, it is recognized in a clinical setting that protocol-specified timings may not 
occur exactly as specified in the protocol. Provided that activities are carried out within the 
identified window, it will not be necessary to file a protocol violation.   
8.7 Early Withdrawal from the Study 
A subject may withdraw from the study at any time for any reason or for one of the reasons listed 
below. The Sponsor or Investigator may also terminate a subject’s study participation after 
discussion with the other party if it is believed it would be unsafe for the subject to continue in the 
study.    
Subjects must be withdrawn from the study if any of the following events occur: 

Significant protocol violation or non-compliance, either on the part of the subject or the 
investigator or other site personnel; 

Decision of the Investigator or Sponsor that removal is in the subject's best interest; 

Severe unrelated medical illness or complication; 

Safety reasons/ significant adverse event; 

Subject request (withdrawal of consent); 

Sponsor decision. 
Collect/conduct all evaluations for subjects who withdraw from the study prior to completing the 
treatment period, unless consent is withdrawn.     
8.8 Early Termination of the Study
If the Sponsor or an Investigator believes it would be unsafe to continue the study, or for any 
reason at the Sponsor’s request, the study may be terminated at that site or the entire study 
terminated after discussion with the other parties. 
The Sponsor will provide a written statement to the IRB and the relevant regulatory authority with 
the reasons for termination of the study. This will be conducted within 15 days of the decision to 
terminate the study.  
If the study is terminated, a close out monitoring visit will be performed and applicable procedures 
will be carried out to close the trial site(s). 
8.9 Short Messaging Service (SMS) Medication Reminders
The Health Insurance Portability and Accountability Act of 1996 (HIPAA) was enacted in part to 
protect the security and privacy of protected health information (PHI). Covered entities (e.g., 
health care providers engaged in certain electronic transactions, health plans, and health care 
clearinghouses) that create, maintain, transmit, use, and disclose an individual’s PHI are required 
to meet HIPAA requirements. 


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HIPAA’s Privacy Rule restricts uses and disclosures of PHI, creates individual rights with respect 
to their PHI, and mandates administrative requirements. Among other requirements, the privacy 
rule requires a covered entity to reasonably safeguard PHI from any intentional or unintentional 
use or disclosure that is in violation of the requirements of HIPAA. 
HIPAA’s Security Rule requires covered entities to ensure confidentiality, integrity, and 
availability of its electronic PHI, to protect against reasonably anticipated threats or hazards to the 
security or integrity of its electronic PHI, to protect against reasonably anticipated impermissible 
uses and disclosure of its electronic PHI, and to ensure compliance by their workforce. 
Additionally, the Security Rule requires covered entities to put in place detailed administrative, 
physical, and technical safeguards to protect electronic PHI. To do this, covered entities are 
required to implement access controls and set up backup and audit controls for electronic PHI in a 
manner commensurate with the associated risk. 
For protocol CCB-01, the Sponsor intends to utilize a third-party vendor with a HIPAA-compliant 
platform to send one-way text message reminders to study participants who have a mobile device. 
The SMS/text message will be sent on the days and times he or she is to take his or her study 
medication, e.g., Monday mornings and Thursday evenings. The exact timings of the reminders 
will be customized for each study participant. The PHI the third-party vendor receives will be 
restricted to the participant’s mobile device number and study identification number. The study 
participant is not to reply to the text message except to "opt out" from the service by sending 
"STOP" in the message body. In any other case if he/she sends a text message, the texting service 
will reply with a message indicating that messages sent by participants are not being monitored. 
Study participants must agree to “opt in” for this service and can "opt out" at any time even if they 
initially agreed. Study participants will need to sign an addendum to the informed consent 
document documenting their decision prior to enrollment in the system (see Appendix 14.5).   
The third-party vendor will sign an agreement with the Sponsor to use participant data only for the 
purposes of this study. Data will be purged from the vendor's servers at the conclusion of the trial 
upon written request by the Sponsor. Data will remain in the vendor's encrypted back-up files that 
will be maintained per HIPAA-compliant standards. 
 


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9
ADVERSE EVENT REPORTING
An adverse event is any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal relationship with 
this treatment.  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of the 
medicinal product, whether or not considered related to the medicinal product.
Events that occur prior to dosing will be entered as medical history; AEs that occur after dosing 
will be entered on the AE form. 
Subjects will be questioned and observed for evidence of AEs, whether or not related to study 
drug. All AEs will be documented in the subject's medical record and CRF.  For any pre-existing 
condition or abnormal laboratory finding that changes in severity after dosing, this change should 
be recorded as an AE. New abnormal laboratory findings that are clinically significant are 
considered AEs. 
AEs will be collected beginning from the time of informed consent through at least 14 days after 
the final dose of study medication. AEs will be specified as pre-treatment or treatment-emergent. 
AE details are to be documented including start and stop date and times, whether continuous or 
intermittent, severity, any intervention utilized to correct the event (e.g., medication, surgery or 
other therapy), outcome and the relationship to the study drug.   
AEs identified in the protocol as critical to the evaluation of safety must be reported to the Sponsor 
by the Investigator according to the reporting requirements within the time periods specified in the 
protocol. 
AEs determined by the Investigator to be related to study drug must be followed until resolution 
or until they are considered stable or for at least 30 days after discontinuation of study drug, or 
until new treatment for AML is initiated, whichever occurs first.   
Any SAEs experienced after 30 days post the last dose of study drug should only be reported to 
the sponsor if the investigator suspects a causal relationship to the study drug.   
Abnormal laboratory values or test results occurring after study enrollment constitute AEs only if 
they induce clinical signs or symptoms, are considered clinically significant, require therapy (e.g., 
hematologic abnormality that requires transfusion or hematological stem cell support), or require 
changes in study drug (e.g., discontinuation of study drug). 
New signs or symptoms or worsening in severity of a cancer symptom that occur in association 
with disease progression should be recorded as AEs. Disease progression should not be reported 
as an AE unless worsening of signs and symptoms occur, or death from disease progression. 
If a death occurs during the SAE reporting period, the cause of death is considered as the AE and 
the death is considered its outcome. Death should be considered an outcome, not an event. The 
event or condition leading to death should be recorded and reported as a single medical concept 
on the Adverse Event eCRF. Generally, only one such event should be reported. “Fatal” will be 
recorded as the outcome of this respective event; death will not be recorded as separate event. If 


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the primary cause of death is disease progression, the cause of death should be clearly identified 
as progression of cancer under study.
In cases of surgical or diagnostic procedures, the condition leading to the procedure is considered 
as the AE instead of the procedure itself. Each AE will be coded by the Sponsor from the verbatim 
text to a preferred term using a thesaurus based on the Medical Dictionary for Regulatory Activities 
(MedDRA).  
The following guidelines will be followed for the recording and reporting of adverse and serious 
adverse events. 
1. Baseline events will be recorded in the medical history section of the case report form and 
will include the terminology event name, grade, and start date of the event.  The medical 
history section of the case report form will serve as the source document for baseline events 
once signed and dated by the principal investigator.   
a.
Baseline events are any medical condition, symptom, or clinically significant lab 
abnormality present before the informed consent is signed. 
i. Hematologic laboratory abnormalities will not be recorded as baseline events 
for patients with acute leukemia, myelodysplastic syndrome, chronic 
lymphocytic leukemia, or chronic myeloid leukemia in blast phase. 
ii. If exact start date is unknown, month and year or year may be used as the start 
date of the baseline event. 
2. The maximum grade of the adverse event will be captured per course or protocol-defined 
visit date. 
3. These adverse events will be recorded in the case report form: 
a.
Any grade adverse event that is possibly, probably, or definitely related to the study 
drug. 
b. All serious adverse events regardless of attribution to the study drug. 
c.
Any grade adverse event regardless of attribution to the study drug that results in any 
dose modification. 
4. Hematologic adverse events will not be recorded or reported for studies in patients with acute 
leukemia, myelodysplastic syndrome, chronic lymphocytic leukemia, or chronic myeloid 
leukemia in blast phase except for: 
a.
Prolonged myelosuppression as defined by the NCI-CTCAE criteria specific for 
leukemia, e.g. marrow hypocellularity on day 42 or later (6 weeks) from start of 
therapy without evidence of leukemia (< 5% blasts), or that results in dose 
modifications, interruptions or meets the protocol definition of DLT or SAE. 
5. Serious adverse events will be reported according to institutional policy. 
6. Protocol specific language regarding the recording and reporting of adverse and serious 
adverse events will be followed in the event of discordance between the protocol and 
Leukemia-specific adverse event recording and reporting guidelines.  
(MD Anderson Cancer Center Leukemia-specific Adverse Event Recording and Reporting 
Guidelines) 
 


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The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html).  
9.1 Classification of Causality
Attribution is the relationship between an adverse event or serious adverse event 
and the study treatment. Attribution will be assigned as follows: 

Definite – The AE is clearly related to the study treatment. 

Probable – The AE is likely related to the study treatment 

Possible – The AE may be related to the study treatment. 

Unlikely - The AE is doubtfully related to the study treatment. 

Unrelated - The AE is clearly NOT related to the study treatment 
Guidance for assessing causality:
The Investigator will need to determine whether an AE is considered related to (“caused by”’) the 
study drug rather than some underlying condition, for example, AML.   
For the purposes of this study, ‘drug related’ shall mean ‘Definite’, ‘Probable’ and ‘Possible’ 
relationship to drug as determined by the PI.
9.2 Classification of Severity
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All appropriate treatment 
areas should have access to a copy of the criteria. The CTCAE version 4.0. A copy of the 
CTCAE version 4.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm and in Appendix D.
AEs that are expected are subject to expedited reporting only if the adverse event varies in nature, 
intensity or frequency from the expected toxicity information that is provided in the Investigator 
Brochure.
9.3 Serious Adverse Event (SAE) Reporting
The regulatory definition of a Serious Adverse Event (SAE) is any untoward medical occurrence 
or effect that at any dose: 

results in death; 

is life threatening (at the time of the event); 

requires in-patient hospitalization or prolongation of existing hospitalization; 

results in persistent or significant disability / incapacity, or 

is a congenital anomaly / birth defect; 

all other events that are considered medically serious by the Investigator. 


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Disability is defined as a substantial disruption of a person’s ability to conduct normal life 
functions. 
A life-threatening adverse event is one that places the patient/subject, in the view of the 
Investigator, at immediate risk of death from the event as it occurred.  It does not include an event 
that, had it occurred in a more severe form, might have caused death.   
An unexpected adverse event is any adverse drug event, the nature or severity of which is not 
consistent with the applicable product information (e.g. Investigator’s brochure for an 
unauthorized investigational product or summary of product characteristics for an authorized
product). 
Enter only one event as the reason for the SAE on the SAE form.  Other non-serious events 
which did not directly result in the SAE should be detailed in the description section on the SAE 
form and listed separately as AEs if necessary. For fatal SAEs, report the cause of death as an 
SAE with a fatal outcome rather than reporting death as the SAE term. 
Note that hospitalizations for the following reasons should not be reported as SAEs:  

Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition;  

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent;  

Social reasons and respite care in the absence of any deterioration in the subject’s general 
condition ; 

Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of an SAE given 
above is not an SAE.  
 
ANY SERIOUS ADVERSE EVENT MUST BE REPORTED IMMEDIATELY (WITHIN 
24 HOURS) BY EMAIL OR FAX TO THE SPONSOR CONTACT USING THE FORM 
PROVIDED. ENTER THE SUBJECT’S AVAILABLE INFORMATION INTO THE ECRF
WITHIN 48 HOURS.
The subjects are to be identified in the immediate and follow-up reports by unique code numbers 
supplied by the sponsor.  The email address and fax telephone number for reporting SAEs can be 
found below and at the front of this protocol.   
Reports relating to the subject’s subsequent medical course following a SAE must be submitted to 
the Sponsor contact until the event has subsided or, in case of permanent impairment, it stabilizes 
and the overall clinical outcome has been ascertained. 
SAE REPORTING FAX:     919-313-1412 (US Toll-free:  1-866-761-1274)
SAE REPORTING EMAIL: safety-inbox@novellaclinical.com 


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MEDICAL MONITOR:
Robert Sims, MD
E-mail:
robert.sims@novellaclinical.com; 
 
YYA36071medmon@novellaclinical.com 
 
 
Telephone:
614-721-2630
24-hour safety line: 1-866-758-2798 or 919-313-7111
Fax:
206-826-0483
Sponsor Representative: 
Barbara Powers, MSN, Ph.D.
E-mail:
bpowers@clearcreekbio.com  
 
 
Telephone:
484-686-0545  
 
 
 
All SAEs will be reported to the IRB periodically, at the end of the study or per local institutional 
guidelines.   
9.4 Suspected Unexpected Serious Adverse Reactions (SUSARs)
Suspected, unexpected, serious adverse reactions (SUSARs) are SAEs that are both related to the 
study drug (Relationship = Related) and unexpected (not previously described in the investigator’s 
brochure). All SUSARs will be reported in an expedited manner to the Sponsor or designee and 
IRB by the Investigators and to all relevant regulatory authorities by the Sponsor. Expectedness 
will be judged by the Medical Monitor and site PI. It is critical that all SAEs are reported within 
the 24-hour guideline so that the expectedness determination can be made. SUSARs require 
immediate attention and expedited reporting to relevant regulatory authorities. 
The Sponsor is to ensure that all relevant information about fatal or life-threatening SUSARs are 
appropriately recorded and reported to the concerned Regulatory Authority and to the concerned 
IRB(s) within seven (7) calendar days of the date of first report to the Medical Monitor/Sponsor. 
Follow-up information is to be subsequently communicated to the relevant Regulatory Authority
within an additional eight calendar days. 
All other SUSARs are to be reported to the Regulatory Authority and to the IRB(s) concerned as 
soon as possible within a maximum of fifteen calendar days of first knowledge by the Medical 
Monitor/Sponsor. 
The Medical Monitor/Sponsor or designee must also inform all Investigators studying the 
investigational medicinal product about SUSARs and ensure that all IRBs have been notified.
For reported deaths of a subject, the Investigator shall supply the Sponsor and the IRB(s) with 
additional information requested on an expedited basis.   
9.5 Pregnancies
Pregnancy occurring in a female subject or a subject’s partner during the study period will be 
documented in the subject’s source documents and reported on a Pregnancy Form to the Sponsor 
Contact and to the IRB/IEC by the investigational staff within 1 working day of their knowledge 
of the event. The pregnancy information should be submitted using a Pregnancy Report Form. The 
collection period for a pregnancy occurring in a subject or a subject’s partner will begin at the first 
dose of study drug and will continue through 90 days after the last dose of study drug. Monitoring 


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of the subject or partner should continue until the conclusion of the pregnancy, if the subject or 
subject’s partner has consented to this. Monitoring of the baby should continue for 3 months after 
birth, if the subject or subject’s partner has consented to this. 
 
Pregnancy itself is not an AE; it should be reported for tracking purposes. The Investigator or 
designee will discontinue the pregnant subject from the treatment aspects of the study, continue to 
follow her per protocol for safety outcomes only, and advise her to seek prenatal care and 
counseling from her primary care provider. Data on fetal outcome and breast-feeding will be 
collected for regulatory reporting and drug safety evaluation. 
  
If the pregnancy is due to a subject’s failure to comply with the contraceptive requirements of this 
protocol, this should also be documented as a protocol deviation.  
 
Complications of pregnancy or congenital abnormalities in the newborn child will be reported 
appropriately as AEs.  
The site clinical staff will request the pregnant subject to notify the site of the outcome of the 
pregnancy (i.e., birth, loss, or termination). To help ensure this, the site clinical staff will follow-
up with the subject until the end of pregnancy, with the subject’s consent. This request and the 
subject’s response will be documented in the subject’s source document. 
9.6 Hematologic Adverse Events
It is recognized that laboratory value variability is a frequent and expected and may be present at 
Baseline when a subject enrolls in the study. In general, mild day to day fluctuation of laboratory 
values should not be classified as AEs. Fluctuations in laboratory values resulting from adverse 
changes in the patient’s medical condition should be reported as AEs. Laboratory abnormalities 
that constitute an AE in their own right as per CTCAE V4.03 criteria if applicable (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study drug), should be recorded on the AE eCRF. 
Whenever possible, a diagnosis, rather than a symptom should be provided (e.g., anemia instead 
of low hemoglobin). Laboratory abnormalities that meet the criteria for AEs should be followed 
until they have returned to normal or an adequate explanation of the abnormality is found. When 
an abnormal laboratory or test result corresponds to a sign/symptom of an already reported AE, it 
is not necessary to separately record the lab/test result as an additional event.  
Laboratory abnormalities that do not meet the definition of an AE should not be reported as AEs. 
A laboratory abnormality designated a Grade 3 or 4 event (severe) as per CTCAE does not 
automatically indicate a SAE unless it meets the definition of serious as defined below and/or as 
per Investigator’s discretion.  
For laboratory abnormalities and any AEs, it should be noted that the terms serious and severe are 
not symptoms. The term severe describes the intensity of the specific event (e.g., Grade 3 or 4). 
The term serious is based on patient and event outcomes or actions required as described in the 
protocol definition of SAEs and is usually associated with events posing a threat to the subject’s 


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life or ability to function. A severe AE (Grade 3 or 4) does not necessarily need to be considered 
serious; laboratory abnormalities (such as WBC or platelet count) may be severe but not serious.
After the subject has completed the first 42 days of treatment, hematologic dose-limiting toxicity 
(DLT) is defined as prolonged neutropenia with ANC < 500 from the start of therapy in the absence 
of disease, 
, and/or 
thrombocytopenia, with a hypocellular bone 
marrow and no greater than 5% marrow blasts lasting for 2 weeks or more. Anemia will not be 
considered a hematologic AE for the definition of unacceptable safety. The timing of the bone 
marrow sampling can be adjusted to ensure that the results are available for the visit on Day 43 
(Day 1 of Cycle 4).
Participants with neutropenia or thrombocytopenia because of disease prior to the start of therapy 
do not require treatment interruption for myelosuppression. Dose reductions of brequinar in these 
participants should be considered on an individual case basis and discussed with the Sponsor. 
9.7 Management of Myelosuppression
Myelosuppression and the related adverse events (thrombocytopenia, anemia, neutropenia, febrile 
neutropenia) are common in both treated and untreated patients with AML. Based on clinical 
observations with DHODH inhibition and with historical evidence from previous studies with 
brequinar, participants treated with brequinar may experience thrombocytopenia and neutropenia.  
If a participant achieves a clinical response including CR, CRi, CRh, or MLFS while on study and 
they have not recovered absolute neutrophil count (ANC) > 500/uL within 14 days of study drug 
interruption, brequinar dosing may be further interrupted until ANC recovers to > 500/uL, unless 
the low ANC is thought to be due to the underlying disease. Brequinar may be reinitiated at an 
adjusted dose per discussion with the Sponsor. Granulocyte colony-stimulating factor (GCSF) may 
be administered if in the best interest of the participant.
9.8 Differentiation Syndrome
Based on its proposed pro-differentiating mechanism of action, it is possible that participants 
receiving treatment with brequinar may develop signs and symptoms of differentiation syndrome 
(DS). Clinical features may include some or all of the following: unexplained fever, skin rash, 
hypoxia, respiratory compromise, interstitial pulmonary infiltrates, pleural and/or pericardial 
effusion, weight gain, and clinical deterioration. Laboratory features may include an increase in 
ANC and/or platelets. An increase in mature leukocytes may be observed in the bone marrow 
aspirate differential if a bone marrow biopsy is conducted during this time. However, no single 
sign or symptom may be considered per se as diagnostic of the syndrome, and other causes should 
be sought and excluded. 
It is recommended that the prophylactic and therapeutic measures indicated below be undertaken 
at the earliest manifestations of suspected differentiation syndrome: 

Temporary hold of brequinar if clinical features cannot be medically managed with the 
following: 
-
Control of leukocytosis with hydroxyurea;  
-
Prompt administration of corticosteroids at a suggested dose of 10 mg of 


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dexamethasone IV every 12 hours until disappearance of symptoms and signs, 
continued for a minimum of 3 days;
-
Initiation of furosemide, if clinically required; 
-
Prompt initiation of leukapheresis, if required. 
If brequinar dosing is held, brequinar may be reinitiated without dose reduction once the 
participant’s clinical condition improves, upon discussion with the Sponsor. 
9.9 Tumor Lysis Syndrome (TLS)
Tumor lysis syndrome (TLS) is characterized by nausea, vomiting, diarrhea, anorexia, lethargy, 
irregular heart rhythms, heart failure, hematuria, seizures, muscle cramps, syncope, tetany and 
possible sudden death due to the acute metabolic irregularities of hyperkalemia, 
hyperphosphatemia and hypocalemia associated with the breakdown of tumor cells secondary to 
cytotoxic therapy. 
While TLS was not observed in the previous extensive clinical experience with brequinar, the 
experience with brequinar in hematologic malignancies is limited. Signs and symptoms of TLS 
will therefore be carefully monitored particularly in the period that tumor lysis is most likely to 
occur (24-48 hours after first dose). The risk stratification in AML for TLS from the international
guidelines by Cairo et al., 2010 [11] is as follows:

Low risk disease: WBC < 25 x 109 /L and LDH < 2 x upper limit of normal (ULN);

Intermediate risk disease (IRD): WBC 25 to 100 x 109 /L or WBC < 25 x 109 /L and LDH 
 2 x ULN;  

High risk disease (HRD): WBC  100 x 109 /L.
The guidelines for the prevention, monitoring and treatment of TLS are described below: 
TLS Prevention [Recommended]:  

IV hydration: aggressive hydration is recommended for patients at intermediate to high risk 
for TLS with a goal of initially 2 to 3 L/m2 per day of IV fluid per the international 
guidelines (Coiffer et al., 2008 [12]). 

Hypouricemic agents: allopurinol for intermediate risk disease (IRD). 
TLS Monitoring: (Howard et al., 2011 [13]) 

Figure 2 provides a flow chart for TLS monitoring. 


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Figure 2.
Monitoring of Tumor Lysis Syndrome
TLS Treatment
TLS requires urgent inpatient management including intense nursing care, cardiac monitoring, 
nephrology consultation, and measurements of uric acid, creatinine, and electrolytes every four 
to six hours. Treat any electrolyte abnormalities and any acute renal injury. 


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9.10 Infection Prophylaxis
Supportive care, including prophylactic antibiotics, antifungal and/or antiviral agents, are 
frequently used in neutropenic patients, and may be used per standard institutional practice and as 
deemed necessary by the investigator. 
9.11 Growth Factor Support
The use of myeloid growth factors (granulocyte-colony stimulating factor [G-CSF] and 
granulocyte-macrophage colony-stimulating factor [GM-CSF]) may be given to support subjects 
who have developed Grade 4 neutropenia or Grade 3 neutropenia with fever and/or infection, per 
institutional guidelines.
9.12 Management of Nausea, Vomiting, and Diarrhea
Recommended management of nausea and vomiting is to administer antiemetics. The 
recommended treatment for managing diarrhea is loperamide antidiarrheal therapy, 4 mg at first 
onset, followed by 2 mg with each loose movement until diarrhea-free for 12 hours (maximum 
dosage: 16 mg/24 hours). Adjunct anti-diarrheal therapy is permitted. 
 


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10
STATISTICAL CONSIDERATIONS
A separate, detailed statistical analysis plan (SAP) will be finalized prior to locking the database. 
All analyses of safety and anti-leukemic activity for this open-label early Phase study will be 
descriptive in nature and presented by dose group and overall, as appropriate, for the dose-
adjustment phase and the expansion phase. Procedures for accounting for missing, unused and 
spurious data will be described in the SAP.   
Summaries for quantitative variables will include the mean, median, quartiles, standard deviation 
and error, minimum, and maximum. For qualitative variables, the summaries will include the 
number and percentage of subjects for each outcome, and the exact 95% CI, when appropriate. No 
hypothesis testing will be performed. Any statistical testing will be considered exploratory and 
descriptive. All computations will be performed using SAS® (Version 9.3 or higher). 
Subject disposition, subject demographics and baseline characteristics will be summarized. 
Subject data listings will also be provided. The following sections will briefly summarize of the 
planned statistical analyses and analysis sets for the primary and secondary endpoints. 
10.1 Study Populations for Analysis
The analysis sets are defined in Table 3. 
Table 3. 
Analysis Sets 
Analysis Set
Description
Enrolled Analysis Set 
All subjects who have been enrolled in the study. 
Safety Analysis Set 
All subjects who were administered brequinar. 
Efficacy Analysis Set 
All subjects with AML disease at baseline and who were administered 
brequinar. 
Pharmacokinetic Analysis Set 
All subjects who take at least 1 dose of brequinar and have at least 1 
quantifiable plasma concentration collected post-dose without important 
protocol deviations/violations or events thought to significantly affect the 
PK. 
The Efficacy Analysis Set will be used for efficacy analyses. The Safety Analysis Set will be used 
for safety analyses.   
10.2 Safety Analyses
All safety analyses will be performed on the Safety Analysis Set.  Safety and tolerability will be 
assessed in terms of AEs, SAEs, safety laboratory data, physical examinations, vital signs, 12-lead 
ECGs and bone marrow sampling.  
Adverse event data will be descriptively evaluated. All AEs will be listed. The incidence and 
duration of TEAEs, defined as AEs occurring after the first dose of study treatment through 30 
days after the last dose of study treatment, will be tabulated by Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term and system organ class, and by severity and relationship to 
study treatment. All laboratory results, vital sign measurements, ECGs and bone marrow 
assessments will be summarized using appropriate descriptive statistics.


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10.3 Efficacy Analyses
Efficacy analyses will be performed using the Efficacy Analysis Set.  Table 4 summarizes the 
planned analysis of primary and secondary efficacy endpoints. 
Table 4.
Efficacy Analyses
Endpoint
Statistical Analysis Methods
Primary 
There is no primary efficacy endpoint for this study. 
Secondary

Assess anti-leukemic activity as follows: 
o
Overall Response rate (ORR) – the proportion of subjects
in the Efficacy Analysis Set with a best overall response of 
CR, CRi, CRh, MLFS and PR  
o
Complete Remission (CR) rate – the proportion of subjects
in the Efficacy Analysis Set with a best overall response of 
CR 
o
Complete Remission with Incomplete Hematologic 
Recovery (CRi) rate – the proportion of subjects in the 
Efficacy Analysis Set with a best overall response of CRi 
o
Complete remission with partial hematological recovery 
(CRh) – the proportion of subjects in the Efficacy Analysis 
Set with a best overall response of CRh 
o
Morphologic Leukemia Free State (MLFS) rate – the 
proportion of subjects in the Efficacy Analysis Set with a 
best overall response of MLFS 
o
Partial Remission (PR) rate – the proportion of subjects in 
the Efficacy Analysis Set with a best overall response of 
PR 
o
Event-free survival (EFS) – the interval between first 
brequinar 
blasts, reappearance of blasts in blood, or development of 
extramedullary disease), disease progression, or death 
o
Overall survival (OS) – the time from first dose of 
brequinar to date of death or last known alive date 
For ORR and other endpoints defined as proportions, estimated 
response rates and two-sided exact binomial 95% CIs will be provided.  
The distributions of EFS and other time-to-event endpoints will be 
summarized using the Kaplan-Meier method.  Time to event analyses 
will be from first dose of brequinar.  Censoring rules for time-to-event 


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endpoints will be described in the SAP. 
Exploratory
Will be described in the SAP finalized before database lock.
Disease response for participants with AML will be assessed based on Döhner et al, 2017 [10]. 
Complete remission (CR):  

Bone marrow showing less than 5% myeloblasts with normal maturation of all cell lines, 

ANC of at least 1000/µL  

Platelet count of 100,000/µL

Absence of blasts in peripheral blood

Absence of identifiable leukemic cells in the bone marrow

Absence of extramedullary disease. 
Complete Remission with Incomplete Blood Count Recovery (CRi): 

Same as for CR but without achievement of ANC at least 1000/uL (CRi) and/or platelet 
count of 100,000/uL (CRp). 
Complete Remission with Partial Hematological Recovery (CRh)

Complete remission with partial hematological recovery defined as <5% of blasts in the 
bone marrow, no evidence of disease, and partial recovery of peripheral blood counts 
(platelets >50,000/microliter and ANC >500/microliter) (Kantarjian HM et al, 2016 [14]). 
Partial Remission: 

All hematologic criteria of CR are fulfilled, and 

A decrease of bone marrow blast percentage to 5% to 25%, and 

Decrease of pretreatment bone marrow blast percentage by at least 50%.
Morphologic Leukemia Free State:

Bone marrow blasts <5%; 

Absence of blasts with Auer rods; 

Absence of extramedullary disease;

No hematologic recovery required
Stable Disease:

Failure to achieve a response

Not meeting criteria for Progressive Disease


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Progressive Disease
Evidence for an increase in bone marrow blast percentage and/or increase of absolute blast counts 
in the blood:

>50% increase in marrow blasts over baseline (a minimum 15% point increase is required 
in cases with <30% blasts at baseline; or persistent marrow blast percentage of >70% over 
at least 3 months; without at least a 100% improvement in absolute neutrophil count (ANC) 
to an absolute level 
 platelet count to >50 x 109/L
 non-transfused]; or  

>50% increase in peripheral blasts (WBC x % blasts) to >25 x 109/L 
absence of differentiation syndrome); or

New extramedullary disease 
Duration of Response  

The duration of response is defined as the number of days from the time response criteria 
are initially met for CR, CRi, CRh, PR, or MLFS (whichever is first recorded) until the 
first date that recurrent or progressive disease is objectively documented, or death due to 
any cause. Participants without events reported are censored at the last disease evaluation.
Clinical Benefit
Requires one of the following in the absence of progression or CR/partial response and 
independent of marrow response to be considered a clinical benefit:

Erythroid response 
o
Transfusion Independence
units 
of packed red blood cell transfusions in the previous 8 weeks. Only red blood cell 
transfusions given based on physician’s 
g/dL will count in the red blood cell TI response evaluation. 

Platelet response 
o
Transfusion independence when previously requiring platelet transfusions of at 
least a rate of 4 platelet transfusions in the previous 8 weeks.
 
10.4 Other Endpoints
Brequinar Pharmacokinetics (PK)
Blood samples for PK analysis will be obtained at pre-specified times. Plasma PK parameters of 
brequinar including steady-state plasma concentration (Css); elimination half-life (T1/2); Area 
under the concentration curve (AUC); systemic clearance (CL) and volume of distribution at 
steady state (Vss) will be estimated by compartmental and non-compartmental analysis 
(WinNonlin or similar).
Concentration data and PK parameters will be tabulated and summarized using descriptive 


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statistics.  Relationships between brequinar PK parameters and clinical outcomes (e.g., efficacy, 
toxicity) may be explored.  PK analyses will be performed on the PK Analysis Set.
Blood samples for DHO analysis will be obtained at pre-specified times and will be summarized.  
Relationships between DHO levels and PK and clinical outcomes (e.g., efficacy, toxicity) will be 
explored. 
Changes in myeloid markers per serial flow cytometry will be studied to look for evidence of 
myeloid differentiation. 
10.5 Sample Size Considerations
Formal sample size calculations are not applicable for this phase 1b/2a, open label study. Up to 27 
subjects are planned to be entered in this trial: Cohort 1 will have 6 subjects; two additional cohorts 
of 3 subjects each will be added if adjustments are required to the cohort starting dose. The cohorts 
with 3 subjects may be expanded to 6 subjects depending on safety outcomes within the cohort. 
An expansion cohort of approximately 15 subjects will be enrolled with a starting dose of the 
highest tolerated starting dose from Cohorts 1 to 3.  
10.6 Randomization
No randomization scheme is needed for this open label study. 
10.7 Pooling of Study Centers
Not applicable to this small, early phase study. 
10.8 Interim Analysis
No interim analysis is planned for this trial. 


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11
INVESTIGATOR RESPONSIBILITIES
11.1 Investigator’s Performance
The Investigator will ensure that all those concerned with conducting the trial are:
provided with copies of the protocol and all safety information prior to the start of the trial;
trained regarding the conduct of the study and the training has been documented.
The Investigator will sign the Investigator’s Statement and Agreement (Appendix 14.6) to indicate 
commitment to comply with the contents. 
11.2 Confidentiality
The Investigator shall assure the subject that his/her identity will be protected and confidentiality 
will be maintained during all audits and inspections of the trial site and documentation. A unique 
number will be assigned to each subject at the start of the trial and this, with the subject’s initials, 
will be used to identify the subject. In some cases, a further step may be taken to assign “fake 
initials” to the subject, per individual site requirements. The subject’s number will be the site 
number followed by the number of this subject at this site and will be used as the unique identifier 
in the source records and on the CRF, on all trial correspondence and in the trial database. The 
Investigator will keep a list of identification codes or initials used for each subject along with the 
unique number assigned. 
All information provided to the Investigator relevant to the investigational medicinal product 
(IMP), as well as information obtained during the course of the trial will be regarded as 
confidential. The Investigator and members of his/her research team agree not to disclose or 
publish such information in any way to any third-party without prior written permission from the 
Sponsor which will not be unreasonably withheld, except as required by law, or as permitted by 
the Publications section of this protocol, Section 11.7. 
The Investigator will take all measures to ensure subject’s confidentiality will be maintained at all 
times. 
11.3 Source Documentation
Investigators are to maintain adequate source documentation of the original study data, for 
example medication records, laboratory reports and pharmacy records as appropriate. The 
Investigator will allow inspections of the trial site and documentation by clinical research and audit 
personnel from the Sponsor, external auditors or representatives of regulatory authorities. The 
purpose of these inspections is to verify and corroborate the data collected on the CRFs. In order 
to do this, direct access to the subjects' medical or clinic records is necessary. The Investigator will 
ensure that certain information is contained in the medical or clinic records of the subject and that 
the entries are signed and dated, as follows: 

sufficient data to allow verification of the entry criteria in terms of past and present medical 
and medication histories; 

a note on the day the subject entered the trial describing the trial number, the IMP being 
evaluated, the trial number assigned to that subject and a statement that consent was obtained;


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
a note of each subsequent trial visit including any concerns about AEs and their resolution;

notes of all concomitant medication taken by the subject, including start and stop dates;

a note of when the subject terminated from the trial, the reason for termination and the subject’s 
general condition at termination; 

a copy of the signed informed consent form should be kept in the medical records of each 
subject during the clinical phase of the study. A signed copy should also be filed in the 
investigator file. 
11.4 Data Collection
Suitably qualified and trained personnel at the trial site will ensure compliance with the protocol, 
adherence to ICH GCP obligations, proper maintenance of trial records including IMP 
accountability records, correct administration of IMP including storage conditions and accurate 
reporting of AEs. In addition, suitably qualified and trained clinical research personnel of the 
Sponsor will visit the trial site at regular intervals during the trial for monitoring purposes and to 
assist the research staff with any queries. All queries and discrepancies relating to the data 
collection are to be resolved at the completion of the trial. 
11.5 Case Report Forms, Investigator’s Site File and Record Retention
The Sponsor may provide the CRFs in paper, electronic (eCRF), or other media. The forms will 
be reviewed against source documentation at each monitoring visit. All CRFs and supporting 
source documentation must be completed and available to the Sponsor in a timely manner. 
Changes or corrections due to data clarification and resolutions will be tracked by paper or 
electronically with an audit trail. 
Prior to review of the case report forms by the Sponsor’s representative, they should be reviewed 
for completeness and accuracy by the Investigator or a member of the research team. 
The Investigator must maintain an Investigator Site File which includes, but is not limited to, the 
Investigator’s Brochure, the protocol plus any amendments, all correspondence with the IRB 
including the approval for the trial to proceed, Regulatory Authority approval/ notification (if 
applicable) including a sample of an approved informed consent, IMP accountability, Source 
Documents, investigator and staff curricula vitae (CVs,) trial documentation, and all trial 
correspondence. The original signed informed consent forms and the final report will be kept in 
the Investigator Site File. 
The Investigator will archive all essential documents. The medical files of trial subjects shall be 
retained in accordance with national legislation and in accordance with the maximum period of 
time permitted by the hospital, institution or private practice. The Investigator has a responsibility 
to retain essential documents for as long as is required by the Sponsor and applicable regulatory 
authorities.  It is the responsibility of the Sponsor to inform the Investigator as to when these 
documents no longer need to be retained. Investigators will be asked to contact the Sponsor prior 
to the destruction of any data or removal to another site if this occurs prior to the Sponsor 
notification that the documentation is no longer required. Any transfer of ownership of the data or 


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of documents will be documented in writing.  The new owner will assume responsibility for data 
retention and archiving.
Should the Investigator retire, relocate, or for other reasons withdraw from the responsibility of 
keeping the trial essential documents, custody must be transferred to a person who will accept that 
responsibility, and the Sponsor must be notified in writing of the name and address of said person.
11.6 Non-Protocol Research
No investigational procedures other than those outlined in this protocol may be undertaken on the 
subjects in this trial without the prior written permission of the subject, the Sponsor, the IRB and, 
when appropriate, the regulatory authority. 
11.7 Publication
The Sponsor acknowledges the benefit of making widely available the results of all clinical trials 
and intends to publish the results of this trial. All publications resulting from the clinical trial must 
be in a form that does not reveal technical information that the Sponsor considers confidential or 
proprietary.  A copy of any abstract, presentation or manuscript proposed for publication must be 
submitted to the Sponsor for review at least 30 days before its submission for any meeting or 
journal. In addition, if deemed necessary by the Sponsor for protection of proprietary information 
prior to patent filing, the Investigator agrees to a further delay of 60 days before any presentation 
or publication is submitted. The Sponsor reserves the right to include the report of this trial in any 
regulatory documentation or submission or in any informational materials prepared for the medical 
profession. 
Authorship determination will be at the discretion of the Sponsor and will include evaluation of 
the following criteria: Investigator must participate in the review of and content of the protocol; 
review and comment on the study results; participate in the writing, reviewing and commenting of 
the manuscript; and approve the final manuscript for submission. 
 
 
 
 
 
 
 
 
 
 


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12
SPONSOR RESPONSIBILITIES
12.1 General
The Sponsor agrees to adhere to the ICH Note for Guidance on Good Clinical Practice 
(CPMP/ICH/135/95, Jan.97) and US FDA Regulations. It is the Sponsor's responsibility to obtain 
appropriate regulatory approval to perform the trial (if applicable). The Sponsor should notify 
promptly all concerned investigator(s), IRB(s) and the Regulatory Authority of findings that could 
adversely affect the health of the patients/ subjects, impact on the conduct of the trial or alter the 
Regulatory Authority’s authorization to continue the trial. If it is necessary to change or deviate 
from the protocol to eliminate an immediate hazard to the subjects the Sponsor will notify the 
relevant regulatory authority and relevant IRB of the new events, the measures taken and the plan 
for further action as soon as possible.  This will be by telephone in the first instance followed by a 
written report.   
On completion of the trial, the Sponsor will inform the regulatory authority that the trial has ended.  
If the study is terminated for any reason the Sponsor will provide a written statement to the relevant 
regulatory authority and the IRB with the reasons for termination of the trial. This will be 
conducted within 15 days of the decision to terminate the trial.  The Sponsor will report in an 
expeditious manner all suspected unexpected serious adverse reactions (SUSARs) to the relevant 
regulatory authority and IRBs.   
12.2
Indemnity
The Sponsor will provide compensation insurance against any risk incurred by a subject as a result 
of participation in this trial. The Sponsor will indemnify the Investigators as detailed in a separate 
document.
12.3
Data Monitoring
Suitably qualified and trained clinical research personnel of the Sponsor will visit the trial site at 
regular intervals during the trial for monitoring purposes and to assist the research staff with any 
queries. CRFs and source documentation will be available for review during monitoring visits to 
the trial site. The function of this monitoring is to ensure compliance with the protocol, adherence 
to regulatory and Good Clinical Practice obligations, proper maintenance of records including IMP 
accountability records, correct administration of IMP including storage conditions and accurate 
reporting of AEs.  
Once the data from the case report forms have been entered onto the database, they will be 
reviewed and the data verified against the subject’s source data. Any discrepancies will be tracked 
by paper or electronically with an electronic audit trail. 
12.4
Audit
The Sponsor has an obligation to audit a proportion of studies.  A department other than the clinical 
department will undertake this obligation. Therefore, the Sponsor, an independent auditor or a 
regulatory authority may audit the trial site and trial documentation. These audits may take place 
while the trial is being conducted or up to several years later.  


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12.5
Confidentiality
The Sponsor will not keep any material on file bearing any subject’s name, and subjects’
confidentiality will be maintained at all times. 
12.6
Finance
This will be the subject of a separate agreement between the Investigator/Institution and Sponsor.


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13
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368390) in patients with solid malignancies. Cancer Chemother Pharmacol. 1990; 25(5): 
345-351. 
9. Brequinar Investigator’s Brochure
10. Döhner H, Estey E, Grimwade D, Amadori S, Applebaum FR, Büchner T, et al. Diagnosis 
and management of AML in adults: 2017 ELN recommendations from an expert 
international expert panel. Blood 2017; 129(4): 424-447.
11. Cairo MS, Coiffier B, Reiter A, et al. Recommendations for the evaluation of risk and 
prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant 
diseases: an expert TLS panel consensus. Br J Haematol 2010; 149:578. 
12. Coiffer B, Altman A, Pui CH, et al. Guidelines for the management of pediatric and adult 
tumor lysis syndrome: an evidence-based review. J Clin Oncol 2008; 26:2767. 
13. Howard SC, Jones, DF, Pui, C-H. The Tumor Lysis Syndrome. N Engl J Med 2011; 
364:1844-1854. 
14. Kantarjian HM, Stein AS, Bargou RC, Grande Garcia C, Larson RA, Stelljes M, et al. 
Blinatumomab treatment of older adults with relapsed/refractory B-precursor acute 
lymphoblastic leukemia: Results from 2 phase 2 studies. Cancer 2016; 122(4): 2178-2185.


PROTOCOL NUMBER:  CCB-01
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CONFIDENTIAL:  Clear Creek Bio, Inc. 
14
APPENDICES
14.1 APPENDIX A:  CCB-01 Schedule of Events


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
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CONFIDENTIAL:  Clear Creek Bio, Inc. 
CCB-01 Schedule of Events
Proceduresa
Screenb
Cycle 1 (Study Days 1 – 14)
Dose 
Adjustment
Cycle (Cycle 2 
and beyond as 
needed)
Maintenance 
Dose Cycle (no 
dose 
adjustment)
Every 2 weeks
Final 
Visit
F/U 
Phone
Call
Survival
D1
D2
D3
D4
D8
D1
D8
D1
Final 
Visit 
+ 2 wks
Informed Consentb 
X 
 
 
 
 
 
 
 
 
 
 
 
AE/Concomitant Medications  
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Medical historyc  
X 
 
 
 
 
 
 
 
 
 
 
Demographicsd 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical Examd 
X 
X 
 
 
 
 
X 
 
X 
X 
 
 
Vital Signsd
X
X
X
X
X
X
X
Pregnancy Teste
X
X
X
ECOG Performance Status
X
Hematology/Chemistryf
X
X
X
X
X
X
X
Flow Cytometryg 
 
 
X 
X 
 
 
 
 
 
 
 
 
Chromosomal/mutational testingh 
X 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG
X
X
X
MUGA/Echocardiogram 
X
Bone Marrow Samplingi
X
X
X
Brequinar/DHO Plasma Samplej
X
X
X
X
X
X
X
X
X
Biobanking samplesk
X
X
X
Ship DHO Plasma Samples
X
X
X
Dispense/Collect Study Medication 
X
X
X
X
Dispense/Collect Subject Calendar/Diary
X
X
X
X
Survival Assessment
X


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a.
Visit window of ± 1 day for dose escalation cycles; window of ± 3 days for non dose escalation cycles.
b.
Obtain informed consent prior to performing any screening or study-specific procedures. Screening procedures must be performed 
within 14 days prior to initial study drug administration.  Procedures at C1D1 that are repeats of Screening may be omitted if <72h 
since Screening assessment. 
c.
Medical history is to include AML diagnosis, previous AML treatment, and standard chromosomal and mutational results per 
institutional guidelines. 
d.
Demographic information is to include date of birth, height, weight, race, and ethnic origin. Rectal examination may be deferred for 
Physical Examination. Vital signs include heart rate, respiratory rate, seated blood pressure, respiratory rate, oral/aural body 
temperature. Physical exam is to include weight. 
e.
For women of childbearing potential only. 
f.
In addition to the already scheduled weekly chemistry assessment during Cycles 1 and 2 for each subject, subjects taking potentially 
hepatotoxic drugs are permitted to have more frequent monitoring than indicated in the schedule of events, if ordered by the study 
team. 
g.
Flow cytometry testing of peripheral blood is to be obtained at 0 (pre-dose C1D1), post dose 48 and 72 hours.  
h.
Testing panel is per institutional standard of care; obtain sample at Screening. 
i.
Bone marrow sampling local testing will include analysis of the aspirate on smear, core biopsy by microscopy, flow cytometry, and 
karyotype for cytogenetics. Local molecular analysis will be performed on the screening bone marrow samples only. Bone marrow 
samples will be sent for biobanking  further analysis. Perform bone marrow sampling at screening, at study Day 22 (C2D8), at Day 43, 
and once every 12 weeks after a stable dose has been reachedTiming of this procedure may be adjusted to ensure results are available 
for the next clinic visit. 
j.
Brequinar/DHO plasma sampling schedule: Cycle 1: 0 (pre-dose), post dose 1, 2, 4, 6, 24, 48, 72 hours and C1D8 pre-dose (+84h after 
C1D4 dose); Cycle 2 and adjustment cycles: pre-dose Days 1 and 8; every 2-week Maintenance Cycle until 3-months on drug: pre-
dose Day 1 and every 2 to 4 week Maintenance Dose Cycle beyond 3-months on drug. Day 1 sample window ±15 minutes through 6h 
draw; window for additional C1 draws ±2h; window for Cycle 2 and beyond plasma brequinar/DHO draws ±4h. Ensure trough 
samples (e.g., C1D1, C2D1, C3D1) are obtained prior to dosing. Plasma samples for brequinar/DHO for expansion cohort are to be 
obtained prior to dosing on Day 1 of each 2-week cycle for the first 3 cycles, then every 12 weeks. 
k.
Biobanking samples (bone marrow) are to be collected whenever bone marrow sampling is performed. 


PROTOCOL NUMBER:  CCB-01
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14.2 APPENDIX B: ECOG Performance Status Criteria
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent 
Description
0
Normal level.  Fully active, able to 
carry 
on 
all 
pre-disease 
performance without restriction.
100 
Normal, no complaints, no evidence 
of disease.
90 
Able to carry on normal level; minor 
signs or symptoms of disease.
1
Symptoms, 
but 
ambulatory.  
Restricted in physically strenuous 
level, but ambulatory and able to 
carry out work of a light or 
sedentary 
nature 
(e.g., 
light 
housework, office work).
80 
Normal level with effort; some signs 
or symptoms of disease.
70 
Cares for self, unable to carry on 
normal level or to do active work. 
2
In 
bed 
<50% 
of 
the 
time.  
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities.  Up and about more 
than 50% of waking hours. 
60 
Requires occasional assistance but is 
able to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance.
30 
Severely disabled, hospitalization 
indicated.  Death not imminent.
4
100% bedridden.  Completely 
disabled.  Cannot carry on any self-
care.  Totally confined to bed or 
chair.
20 
Very sick, hospitalization indicated. 
Death not imminent.
10 
Moribund, 
fatal 
processes 
progressing rapidly.
5
Dead. 
0 
Dead. 
 


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CONFIDENTIAL:  Clear Creek Bio, Inc. 
14.3 APPENDIX C: Brequinar/DHO Plasma Sampling
Information is provided in a separate laboratory manual regarding collection, processing, storing, 
and shipment of samples.  
Brequinar and DHO plasma samples are to be obtained at the following time points (±30 minutes 
through 6h, then ±2h for the 24h, 48h, 72h and 84h samples:
Cycle 1
Cycle 2*
Maintenance 
Dose Cycle 
Final 
Visit 
D1 
D2 
D 3 
D 4 
D8 
D1 
D8 
D1 
 
Time 
Point 
Pre-
dose 
1h 
2h 
4h 
6h 
24h 
48h 
72h 
84h 
after 
prev. 
dose 
84h 
after 
prev. 
dose 
84h 
after 
prev. 
dose 
84h after prev. 
dose 
84h 
after 
prev. 
dose 
*Or any cycle where the brequinar dose has been adjusted from the previous 2-week dose.


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CONFIDENTIAL:  Clear Creek Bio, Inc. 
14.4 APPENDIX D: Common Terminology Criteria for Adverse Events (CTCAE)
https://evs.nci.nih.gov/ftp1/CTCAE/About.html


PROTOCOL NUMBER:  CCB-01
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CONFIDENTIAL:  Clear Creek Bio, Inc. 
14.5
APPENDIX E:
Sample Subject Consent Form 
TITLE:
A Phase 1b/IIa open-label, multi-center study to assess the safety, efficacy and 
pharmacokinetics of intrapatient dose-adjusted brequinar and inhibition of 
dihydroorotate dehydrogenase (DHODH) in adult subjects with acute myelogenous 
leukemia (AML)
PROTOCOL NO.:
CCB-01
SPONSOR: 
 
Clear Creek Bio, Inc. 
 
585 Massachusetts Avenue, 4th Floor, 
 
 
Cambridge MA 02139 
 
INVESTIGATOR: 
 
<insert PI name> 
Site(s):
<insert name> 
 
 
<insert address> 
STUDY-RELATED
PHONE NUMBER(S): <insert name(s)>
 
<insert number>
<insert alternate number (24-hour contact number)> 
VERSION and DATE: <e.g. CCB-01 Master ICF Version 2.0 04June2018>
 
You are being asked to take part in a research study. Before you decide to participate, it is important 
for you to understand why the research is being done and what it will involve. Please take time to 
read the following information carefully and discuss it with others, if you wish, before deciding 
whether or not to take part. Ask us if there is anything that is not clear or if you would like more 
information. 
WHAT IS THE PURPOSE OF THE STUDY?
The purpose of the study is to evaluate the safety, efficacy, pharmacokinetics (PK) (level of study 
medication in the blood) and the inhibition (decrease in level) of an enzyme called “dihydroorotate 
dehydrogenase” (DHODH). DHODH blocks the ability of blood cells formed in the bone marrow 
to differentiate (grow into mature white blood cells that can fight infection and platelets that help 
blood to clot). Brequinar is a drug that has been shown in animals in the laboratory to be able to 
decrease the level of DHODH and decrease leukemic cells in the bone marrow. Reducing DHODH 
level in patients with AML may help treat this type of leukemia by allowing cells in the bone 
marrow to grow into different types of mature cells.


PROTOCOL NUMBER:  CCB-01
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WHY HAVE I BEEN ASKED TO PARTICIPATE?
You have been asked to consider participating in this study because you because you have AML 
that has not responded to treatment (refractory), or the leukemia has recurred (relapsed).
HOW LONG WILL I BE IN THE STUDY?
Your participation in this study will last approximately 7 months and approximately 27 subjects 
will be participating in this study. If you respond (your leukemia improves) due to the effects of 
the study medication, you may be able to continue being treated for up to one year. You will take 
the study medication about every three-and-one-half (3.5) days, for example on Monday mornings 
and Thursday evenings. You and your study team can decide on the exact schedule for you to take 
your medication.
WHAT WILL HAPPEN TO ME IF I TAKE PART?
If you decide to take part in the study, you will have the following procedures: 
Screening Assessment
The Screening period is defined as the period prior to the administration of study drug. During this 
period, the investigator or designee will obtain/perform the following: 

Written, informed consent; 

Demographic details (height, weight, date of birth, race, ethnicity). 

Pertinent medical/surgical history, medications you are currently taking or have taken 
recently. 

Physical examination.  

Vital signs (heart rate, respiratory rate, blood pressure, body temperature).  

Pregnancy test for women of childbearing potential (WOCBP).  

ECOG performance assessment (a measure of your ability to perform activities of daily 
living).  

Blood samples for hematology/chemistry. 

Standard chromosomal and mutational testing (blood samples) if not already done. 

Bone marrow sampling (aspiration and biopsy). 

12-lead ECG with QTcF and MUGA scan or echocardiogram to assess cardiac 
function.  
If you qualify for the study, the treatment period begins with Cycle 1, Day 1 of the first 2-week 
dosing cycle. 
Cycle 1 Day 1:
At this visit you will: 

Be asked about any new medical events or new or changed medications since your last 
visit. 

Have blood samples taken for baseline brequinar/DHO, flow cytometry, and 
hematology/chemistry.  


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
Have a physical examination (including weight) (unless within one week of Screening), 
vital signs, urine pregnancy test for women able to bear children, and 12-lead ECG. 

If you qualify for the study and still choose to participate, you will be given adequate 
study medication for 2 weeks (4 doses). 

You will take the first dose at the clinic and remain at the clinic for pharmacokinetic 
(PK) and dihydroorotate (DHO) blood sampling at 1, 2, 4, and 6 hours after this first
dose. Each dose of study medication will be made up of several capsules, depending 
on what dose you will be taking. Take the medication with about 8 ounces of plain 
water. You can take more water than 8 ounces if needed. 

Be given a calendar/diary you will use to write down the dates/times of study 
medication administration and any new medical events, new medications or a change 
in dose of any medications. Please bring your study medication and diary to every visit. 
Cycle 1 Day 2: You will come back to the clinic approximately 24 hours (the next day) after 
your first dose to have blood samples taken for brequinar/DHO. Your diary will be checked 
for any new medical events, new medications or a change in dose of any medications since the 
last visit.
Cycle 1 Day 3: You will come back to the clinic approximately 48 hours (2 days) after your 
first dose to have blood samples taken for brequinar/DHO and flow cytometry. Your diary will 
be checked for any new medical events, new medications or a change in dose of any 
medications since the last visit. 
Cycle 1 Day 4: You will come back to the clinic approximately 72 hours (3 days) after your 
first dose to have blood samples taken for brequinar/DHO and flow cytometry. Your diary will 
be checked for any new medical events, new medications or a change in dose of any 
medications since the last visit. You will take your second dose of study medication this 
evening. 
Cycle 1 Day 8:  
At this visit, you will: 
-
Have your vital signs checked. 
-
Before you take your morning dose, you will have blood samples taken for brequinar/DHO 
and hematology/chemistry.  
-
Take your next dose of study medication in the clinic. 
-
Your diary will be checked for any new medical events, new medications or a change in 
dose of any medications since the last visit. 
Cycle 2 
You will return to the clinic 2 weeks after starting the study medication. The study team may adjust 
your dose of study medication (you may be given more or less of the drug) depending on your
safety results, laboratory, and DHO levels. This visit may be repeated as needed if your dose 
adjustment continues. 
Day 1:  
-
Your unused study medication will be collected (if you have any), and your diary will be 
checked for any new medical events, new medications or a change in dose of any 
medications since the last visit.
-
Your vital signs will be checked and a physical examination performed.


PROTOCOL NUMBER:  CCB-01
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-
Before you take your morning dose, you will have blood samples taken for brequinar/DHO
and hematology/chemistry.
-
If you are not having any side effects that may indicate it is not safe for you to continue 
taking the study medication, you will be given adequate medication for another 2 weeks (4 
doses). Take your next dose of study medication in the clinic. 
Day 8: 
At this visit, you will: 
-
Have your vital signs checked.
-
Have a bone marrow sample taken for flow cytometry (window ±7 days). 
-
Before you take your morning dose, you will have blood samples taken for brequinar/DHO
and hematology/chemistry.  
-
Your diary will be checked for any new medical events, new medications or a change in 
dose of any medications since the last visit.
-
If you are not having any side effects that may indicate it is not safe for you to continue 
taking the study medication, you will continue to take the medication dispensed to you.
 
Maintenance Dose Cycle (visit every 2 - 4 weeks)
Once you have reached a “stable dose” where no more dose adjustments seem to be needed, you 
will return to the clinic every 2 weeks and have the procedures below. After you've been taking 
the study medication for 3 months, your study doctor may space your visits out to every 4 weeks.
Day 1:
At this visit, you will: 
-
Be asked about any new medical events or new or changed medications since your last visit.  
-
Have blood samples taken for pre-dose brequinar/DHO and hematology/chemistry.  
-
Have a physical examination, vital signs, urine pregnancy test for women able to bear 
children, 12-lead ECG. 
-
Have a bone marrow sampling (the bone marrow aspiration sampling is performed at study 
Day 22 ±7 days, at study Day 43 and repeated every 12 weeks or more often if there is a 
safety concern).  
-
Your study team will review the laboratory results/safety information and determine 
whether you should stay at the same dose or whether you should temporarily stop taking 
the study medication or whether the dose should be changed.  
-
If you are not having any side effects that may indicate it is not safe for you to continue 
taking the study medication, you will be given additional medication and continue to take 
the medication dispensed to you as directed by the study team. 
-
Your diary/calendar will be collected and a new one provided to you.  
Final Visit
This visit is to take place if you or your study team decide you should stop participation in the 
study or you have reached 12 months of study participation. At this visit, you will: 


PROTOCOL NUMBER:  CCB-01
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CONFIDENTIAL:  Clear Creek Bio, Inc. 
-
Be asked about any new medical events or new or changed medications since your last visit. 
-
Have blood samples taken for brequinar/DHO, flow cytometry and hematology/chemistry. 
-
Have a physical examination (including weight), vital signs, urine pregnancy test for women 
able to bear children, 12-lead ECG and bone marrow sampling (unless it has been less than 
4 weeks since the previous bone marrow sampling).  
-
Turn in any unused study medication. 
-
Turn in your calendar/diary. 
Follow Up Visit (2 weeks after Final Visit)
-
You will be contacted by phone to be asked about any new medical events or new or 
changed medications since your last clinic visit.  
WHAT ARE THE POSSIBLE DISADVANTAGES AND RISKS OF TAKING PART IN 
THIS RESEARCH?
Risks from brequinar:
While participating in this study, you are at risk for side effects. These side effects will vary from 
person to person. The more commonly occurring side effects are listed in this form, as are rare but 
serious side effects. You should discuss these with the study doctor. You may also want to ask 
about uncommon side effects that have been observed in small numbers of patients but are not 
listed in this form.  
Brequinar has been given to more than 800 patients with various forms of cancer in more than 20 
clinical trials and has also been tested in patient with psoriasis (a skin condition) and those who 
have had a kidney or liver transplant. The most common side effects have been: 

Thrombocytopenia (low platelet count, platelets are a part of the blood that help your blood 
clot, they may need to be replaced) 

Stomatitis/mucositis (the inside of your mouth and intestines may develop ulcers which 
make eating and drinking difficult)

Skin rash

Nausea

Vomiting 

Diarrhea

Neutropenia (low white blood cell count, which may reduce the body’s ability to fight 
infections) 

Anemia (low red blood cell count, red cells carry oxygen) 

Fatigue  
In most cases, these side effects went away within about 2 weeks after patients stopped taking 
brequinar, but that cannot be guaranteed as the drug may work differently for you. If you develop 
these side effects during the study, your study team may decide to have you temporarily stop taking 
brequinar to see if the side effects get better. You and your study team may also decide to either 


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stop your study participation or reduce the dose of the study medication to see if you can tolerate 
a lower dose.
Brequinar may cause differentiation syndrome. This is a condition that affects your blood cells 
which may be life-threatening or lead to death if not treated. Differentiation syndrome has not been 
previously seen with brequinar. Call your healthcare provider or go to the nearest hospital 
emergency room right away if you develop any of the following symptoms of differentiation 
syndrome: 

Fever

Cough

Shortness of breath

Swelling of arms and legs, around the neck, groin, or underarm area

Fast weight gain (more than 10 pounds within a week)

Bone pain
If you develop differentiation syndrome, your healthcare provider may start you on corticosteroids 
which you will either take by mouth or receive by vein. You may be monitored in the hospital. 
You may also develop Tumor Lysis Syndrome (TLS). TLS is characterized by nausea, vomiting, 
diarrhea, anorexia, lethargy, irregular heart rhythms, heart failure, hematuria, seizures, muscle 
cramps, syncope, tetany and possible sudden death due to the acute metabolic irregularities of 
low blood levels of potassium, phosphorous, and calcium associated with the breakdown of 
tumor cells secondary to cytotoxic therapy.  
While TLS was not observed in the previous subjects who took brequinar in a clinical trial, the 
experience with brequinar in AML is limited. Signs and symptoms of TLS will therefore be 
carefully monitored particularly in the period that tumor lysis is most likely to occur (24-48 hours 
after first dose). If you develop this condition, you will be carefully monitored and may need to be 
treated in the hospital.
Risks from Study Procedures: 
Blood draws may cause pain, bleeding, and/or bruising. You may faint and/or develop an infection 
with redness and irritation of the vein at the site where blood is drawn. Frequent blood collection 
may cause anemia (low red blood cell count), which may create a need for blood transfusions. 
Having bone marrow sampling (biopsies and aspirations) performed may cause pain, bruising, 
bleeding, redness, low blood pressure, swelling, and/or infection at the site of the biopsies. An 
allergic reaction to the anesthetic may occur. A scar may form at the biopsy site. 
Bone marrow sampling will include analysis of the aspirate on smear, core biopsy by microscopy, 
flow cytometry, and karyotype for cytogenetics. You can talk with the study team about this 
testing. The type of genetic testing being performed for this study will not provide you or your 
doctor information about diseases that are passed down in families. It will not tell the study 
researchers anything that will prevent you from getting health insurance, and it will not tell the 
study researchers anything about any diseases or conditions you may get in the future.
There may be risks or side effects that are unknown at this time.


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If a condition of which you were unaware is discovered during the study, a full report will be sent 
to your doctor if you request this. You will be advised of the appropriate action to take for 
treatment. 
Pregnancy-Related Risks
Taking part in this study can result in risks to an unborn or breastfeeding baby, so you should not 
become pregnant, breastfeed a baby, or father a child while participating in this study. If you are 
able to become pregnant or father a child, you must use birth control during the study and for at 
least 3 months after your last dose of study drug if you are sexually active. 
Birth control specifications: Female participants who are able to become pregnant must use 2 
methods of birth control while on this study. Male participants must use an effective barrier method 
(such as a condom) while on this study. 
Talk with the study team about acceptable methods of birth control to use while taking part in this 
study.
Males: Tell the study team right away if your partner becomes pregnant or suspects pregnancy. 
Females: If you are pregnant, you will not be enrolled into this study. If you become pregnant or 
suspect that you are pregnant during the study, you must tell your doctor right away. 
Getting pregnant may result in your removal from this study.  
WHAT ARE THE POSSIBLE BENEFITS?
The study drug may help to control the disease. Future patients may benefit from what is learned. 
There may be no benefits for you in this study. 
WILL IT COST ANYTHING TO BE IN THE STUDY?
If you participate in this study, you will not have to pay for the cost of the study drug used in the 
study. 
You or your insurer will be responsible for the cost of your usual ongoing medical care, including 
procedures and non-study medications that the doctor or your regular doctor requires during this 
study as part of your usual medical care. If you have any questions, please ask the doctor and/or a 
member of the study staff about the costs that will or will not be covered by the sponsor. 
IS THERE PAYMENT FOR PARTICIPATION?
You will not receive any payment for participation in this study. 


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WHAT ARE THE ALTERNATIVES FOR TREATMENT?
You do not have to participate in this research study to receive treatment. Instead, you may be 
eligible for recently approved therapies, and may be able to have a bone marrow transplant outside 
of this study. You may choose to receive other investigational therapies, if available. You may 
also choose not to have treatment for cancer at all. Regardless of your choices, you will receive 
appropriate medical care, including treatment for pain and other symptoms of cancer. Please note 
that you will be informed in a timely manner if new information becomes available that is relevant 
during your participation in this study. 
WHAT IF SOMETHING GOES WRONG?
An important part of this study is to see if the investigational product causes side effects. You must 
inform the staff if you feel unwell or have any unusual symptoms at any time during the study, no 
matter how minor you think they are. If you experience such events, treatment will be made 
available by the doctor. 
You will be provided any reasonably necessary medical treatment for any injuries sustained as a 
result of participating in this study, except to the extent such costs are covered by your medical or 
hospital insurance or by governmental programs providing such coverage. You must follow the 
directions of the doctor to be eligible for this coverage. Neither the sponsor nor the doctor have 
plans to provide other compensation in the event of an injury. You are not giving up any of your 
legal rights by signing this consent form. 
Certain tests, procedures, and/or drugs that you may receive as part of this study may be without 
cost to you because they are for research purposes only. However, your insurance provider and/or 
you may be financially responsible for the cost of care and treatment of any complications resulting 
from the research tests, procedures, and/or drugs. Standard medical care that you receive under 
this research study will be billed to your insurance provider and/or you in the ordinary manner. 
Before taking part in this study, you may ask about which parts of the research-related care may 
be provided without charge, which costs your insurance provider may pay for, and which costs 
may be your responsibility. You may ask that a financial counselor be made available to you to 
talk about the costs of this study. 
WILL ALL THE DOCUMENTS CONCERNING ME REMAIN CONFIDENTIAL?
Yes. The company that is conducting this study will not keep any document on file that contains 
your name; you will only be identified by your initials and a subject number. It will be necessary 
for the sponsor, its representatives, the regulatory authorities, other institutions participating in the 
study, and possibly the Institutional Review Board (an IRB is a group of people who review the 
risks and benefits of a study) to review your medical records, but these will be treated in the 
strictest confidence permitted by law. If the results of the study are published, you will not be 
identified by name. Your personal health information (PHI) will be kept as confidentially as 
possible according to state and federal laws. However, in some situations, the Food and Drug 
Administration (FDA) could be required to reveal the names of participants. 


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The permission to use your PHI will continue indefinitely unless you withdraw your authorization 
in writing. 
WILL INFORMATION ABOUT ME BEING IN THIS STUDY BE USED AND SHARED?
This section explains how your medical and health records might be used and shared if you agree 
to participate in this study. If you do not sign this consent form, you cannot participate in the study.
During the study, the doctor and/or a member of the study staff will record health information 
about you (your “records”).  Your records include the data collected or reviewed during the study, 
including data about the physical examination, tests, and other procedures described above. Your 
records also will include identifying information, such as your name and address. 
By signing this consent form, you:

Allow the doctor and/or a member of the study staff to use your records to carry out this 
study.

Allow the doctor and/or a member of the study staff to share your records with the company 
paying for this study, Clear Creek Bio, Inc., their representatives, and other researchers 
involved in this study. These people will use these records to review the study and to check 
the safety of the study. 

Allow the doctor or sponsor to publish results of the study in medical journals or to present 
results at meetings. If this happens, your name will not be used. The doctor also may share 
all of your records and this signed consent form with government agencies, including the 
U.S. Food and Drug Administration (FDA), and government agencies in other countries. 
They may also share your records with regulatory agencies. These agencies may use these 
records to check the information collected in this study, to check how the study is carried 
out, and to check subjects’ safety. 
There are national and state laws that state that the doctor must protect the privacy of your records.  
However, you do not have a guarantee of absolute privacy because of the need to share your 
information as described above. After the doctor shares your records with the sponsor and others, 
the laws may no longer protect the privacy of your records. These records might be shared with 
other people who do not have to protect the privacy of your records. 
If you get hurt or sick possibly because of being in the study, and you seek medical treatment:

The doctor and sponsor may obtain study-related records from your or other health care 
providers to learn more about the effects of the study and your condition. 

Information about this study might be given to your insurance company or health care 
payer for the purpose of resolving your claim. 

The sponsor might give information that identifies you to its insurance carrier for the 
purpose of resolving your insurance claim. 
You have the right to see and copy your records in the doctor’s possession. However, by signing 
this consent form, you agree that you might not be able to review some of these records related to 


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the study until after the study is complete. At that time, your right to see these records will be 
restored.
This consent form has no expiration date.  If you do not cancel this consent form, then it will 
remain valid indefinitely.
You will receive a signed and dated copy of this consent for your records. 
WHAT WILL HAPPEN TO THE RESULTS OF THE RESEARCH STUDY?
The results of the study will be reported in a Clinical Study Report and may be published in 
scientific journals or presented in scientific meetings. The results of this study may also be used to 
support regulatory filings by the sponsor in support of the use of this medication for treating AML 
or other blood cancers or diseases. A description of this clinical trial will be available on 
http://www.ClinicalTrials.gov, as required by U.S. law. This web site will not include information 
that can identify you. At most, the web site will include a summary of the results. You can search 
this web site at any time.
WHO IS ORGANIZING AND FUNDING THE RESEARCH?
The study has been organized and funded by Clear Creek Bio, Inc. The investigational medicinal 
product (study drug) is being provided by Clear Creek Bio, Inc. 
DO I HAVE TO TAKE PART?
Your participation in this study is voluntary. You may decide not to participate, or you may leave 
the study at any time. Your decision will not result in any penalty or loss of benefits to which you 
are entitled. If you decide to take part, you will be asked to sign and date this consent form and 
given a copy to keep.   
Your participation in this study may be ended by the doctor, sponsor, the regulatory agencies or 
the Institutional Review Board (an IRB is a group of people who review the risks and benefits of 
a study).  They can end your participation for any of the following reasons without your consent:

if it is in your best interest;

you do not later consent to any future changes that may be made in the study plan; or

for any other reason. 
If this is the case, you will be given further instructions by the doctor for any final evaluations that 
may be needed. 
CONTACT FOR FURTHER INFORMATION
Any questions, concerns, or complaints about this study or if you feel you have had a 
research-related injury or reaction to the study drug should be directed to <insert PI name and 
contact information [24-hour contact]>.
If you have questions about your rights as a research subject or for questions, concerns or 
complaints about the research, you may contact:


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<Insert IRB name >
<Insert address>
<Insert telephone number> 
<Insert email if applicable> 
The IRB will not be able to answer some study-specific questions however, you may contact the 
IRB if the research staff cannot be reached or if you wish to talk to someone other than the research 
staff. 
Do not sign this consent form unless you have had a chance to ask questions and have received 
satisfactory answers to all of your questions. 
You will be given a signed and dated copy of this consent form to keep.
Thank you for taking the time to read this consent form. 


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Consent Form Signature Page
SUBJECT’S DATE OF BIRTH:  ______/______/______ 
mmm / dd
/ yyyy
Print Name of Investigator:
Please initial 
box:
1.
I confirm that I have read this consent form for the above study and have 
had the opportunity to ask questions. 
 
2.
I understand my participation is voluntary and I am free to withdraw at any 
time, without giving any reason, without my medical care or legal rights 
being affected.
3.
I understand that sections of any of my medical records may be looked at 
by responsible individuals from Clear Creek Bio, Inc. and/or its 
representatives or from regulatory authorities and the IRB where it is 
relevant to my taking part in research. I give permission for these individuals 
to have access to my records. 
 
4.
I understand that my data may be transmitted outside the country to 
countries with less strict data protection laws.
 
5.
I agree to take part in the above study. 
 
By signing this consent form, I have not given up any of my legal rights. 
Printed Name of Subject                       Signature of Subject 
Date 
Time
 
 
                                                                      
Printed Name of person conducting      Sign  
Date 
Time
informed consent discussion 
Original with Investigator File
1 copy for subject
1 copy for Subject’s Medical Records
 
 


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CONFIDENTIAL:  Clear Creek Bio, Inc. 
Addendum to Informed Consent for Short Messaging Service (SMS/text)
Reminders for Protocol CCB-01
 
 
TITLE:
A Phase 1b/IIa open-label, multi-center study to assess the safety, efficacy and 
pharmacokinetics of intrapatient dose-adjusted brequinar and inhibition of 
dihydroorotate dehydrogenase (DHODH) in adult subjects with acute myelogenous 
leukemia (AML)
PROTOCOL NO.: 
CCB-01 
SPONSOR: 
 
Clear Creek Bio, Inc. 
 
585 Massachusetts Avenue, 4th Floor, 
 
 
Cambridge MA 02139 
 
INVESTIGATOR: 
 
<insert PI name> 
Site(s):
<insert name> 
 
 
<insert address> 
STUDY-RELATED
PHONE NUMBER(S): <insert name(s)>
 
<insert number>
<insert alternate number (24-hour contact number)> 
VERSION and DATE: <e.g. CCB-01 Addendum ICF Version 1.0 31May2018> 
 
WHY AM I BEING ASKED TO SIGN THIS ADDENDUM TO THE CONSENT?
You are being asked to sign this addendum to the consent because you have agreed to participant 
in study CCB-01 and because it is very important for you to take your study medication at the 
correct times (e.g., Monday mornings and Thursdays evenings). One effective way to help you 
remember to take your medication on time is for you to receive a text reminder on your phone. 
The sponsor of the study (Clear Creek Bio, Inc.) is using an external vendor to generate a text 
message reminder that will be sent to your mobile device when it is time for you to take your study 
medication.  
 
VOLUNTARY NATURE OF THIS SERVICE
It is entirely optional for you to receive this service. Your decision to receive text message 
reminders for your medications will not in any way affect your ability to enroll in the study. You 
may also "opt out" at any time by responding "STOP" to the messages, or by contacting your study 
team. 


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DESCRIPTION OF THE NATURE OF THE DATA YOU WILL PROVIDE
You will provide your mobile device number to the study team who will then enter the number 
into the third-party vendor's system for sending out the text reminders.  
 
DESCRIPTION OF HOW THE DATA WILL BE USED
The only information that will be shared with the third-party vendor is your mobile device number 
and your study participant identification number. The system is set up so that one-way messages 
are sent from the service to you. You should not reply to the messages you receive except to "opt 
out". If you do send a message, the texting service will reply with a message indicating that the 
messages you may send are not being monitored. 
 
WHAT WILL THE MESSAGE SAY?
On the twice-weekly schedule (i.e., Monday mornings and Thursday evenings), you will receive a 
text with the following information: “It is time for you to take your CCB-01 study medication. 
Thank you for participating in this study.” You may delete this message after reading. 
 
DESCRIPTION OF HOW THIS DATA WILL BE SECURELY MANAGED
The mobile device number you provide to be used for these reminders will be managed in a manner 
that ensures the best possible security. The mobile device number will not be shared with any other 
third-party vendor or the sponsor of this study (Clear Creek Bio, Inc.). 
 
WHAT IF I DON’T HAVE A PHONE THAT CAN RECEIVE TEXT MESSAGES?
If you do not have a mobile phone or cannot receive text messages, you cannot participate in 
receiving these text message reminders. 
DISCLOSURES OF RISKS AND VULNERABILITIES
Although unlikely, it is possible that the unencrypted text messages you receive could 
inadvertently be seen by someone else. Because the messages are de-identified (your name will 
not appear), the most information that could be seen would be that you are participating in a study. 
You are not sending any information back to the third-party vendor, so nothing you send could be 
seen by mistake. 
 
The study team members are not responsible for any loss or breach of data that results from 
something beyond their control, e.g., you lose your mobile device containing text messages 
reminders, or a third-party vendor or host experiences a server/data breach.  
 
Standard text/data messaging rates apply to these messages, and because some mobile phone 
providers charge an additional fee for the sending and receiving of text messages, you might be 
charged additionally by your mobile phone provider if you choose to receive the text message 
reminders.  
 


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PROCESS FOR NOTIFYING PARTICIPANT IN CASE OF AN ACTUAL OR 
POTENTIAL SECURITY BREACH
If the third-party vendor that has your mobile device number experiences a breach or a potential 
breach, the third-party vendor will notify the sponsor of this study, Clear Creek Bio, Inc. The 
sponsor will notify the study team at each participating institution, and the study team will contact 
you regarding the possible risks associated with the breach/potential breach regarding your mobile 
device number.  
 
Consent Form SMS/Text Addendum Signature 
SUBJECT’S DATE OF BIRTH:  ______/______/_____
mmm / dd
/ yyyy
Print Name of Investigator: 
Please initial 
box:
1. I confirm that I have read this consent form for receiving text message 
medication reminders for the above study and have had the opportunity to 
ask questions. 
 
2. I understand my participation is voluntary in this text messaging service and 
I am free to withdraw at any time, without giving any reason, without my 
medical care or legal rights being affected. 
 
3. I give permission for the study team and third-party vendor to have access 
to my mobile device number. 
 
4. I agree to take part in the mobile device text message reminder for the above 
study.
 
By signing this consent form, I have not given up any of my legal rights. 
Printed Name of Subject                       Signature of Subject 
Date 
Time
 
                                                                      
Printed Name of person conducting      Sign 
Date 
Time
informed consent discussion
Original with Investigator File
1 copy for subject
1 copy for Subject’s Medical Records


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


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


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


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


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32. The benefits, risks, burdens and effectiveness of a new intervention must be tested against 
those of the best current proven intervention, except in the following circumstances:
The use of placebo, or no treatment, is acceptable in studies where no current proven 
intervention exists; or 
Where for compelling and scientifically sound methodological reasons the use of placebo 
is necessary to determine the efficacy or safety of an intervention and the patients who 
receive placebo or no treatment will not be subject to any risk of serious or irreversible 
harm. Extreme care must be taken to avoid abuse of this option. 
33. At the conclusion of the study, patients entered into the study are entitled to be informed about 
the outcome of the study and to share any benefits that result from it, for example, access to 
interventions identified as beneficial in the study or to other appropriate care or benefits. 
34. The physician must fully inform the patient which aspects of the care are related to the 
research. The refusal of a patient to participate in a study or the patient's decision to withdraw 
from the study must never interfere with the patient-physician relationship. 
35. In the treatment of a patient, where proven interventions do not exist or have been ineffective, 
the physician, after seeking expert advice, with informed consent from the patient or a legally 
authorized representative, may use an unproven intervention if in the physician's judgment it 
offers hope of saving life, re-establishing health or alleviating suffering. Where possible, this 
intervention should be made the object of research, designed to evaluate its safety and efficacy. 
In all cases, new information should be recorded and, where appropriate, made publicly 
available. 
22.10.2008 


PROTOCOL NUMBER:  CCB-01
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CONFIDENTIAL: Clear Creek Bio, Inc.
CCB-01 Approvals and Revision History
Protocol agreed by:
Clinical Development
Date:
PRINT NAME:
Research & Development
Date:
PRINT NAME:
Chemistry and Manufacturing/Quality
Date:
PRINT NAME:
Sponsor Representative
Date:
PRINT NAME:
Revision History/Amendments:
Version Number
Date
1.0
31 May 2018
2.0
04 June 2018
3.0
04 October 2018
4.0
11 October 2018
5.0
16 October 2018


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STUDY PROTOCOL
A Phase 1b/2a open-label, multi-center study to assess the safety, 
efficacy and pharmacokinetics of intrapatient dose-adjusted 
brequinar and inhibition of dihydroorotate dehydrogenase 
(DHODH) in adult subjects with acute myelogenous leukemia 
(AML)
Study No: CCB-01
Version Date: 16 October 2018
Sponsor:
Clear Creek Bio, Inc.
585 Massachusetts Avenue, 4th Floor,
Cambridge MA 02139
Sponsor Telephone: (617) 765-2252
Sponsor Facsimile: (617) 863-2082
IND Number: 138335
This confidential document is the property of Clear Creek Bio, Inc. No unpublished information contained herein 
may be disclosed without the prior written approval of Clear Creek Bio, Inc. This trial will be conducted in 
accordance with the ICH Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95, Jan.97), the Declaration 
of Helsinki (1964, 1975, 1983, 1989, 1996, 2000 (Note for Clarification 2002 & 2004) and 2008), FDA Regulations 
and locally applicable regulations.


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TABLE OF CONTENTS
1
SYNOPSIS..........................................................................................................................11
2
INTRODUCTION ..............................................................................................................27
2.1 Background: Acute Myeloid Leukemia.....................................................................27
2.2 Dihydroorotate dehydrogenase (DHODH) ................................................................27
2.3 Brequinar....................................................................................................................27
2.4 Rationale for the Planned Trial ..................................................................................29
2.4.1 Brequinar Starting Dose Selection ............................................................................... 29
2.5 Risk/Benefit of Brequinar ..........................................................................................30
2.6 Risks Associated with Participation in the Clinical Study.........................................30
2.7 Possible Interactions with Concomitant Medical Treatments ....................................31
2.7.1 CYP Interactions .......................................................................................................... 31
2.8 Steps to be Taken to Control or Mitigate Risks .........................................................31
3
TRIAL OBJECTIVES ........................................................................................................32
3.1 Primary Objective ......................................................................................................32
3.2 Secondary Objectives.................................................................................................32
3.3 Exploratory Objectives...............................................................................................32
4
TRIAL DESIGN.................................................................................................................33
5
TRIAL ENDPOINTS..........................................................................................................34
5.1 Primary Endpoint .......................................................................................................34
5.2 Secondary Endpoints..................................................................................................34
5.3 Exploratory Endpoints................................................................................................34
6
TRIAL POPULATION .......................................................................................................35
6.1 Number of Subjects....................................................................................................35
6.2 Inclusion criteria .........................................................................................................35
6.3 Exclusion Criteria.......................................................................................................35
6.4 Inclusion of Women and Minorities...........................................................................36


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CONFIDENTIAL:  Clear Creek Bio, Inc. 
7
STUDY TREATMENTS....................................................................................................37
7.1 Description of Brequinar: ...........................................................................................37
7.2 Treatment Administration ..........................................................................................37
7.3 Safety/Tolerability......................................................................................................37
7.3.1 Safety/Tolerability – Subject Level .............................................................................. 38
7.3.2 Safety/Tolerability – Cohort Level............................................................................... 39
7.3.3 Safety/Tolerability – Expansion Cohort....................................................................... 39
7.4 Cohort Starting Doses ................................................................................................39
7.5 Individual Dose Adjustment Guidelines ....................................................................40
7.5.1 DHO Threshold ............................................................................................................ 40
7.6 Medication/AE Diary.................................................................................................43
7.7 Bone Marrow Biopsy .................................................................................................43
7.8 Flow Cytometry..........................................................................................................43
7.9 Expansion Cohort.......................................................................................................43
7.10Study Drug Discontinuation .......................................................................................43
7.11Brequinar Pharmacokinetics (PK) / Dihydroorotate (DHO) Plasma Levels..............44
7.12Concomitant Medication/Treatment ..........................................................................44
7.12.1
Gastric pH............................................................................................................... 44
7.13Treatment Compliance...............................................................................................44
7.14Storage, Stability, Labeling and Packaging ...............................................................45
7.14.1
Storage and Stability............................................................................................... 45
7.14.2
Labeling and Packaging.......................................................................................... 45
7.14.3
Blinding and Randomization .................................................................................. 45
7.14.4
Unblinding/Expectedness ....................................................................................... 45
7.14.5
Study Drug Accountability ..................................................................................... 45
8
CONDUCT OF THE TRIAL..............................................................................................47
8.1 Ethical and Regulatory Considerations ......................................................................47
8.2 Informed Consent.......................................................................................................47


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8.3 Institutional Review Board / Ethics Committees.......................................................48
8.4 Schedule of Events .....................................................................................................48
8.5 Study Conduct............................................................................................................49
8.5.1 Screening Visit (Study Days -14 to -1) ........................................................................ 49
8.5.2 Cycle 1.......................................................................................................................... 49
8.5.3 Cycle 2 (and any Dose Adjustment Cycle) .................................................................. 50
8.5.4 Maintenance Dose Cycle (visit every 2 - 4 weeks) ...................................................... 51
8.5.5 Final Visit..................................................................................................................... 52
8.5.6 Follow Up Visit (2 weeks after Final Visit)................................................................. 52
8.5.7 Unscheduled Visits ....................................................................................................... 53
8.6 Compliance with Study Procedures ...........................................................................53
8.7 Early Withdrawal from the Study ..............................................................................53
8.8 Early Termination of the Study..................................................................................53
8.9 Short Messaging Service (SMS) Medication Reminders...........................................53
9
ADVERSE EVENT REPORTING.....................................................................................55
9.1 Classification of Causality .........................................................................................57
9.2 Classification of Severity ...........................................................................................57
9.3 Serious Adverse Event (SAE) Reporting ...................................................................57
9.4 Suspected Unexpected Serious Adverse Reactions (SUSARs) .................................59
9.5 Pregnancies.................................................................................................................59
9.6 Hematologic Adverse Events.....................................................................................60
9.7 Management of Myelosuppression ............................................................................61
9.8 Differentiation Syndrome...........................................................................................61
9.9 Tumor Lysis Syndrome (TLS)...................................................................................62
9.10Infection Prophylaxis .................................................................................................64
9.11Growth Factor Support ...............................................................................................64
9.12Management of Nausea, Vomiting, and Diarrhea......................................................64
10 STATISTICAL CONSIDERATIONS................................................................................65


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10.1Study Populations for Analysis..................................................................................65
10.2Safety Analyses ..........................................................................................................65
10.3Efficacy Analyses.......................................................................................................66
10.4Other Endpoints..........................................................................................................68
10.5Sample Size Considerations .......................................................................................69
10.6Randomization ...........................................................................................................69
10.7Pooling of Study Centers............................................................................................69
10.8Interim Analysis.........................................................................................................69
11 INVESTIGATOR RESPONSIBILITIES ...........................................................................70
11.1Investigator’s Performance ........................................................................................70
11.2Confidentiality............................................................................................................70
11.3Source Documentation ...............................................................................................70
11.4Data Collection ...........................................................................................................71
11.5Case Report Forms, Investigator’s Site File and Record Retention ...........................71
11.6Non-Protocol Research ..............................................................................................72
11.7Publication..................................................................................................................72
12 SPONSOR RESPONSIBILITIES ......................................................................................73
12.1General .......................................................................................................................73
12.2Indemnity ...................................................................................................................73
12.3Data Monitoring.........................................................................................................73
12.4Audit...........................................................................................................................73
12.5Confidentiality............................................................................................................74
12.6Finance .......................................................................................................................74
13 REFERENCES ...................................................................................................................75
14 APPENDICES ....................................................................................................................76
14.1APPENDIX A:  CCB-01 Schedule of Events............................................................76
14.2APPENDIX B: ECOG Performance Status Criteria ..................................................79
14.3APPENDIX C: Brequinar/DHO Plasma Sampling....................................................80


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14.4APPENDIX D: Common Terminology Criteria for Adverse Events (CTCAE) .......81
14.5APPENDIX E:  Sample Subject Consent Form.........................................................82
14.6Appendix G: Investigator’s Statement and Agreement............................................102
 


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LIST OF TABLES
Table 1.
Exceptions to Grade 3 Nonhematologic AEs ............................................................. 38
Table 2.
Intra-Subject Dose Adjustment .................................................................................. 41
Table 3.
Analysis Sets............................................................................................................... 65
Table 4.
Efficacy Analyses....................................................................................................... 66


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LIST OF FIGURES
Figure 1.
Dose Adjustment – Subject Level .............................................................................. 42
Figure 2.
Monitoring of Tumor Lysis Syndrome....................................................................... 63


PROTOCOL NUMBER:  CCB-01
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CONFIDENTIAL:  Clear Creek Bio, Inc. 
ABBREVIATIONS
Abbreviation
Definition 
µg
Microgram 
5-FU
5-Fluorouracil  
AUC
Area Under Curve
BID
Bis in die (two times a day)
C6min
Concentration at 6 minutes
CHO/HGPRT
Chinese hamster ovary cell/hypoxanthine-guanine phosphoribosyl-transferase
CL
Clearance 
ClR
Low Renal Clearance 
ClT 
Low Plasma Total Clearance 
CRh
Partial hematological response 
CRi
Incomplete hematological response
CT
Computerized Tomography
CYP
Cytochrome P450
DHO
Dihydroorotate 
DHODH
Dihydroorotate dehydrogenase
DLT(s) 
Dose-Limiting Toxicity(ies) 
DNA
Deoxyribonucleic Acid
ECGs 
Electrocardiograms 
ECOG 
Eastern Cooperative Oncology Group 
ED50
Median Effective Dose 
EORTC
European Organisation for the Research and Treatment of Cancer
ESR
Erythrocyte Sedimentation Rate
F
Bioavailability 
FDA
United States Food and Drug Administration 
g
Grams 
GI 
Gastrointestinal 
G-R 
Good Risk Patients
HPLC 
High-Performance Liquid Chromatography
HIPAA 
Health Insurance Privacy and Portability Act 
Hr 
Hour 
IB 
Investigator Brochure 
IP 
Intraperitoneal
IV 
Intravenous 
kg 
Kilograms 
l
Liters
LD(10, 50, 90) 
Lethal Dose(10%, 50%, 90%) 
LPS 
Lipopolysaccharide
M 
Molar
Mg 
Milligram
mL 
Milliliters 
MLED10
Mouse Equivalent Lethal Dose for 10% of population
mM 
Micromolar


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Mm
Millimeters
MRD
Minimal Residual Disease
MRT
Long Median Residence Time 
MS
Mucositis/stomatitis
MTD 
Maximum Tolerated Dose 
NCI
National Cancer Institute
NCI
United States National Cancer Institute
NMR
Nuclear Magnetic Resonance Spectroscopy
NSC
National Service Center
ORR
Overall Response Rate
PK
Pharmacokinetic(s)
PO
Per Orem 
P-R
Poor Risk Patients
PR 
Partial Response 
PS
Performance Status 
Pts.
Patients
QTcF 
Corrected QT interval by Fredericia
RDP2
Recommended Dose for Phase II
RNA
Ribonucleic Acid 
SC 
Subcutaneous  
SD
Standard Deviation
SE 
Standard Error 
SEM
Standard error of the means
SI 
Simulation Index
t½ 
Half-Life 
TEAE 
Treatment-emergent adverse event
USP
United States Pharmacopeia
UV
Ultraviolet 
V 
Volume 
Vd 
Volume of Distribution
VdSS 
Steady-State Volume of Distribution
WBC
White Blood Cell
WHO 
World Health Organization


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1
SYNOPSIS
IND 
138,335 
Title
A Phase 1b/2a open-label, multi-center study to assess the safety, efficacy 
and pharmacokinetics of intrapatient dose-adjusted brequinar and inhibition 
of dihydroorotate dehydrogenase (DHODH) in adult subjects with acute 
myelogenous leukemia (AML) 
Protocol 
CCB-01
Investigational 
Medicinal 
Product and 
Dosage 
Brequinar is available as 100 and 250 mg oral capsules to be taken every 3.5 
days with approximately 240 mL of water. Each subject’s mg/m2 dose will 
be calculated based on body surface area at study entry; actual dose will be 
rounded down to the nearest mg based on available oral capsule doses.  
Primary 
Objective
To determine the safety and tolerability of brequinar and the DHODH 
inhibitory level of brequinar in adult patients with AML.
Secondary 
Objectives 
 
 
To determine the overall response rate (ORR) including complete 
remission (CR), CR with incomplete hematologic recovery (CRi),
morphologic leukemia-free state (MLFS), and partial remission (PR) 
(criteria as defined in the ELN Guidelines, Döhner et al., 2017) and 
complete remission with partial hematological recovery (CRh). 
To assess the rate of overall survival (OS) and event-free survival (EFS). 
To evaluate duration of response.  
To characterize the pharmacokinetic (PK) profile of brequinar. 
To characterize the dihydroorotate (DHO) plasma levels of brequinar 
after oral dosing. 
Exploratory 
Objectives 
To assess the relationship between DHODH inhibition and the efficacy 
and safety of brequinar. 
To evaluate molecular and cellular biomarkers that may be predictive of 
antitumor level and/or treatment resistance including cytogenetics, 
molecular profiling, and flow cytometry during and after treatment.
To evaluate global gene expression profiles, DNA methylation profiles, 
and other potential prognostic markers to explore predictors of antitumor 
activity and/or resistance to treatment. 
Design 
This will be a Phase 1b/2a multi-center, open-label, non-randomized clinical 
trial to assess the safety, tolerability and efficacy of dose-adjusted brequinar 
in adult subjects with AML. The study will also assess the inhibition of 


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DHODH and the PK profile of brequinar in plasma. Subject dosing will be 
adjusted based on safety/tolerability and DHO level. 
Up to 27 subjects are planned to be entered in this trial: Cohort 1 will have 6 
subjects; two additional cohorts of 3 subjects each may be added if the 
Cohort 1 starting dose requires adjustment. Cohorts 2 and 3 may be 
expanded to 6 subjects using a 3 + 3 design if required by safety assessments 
as described in Section 7.3.2. Following completion of enrollment in the 
starting dose-adjustment part of the study, an expansion cohort of 
approximately 15 subjects will be enrolled with a starting dose of the highest 
tolerated dose from Cohorts 1 – 3. Safety and tolerability will be assessed 
utilizing physical examination, vital sign measurements, safety laboratory 
testing, 12-lead ECGs, and bone marrow sampling, and adverse event 
reporting. Bone marrow sampling (bone marrow aspirate and core biopsy)
will also be utilized for efficacy. DHO level will be measured using a 
validated assay. PK will be analyzed using standard PK parameters. 
Dosing will continue for up to 12 months in the absence of unacceptable 
toxicity or disease progression.  
Primary 
endpoints: 
Safety/tolerability and DHO level relationship with safety and 
therapeutic brequinar levels   
Secondary 
endpoints: 
Rates of treatment-emergent adverse events. 
Overall Response Rate (ORR) including CR, CRi, CRh, MLFS, or PR. 
Event free survival (EFS). 
Duration of response. 
PK profile of brequinar. 
DHO plasma profile. 
Exploratory 
endpoints: 
Relationship between DHODH inhibition and the efficacy and safety of 
brequinar. 
Antitumor level based on molecular and cellular biomarkers including 
cytogenetics, molecular profiling, and flow cytometry during and after 
treatment. 
Global gene expression profiles, DNA methylation profiles, and other 
potential prognostic markers to explore predictors of antitumor activity 
and/or resistance to treatment 
Sample Size: 
Up to 27 subjects  


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Number of 
Sites: 
3 – 5 
Study Period:
An enrollment period of 18 - 24 months is expected.
Inclusion 
Criteria: 
 
1. Willing and able to provide written informed consent for the trial. 
2. Patients 18 years of age or older, with relapsed/refractory AML by 
World Health Organization classification who have exhausted 
available therapy. 
3. ECOG Performance Status 0 to 2. 
4. 12-lead ECG with no clinically unacceptable findings; adequate 
cardiac function/NYHA Class 0 to 2. 
5. Adequate hepatic function (unless deemed to be related to underlying 
leukemia). 
1.
 
2.
 
3.
 
6.
mL/min based on the Cockcroft-Gault equation. 
7. In the absence of rapidly proliferative disease, the interval from prior 
leukemia-directed therapy to first dose of study drug will be at least 7 
days for cytotoxic or non-cytotoxic (immunotherapy) agents. Hydrea 
is allowed up to 48 hours prior to the first dose for patients with 
rapidly proliferative disease.  
8. The effects of brequinar on the developing human fetus are unknown. 
For this reason, women of child-bearing potential and men must 
agree to use adequate contraception (hormonal or barrier method of 
birth control; abstinence) prior to study entry and for the duration of 
study participation. Should a woman become pregnant or suspect she 
is pregnant while she or her partner is participating in this study, she 
should inform her treating physician immediately. Men treated or 
enrolled on this protocol must also agree to use adequate 
contraception prior to the study, for the duration of study 
participation, and for 90 days after completion of brequinar 
administration.
9. Male subjects must agree to refrain from sperm donation from initial 
study drug administration until 90 days after the last dose of study 
drug.


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Exclusion 
Criteria: 
1. Patients in need of immediate leukapheresis. 
2. Any concurrent uncontrolled clinically significant medical condition, 
laboratory abnormality, or psychiatric illness that could place the 
participant at unacceptable risk of study treatment.
3. QTc interval using Fridericia’s formula 
Participants with a bundle branch block and prolonged QTc interval 
may be eligible after discussion with the medical monitor.
4. Pre-existing liver disease.
5. The use of other chemotherapeutic agents or anti-leukemic agents is 
not permitted during study with the following exceptions:
a.
Intrathecal chemotherapy for prophylactic use or maintenance of 
controlled CNS leukemia. 
6. Use of hydroxyurea for the purpose of leukemic cytoreduction may 
be allowed during the first 2 weeks of therapy if in the best interest of 
the participant and is approved by the medical monitor. Hydroxyurea 
can be used to treat leukocytosis if concurrent with and thought to be 
associated with presumed differentiation syndrome.  
7. Presence of graft versus host disease (GVHD) which requires an 
systemic corticosteroids (e.g. cyclosporine or other calcineurin 
inhibitors or other immunosuppressive agents used for GVHD).
8. Active cerebrospinal involvement of AML.
9. Diagnosis of acute promyelocytic leukemia (APL) 
10. Clinically active hepatitis B (HBV) or hepatitis C (HCV) infection.
11. Severe gastrointestinal or metabolic condition that could interfere 
with the absorption of oral study medication. 
12. Prior malignancy, unless it has not been active or has remained stable 
for at least 2 years. Participants with treated non-melanoma skin 
cancer, in situ carcinoma or cervical intraepithelial neoplasia, 
regardless of the disease-free duration, are eligible if definitive 
treatment for the condition has been completed. Participants with 
organ-confined prostate cancer with no evidence of recurrent or 
progressive disease are eligible if at the active surveillance stage, 
hormonal therapy has been initiated, or the malignancy has been 
surgically removed or treated with definitive radiotherapy.
13. Nursing women or women of childbearing potential (WOCBP) with a 
positive urine pregnancy test. 


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Treatment 
Subjects will self-administer oral brequinar twice weekly (every 84 hours +/- 
6 hours). Treatment cycles will be 2 weeks. Visits will take place at least 
every 2 weeks through 3 months; visits thereafter will be every 2 – 4 weeks 
at the discretion of the investigator at each site. Inter-cohort and intra-subject 
dose adjustments may occur throughout the study as outlined in the sections 
below. Subjects in Cohort 1 may not escalate beyond the initial 500 mg/m2
starting dose.
Procedures
Screening Visit (Study Days -14 to -1)
These procedures must be completed within the 14 days prior to starting 
dosing. Obtain the subject’s written informed consent, then collect baseline 
information:
-
Demographics (height, weight, date of birth, gender, race, ethnicity)
-
Pertinent medical/surgical history (including AML diagnosis and 
laboratory and clinical evidence of progression, previous AML 
treatment, and any available chromosomal and mutational testing 
results per institutional guidelines) 
-
Concomitant medications. 
-
Physical examination (including weight).  
-
Vital signs (heart rate, respiratory rate, blood pressure, body 
temperature).  
-
Pregnancy test for women of childbearing potential (WOCBP).  
-
ECOG performance assessment.  
-
Hematology/chemistry. 
-
12-lead ECG to assess cardiac function. 
-
Bone marrow sampling  
-
Confirm subject meets all inclusion and no exclusion criteria. 
Treatment
The treatment period begins with Cycle 1, Day 1 of the first 2-week dosing 
cycle. 
Cycle 1 Day 1:
-
Collect any adverse events or new concomitant medications since 
Screening.  
-
Draw samples for baseline (pre-dose) brequinar/DHO, flow 
cytometry, and hematology/chemistry. 
-
Conduct physical examination (including weight), vital signs, urine 
pregnancy test for WOCBP, and 12-lead ECG (if >4 weeks since 
previous ECG or pregnancy test or per institutional guidelines).
-
Review results and confirm subject remains eligible for the study. 
-
Determine subject’s starting dose based on the respective cohort 
mg/m2 starting dose. 
-
Dispense study medication.  


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-
Subject is to take the first dose at the clinic and remain for 
brequinar/DHO sampling. Collect brequinar/DHO samples at 1, 2, 4, 
and 6 hours post dose.
-
Process and store brequinar/DHO samples per the supplied laboratory 
manual.
-
Dispense the subject’s calendar/diary. The diary will collect 
dates/times of study medication administration and AEs/new 
concomitant medications.
-
Enroll subject for text message reminders if the subject consents to 
that service.  
-
Ship the flow cytometry sample per the supplied laboratory manual. 
Cycle 1 Day 2:  
-
Collect 24h post dose brequinar/DHO and flow cytometry samples. 
Check the diary/elicit information about AEs/new concomitant 
medications since the last visit. 
-
Process and store brequinar/DHO samples per the supplied laboratory 
manual. 
-
Ship the flow cytometry sample per the supplied laboratory manual. 
Cycle 1 Day 3:  
-
Collect 48h post dose brequinar/DHO and flow cytometry samples. 
Check the diary/elicit information about AEs/new concomitant 
medications since the last visit.  
-
Process and store brequinar/DHO samples per the supplied laboratory 
manual. 
-
Ship the flow cytometry sample per the supplied laboratory manual. 
Cycle 1 Day 4:  
-
Collect 72h post dose brequinar/DHO samples. Check the diary/elicit 
information about AEs/new concomitant medications since the last 
visit. 
-
Process and store brequinar/DHO samples per the supplied laboratory 
manual. 
Cycle 1 Day 8:  
-
Vital signs. 
-
Check the diary/elicit information about AEs/new concomitant 
medications since the last visit. 
-
Prior to the morning dose, collect brequinar/DHO samples 
(approximately 84h post the second dose of Cycle 1) and 
hematology/chemistry samples, then have subject take study 
medication.  
-
Process and store brequinar/DHO samples per the supplied laboratory 
manual.


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-
Notify DHO assay laboratory of incoming shipment and ship Cycle 1 
brequinar/DHO samples (samples from Days 1, 2, 3, 4 and 8).
Cycle 2 (and any Dose Adjustment Cycle)
Repeat this visit as needed whenever any dose adjustment is required.
Day 1: 
-
Collect unused study medication and check the diary/elicit 
information about AEs/new concomitant medications since the last 
visit.  
-
Take vital signs and perform physical examination (including weight).
-
Collect pre-dose brequinar/DHO samples (approximately 84h post the 
fourth dose of the previous cycle) and hematology/chemistry samples.  
-
Process and store brequinar/DHO samples per the supplied laboratory 
manual. 
-
Review laboratory results/safety information and determine whether 
the subject should adjust the dose (based on acceptable safety and 
DHO level), continue with the current dose or hold study medication 
(unacceptable safety) per the guidelines below.  
-
If dosing will continue, dispense study medication.  
-
Dispense calendar/diary. 
-
Manage text message reminders as needed (as a default do nothing, 
pause if study medication is put on hold, and restart if study 
medication is restarted) 
Day 8: 
-
Collect and check the diary/elicit information about AEs/new 
concomitant medications since the last visit. 
-
Vital signs. 
-
Collect pre-dose brequinar/DHO and hematology/chemistry samples. 
-
Perform bone marrow sampling (window ±7 days). 
-
If the subject is being dosed (i.e., has acceptable safety), have the 
subject take the morning dose.  
-
Process and store brequinar/DHO samples per the supplied laboratory 
manual.
-
If the subject’s medication was held, review safety information and 
determine whether dosing can resume. If dosing can resume, 
determine dose, dispense adequate medication for 4 doses and have 
the subject take the morning dose. 
-
Continue to withhold study drug if safety remains unacceptable.
-
Dispense calendar/diary. 
-
Manage text message reminders as needed (as a default do nothing, 
pause if study medication is put on hold, and restart if study 
medication is restarted)


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-
Notify DHO assay laboratory of incoming shipment and ship 
brequinar/DHO samples (samples from current cycle's Days 1 and 8).
 
Subjects may undergo dose adjustments at any time using the guidelines 
presented in Section 7 of the protocol. Subjects with acceptable safety can 
continue to escalate every 2 weeks by 150 mg/m2 increments through 800 
mg/m2, with the exception of Cohort 1 subjects who may not escalate above 
the 500 mg/m2 starting dose. Subjects with unacceptable safety can continue 
to undergo dose reductions of 75 mg/m2 with no lower limit. Re-escalation to 
a dose previously shown as not tolerated for an individual subject is not 
permitted for these subjects.
Dose adjustments are permitted throughout the study (except for the 
restriction of no escalation in Cohort 1) for an individual subject based on 
safety, DHO level, and clinical response with an upper limit of 800 mg/m2.
Maintenance Dose Cycle (visit every 2 - 4 weeks)
Once a subject reaches a stable or maintenance dose (see Figure 1), the 
subject will be in the Maintenance Dose Cycle. 
In the first 3 months from starting study drug, the Maintenance Dose Cycle 
procedures will occur every 2 weeks (with the exception of bone marrow 
aspiration as discussed below). After completing 3 months from starting 
study drug, subjects may come to the clinic for a Maintenance Dose Cycle 
visit every 2 - 4 weeks (visit interval at the investigator’s discretion).
A subject may still move into a Dose Adjustment Cycle after a maintenance 
dose if required for a change in safety, DHO level or clinical response
(Figure 1).  
Day 1:
-
Collect unused study medication and check the diary/elicit 
information about AEs/new concomitant medications since the last 
visit. 
-
Collect pre-dose brequinar/DHO and hematology/chemistry samples.  
-
Conduct physical examination, vital signs, urine pregnancy test for 
WOCBP, 12-lead ECG and bone marrow sampling (note that bone 
marrow is collected on study Day 22 (C2D8 ± 7 days), at Day 43, and 
then every 12 weeks or per institutional guidelines; the Day 43 sample 
will be assessed for hematological toxicity).  
-
Review the laboratory results/safety information and determine 
whether the subject should maintain current dose (acceptable safety) 
or hold study medication (unacceptable safety).  
-
Dispense study medication. 
-
Dispense calendar/diary. 


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-
Manage text message reminders as needed (as a default do nothing, 
pause if study medication is put on hold, and restart if study 
medication is restarted) 
-
Notify DHO assay laboratory of incoming shipment and ship 
brequinar/DHO samples.
Final Visit
This visit is to take place when a subject is discontinuing from the study.
-
Collect and check the diary/elicit information about AEs/new 
concomitant medications since the last visit.  
-
Collect brequinar/DHO and hematology/chemistry samples.  
-
Collect unused study medication. 
-
Conduct physical examination, vital signs, urine pregnancy test for 
WOCBP, 12-lead ECG and bone marrow sampling (do not collect 
bone marrow or perform ECG if < 4 weeks since previous bone 
marrow sample or ECG obtained).  
-
Review the safety information and determine whether the subject has 
acceptable safety or unacceptable safety. 
-
Notify DHO assay laboratory of incoming shipment and ship 
brequinar/DHO samples.  
-
Stop text message reminders. 
Follow Up Visit (2 weeks after Final Visit)
-
Contact subject to elicit information about AEs/new concomitant 
medications since the last visit. 
Survival information will be collected while the study is ongoing. 
Unscheduled Visits
Unscheduled visits and tests to assess AEs are permitted as needed. 
Safety/ 
Tolerability 
Safety/Tolerability – Subject Level
Grade 3, treatment-emergent, study-drug-related, non-hematologic adverse 
events. Due to the expected hematologic profile associated with AML, 
hematologic AEs of any grade will not be considered dose-limiting during 
the first 42 days of dosing. Exceptions to the non-hematologic Grade 3 
criterion are provided in the table below.  
Exceptions to Grade 3 Nonhematologic AEs 
Condition
Exception Description 
Nausea/ 
Emesis 
Grade 3 nausea and/or emesis resolving to less than or equal 
to Grade 2 or baseline within 1 week after the use of an 
optimal antiemetic regimen based on standard practice.


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Diarrhea 
Grade 3 diarrhea resolving to less than or equal to Grade 1 or 
baseline within 1 week after receiving the maximal 
supportive therapy based on standard practice.
Laboratory 
abnormalities 
Asymptomatic Grade 3 laboratory abnormalities that are not 
considered to be clinically significant.
Mucositis 
Grade 3 with duration < 2 weeks 
Fatigue 
Grade 3 with duration < 2 weeks 
For the expansion cohort, the definition of unacceptable safety is expanded 
Dosing is to be held for subjects who experience hepatotoxicity; dosing may 
hepatotoxicity after resuming dosing, dosing is to be discontinued for that 
subject.
Hematologic Toxicity
After the subject has completed the first 42 days of treatment, the definition 
of unacceptable safety expands to include hematologic AEs defined as 
prolonged neutropenia with ANC < 500 from the start of therapy in the 
absence of disease, 
, and/or 
thrombocytopenia, with a hypocellular bone marrow and no greater than 5% 
hematologic AE for the definition of unacceptable safety. Febrile 
neutropenia is also excluded from the DLT definition for this population.  
For clinic visits when bone marrow sampling is scheduled, the timing of the 
bone marrow sampling can be adjusted to ensure that the results are available 
at the time of the clinic visit. 
Safety/Tolerability – Cohort Level
Acceptable safety/tolerability at the cohort level is defined below:
a)
safety/tolerability 
leading 
to 
dose 
reduction 
or 
treatment 
discontinuation (a dose limiting toxicity or DLT), then that dose is 
considered to have unacceptable safety/tolerability and the previous 
dose which was safe/tolerated must be considered as the highest 
safe/tolerated dose.  
b) If 1 out of 3 subjects at a dose level experiences a DLT, then 3 
additional subjects will be added to the cohort and treated at the same 
dose that led to the DLT. Upon cohort expansion to 6 subjects, if a total 
considered a safe/tolerated dose. However, if >2 out of 6 subjects at a 
dose level experience a DLT, then that dose is considered to have 
unacceptable safety/tolerability and the previous dose which was 
safe/tolerated must be considered as the highest safe/tolerated dose.


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Cohort Starting 
Doses 
Cohort 1 will treat 6 subjects at 500 mg/m2 twice weekly. No dose escalation 
is permitted for Cohort 1 subjects, but the dose may be reduced for an 
individual subject in this cohort if the subject experiences unacceptable safety. 
After all subjects in Cohort 1 have completed a 42-day treatment period, up to 
two additional cohort(s) of 3 subjects each will be added with the starting doses 
adjusted (escalated or de-escalated) based on both safety/tolerability and 
adequacy of DHO level results in Cohort 1. As noted above, additional 
subjects may be added to each of these cohorts if safety needs to be further 
explored.
If all subjects in a cohort have acceptable safety at a dose level, the next 
cohort’s starting dose may be escalated by 150 mg/m2. If the safety rules are 
not met at a cohort’s starting dose, the next cohort’s starting dose will be 
reduced to the highest dose found to be safe/tolerated in the previous cohort. 
The planned upper limit for cohort starting dose is 800 mg/m2. There is no 
lower limit. 
See the “Intra-subject dose adjustment” section for individual subject dosing 
adjustment criteria.
Expansion 
Cohort 
Once a dose has been reached that has adequate DHO level and acceptable 
safety/tolerability, approximately 15 subjects will be added starting at the 
highest safe/tolerated dose identified in the earlier cohorts. Decisions about 
adequacy of DHO threshold level will be made following review of these 
data from each cohort. These subjects may also undergo individual dose 
adjustment. See Section 7.3.3 for the expansion cohort safety rules.
Individual Dose 
Adjustment 
Guidelines
With the exception of subjects in Cohort 1 whose dose may not be escalated 
above the 500 mg/m2 starting dose, intra-subject dose adjustment will be 
considered every 2 weeks depending on safety and DHO levels. There is a 
maximum of 2 dose adjustments for each subject within the first 42 days of 
initiating treatment. Each subject’s dose can be escalated, maintained (stable 
dose), held then reduced, or discontinued. The highest dose planned is 800 
mg/m2, however, this upper limit may be adjusted depending on safety, DHO 
level, and clinical response. There is no lower limit planned. 
As noted above, safety will be a key part of determining dose adjustments. 
Subjects who resume dosing at a lower dose after experiencing unacceptable 
safety may not undergo later dose escalations beyond the dose where the 
unacceptable safety occurred. 
Each subject will continue dosing twice weekly at the individually adjusted 
dose for up to 12 months in the absence of unacceptable toxicity or disease 
progression. Intra-subject dose adjustment is permitted at any time 
throughout the study based on safety/tolerability and DHO level (with the 
exception of no escalation for Cohort 1 subjects). Subjects who discontinue 


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due to unacceptable safety/tolerability or die prior to Day 42 will not be 
replaced. 
Intra-subject dose adjustment increments and duration of dosing may be 
revised from planned amounts after each preceding cohort’s safety, DHO 
plasma levels and bone marrow results have been reviewed.  
Each subject’s baseline DHO sample will be obtained at C1D1 prior to 
dosing. Dose adjustment decisions based on DHO will be determined by 
DHO trough level (i.e., DHO level obtained pre-dose D8 of the previous 
cycle). The initial target for “adequate” trough DHO level will be set at 100 
ng/mL. This target may be adjusted during the study depending on safety or 
efficacy signals observed during the study. As described below, dose 
adjustments are also based on safety and whether the dose has reached the 
planned upper limit (currently planned to be 800 mg/m2). 
The intrasubject dose-adjustment criteria are presented below.  
Intra-subject Dose Adjustment Criteria*
Acceptable 
Safety/Tolerability?
(see safety definition 
above)
Adequate 
DHO Level?
Planned Intra-Subject Dose 
Adjustment
Yes
Yes
Maintain; continue at same dose. 
Yes
No 
Escalate by 150 mg/m2 for the next 2-
week cycle up to a maximum of 800 
mg/m2. 
No 
Regardless of 
DHO 
Hold two doses (one week), then reassess 
-
escalate dose by 75 mg/m2 and resume 
dosing. If AE has not resolved, reassess 
again in one week.  
weeks after dosing held, discontinue 
further dosing. Subject will remain in the 
study for safety follow up for 42 days 
after last dose of study drug or until AEs 
have resolved or become stable. 
*Note that Subjects in Cohort 1 may not escalate above the initial 500 mg/m2 
starting dose and may have dose reductions based on safety only.
Brequinar/DHO  Plasma brequinar/DHO samples are to be obtained for each subject for the 
first study dose (Cycle 1 Dose 1 for that subject). Sample scheduling is 0 
hours (prior to dosing), and post dose at 1, 2, 4, 6, 24, 48, and 72 hours. Note 
that this schedule does not apply to subjects in the expansion cohort who will 
have trough sampling only prior to the start of each two-week cycle.
A brequinar/DHO trough sample is to be obtained prior to dosing on Day 8 
(C84, 84 hours after the Cycle 1 Day 4 dose) of Cycle 1, and prior to dosing 
on Days 1 and 8 of Cycles 2 and 3.  


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The 84-hour post dose brequinar/DHO sample is to be repeated prior to 
dosing at the beginning of each 2-week cycle and at the Final Visit. This 
sampling schedule also applies for the expansion cohort subjects.  
Statistical 
Analysis 
A separate, detailed statistical analysis plan (SAP) will be finalized prior to 
locking the database. All analyses of safety and anti-leukemic activity for 
this open-label, early Phase study will be descriptive in nature and presented 
by dose group and overall, as appropriate, for the dose-adjustment phase and 
the expansion phase. Procedures for accounting for missing, unused and 
spurious data will be described in the SAP.   
Summaries for quantitative variables will include the mean, median, 
quartiles, standard deviation and error, minimum, and maximum. For 
qualitative variables, the summaries will include the number and percentage 
of subjects for each outcome, and the exact 95% CI, when appropriate. No 
hypothesis testing will be performed. Any statistical testing will be 
considered exploratory and descriptive. All computations will be performed 
using SAS® (Version 9.3 or higher).
Subject disposition, subject demographics and baseline characteristics will be 
summarized. Subject data listings will also be provided.  
All safety analyses will be performed on the Safety Analysis Set.  Safety and 
tolerability will be assessed in terms of AEs, SAEs, safety laboratory data, 
physical examinations, vital signs, 12-lead ECGs and bone marrow 
sampling.  
Adverse event data will be descriptively evaluated. All AEs will be listed. 
The incidence and duration of treatment-emergent adverse events (TEAEs), 
defined as AEs occurring after the first dose of study treatment through 30 
days after the last dose of study treatment will be tabulated by Medical 
Dictionary for Regulatory Activities (MedDRA) preferred term and system 
organ class, and by severity and relationship to study treatment. All 
laboratory results, vital sign measurements, ECGs and bone marrow 
assessments will be summarized using appropriate descriptive statistics.
Efficacy analysis is described below. 
Assess anti-leukemic activity by ELN Guidelines including CRh, as follows:  

Overall Response rate (ORR) – the proportion of subjects in the 
Efficacy Analysis Set with a best overall response of CR, CRi, CRh, 
MLFS and PR  

Complete Remission (CR) rate – the proportion of subjects in the 
Efficacy Analysis Set with a best overall response of CR 

Complete Remission with Incomplete Hematologic Recovery (CRi) 
rate – the proportion of subjects in the Efficacy Analysis Set with a 
best overall response of CRi 


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
Complete remission with partial hematological recovery (CRh) –
the proportion of subjects in the Efficacy Analysis Set with a best 
overall response of CRh

Morphologic Leukemia Free State (MLFS) rate – the proportion of 
subjects in the Efficacy Analysis Set with a best overall response of 
MLFS

Partial Remission (PR) rate – the proportion of subjects in the 
Efficacy Analysis Set with a best overall response of PR 

Event-free survival (EFS) – the interval between first brequinar 
 reappearance of blasts 
in blood, or development of extramedullary disease), disease 
progression, or death

Overall survival (OS) – the time from first dose of brequinar to date 
of death or last known alive date
For ORR and other endpoints defined as proportions, estimated response 
rates and two-sided exact binomial 95% CIs will be provided. The 
distributions of EFS and other time-to-event endpoints will be summarized 
using the Kaplan-Meier method. Time to event analyses will be from first 
dose of brequinar. Censoring rules for time-to-event endpoints will be 
described in the SAP. 


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STUDY PERSONNEL
SPONSOR CONTACT
Name:
Title:
Address:
Telephone No.: 
Fax No.:
E-mail:
Barbara Powers, MSN, Ph.D. 
Clinical Operations 
Clear Creek Bio, Inc.
585 Massachusetts Avenue, 4th Floor, 
Cambridge, MA 02139
484-686-0545
617-863-2082
bpowers@clearcreekbio.com
SPONSOR MEDICAL CONTACT
Name: 
Title:
Address:
Telephone No.: 
24-hour Safety No.:
E-mail:
Robert Sims, MD
Senior Medical Director / Medical Monitor 
Novella Clinical
1700 Perimeter Park Drive 
Morrisville, NC 27560
614-721-2630
1-866-758-2798 or 919-313-7111
robert.sims@novellaclinical.com; 
YYA36071medmon@novellaclinical.com
Medical Monitor Fax No.: 
SAE Reporting Fax:
SAE Reporting email: 
206-826-0483
 919.313.1412 (US Toll-free:  
1-866-761-1274) safety-
inbox@novellaclinical.com 
LEAD INVESTIGATOR
Name:
Title:
Affiliation: 
Telephone No.: 
E-mail:
Amir Fathi, MD
Assistant Professor of Medicine 
Massachusetts General Hospital 
617-724-1124
afathi@mgh.harvard.edu


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SUPPORT SERVICES
CRO Project Manager
Name:
Company:
Address:
Telephone No.: 
Mobile No.:
Fax No.:
E-mail:
Daniel Ferrone
Novella Clinical 
1700 Perimeter Park Drive 
Morrisville, NC 27560
919-972-7158
704-806-7219
919-710-8769
dferrone@novellaclinical.com
Data Management/eCRF PROVIDER
Name:
Company:
Address:
Telephone No.: 
Help Desk: 
Help Desk E-mail: 
Kari Hayden
Novella Clinical 
1700 Perimeter Park Drive 
Morrisville, NC 27560 
919-972-2397
1-866-342-0693
sitesupport@novellaclinical.com
STATISTICAL ANALYSIS
Name:
Title:
Telephone No.: 
Fax No.:
E-mail:
Young Choy 
Senior Biostatistician 
919-972 -7423
919-710-8769
ychoy@novellaclinical.com
STUDY DRUG HOLDING COMPANY
Name:
Address:
Telephone No.: 
Email: 
Almac Clinical Services 
25 Fretz Road
Souderton, PA 18964 
215-660-8500
clinicalservices@almacgroup.com


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2
INTRODUCTION
2.1 Background: Acute Myeloid Leukemia
Acute myeloid leukemia (AML) is a malignant disorder of immature hematopoietic cells, 
characterized by differentiation arrest and rapid proliferation of abnormal myeloid precursors. 
These abnormal cells accumulate in the bone marrow and interfere with the production of normal 
blood cells. More than 20,000 people are diagnosed with AML per year in the United States (US) 
(SEER, 2015 [1]). The median age at diagnosis is 67 years. 
Although there have been recent advances including midostaurin, enasidenib, CPX-351, 
gemtuzumab ozogomycin and venetoclax, outcomes for patients with AML remain poor. With 
modern treatment regimens, expected complete remission (CR) rates are 60-70%, but long-term 
cure rates are 15-25%. Younger patients (i.e. those 50 years of age or younger) with diploid 
karyotypes have a CR rate of 70-80% and cure rates of 20-25%, while older patients and/or those 
with adverse cytogenetics have CR rates of 35-50% and cure rates of < 10%.1 It is therefore critical
to improve both the remission rate and the durability of remission in AML patients of all ages.
2.2 Dihydroorotate dehydrogenase (DHODH)
Dihydroorotate dehydrogenase (DHODH) catalyzes the fourth step in pyrimidine synthesis, the 
conversion of dihydroorotate (DHO) to orotate. The enzyme is located on the inner mitochondrial 
membrane and transfers electrons between DHO and complex III of the electron-transport chain 
via the reduction of its ubiquinone (coenzyme Q10) cofactor.  
DHODH is a ubiquitous, essential enzyme. The Miller syndrome, a rare autosomal recessive 
disorder in which patients have inherited hypomorphic mutations in both alleles of DHODH, 
results in multi-organ dysfunction (Ng et al., 2010 [2]). Two weak inhibitors of human DHODH 
are approved for clinical use. Leflunomide, a pro-drug, is used in the treatment of patients with 
rheumatoid arthritis. Its active form, teriflunomide, is marketed for multiple sclerosis. Leflunomide 
is known to affect erythroid differentiation of K562 cells in vitro, via the depletion of uridine 
triphosphate (UTP) and cytidine triphosphate (CTP) ribonucleotides (Huang et al., 2002 [3]). 
Despite the connection between bone marrow level, blood cell differentiation and DHODH, 
leukemia models of leflunomide have not been very promising. Leukemic mice treated with 
leflunomide demonstrated no reduction in leukemic burden and experienced significant weight 
loss and lethargy. 
Recent nonclinical studies have demonstrated that inhibition of DHODH can overcome myeloid 
differentiation arrest (Sykes et al., 2016 [4]). The mechanism through which a reduction in de novo 
pyrimidine biosynthesis modulates myeloid differentiation is not clear. The differentiation effect 
of DHODH inhibitors appears to involve a combination of inhibition of nucleic acid synthesis, 
cell-cycle arrest, and changes in the post-translational glycosylation of important protein targets.  
2.3 Brequinar
It is well known that brequinar is a potent inhibitor of DHODH. Brequinar is one of more than 300 
quinoline-carboxylic acid derivatives prepared in an analog synthesis program in the 1980s, which 
was started after it was found that a compound of this class had antitumor activity. Brequinar was 
selected by DuPont for further development as a potential clinical drug because of its activity 


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against experimental tumors and because its water solubility made it relatively straightforward to 
formulate. Ultimately, the rationale to use brequinar for the treatment of multiple solid tumors did 
not translate into efficacy after extensive clinical development and the project was terminated by 
DuPont in 1994. Clear Creek Bio exclusively licensed the historic data from Bristol Myers Squibb 
(that acquired DuPont in 2001). 
Sykes et al. showed that brequinar’s pro-myeloid differentiation activity might be useful for the 
treatment of AML. Utilizing a high throughput screening technique, brequinar was identified as a 
compound that overcame arrest of myeloid differentiation. Brequinar triggers myeloid 
differentiation in vitro and in vivo. Brequinar was highly active in vivo, as demonstrated in 
syngeneic murine AML models (HoxA9+Meis1 and MLL/AF9) as well as xenotransplant AML 
models (THP1, HL60, MOLM13, OCI/AML3). In an aggressive MLL/AF9 murine model of 
AML, treatment with brequinar promoted myeloid differentiation, reduced leukemic cell burden, 
and improved overall survival. Brequinar also led to a reduction in the number of leukemia stem 
cells, reduced colony-formation level, and depleted the number of leukemia-initiating cell level.  
In addition, Sykes and colleagues demonstrated that treatment with brequinar was better-tolerated 
and more effective than treatment with cytotoxic chemotherapy in animal models. Brequinar was 
given for many weeks without cumulative toxicity. The effect of brequinar and DHODH inhibition 
on normal cells was also assessed through study of competitive bone marrow transplantation 
assays. Mice were treated with brequinar, 5-fluorouracil (5-FU), or induction chemotherapy, and 
their bone marrow was transplanted in competition (1:1) with normal (untreated) bone marrow to 
gauge the effect of therapy on hematopoietic stem cell (HSC) function. The fitness of HSCs from 
mice treated with brequinar were functionally equivalent to those of untreated mice when 
compared to that of HSCs exposed to 5-FU and induction chemotherapy, which promoted a 
marked decrease in fitness.  
Sykes et al. administered brequinar at a dose and schedule (every 72 hours) that was non-toxic to 
the animals yet led to eradication of the leukemia cells. This schedule of administration was based 
on data demonstrating that the pro-differentiation effect of brequinar required a period of sustained 
DHODH-inhibition of approximately three days. This observation suggests that brequinar’s 
efficacy depends on producing approximately 72-hours “time-above-threshold” to maintain 
sustained DHODH inhibition. The hypothesis is that pyrimidine starvation via inhibition of 
DHODH for approximately 72 hours elicits pro-myeloid differentiation and leads to the anti-
leukemia efficacy of brequinar.  
Sykes et al. also showed that normal cells could tolerate longer periods of pyrimidine starvation 
than their leukemic counterparts. The proposed dosing regimen of brequinar in this clinical trial, 
CCB-01, is intended to take advantage of the different sensitivity of normal and leukemic cells 
and thus spare normal cells while eradicating leukemic cells.  
A pharmacodynamic marker of enzyme inhibition (i.e. target engagement) is required to 
accomplish this type of rational dosing approach. Sykes and colleagues demonstrated how 
DHODH inhibition could be monitored by the accumulation of the substrate DHO. Indeed, 
inhibition of the DHODH enzyme led to the rapid accumulation of intracellular DHO, which was 
reflected by accumulation of DHO in plasma hence the rationale for measuring plasma DHO as 
the pharmacodynamic marker in CCB-01.  


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Given this new information, real-time monitoring of target engagement via plasma DHO of 
DHODH inhibition in each patient should permit identification of a brequinar dose that is both 
efficacious and well-tolerated. Maintaining intermittent DHODH inhibition for prolonged 
treatment cycles may be efficacious compared to previous studies using short periods and high 
doses followed by long periods of recovery. 
The prior data on the clinical evaluation of brequinar in patients with multiple solid tumors 
provides valuable safety data that supports the safety of the proposed dosage regimen. Brequinar 
has not been studied clinically in myeloid malignancies in the past. Given encouraging pre-clinical 
results, brequinar has been evaluated in phase 1 and phase 2 trials of more than 800 patients with 
advanced solid tumor malignancies (Arteaga 1989 [5], Burris 1998 [6], Noe 1990 [7], 
Schwartsmann 1990 [8]). These studies indicated a lack of efficacy for brequinar at the doses and 
schedules evaluated. However, many of these trials studied brequinar administered as a single,
high dose infusion given weekly or daily x 5 days every 3-4 weeks or every day for 21 days. The 
lack of efficacy in the previous trials may have been due to the narrow therapeutic window with 
the high doses studied, and to the inability, or lack of knowledge, to use a pharmacodynamic 
marker such as plasma DHO to fine-tune a therapeutic window based on differential pyrimidine 
starvation of myeloid precursors versus normal cells.  
2.4 Rationale for the Planned Trial
This study is designed to obtain safety and efficacy data for brequinar in patients with AML. 
Subject Population 
The population for this study is patients 18 years of age or older, with relapsed/refractory AML by 
World Health Organization classification that have failed prior standard therapy and for which no 
standard therapies are available that result in a durable remission. 
Study Treatments 
This is an open label study of oral brequinar using intra-subject dose adjustment. The dose-
adjustment scheme is presented in more detail in Section 7.5.  
2.4.1
Brequinar Starting Dose Selection
The rationale underlying the proposed dosage regimen for brequinar and the use of plasma DHO 
to guide dosing is the prior demonstration using nonclinical models by Sykes et al. (2016) [4] that 
malignant cells are more sensitive than normal cells to periods of DHODH inhibition. The 
objective is to identify a dose and regimen of brequinar that maintains suppression of DHODH 
adequate to induce differentiation and stop myeloid proliferation but avoid harming normal cells. 
These features have been realized in vivo in animal models. Specifically, intermittent dosing that 
preserved elevated levels of the metabolite DHO markedly reduced AML cells, preserved normal 
hematopoietic stem cells, and improved animal survival. These recent findings and historic 
pharmacokinetic (PK) and safety data from humans support the planned approach.  
Rather than intermittent high doses as were given by DuPont, Clear Creek will use relatively low 
doses and prolonged exposure to brequinar. There will not be a lengthy conventional rest period 
as is generally required between infrequent high doses. There will instead be twice-a-week 


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administration of lower doses with a dosing interval that allows enough time for normal cells to 
recover from or avoid pyrimidine starvation in between the periods of DHODH inhibition. Based 
on its average half-life of 10.5 hours and what has been observed in the clinical PK data (see the 
Brequinar IB [9]), brequinar plasma levels return to baseline at about 3.5 days or 84 hours after an 
oral dose. For this reason, the proposed clinical study includes a biweekly schedule of brequinar 
dosed approximately every 84 hours, while measuring plasma DHO to fine-tune the dosing 
schedule that ensures sustained DHODH inhibition while avoiding adverse effects to normal cells. 
Safety data from previous oncology clinical studies of brequinar (see Brequinar IB, Section 5) with 
maximum tolerated doses as high as 2250 mg/m2 repeated every 3 weeks suggest that a starting 
dose for Cohort 1 of 500 mg/m2 p.o. will be safe and well-tolerated in subjects with AML. Each 
subject’s subsequent dosing may be adjusted depending on the safety, tolerability and DHO level
obtained during the period following dose adjustment. Each of the two planned subsequent cohorts 
may also have an adjusted starting dose, again depending on safety, tolerability and DHO level 
observed in previous cohorts. See Section 7.4. 
2.5 Risk/Benefit of Brequinar
As presented in the brequinar IB, more than 800 patients have been exposed to this compound for 
treatment of a variety of solid tumors at various treatment regimens, doses, and routes including a 
single dose, once weekly, twice weekly, single dose every 3 weeks, daily times 5 every 4 weeks, 
and daily times 21 days for multiple courses. The maximum intravenous dose given was 2,250 
mg/m2 every 3 weeks, and the maximum oral dose was 100 mg/m2 daily for 21 days. Study results 
have not shown evidence of efficacy in solid tumors at the doses and regimens studied. However, 
the preclinical work of Sykes et al (2016) [4] have demonstrated the efficacy of brequinar in a 
mouse model of leukemia, indicating that brequinar may be effective in patients with this type of 
leukemia. It is for this reason that study CCB-01 will study patients with AML.   
A universal hallmark of AML is the arrest of leukemic myeloblasts at an immature and self-
renewing stage of development. Therapies that can overcome differentiation arrest caused by 
DHODH represent a powerful treatment strategy. A potential benefit of brequinar treatment in 
patients with AML is that brequinar has been identified as a compound that can inhibit DHODH.  
The major risk associated with brequinar is myelosuppression, particularly a decrease in platelet 
count. Patients with AML typically have a low platelet count due to their disease, and there is a 
risk that treatment with brequinar may worsen existing thrombocytopenia. 
2.6 Risks Associated with Participation in the Clinical Study
In studies utilizing the weekly schedule of administration in patients with refractory solid tumors, 
reversible myelosuppression, in particular thrombocytopenia, and mucositis have been the primary 
dose-limiting toxicities. In addition, skin rash, nausea/vomiting, fatigue, and leukopenia have been 
dose-limiting in trials utilizing other schedules of drug administration. The majority of these 
adverse effects have been less than grade IV in severity and resolve following discontinuation of 
dosing. Symptoms of tumor lysis syndrome have not previously been reported following exposure 
to brequinar, however clinicians will monitor for and treat this condition should it arise per the 
guidelines presented in Section 9.9. An increased risk of infection may occur due to the 
myelosuppressive effects of brequinar (particularly neutropenia); infection prophylaxis and 


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treatment are described in Sections 9.10 and 9.11. Differentiation syndrome has been seen in other 
pro-differentiating agents and will be closely followed as described in Section 9.7. 
2.7 Possible Interactions with Concomitant Medical Treatments
Brequinar has been administered to subjects taking a variety of concomitant medications that are 
typical in cancer patients. No formal interaction studies have been conducted for these 
medications, however, there have not been any reports of interactions with any medications during 
the clinical trials with more than 800 cancer patients.  
2.7.1
CYP Interactions
No formal drug-drug interaction studies have been performed with medications commonly used 
in treating AML. The nonclinical studies have demonstrated there is no first-pass metabolism, and 
there have been no apparent hepatotoxic effects in the clinical studies performed to date. 
2.8 Steps to be Taken to Control or Mitigate Risks
Guidelines for the prevention, monitoring and treatment of differentiation syndrome, tumor lysis 
syndrome, infection prophylaxis and growth factor support are provided in Section 9. 


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3
TRIAL OBJECTIVES
3.1 Primary Objective
The primary objective of this study is to determine the safety and tolerability of brequinar and the 
dihydroorotate dehydrogenase (DHODH) inhibitory activity of brequinar in adult patients with 
AML. 
3.2 Secondary Objectives
The secondary objectives of this study are:

To determine the overall response rate (ORR) including complete remission (CR), CR with 
incomplete hematologic recovery (CRi), morphologic leukemia-free state (MLFS), partial 
remission (PR) (criteria as defined in the ELN Guidelines, by Döhner et al., 2017 [10]) and 
complete remission with partial hematological recovery (CRh).

To assess the rate of overall survival (OS) and event-free survival (EFS)  

To evaluate duration of response 

To characterize the pharmacokinetic (PK) profile of brequinar. 

To characterize the DHO plasma levels after oral dosing with brequinar.
3.3 Exploratory Objectives
The exploratory objectives of this study are: 

To assess the relationship between DHODH inhibition and the efficacy and safety of brequinar. 

To evaluate molecular and cellular biomarkers that may be predictive of antitumor level and/or 
treatment resistance including cytogenetics, molecular profiling, and flow cytometry during 
and after treatment. 

To evaluate global gene expression profiles, DNA methylation profiles, and other potential 
prognostic markers to explore predictors of antitumor activity and/or resistance to treatment.


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4
TRIAL DESIGN
This will be a Phase 1b/2a multi-center, open-label, non-randomized clinical trial to assess the 
safety, tolerability and efficacy of dose-adjusted brequinar in adult subjects with AML. The study 
will also assess the inhibition of DHODH and the PK profile of brequinar in plasma. Intra-subject 
dosing may be adjusted based on safety/tolerability and DHO level.  
Up to 27 subjects are planned to be entered in this trial: Cohort 1 will have 6 subjects; two 
additional cohorts of 3 subjects each will be added if adjustments are required to the cohort starting 
doses. Cohorts 2 and 3 may be expanded to 6 subjects if required by safety assessments as 
described in Section 7.3.2. Following completion of enrollment in the cohort dose-adjustment part 
of the study, an expansion cohort of 15 subjects will be enrolled with a starting dose of the highest 
tolerated starting dose from Cohorts 1 to 3. Safety will be assessed utilizing physical examination, 
vital sign measurements, safety laboratory testing, 12-lead ECGs and bone marrow sampling. Bone 
marrow sampling will also be utilized for efficacy. Tolerability will be assessed by spontaneously 
reported and elicited adverse events. DHO level will be measured using a validated assay. PK will 
be analyzed using standard PK parameters.  
Dosing will continue for up to 12 months in the absence of unacceptable toxicity or disease 
progression. 
Study procedures are presented in more detail in Section 7. 


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5
TRIAL ENDPOINTS
5.1 Primary Endpoint

Safety/tolerability and DHO level relationship with safety and therapeutic brequinar levels  
5.2 Secondary Endpoints

Rates of treatment-emergent adverse events.

Overall Response Rate (ORR) including CR, CRh, CRi, MLFS, or PR

Event-free survival (EFS).

Duration of response

PK profile of brequinar.

DHO plasma profile.
5.3 Exploratory Endpoints

Relationship between DHODH inhibition and the efficacy and safety of brequinar.  

Antitumor level based on molecular and cellular biomarkers including cytogenetics, molecular 
profiling, and flow cytometry during and after treatment.

Global gene expression profiles, DNA methylation profiles, and other potential prognostic 
markers to explore predictors of antitumor activity and/or resistance to treatment 


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6
TRIAL POPULATION
6.1 Number of Subjects
Subjects who meet all the inclusion and none of the exclusion criteria will be enrolled in the study
until approximately 27 subjects have completed the study.     
6.2 Inclusion criteria
1. Willing and able to provide written informed consent for the trial. 
2. Patients 18 years of age or older, with relapsed/refractory AML by World Health 
Organization (WHO) classification who have exhausted available therapy. 
3. ECOG Performance Status 0 to 2.
4. 12-lead ECG with no clinically unacceptable findings; adequate cardiac function/NYHA 
Class 0 to 2.
5. Adequate hepatic function (unless deemed to be related to underlying leukemia).
a.
b.
c.
6.
Cockcroft-Gault equation. 
7. In the absence of rapidly proliferative disease, the interval from prior leukemia-directed 
therapy to time of first dose of study drug will be at least 7 days for cytotoxic or non-
cytotoxic (immunotherapy) agents. Hydrea is allowed up to 48 hours prior to the first dose 
for patients with rapidly proliferative disease.  
8. The effects of brequinar on the developing human fetus are unknown.  For this reason, 
women of child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry and for the 
duration of study participation.  Should a woman become pregnant or suspect she is 
pregnant while she or her partner is participating in this study, she should inform her 
treating physician immediately.  Men treated or enrolled on this protocol must also agree 
to use adequate contraception prior to the study, for the duration of study participation, and 
for 90 days after completion of brequinar administration. 
9. Male subjects must agree to refrain from sperm donation from initial study drug 
administration until 90 days after the last dose of study drug. 
6.3 Exclusion Criteria
1. Patients in need of immediate leukapheresis. 
2. Any concurrent uncontrolled clinically significant medical condition, laboratory 
abnormality, or psychiatric illness that could place the participant at unacceptable risk of 
study treatment. 


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3. QTc interval using Fridericia’s formula
branch block and prolonged QTc interval may be eligible after discussion with the medical 
monitor. 
4. Pre-existing liver disease. 
5. The use of other chemotherapeutic agents or anti-leukemic agents is not permitted during 
study with the following exceptions:
a.
Intrathecal chemotherapy for prophylactic use or maintenance of controlled CNS 
leukemia.
b. Use of hydroxyurea for the purpose of leukemic cytoreduction may be allowed 
during the first 2 weeks of therapy if in the best interest of the participant and is 
approved by the medical monitor. Hydroxyurea can be used to treat leukocytosis 
if concurrent with and thought to be associated with presumed differentiation 
syndrome.  
6.
0.5mg/kg/day of prednisone or therapy beyond systemic corticosteroids (e.g. cyclosporine 
or other calcineurin inhibitors or other immunosuppressive agents used for GVHD).
7. Active cerebrospinal involvement of AML.
8. Diagnosis of acute promyelocytic leukemia (APL).
9. Clinically active hepatitis B (HBV) or hepatitis C (HCV) infection.
10. Severe gastrointestinal or metabolic condition that could interfere with the absorption of 
oral study medication. 
11. Prior malignancy, unless it has not been active or has remained stable for at least 2 years. 
Participants with treated non-melanoma skin cancer, in situ carcinoma or cervical 
intraepithelial neoplasia, regardless of the disease-free duration, are eligible if definitive 
treatment for the condition has been completed. Participants with organ-confined prostate 
cancer with no evidence of recurrent or progressive disease are eligible if at the active 
surveillance stage, if hormonal therapy has been initiated or the malignancy has been 
surgically removed or treated with definitive radiotherapy. 
12. Nursing women or women of childbearing potential (WOCBP) with a positive urine 
pregnancy test. 
6.4 Inclusion of Women and Minorities
Both men and women of all races and ethnic groups are eligible for this trial.


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7
STUDY TREATMENTS
Subjects will self-administer oral brequinar twice weekly (approximately every 84 hours). 
Treatment cycles will be 2 weeks. Dose adjustment is to occur as outlined below. Visits will take 
place at least every 2 weeks through 3 months. More frequent visits are permitted to assess and/or 
treat adverse events. Less frequent visits (up to 4-week intervals) are permitted after 3 months 
depending on subject safety/tolerability and response. Cohort 1 will begin at 500 mg/m2 twice 
weekly. Subjects in Cohort 1 may not escalate above the initial 500 mg/m2 starting dose, but the 
intra-subject dose may be reduced if unacceptable safety occurs. Subsequent cohorts will have a 
starting dose that may be adjusted based on the safety/tolerability (Section 7.3.1, Section 7.3.2) 
and DHO levels of the previous cohort. The dosing for individual subjects may be adjusted based 
on the safety/tolerability and DHO levels as shown in Section 7.5. 
7.1 Description of Brequinar:
Brequinar will be supplied as 100 and 250 mg capsules. Dosing will be determined on a mg/m2
basis based on the starting dose of a subject’s cohort and the tolerability, safety and DHO level
assessed following each dose. Brequinar capsules should be taken whole; they should not be 
crushed or chewed. If the participant forgets to take the daily dose, he/she should make up the dose 
within 8 hours after the missed dose. If more than 8 hours have elapsed or if the dose was vomited
or if the subject for any reason is unable to take the scheduled dose within 8 hours, omit that dose, 
and the subject should resume treatment with the next scheduled dose. Any medication remaining 
from extra supplies or missed doses should not be taken beyond the last scheduled day of brequinar 
administration but should be documented in the subject diary and returned by the participant for 
drug accountability purposes.  
7.2 Treatment Administration
Subjects will take oral brequinar twice weekly (approximately every 3.5 days) e.g., Monday 
morning and Thursday evening. Each dose is to be taken with approximately 240 mL of water. 
The subject does not need to be fasting. Each dose will generally consist of multiple capsules; all 
capsules do not need to be swallowed at once but can be spread over up to 15 minutes as needed. 
The chosen dosing schedule needs to accommodate clinic visits as well as shipping and receipt of 
the brequinar brequinar/DHO samples. Sample processing and shipping procedures will be 
addressed in a separate laboratory manual.  
7.3 Safety/Tolerability
Safety/tolerability is assessed for each subject at each study visit using the Common Terminology 
Criteria for Adverse Events v4.0 (CTCAE). After completion of Cohort 1 (which will have a fixed 
starting dose of 500 mg/m2 with no dose escalation permitted), safety/tolerability will be used to 
determine both individual cohort starting doses for subsequent cohorts and individual dosing 
adjustments. Safety at the subject level is defined in Section 7.3.1; hematologic toxicity is defined 
in Section 7.3.1.1; and safety at the cohort level is defined in Section 7.4. 
The following adverse events are commonly observed in patients with AML and should be 
differentiated from possible adverse effects of brequinar: 


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Fatigue, fever, thrombocytopenia, infection, pallor, shortness of breath, weight loss, night sweats, 
and anorexia.
Prescriptions can be provided in advance for supportive care for common brequinar-related AEs 
such as mucositis. 
7.3.1
Safety/Tolerability – Subject Level
Acceptable safety/tolerability for a subject through Day 42 is defined as no 
Grade 3, treatment-
emergent, study-drug-related, non-hematologic adverse events. Due to the expected hematologic 
profile associated with AML, hematologic AEs of any grade will not be considered dose-limiting 
during the first 42 days of dosing (i.e., assessed at the visit conducted on Day 43). Exceptions to 
the non-hematologic Grade 3 criterion are provided in Table 1.  
If a dose is held due to safety/tolerability issues, the subject should continue to come to the clinic 
for scheduled visits and to have scheduled assessments. 
 Grade 2 after two weeks without dosing, dosing is to be discontinued
for this subject.
Table 1.
Exceptions to Grade 3 Nonhematologic AEs 
Condition
Exception Description 
Nausea/
Emesis
week after the use of an optimal antiemetic regimen based on standard 
practice. 
Diarrhea
within 1 week after 
receiving the maximal supportive therapy based on standard practice.
Fatigue
Grade 3 fatigue with duration < 2 weeks.
Laboratory 
abnormalities
Asymptomatic Grade 3 laboratory abnormalities that are not considered to 
be clinically significant.
Mucositis
Grade 3 with duration < 2 weeks
For the expansion cohort, the definition of unacceptable safety is expanded to include signs of 
who 
resuming dosing, dosing is to be discontinued for that subject.


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Hematologic Toxicity
After the subject has completed the first 42 days of treatment, the definition of unacceptable safety 
expands to include hematologic AEs defined as prolonged neutropenia with ANC < 500 from the 
start of therapy in the absence of disease, 
, and/or 
thrombocytopenia, with a hypocellular bone marrow and no greater than 5% marrow blasts lasting 
for 2 weeks or more. Anemia will not be considered a hematologic AE for the definition of 
unacceptable safety. Febrile neutropenia is also excluded from the DLT definition for this 
population. For clinic visits when bone marrow sampling is scheduled, the timing of the bone 
marrow sampling can be adjusted to ensure that the results are available at the time of the clinic 
visit. 
7.3.2
Safety/Tolerability – Cohort Level
Acceptable safety/tolerability at the cohort level is defined below: 
a)
dose reduction or treatment discontinuation (a dose limiting toxicity or DLT), then that 
dose is considered to have unacceptable safety/tolerability and the previous dose which 
was safe/tolerated must be considered as the highest safe/tolerated dose.  
b) If 1 out of 3 subjects at a dose level experiences a DLT, then 3 additional subjects will be
6 subjects has a DLT at that dose, then this dose is considered a safe/tolerated dose. 
However, if >2 out of 6 subjects at a dose level experience a DLT, then that dose is 
considered to have unacceptable safety/tolerability and the previous dose which was 
safe/tolerated must be considered as the highest safe/tolerated dose. 
7.3.3
Safety/Tolerability – Expansion Cohort
The safety and tolerability of the starting dose for the Expansion Cohort will have been determined 
during the Cohort Level adjustments defined in the preceding section. If >1 of the first 5 subjects 
in the Expansion Cohort cannot tolerate this starting dose based on the rules for safety and 
tolerability at the subject level (Section 7.3.1), the starting dose for the next 5 subjects in this cohort 
will be reduced by 75 mg/m2. If >1 of the second 5 subjects cannot tolerate the reduced starting 
dose, the starting dose will be again reduced by 75 mg/m2 for the final 5 subjects planned for this 
cohort. All of these subjects are eligible for intra-subject dose adjustment and will follow the same 
individual subject safety rules for either stopping dosing or dose adjustment as presented in 
Section 7.3.1 and Section 7.5. 
7.4 Cohort Starting Doses
Cohort 1 will treat 6 subjects at 500 mg/m2 twice weekly. No dose escalation is permitted for 
Cohort 1 subjects, but the dose may be reduced for an individual subject in this cohort if the subject 
experiences unacceptable safety.   
After all subjects in Cohort 1 have completed a 42-day treatment period, up to two additional 
cohort(s) of 3 subjects each will be added with the starting doses adjusted (escalated or de-
escalated) based on both safety/tolerability and adequacy of DHO level results in Cohort 1. As 


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noted in Section 7.3.2, additional subjects may be added to Cohorts 2 and 3 to further explore 
safety, if needed.
If all subjects in a cohort have acceptable safety at a dose level, the next cohort’s starting dose may 
be escalated by 150 mg/m2. If the safety rules are not met at a cohort’s starting dose, the next 
cohort’s starting dose will be reduced to the highest dose found to be safe/tolerated in the previous
cohort. The planned upper limit for cohort starting dose is 800 mg/m2. There is no lower limit.
See the “Intra-subject dose adjustment” section for individual subject dosing adjustment criteria.
7.5 Individual Dose Adjustment Guidelines
With the exception of subjects in Cohort 1 whose dose may not be escalated above the 500 mg/m2
starting dose, intra-subject dose adjustment will be considered every 2 weeks depending on safety 
and DHO levels. There is a maximum of 2 dose adjustments for each subject within the first 42 
days of initiating treatment. Each subject’s dose can be adjusted from the starting dose by being 
escalated, maintained (stable dose), held then reduced, or discontinued (except in Cohort 1 where 
subjects’ doses may not be escalated beyond the 500 mg/m2 starting dose). The highest dose 
planned is 800 mg/m2, however, this upper limit may be adjusted depending on safety, DHO level, 
and clinical response. There is no lower limit planned. As noted above, safety will be a key part of 
determining dose adjustments. Subjects who resume dosing at a lower dose after experiencing 
unacceptable safety may not undergo later dose escalations beyond the dose where the 
unacceptable safety occurred.  
Each subject will continue dosing twice weekly at the individually adjusted dose for up to 12 
months (total time from first dose) in the absence of unacceptable toxicity or disease progression. 
Intra-subject dose adjustment is permitted at any time throughout the study based on 
safety/tolerability and DHO levels (except in Cohort 1). Subjects who discontinue due to 
unacceptable safety/tolerability or die prior to Day 43 will not be replaced.  
Intra-subject dose adjustment increments and duration of dosing may be revised from planned 
amounts after each preceding cohort’s safety, DHO plasma levels, and bone marrow results have 
been reviewed.
7.5.1
DHO Threshold
Each subject’s baseline DHO sample will be obtained at C1D1 prior to dosing. Dose adjustment 
decisions based on DHO will be determined by DHO trough level (i.e., DHO level obtained pre-
dose D8 of the previous cycle). The initial target for “adequate” trough DHO level will be set at 
100 ng/mL. This target may be adjusted during the study depending on safety or efficacy signals 
observed during the study. As described below, dose adjustments are also determined by the 
investigator based on safety and whether the dose has reached the planned upper limit (currently 
planned to be 800 mg/m2). If the DHO level is not available for any reason, the subject is to 
continue treatment at the current dose unless there is unacceptable safety.
Table 2 and Figure 1 present the intra-subject dose-adjustment criteria. Note that there is no dose 
escalation in Cohort 1. 


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Table 2.
Intra-Subject Dose Adjustment*
Acceptable Safety/Tolerability?
(see safety definition above)
Adequate 
DHO Level?
Planned Intra-Subject Dose Adjustment
Yes
Yes
Maintain; continue at same dose.
Yes
No
Escalate by 150 mg/m2 for the next 2-week cycle up to a 
maximum of 800 mg/m2. 
No 
Regardless of 
DHO  
Hold two doses (one week), then reassess AE; if AE has 
-escalate dose by 75 mg/m2 and resume 
dosing. If AE has not resolved, reassess again in one week.  
held, discontinue further dosing. Subject will remain in the 
study for safety follow up for 42 days after last dose of study 
drug or until AEs have resolved or become stable.
*Note that Subjects in Cohort 1 may not escalate above the initial 500 mg/m2 starting dose and may have dose 
reductions based on safety only. 


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Figure 1.
Dose Adjustment – Subject Level


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7.6 Medication/AE Diary
The participant will be provided with a study calendar of events and will be required to maintain 
a medication diary of each dose of medication. Subjects will be instructed to record the date and 
time each dose of brequinar is taken, indicating if any doses are missed. Subjects will be instructed 
to record adverse events and changes in concomitant medications in the subject calendars/diaries. 
Subjects will be instructed and reminded to bring the medication diary to each clinic visit for 
review. The diary will be returned to clinic staff at the end of each cycle and a new diary dispensed.
7.7 Bone Marrow Biopsy
The participant will have a bone marrow sampling (aspiration and core biopsy) at baseline (prior 
to dosing), one for research purposes at the C2D8 visit ± 7 days, and one at Day 43 ± 7 days; 
thereafter, bone marrow sampling will be obtained every 12 weeks (or per institutional standard 
of care) and at the Final Visit. If a participant develops frank evidence of progression of AML 
during the course of treatment based on laboratory or clinical assessment, then he/she will be 
discontinued from study treatment and can proceed with additional management off-study per 
discretion of the treating oncologist. If the results of the bone marrow sampling reveal disease 
progression at the Day 43 visit (defined as 43 days after initiating treatment or after 6 complete 
weeks after initiating study drug treatment regardless of number of doses), then the participant will 
be taken off treatment. Timing of the bone marrow biopsy procedure may be adjusted to ensure 
that results are available for the Day 43 visit. Bone marrow sampling will include analysis of the 
aspirate on smear, core biopsy by microscopy, flow cytometry, and karyotype for cytogenetics. 
Molecular analysis will be performed on the screening bone marrow samples. 
7.8 Flow Cytometry
Peripheral blood samples are to be obtained for flow cytometry in Cycle 1 at baseline (Day 1 pre-
dose), Day 2 (24 hours after initiating treatment), and Day 3 (48 hours after initiating treatment). 
7.9 Expansion Cohort
Once a dose has been reached that has an adequate DHO level (as mentioned above, “adequate” 
trough DHO may be adjusted after reviewing DHO level, safety and clinical response data) and 
acceptable safety/tolerability, approximately 15 subjects will be added starting at the highest 
safe/tolerated dose identified in the earlier cohorts. Decisions regarding adequacy of DHO 
threshold level will be made following review of these data from each cohort. These subjects are 
eligible for intra-subject dose adjustment (see Section 7.3.1 and Section 7.5). 
The expansion cohort will follow the same visit procedures as the Maintenance Dose cohort 
(Section 8.5.4) and visit frequency may vary from 2 to 4 weeks per the investigator’s discretion.  
7.10 Study Drug Discontinuation
If there is evidence of stable disease, partial response, or complete remission (CR, CRi, or CRh), 
the participant may continue with brequinar treatment until there is evidence of disease 
progression, intolerable toxicity, or for a maximum of one year. Study drug will be discontinued 
if there is evidence of unacceptable safety/tolerability that does not resolve 
 within 2 
weeks after stopping brequinar dosing.  


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After treatment discontinuation, participants will be monitored for a minimum of 30 days after the 
last dose of brequinar or until they receive another treatment for their AML. Participants may 
discontinue treatment to receive a stem cell transplantation upon remission, if indicated. 
The reason for study drug discontinuation will be recorded in the source document and the eCRF.  
7.11 Brequinar Pharmacokinetics (PK) / Dihydroorotate (DHO) Plasma Levels
Plasma samples for brequinar/DHO levels are to be obtained for each subject for the subject’s first 
study dose (Cycle 1 Dose 1 for that subject). Sample scheduling is baseline at 0 hours (prior to 
dosing), and post dose at 1, 2, 4, 6, 24, 48, and 72 hours. Note that this schedule does not apply to 
Cycle 1 for subjects in the expansion cohort, see below. 
A brequinar/DHO trough sample is to be obtained prior to dosing on Day 8 (C84h, 84 hours after 
the Cycle 1 Day 4 dose) of Cycle 1, and prior to dosing on Days 1 and 8 of Cycles 2 and 3. 
The 84-hour brequinar/DHO sample is to be repeated prior to dosing at the beginning of each 2-
week cycle and at the Final Visit. This sampling schedule also applies for the expansion cohort 
subjects. 
Directions regarding sample processing are presented in a separate laboratory manual.
7.12 Concomitant Medication/Treatment
The name, start date (if known), indication for use and whether ongoing or stopped for 
medications/treatments taken within two weeks prior to study entry as well as any medications 
taken during the study are to be recorded. The use of other chemotherapeutic agents or anti-
leukemic agents is not permitted during study with the following exceptions: 

Intrathecal chemotherapy for prophylactic use or maintenance of controlled CNS leukemia; 

Use of hydroxyurea for the purpose of leukemic cytoreduction may be allowed during the 
first 2 weeks of therapy if in the best interest of the participant and is approved by the 
medical monitor. Hydroxyurea can be used to treat leukocytosis if concurrent with and 
thought to be associated with presumed differentiation syndrome.  
7.12.1 Gastric pH
Whenever possible, participants should discontinue proton pump inhibitors, antacids, and H2-
receptor antagonists which increase the gastric pH and may reduce absorption of oral medications 
including brequinar resulting in decreased systemic exposure. Discontinuation of these 
medications is not required but is strongly recommended. 
7.13 Treatment Compliance
Compliance will be assessed by reviewing the subject’s medication diary and accounting of 
returned clinical supplies. 


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7.14 Storage, Stability, Labeling and Packaging
7.14.1 Storage and Stability
The study drug is stored at room temperature. Stability testing is ongoing. 
7.14.2 Labeling and Packaging 
Each bottle for subject use will be labeled with at least the following information: 
For Clinical Trial Use Only
Study Number: 
CCB-01
Contents: 100 or 250 mg Brequinar capsules 
For oral use only. Take with approximately 8 ounces water every 3.5 days. 
Subject Number: XX-XXXX
Treatment Duration: As directed
IND: 138355             Clinical Batch Number: XXXXXXX
Expiration Date: 
TBD 
Storage: Store at controlled room temperature  
Study Sponsor:  Clear Creek Bio, Inc., 585 Massachusetts Avenue, 4th 
Floor, Cambridge MA 02139 
Caution: New Drug – Limited by US Federal Law to Investigational Use
Only. To be used by Qualified Investigators only.
7.14.3 Blinding and Randomization
The trial will be conducted in an open-label manner. The brequinar capsules will be provided to 
each participating institution. No randomization codes are necessary for this open-label study.
7.14.4 Unblinding/Expectedness
It is not necessary to break the blind for this open label study as the treatment is known for each 
subject. 
Expectedness will be determined by establishing whether the adverse event is among those 
identified in the Investigator’s Brochure.   
7.14.5 Study Drug Accountability
The study drug provided is for use only as directed in this protocol. 
The Investigator must keep a record of all study medication received, used and discarded.  It must 
be clear from the records which subject received which medication. Adequate drug is to be 
dispensed for each dosing period to allow for dosing every 3.5 days during the period until the 


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next clinic visit, plus one additional dose to act as a spare in the event medication is unable to be 
used.
The pharmacist/staff member responsible for drug accountability is to document the date and time 
of dispensing and for what subject the study drug was intended (i.e., record subject initials and 
birth date or other unique identifier). A pharmacy manual will be provided by the Sponsor detailing 
how to calculate the mg/m2 dose together with examples of combinations of the 100 and 250 mg 
capsules to provide the most efficient use of the clinical supplies.
At the end of the study, any unused study drug will be returned to the Sponsor for destruction or 
destroyed locally; disposition of study drug will be documented.   
The Sponsor will be permitted access to the trial supplies at any time within usual business hours 
and with appropriate notice during or after completion of the study to perform drug accountability 
reconciliation.


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8
CONDUCT OF THE TRIAL
8.1 Ethical and Regulatory Considerations
The trial will be performed in accordance with the Declaration of Helsinki (1964) (Appendix F) 
as revised in Tokyo (1975), Venice (1983), Hong Kong (1989), South Africa (1996), Scotland 
(2000, Note of Clarification 2002 & 2004) and Seoul 2008 (Appendix A), and Fortaleza (Brazil) 
(2013), and with the ICH Tripartite Guideline on Good Clinical Practice (CPMP/ICH/135/95, 
Jan.97) and US FDA Regulations. 
8.2 Informed Consent
The principles of informed consent in the current edition of the Declaration of Helsinki must be 
implemented in each clinical study before protocol-specified procedures are carried out.  Informed 
consent must be obtained in accordance with US Code of Federal Regulations (21 CFR Part 50) 
as well as local and national regulations. Information should be given in both oral and written form 
whenever possible and deemed appropriate by the Institutional Review Board (IRB). Subjects and 
their relatives, if necessary, must be given ample opportunity to inquire about details of the study.
The Investigator or qualified designated person will verbally inform subjects as to the nature, 
expected duration and purpose of the trial, the administration of the Investigational Medicinal 
Product (IMP), and the hazards involved, as well as the potential benefits that may come from 
treatment with this IMP. The trial procedures will be explained in lay language and any questions 
will be answered. The subjects will be given an IRB-approved consent form. The subjects will be 
given appropriate time to consider their participation in the trial and have any questions answered 
prior to signing the consent form. If a subject agrees to participate, he/she will sign and date an 
informed consent form and be provided with a copy of the signed consent. All subjects who sign 
an informed consent form are to be recorded on the applicable screening log.   
The subject will be informed that his/her medical records will be subject to review by the Sponsor, 
Sponsor’s representatives, and possibly by a representative of the Food and Drug Administration 
and other relevant regulatory authorities. Subjects will be informed that they are free to refuse 
participation in this clinical investigation, and if they should participate, it will be made clear to 
them that they may withdraw from the trial at any time without prejudicing further medical care 
they may require. The subject will receive a copy of the consent form as well as an information 
sheet about the trial.  
Signed written informed consent must be obtained from every subject prior to any study-specific 
procedures.  Standard procedures carried out prior to signing the informed consent but within the 
time constraints of the protocol may be used for baseline evaluation; they need not be repeated. 
An original signed informed consent form will be filed in the Investigator Site File and will be 
subject to review by the Sponsor; a copy will be given to the subject and a copy will be filed with 
the subject’s medical notes. 
The study should be discussed with the potential participant only after an initial review of his/her 
clinical status and appropriateness for participation have been evaluated to determine if he/she 
meets the subject selection criteria. 


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A sample subject information sheet and consent form is attached to this protocol as Appendix E.
The final version at each institution may differ depending on institutional requirements and 
standard formats. This protocol will not be amended for site specific changes to the sample.
8.3 Institutional Review Board / Ethics Committees
It is the responsibility of the Investigator to submit the protocol, consent form and information 
sheet to the IRB. An Investigator’s brochure will be available for review by the IRB. The protocol 
and consent form must be approved by the IRB prior to the recruitment of the first subject. The 
template consent form may be revised in accordance with site-specific requirements with Sponsor 
review and approval. A copy of the IRB written approval must be provided to the Sponsor and 
investigator before the trial may start at that institution. Written approval from the IRB is also 
required for substantial protocol amendments prior to their implementation.    
A substantial amendment may arise from changes to the protocol or from new information relating 
to the scientific documents in support of the trial.  Amendments are “substantial” when they are 
likely to have an impact on:

the safety or physical or mental integrity of the subjects; 

the scientific value of the trial; 

the conduct or management of the trial; or

the quality or safety of any IMP used in the trial. 
If it is necessary to change or deviate from the protocol to eliminate an immediate hazard to the 
subjects, the Investigator will notify the Sponsor and the IRB of the new events and the measures 
taken as soon as possible.   
The Investigator will report promptly to the Sponsor and IRB any new information that may 
adversely affect the safety of the subjects or the conduct of the trial. On completion of the trial, the 
Investigator will inform the applicable IRB as per local IRB requirements that the trial has ended. 
If the study is terminated for any reason, the investigator will return all clinical supplies and study-
related equipment supplied by the Sponsor to the Sponsor unless otherwise specified. 
8.4 Schedule of Events
Physical examinations, vital signs, ECG, laboratory assessments, bone marrow sampling and other 
observations will be undertaken by experienced personnel throughout the study based on the 
Schedule of Events. Standard chromosomal and mutational testing will be performed per 
institutional guidelines.
See 14.1 Schedule of Events in Appendix A for the full list of study assessments and timings.
Blood chemistry tests include: blood urea nitrogen (BUN), creatinine, alkaline phosphatase (ALP), 
alanine amino transferase (ALT), aspartate amino transferase (AST), bilirubin, total protein, 
albumin, glucose, serum electrolytes (sodium, potassium, chloride, carbon dioxide/bicarbonate, 
and calcium). 


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Hematology tests include: hemoglobin, hematocrit, complete blood count with differential and 
platelet count. 
In addition to the already scheduled weekly chemistry assessment during Cycles 1 and 2 for each 
subject, subjects taking potentially hepatotoxic drugs are permitted to have more frequent 
monitoring than indicated in the schedule of events, if ordered by the study team. 
8.5 Study Conduct
8.5.1
Screening Visit (Study Days -14 to -1)
These procedures must be completed within the 14 days prior to starting dosing. Obtain the 
subject’s written informed consent, then collect baseline information:
-
Demographics (height, weight, date of birth, gender, race, ethnicity); body surface area 
(BSA) determined at Screening will be utilized for all BSA-driven mg/m2 dosing 
calculations throughout the study. 
-
Pertinent medical/surgical history (including AML diagnosis and laboratory and clinical 
evidence of progression, previous AML treatment, and any available chromosomal and 
mutational testing results per institutional guidelines) and concomitant medications. 
-
Physical examination (including weight).  
-
Vital signs (heart rate, respiratory rate, seated blood pressure, body temperature).  
-
Pregnancy test for women of childbearing potential (WOCBP).  
-
ECOG performance assessment.  
-
Hematology/chemistry. 
-
12-lead ECG with QTcF.  
-
Bone marrow sampling. 
-
Confirm subject meets all inclusion and no exclusion criteria. 
Treatment
The treatment period begins with Cycle 1, Day 1 of the first 2-week dosing cycle. 
8.5.2
Cycle 1
Cycle 1 Day 1: 
-
Collect any adverse events or new concomitant medications since Screening.  
-
Draw samples for baseline (pre-dose) brequinar/DHO, flow cytometry, and 
hematology/chemistry.  
-
Conduct physical examination (including weight), vital signs, urine pregnancy test for 
WOCBP if >4 weeks since last test, and 12-lead ECG if >4 weeks since last test.  
-
Review results and confirm subject remains eligible for the study.  
-
Determine subject’s starting dose based on the respective cohort mg/m2 starting dose.
-
Dispense study medication.  
-
Subject is to take the first dose at the clinic and remain for brequinar/DHO sampling. Collect 
brequinar/DHO samples at 1, 2, 4, and 6 hours post dose. 
-
Process and store brequinar/DHO samples per the supplied laboratory manual.


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-
Dispense the subject’s calendar/diary. The diary will collect dates/times of study medication 
administration and AEs/new concomitant medications. 
-
Enroll subject for text message reminders if the subject consents to that service.  
-
Ship the flow cytometry sample per the supplied laboratory manual. 
Cycle 1 Day 2:  
-
Collect 24h post dose brequinar/DHO and flow cytometry samples. Check the diary/elicit 
information about AEs/new concomitant medications since the last visit. 
-
Process and store brequinar/DHO samples per the supplied laboratory manual. 
-
Ship the flow cytometry sample per the supplied laboratory manual 
Cycle 1 Day 3:  
-
Collect 48h post dose brequinar/DHO and flow cytometry samples. Check the diary/elicit 
information about AEs/new concomitant medications since the last visit.  
-
Process and store brequinar/DHO samples per the supplied laboratory manual. 
-
Ship the flow cytometry sample per the supplied laboratory manual. 
Cycle 1 Day 4:  
-
Collect 72h post dose brequinar/DHO samples. Check the diary/elicit information about 
AEs/new concomitant medications since the last visit. 
-
Process and store brequinar/DHO samples per the supplied laboratory manual. 
Cycle 1 Day 8:  
-
Vital signs. 
-
Check the diary/elicit information about AEs/new concomitant medications since the last 
visit. 
-
Prior to the morning dose, collect brequinar/DHO samples (approximately 84h post the 
second dose of Cycle 1) and hematology/chemistry samples, then have subject take study 
medication.  
-
Process and store brequinar/DHO samples per the supplied laboratory manual. 
-
Notify DHO assay laboratory of incoming shipment and ship Cycle 1 brequinar/DHO 
samples (samples from Days 1, 2, 3, 4 and 8). 
8.5.3
Cycle 2 (and any Dose Adjustment Cycle)
Repeat this visit as needed when dose adjustment is ongoing. 
Day 1:   
-
Collect unused study medication and check the diary/elicit information about AEs/new 
concomitant medications since the last visit.  
-
Take vital signs and perform physical examination (including weight). 
-
Collect pre-dose brequinar/DHO samples (approximately 84h post the fourth dose of the 
previous cycle) and hematology/chemistry samples.  
-
Process and store brequinar/DHO samples per the supplied laboratory manual. 


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-
Review laboratory results/safety information and determine whether the subject should 
adjust the dose (based on acceptable safety and DHO level), continue with the current dose 
or hold study medication (unacceptable safety) per the guidelines below.  
-
If dosing will continue, dispense study medication. 
-
Dispense calendar/diary. 
-
Manage text message reminders as needed (as a default do nothing, pause if study 
medication is put on hold, and restart if study medication is restarted)
Day 8: 
-
Collect and check the diary/elicit information about AEs/new concomitant medications 
since the last visit.
-
Vital signs. 
-
Collect pre-dose brequinar/DHO and hematology/chemistry samples.
-
Perform bone marrow sampling (window ±7 days). 
-
If the subject is being dosed (i.e., has acceptable safety), have the subject take the morning 
dose.  
-
If the subject’s medication was held, review safety information and determine whether 
dosing can resume. If dosing can resume, determine dose, dispense adequate medication for 
4 doses and have the subject take the morning dose.  
-
Process and store brequinar/DHO samples per the supplied laboratory manual. 
-
Continue to withhold study drug if safety remains unacceptable.
-
Dispense calendar/diary. 
-
Manage text message reminders as needed (as a default do nothing, pause if study 
medication is put on hold, and restart if study medication is restarted)
-
Notify DHO assay laboratory of incoming shipment and ship brequinar/DHO samples 
(samples from current cycle's Days 1 and 8). 
 
Subjects may undergo dose adjustments at any time using the guidelines presented above except 
in Cohort 1. Subjects with acceptable safety can continue to escalate every 2 weeks by 150 mg/m2
increments through 800 mg/m2. Subjects with unacceptable safety can continue to undergo dose 
reductions of 75 mg/m2 with no lower limit. Re-escalation to a dose previously shown as not 
tolerated for an individual subject is not permitted for these subjects. 
Dose adjustments are permitted throughout the study for an individual subject based on safety, 
DHO level, and clinical response with an upper limit of 800 mg/m2. This upper limit may be 
adjusted depending on safety/tolerability/DHO/brequinar PK or other factors during the study.
8.5.4
Maintenance Dose Cycle (visit every 2 - 4 weeks)
Once a subject reaches a stable or maintenance dose (see Figure 1), the subject will be in the 
Maintenance Dose Cycle.  
In the first 3 months from starting study drug, the Maintenance Dose Cycle procedures will occur 
every 2 weeks (with the exception of bone marrow sampling as discussed below). After completing 
3 months from starting study drug, subjects may come to the clinic for a Maintenance Dose Cycle 
visit every 2 - 4 weeks per the investigator’s discretion.


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A subject may still move into a Dose Adjustment Cycle after a maintenance dose if required for 
a change in safety, DHO level or clinical response. 
Day 1: 
-
Collect unused study medication and check the diary/elicit information about AEs/new 
concomitant medications since the last visit.
-
Collect pre-dose brequinar/DHO and hematology/chemistry samples. 
-
Conduct physical examination and obtain vital signs; urine pregnancy test for WOCBP
(every 4 weeks), 12-lead ECG (every 4 weeks), and bone marrow sampling (note that bone 
marrow is collected at the C2D8 visit (window ±7 days), at Day 43, then every 12 weeks or 
per institutional standard of care; the Day 43 sample will be assessed for hematological 
toxicity). 
-
Review the laboratory results/safety information and determine whether the subject should 
maintain current dose (acceptable safety) or hold study medication (unacceptable safety). 
-
Dispense study medication. 
-
Dispense calendar/diary. 
-
Manage text message reminders as needed (as a default do nothing, pause if study 
medication is put on hold, and restart if study medication is restarted)
-
Notify DHO assay laboratory of incoming shipment and ship brequinar/DHO samples. 
8.5.5
Final Visit
This visit is to take place when a subject is discontinuing from the study. 
-
Collect and check the diary/elicit information about AEs/new concomitant medications 
since the last visit.  
-
Collect brequinar/DHO and hematology/chemistry samples.  
-
Collect unused study medication. 
-
Conduct physical examination, vital signs, urine pregnancy test for WOCBP (if <4 weeks 
since previous), 12-lead ECG (if <4 weeks since previous), and bone marrow sampling (if 
> 4 weeks since previous bone marrow sample obtained).  
-
Review the safety information and determine whether the subject has acceptable safety or 
unacceptable safety.  
-
Notify DHO assay laboratory of incoming shipment and ship brequinar/DHO samples.  
-
Stop text message reminders. 
8.5.6
Follow Up Visit (2 weeks after Final Visit)
-
Contact subject two weeks after Final Visit to determine subject’s survival status. Survival 
information will be collected while the subject is participating in the study (i.e., up to 2 
weeks after last dose of study medication). 


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8.5.7
Unscheduled Visits
Unscheduled visits and tests to assess AEs are permitted as needed providing the AE onset occurs 
within four (4) weeks after the final dose.
8.6 Compliance with Study Procedures
The time at which study procedures are conducted should follow the protocol timelines as closely 
as possible.  However, it is recognized in a clinical setting that protocol-specified timings may not 
occur exactly as specified in the protocol. Provided that activities are carried out within the 
identified window, it will not be necessary to file a protocol violation.   
8.7 Early Withdrawal from the Study 
A subject may withdraw from the study at any time for any reason or for one of the reasons listed 
below. The Sponsor or Investigator may also terminate a subject’s study participation after 
discussion with the other party if it is believed it would be unsafe for the subject to continue in the 
study.    
Subjects must be withdrawn from the study if any of the following events occur: 

Significant protocol violation or non-compliance, either on the part of the subject or the 
investigator or other site personnel; 

Decision of the Investigator or Sponsor that removal is in the subject's best interest; 

Severe unrelated medical illness or complication; 

Safety reasons/ significant adverse event; 

Subject request (withdrawal of consent); 

Sponsor decision. 
Collect/conduct all evaluations for subjects who withdraw from the study prior to completing the 
treatment period, unless consent is withdrawn.     
8.8 Early Termination of the Study
If the Sponsor or an Investigator believes it would be unsafe to continue the study, or for any 
reason at the Sponsor’s request, the study may be terminated at that site or the entire study 
terminated after discussion with the other parties. 
The Sponsor will provide a written statement to the IRB and the relevant regulatory authority with 
the reasons for termination of the study. This will be conducted within 15 days of the decision to 
terminate the study.  
If the study is terminated, a close out monitoring visit will be performed and applicable procedures 
will be carried out to close the trial site(s). 
8.9 Short Messaging Service (SMS) Medication Reminders
The Health Insurance Portability and Accountability Act of 1996 (HIPAA) was enacted in part to 
protect the security and privacy of protected health information (PHI). Covered entities (e.g., 


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health care providers engaged in certain electronic transactions, health plans, and health care 
clearinghouses) that create, maintain, transmit, use, and disclose an individual’s PHI are required 
to meet HIPAA requirements. 
HIPAA’s Privacy Rule restricts uses and disclosures of PHI, creates individual rights with respect 
to their PHI, and mandates administrative requirements. Among other requirements, the privacy 
rule requires a covered entity to reasonably safeguard PHI from any intentional or unintentional 
use or disclosure that is in violation of the requirements of HIPAA. 
HIPAA’s Security Rule requires covered entities to ensure confidentiality, integrity, and 
availability of its electronic PHI, to protect against reasonably anticipated threats or hazards to the 
security or integrity of its electronic PHI, to protect against reasonably anticipated impermissible 
uses and disclosure of its electronic PHI, and to ensure compliance by their workforce. 
Additionally, the Security Rule requires covered entities to put in place detailed administrative, 
physical, and technical safeguards to protect electronic PHI. To do this, covered entities are 
required to implement access controls and set up backup and audit controls for electronic PHI in a 
manner commensurate with the associated risk. 
For protocol CCB-01, the Sponsor intends to utilize a third-party vendor with a HIPAA-compliant 
platform to send one-way text message reminders to study participants who have a mobile device. 
The SMS/text message will be sent on the days and times he or she is to take his or her study 
medication, e.g., Monday mornings and Thursday evenings. The exact timings of the reminders
will be customized for each study participant. The PHI the third-party vendor receives will be 
restricted to the participant’s mobile device number and study identification number. The study 
participant is not to reply to the text message except to "opt out" from the service by sending 
"STOP" in the message body. In any other case if he/she sends a text message, the texting service 
will reply with a message indicating that messages sent by participants are not being monitored. 
Study participants must agree to “opt in” for this service and can "opt out" at any time even if they 
initially agreed. Study participants will need to sign an addendum to the informed consent 
document documenting their decision prior to enrollment in the system (see Appendix 14.5).   
The third-party vendor will sign an agreement with the Sponsor to use participant data only for the 
purposes of this study. Data will be purged from the vendor's servers at the conclusion of the trial 
upon written request by the Sponsor. Data will remain in the vendor's encrypted back-up files that 
will be maintained per HIPAA-compliant standards. 


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9
ADVERSE EVENT REPORTING
An adverse event is any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal relationship with 
this treatment.  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of the 
medicinal product, whether or not considered related to the medicinal product.
Events that occur prior to dosing will be entered as medical history; AEs that occur after dosing 
will be entered on the AE form. 
Subjects will be questioned and observed for evidence of AEs, whether or not related to study 
drug. All AEs will be documented in the subject's medical record and CRF.  For any pre-existing 
condition or abnormal laboratory finding that changes in severity after dosing, this change should 
be recorded as an AE. New abnormal laboratory findings that are clinically significant are 
considered AEs. 
AEs will be collected beginning from the time of informed consent through at least 14 days after 
the final dose of study medication. AEs will be specified as pre-treatment or treatment-emergent. 
AE details are to be documented including start and stop date and times, whether continuous or 
intermittent, severity, any intervention utilized to correct the event (e.g., medication, surgery or 
other therapy), outcome and the relationship to the study drug.   
AEs identified in the protocol as critical to the evaluation of safety must be reported to the Sponsor 
by the Investigator according to the reporting requirements within the time periods specified in the 
protocol. 
AEs determined by the Investigator to be related to study drug must be followed until resolution 
or until they are considered stable or for at least 30 days after discontinuation of study drug, or 
until new treatment for AML is initiated, whichever occurs first.   
Any SAEs experienced after 30 days post the last dose of study drug should only be reported to 
the sponsor if the investigator suspects a causal relationship to the study drug.   
Abnormal laboratory values or test results occurring after study enrollment constitute AEs only if 
they induce clinical signs or symptoms, are considered clinically significant, require therapy (e.g., 
hematologic abnormality that requires transfusion or hematological stem cell support), or require 
changes in study drug (e.g., discontinuation of study drug).
New signs or symptoms or worsening in severity of a cancer symptom that occur in association 
with disease progression should be recorded as AEs. Disease progression should not be reported 
as an AE unless worsening of signs and symptoms occur, or death from disease progression.
If a death occurs during the SAE reporting period, the cause of death is considered as the AE and 
the death is considered its outcome. Death should be considered an outcome, not an event. The 
event or condition leading to death should be recorded and reported as a single medical concept 
on the Adverse Event eCRF. Generally, only one such event should be reported. “Fatal” will be 
recorded as the outcome of this respective event; death will not be recorded as separate event. If 


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the primary cause of death is disease progression, the cause of death should be clearly identified 
as progression of cancer under study.
In cases of surgical or diagnostic procedures, the condition leading to the procedure is considered 
as the AE instead of the procedure itself. Each AE will be coded by the Sponsor from the verbatim 
text to a preferred term using a thesaurus based on the Medical Dictionary for Regulatory Activities 
(MedDRA).  
The following guidelines will be followed for the recording and reporting of adverse and serious 
adverse events. 
1. Baseline events will be recorded in the medical history section of the case report form and 
will include the terminology event name, grade, and start date of the event.  The medical 
history section of the case report form will serve as the source document for baseline events 
once signed and dated by the principal investigator.  
a.
Baseline events are any medical condition, symptom, or clinically significant lab 
abnormality present before the informed consent is signed. 
i. Hematologic laboratory abnormalities will not be recorded as baseline events 
for patients with acute leukemia, myelodysplastic syndrome, chronic 
lymphocytic leukemia, or chronic myeloid leukemia in blast phase. 
ii. If exact start date is unknown, month and year or year may be used as the start 
date of the baseline event. 
2. The maximum grade of the adverse event will be captured per course or protocol-defined 
visit date. 
3. These adverse events will be recorded in the case report form: 
a.
Any grade adverse event that is possibly, probably, or definitely related to the study 
drug. 
b. All serious adverse events regardless of attribution to the study drug. 
c.
Any grade adverse event regardless of attribution to the study drug that results in any 
dose modification. 
4. Hematologic adverse events will not be recorded or reported for studies in patients with acute 
leukemia, myelodysplastic syndrome, chronic lymphocytic leukemia, or chronic myeloid 
leukemia in blast phase except for: 
a.
Prolonged myelosuppression as defined by the NCI-CTCAE criteria specific for 
leukemia, e.g. marrow hypocellularity on day 42 or later (6 weeks) from start of 
therapy without evidence of leukemia (< 5% blasts), or that results in dose 
modifications, interruptions or meets the protocol definition of DLT or SAE. 
5. Serious adverse events will be reported according to institutional policy. 
6. Protocol specific language regarding the recording and reporting of adverse and serious 
adverse events will be followed in the event of discordance between the protocol and 
Leukemia-specific adverse event recording and reporting guidelines.  
(MD Anderson Cancer Center Leukemia-specific Adverse Event Recording and Reporting 
Guidelines) 
 


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The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html).  
9.1 Classification of Causality
Attribution is the relationship between an adverse event or serious adverse event
and the study treatment. Attribution will be assigned as follows:

Definite – The AE is clearly related to the study treatment.

Probable – The AE is likely related to the study treatment

Possible – The AE may be related to the study treatment.

Unlikely - The AE is doubtfully related to the study treatment.

Unrelated - The AE is clearly NOT related to the study treatment
Guidance for assessing causality:
The Investigator will need to determine whether an AE is considered related to (“caused by”’) the 
study drug rather than some underlying condition, for example, AML.
For the purposes of this study, ‘drug related’ shall mean ‘Definite’, ‘Probable’ and ‘Possible’ 
relationship to drug as determined by the PI. 
9.2 Classification of Severity
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All appropriate treatment 
areas should have access to a copy of the criteria. The CTCAE version 4.0. A copy of the 
CTCAE version 4.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm and in Appendix D.
AEs that are expected are subject to expedited reporting only if the adverse event varies in nature, 
intensity or frequency from the expected toxicity information that is provided in the Investigator 
Brochure.
9.3 Serious Adverse Event (SAE) Reporting
The regulatory definition of a Serious Adverse Event (SAE) is any untoward medical occurrence 
or effect that at any dose: 

results in death;

is life threatening (at the time of the event);

requires in-patient hospitalization or prolongation of existing hospitalization;

results in persistent or significant disability / incapacity, or

is a congenital anomaly / birth defect;

all other events that are considered medically serious by the Investigator.


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Disability is defined as a substantial disruption of a person’s ability to conduct normal life 
functions. 
A life-threatening adverse event is one that places the patient/subject, in the view of the 
Investigator, at immediate risk of death from the event as it occurred.  It does not include an event 
that, had it occurred in a more severe form, might have caused death.   
An unexpected adverse event is any adverse drug event, the nature or severity of which is not 
consistent with the applicable product information (e.g. Investigator’s brochure for an 
unauthorized investigational product or summary of product characteristics for an authorized 
product). 
Enter only one event as the reason for the SAE on the SAE form.  Other non-serious events 
which did not directly result in the SAE should be detailed in the description section on the SAE 
form and listed separately as AEs if necessary. For fatal SAEs, report the cause of death as an 
SAE with a fatal outcome rather than reporting death as the SAE term. 
Note that hospitalizations for the following reasons should not be reported as SAEs: 

Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition;  

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent;  

Social reasons and respite care in the absence of any deterioration in the subject’s general 
condition ; 

Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of an SAE given 
above is not an SAE.  
 
ANY SERIOUS ADVERSE EVENT MUST BE REPORTED IMMEDIATELY (WITHIN 
24 HOURS) BY EMAIL OR FAX TO THE SPONSOR CONTACT USING THE FORM 
PROVIDED. ENTER THE SUBJECT’S AVAILABLE INFORMATION INTO THE ECRF
WITHIN 48 HOURS.
The subjects are to be identified in the immediate and follow-up reports by unique code numbers 
supplied by the sponsor.  The email address and fax telephone number for reporting SAEs can be 
found below and at the front of this protocol.   
Reports relating to the subject’s subsequent medical course following a SAE must be submitted to 
the Sponsor contact until the event has subsided or, in case of permanent impairment, it stabilizes 
and the overall clinical outcome has been ascertained. 
SAE REPORTING FAX:     919-313-1412 (US Toll-free:  1-866-761-1274)
SAE REPORTING EMAIL: safety-inbox@novellaclinical.com 


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MEDICAL MONITOR:
E-mail:
Robert Sims, MD
robert.sims@novellaclinical.com; 
YYA36071medmon@novellaclinical.com 
Telephone:
614-721-2630
24-hour safety line: 1-866-758-2798 or 919-313-7111
Fax:
206-826-0483
Sponsor Representative: 
Barbara Powers, MSN, Ph.D.
E-mail:
bpowers@clearcreekbio.com  
Telephone:
484-686-0545
All SAEs will be reported to the IRB periodically, at the end of the study or per local institutional 
guidelines.   
9.4 Suspected Unexpected Serious Adverse Reactions (SUSARs)
Suspected, unexpected, serious adverse reactions (SUSARs) are SAEs that are both related to the 
study drug (Relationship = Related) and unexpected (not previously described in the investigator’s 
brochure). All SUSARs will be reported in an expedited manner to the Sponsor or designee and 
IRB by the Investigators and to all relevant regulatory authorities by the Sponsor. Expectedness 
will be judged by the Medical Monitor and site PI. It is critical that all SAEs are reported within 
the 24-hour guideline so that the expectedness determination can be made. SUSARs require 
immediate attention and expedited reporting to relevant regulatory authorities. 
The Sponsor is to ensure that all relevant information about fatal or life-threatening SUSARs are 
appropriately recorded and reported to the concerned Regulatory Authority and to the concerned 
IRB(s) within seven (7) calendar days of the date of first report to the Medical Monitor/Sponsor. 
Follow-up information is to be subsequently communicated to the relevant Regulatory Authority 
within an additional eight calendar days. 
All other SUSARs are to be reported to the Regulatory Authority and to the IRB(s) concerned as 
soon as possible within a maximum of fifteen calendar days of first knowledge by the Medical 
Monitor/Sponsor. 
The Medical Monitor/Sponsor or designee must also inform all Investigators studying the 
investigational medicinal product about SUSARs and ensure that all IRBs have been notified.
For reported deaths of a subject, the Investigator shall supply the Sponsor and the IRB(s) with 
additional information requested on an expedited basis.   
9.5 Pregnancies
Pregnancy occurring in a female subject or a subject’s partner during the study period will be 
documented in the subject’s source documents and reported on a Pregnancy Form to the Sponsor 
Contact and to the IRB/IEC by the investigational staff within 1 working day of their knowledge 
of the event. The pregnancy information should be submitted using a Pregnancy Report Form. The 
collection period for a pregnancy occurring in a subject or a subject’s partner will begin at the first 
dose of study drug and will continue through 90 days after the last dose of study drug. Monitoring 


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of the subject or partner should continue until the conclusion of the pregnancy, if the subject or 
subject’s partner has consented to this. Monitoring of the baby should continue for 3 months after 
birth, if the subject or subject’s partner has consented to this.  
Pregnancy itself is not an AE; it should be reported for tracking purposes. The Investigator or 
designee will discontinue the pregnant subject from the treatment aspects of the study, continue to 
follow her per protocol for safety outcomes only, and advise her to seek prenatal care and 
counseling from her primary care provider. Data on fetal outcome and breast-feeding will be 
collected for regulatory reporting and drug safety evaluation.
  
If the pregnancy is due to a subject’s failure to comply with the contraceptive requirements of this 
protocol, this should also be documented as a protocol deviation.  
 
Complications of pregnancy or congenital abnormalities in the newborn child will be reported 
appropriately as AEs.  
The site clinical staff will request the pregnant subject to notify the site of the outcome of the 
pregnancy (i.e., birth, loss, or termination). To help ensure this, the site clinical staff will follow-
up with the subject until the end of pregnancy, with the subject’s consent. This request and the 
subject’s response will be documented in the subject’s source document. 
9.6 Hematologic Adverse Events
It is recognized that laboratory value variability is a frequent and expected and may be present at 
Baseline when a subject enrolls in the study. In general, mild day to day fluctuation of laboratory 
values should not be classified as AEs. Fluctuations in laboratory values resulting from adverse 
changes in the patient’s medical condition should be reported as AEs. Laboratory abnormalities 
that constitute an AE in their own right as per CTCAE V4.03 criteria if applicable (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study drug), should be recorded on the AE eCRF. 
Whenever possible, a diagnosis, rather than a symptom should be provided (e.g., anemia instead 
of low hemoglobin). Laboratory abnormalities that meet the criteria for AEs should be followed 
until they have returned to normal or an adequate explanation of the abnormality is found. When 
an abnormal laboratory or test result corresponds to a sign/symptom of an already reported AE, it 
is not necessary to separately record the lab/test result as an additional event.  
Laboratory abnormalities that do not meet the definition of an AE should not be reported as AEs. 
A laboratory abnormality designated a Grade 3 or 4 event (severe) as per CTCAE does not 
automatically indicate a SAE unless it meets the definition of serious as defined below and/or as 
per Investigator’s discretion.  
For laboratory abnormalities and any AEs, it should be noted that the terms serious and severe are 
not symptoms. The term severe describes the intensity of the specific event (e.g., Grade 3 or 4). 
The term serious is based on patient and event outcomes or actions required as described in the 
protocol definition of SAEs and is usually associated with events posing a threat to the subject’s 


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life or ability to function. A severe AE (Grade 3 or 4) does not necessarily need to be considered 
serious; laboratory abnormalities (such as WBC or platelet count) may be severe but not serious.
After the subject has completed the first 42 days of treatment, hematologic dose-limiting toxicity 
(DLT) is defined as prolonged neutropenia with ANC < 500 from the start of therapy in the absence 
of disease, 
, and/or 
thrombocytopenia, with a hypocellular bone 
marrow and no greater than 5% marrow blasts lasting for 2 weeks or more. Anemia will not be 
considered a hematologic AE for the definition of unacceptable safety. The timing of the bone 
marrow sampling can be adjusted to ensure that the results are available for the visit on Day 43 
(Day 1 of Cycle 4). 
Participants with neutropenia or thrombocytopenia because of disease prior to the start of therapy 
do not require treatment interruption for myelosuppression. Dose reductions of brequinar in these 
participants should be considered on an individual case basis and discussed with the Sponsor. 
9.7 Management of Myelosuppression
Myelosuppression and the related adverse events (thrombocytopenia, anemia, neutropenia, febrile 
neutropenia) are common in both treated and untreated patients with AML. Based on clinical 
observations with DHODH inhibition and with historical evidence from previous studies with 
brequinar, participants treated with brequinar may experience thrombocytopenia and neutropenia.  
If a participant achieves a clinical response including CR, CRi, CRh, or MLFS while on study and 
they have not recovered absolute neutrophil count (ANC) > 500/uL within 14 days of study drug 
interruption, brequinar dosing may be further interrupted until ANC recovers to > 500/uL, unless 
the low ANC is thought to be due to the underlying disease. Brequinar may be reinitiated at an 
adjusted dose per discussion with the Sponsor. Granulocyte colony-stimulating factor (GCSF) may 
be administered if in the best interest of the participant.
9.8 Differentiation Syndrome
Based on its proposed pro-differentiating mechanism of action, it is possible that participants 
receiving treatment with brequinar may develop signs and symptoms of differentiation syndrome 
(DS). Clinical features may include some or all of the following: unexplained fever, skin rash, 
hypoxia, respiratory compromise, interstitial pulmonary infiltrates, pleural and/or pericardial 
effusion, weight gain, and clinical deterioration. Laboratory features may include an increase in 
ANC and/or platelets. An increase in mature leukocytes may be observed in the bone marrow 
aspirate differential if a bone marrow biopsy is conducted during this time. However, no single 
sign or symptom may be considered per se as diagnostic of the syndrome, and other causes should 
be sought and excluded. 
It is recommended that the prophylactic and therapeutic measures indicated below be undertaken 
at the earliest manifestations of suspected differentiation syndrome: 

Temporary hold of brequinar if clinical features cannot be medically managed with the 
following: 
-
Control of leukocytosis with hydroxyurea;  
-
Prompt administration of corticosteroids at a suggested dose of 10 mg of 


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dexamethasone IV every 12 hours until disappearance of symptoms and signs, 
continued for a minimum of 3 days;
-
Initiation of furosemide, if clinically required; 
-
Prompt initiation of leukapheresis, if required. 
If brequinar dosing is held, brequinar may be reinitiated without dose reduction once the 
participant’s clinical condition improves, upon discussion with the Sponsor. 
9.9 Tumor Lysis Syndrome (TLS)
Tumor lysis syndrome (TLS) is characterized by nausea, vomiting, diarrhea, anorexia, lethargy, 
irregular heart rhythms, heart failure, hematuria, seizures, muscle cramps, syncope, tetany and 
possible sudden death due to the acute metabolic irregularities of hyperkalemia, 
hyperphosphatemia and hypocalemia associated with the breakdown of tumor cells secondary to 
cytotoxic therapy. 
While TLS was not observed in the previous extensive clinical experience with brequinar, the 
experience with brequinar in hematologic malignancies is limited. Signs and symptoms of TLS 
will therefore be carefully monitored particularly in the period that tumor lysis is most likely to 
occur (24-48 hours after first dose). The risk stratification in AML for TLS from the international
guidelines by Cairo et al., 2010 [11] is as follows:

Low risk disease: WBC < 25 x 109 /L and LDH < 2 x upper limit of normal (ULN);

Intermediate risk disease (IRD): WBC 25 to 100 x 109 /L or WBC < 25 x 109 /L and LDH 
 2 x ULN;  

High risk disease (HRD): WBC  100 x 109 /L.
The guidelines for the prevention, monitoring and treatment of TLS are described below: 
TLS Prevention [Recommended]:  

IV hydration: aggressive hydration is recommended for patients at intermediate to high risk 
for TLS with a goal of initially 2 to 3 L/m2 per day of IV fluid per the international 
guidelines (Coiffer et al., 2008 [12]). 

Hypouricemic agents: allopurinol for intermediate risk disease (IRD). 
TLS Monitoring: (Howard et al., 2011 [13]) 

Figure 2 provides a flow chart for TLS monitoring. 


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Figure 2.
Monitoring of Tumor Lysis Syndrome
TLS Treatment
TLS requires urgent inpatient management including intense nursing care, cardiac monitoring, 
nephrology consultation, and measurements of uric acid, creatinine, and electrolytes every four 
to six hours. Treat any electrolyte abnormalities and any acute renal injury. 


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9.10 Infection Prophylaxis
Supportive care, including prophylactic antibiotics, antifungal and/or antiviral agents, are 
frequently used in neutropenic patients, and may be used per standard institutional practice and as 
deemed necessary by the investigator. 
9.11 Growth Factor Support
The use of myeloid growth factors (granulocyte-colony stimulating factor [G-CSF] and 
granulocyte-macrophage colony-stimulating factor [GM-CSF]) may be given to support subjects 
who have developed Grade 4 neutropenia or Grade 3 neutropenia with fever and/or infection, per 
institutional guidelines. 
9.12 Management of Nausea, Vomiting, and Diarrhea
Recommended management of nausea and vomiting is to administer antiemetics. The 
recommended treatment for managing diarrhea is loperamide antidiarrheal therapy, 4 mg at first 
onset, followed by 2 mg with each loose movement until diarrhea-free for 12 hours (maximum 
dosage: 16 mg/24 hours). Adjunct anti-diarrheal therapy is permitted. 
 


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10
STATISTICAL CONSIDERATIONS
A separate, detailed statistical analysis plan (SAP) will be finalized prior to locking the database. 
All analyses of safety and anti-leukemic activity for this open-label early Phase study will be 
descriptive in nature and presented by dose group and overall, as appropriate, for the dose-
adjustment phase and the expansion phase. Procedures for accounting for missing, unused and 
spurious data will be described in the SAP.  
Summaries for quantitative variables will include the mean, median, quartiles, standard deviation 
and error, minimum, and maximum. For qualitative variables, the summaries will include the 
number and percentage of subjects for each outcome, and the exact 95% CI, when appropriate. No 
hypothesis testing will be performed. Any statistical testing will be considered exploratory and 
descriptive. All computations will be performed using SAS® (Version 9.3 or higher). 
Subject disposition, subject demographics and baseline characteristics will be summarized. 
Subject data listings will also be provided. The following sections will briefly summarize of the 
planned statistical analyses and analysis sets for the primary and secondary endpoints. 
10.1 Study Populations for Analysis
The analysis sets are defined in Table 3. 
Table 3.
Analysis Sets
Analysis Set
Description
Enrolled Analysis Set 
All subjects who have been enrolled in the study. 
Safety Analysis Set 
All subjects who were administered brequinar. 
Efficacy Analysis Set 
All subjects with AML disease at baseline and who were administered 
brequinar. 
Pharmacokinetic Analysis Set 
All subjects who take at least 1 dose of brequinar and have at least 1 
quantifiable plasma concentration collected post-dose without important 
protocol deviations/violations or events thought to significantly affect the 
PK. 
The Efficacy Analysis Set will be used for efficacy analyses. The Safety Analysis Set will be used 
for safety analyses.   
10.2 Safety Analyses
All safety analyses will be performed on the Safety Analysis Set.  Safety and tolerability will be 
assessed in terms of AEs, SAEs, safety laboratory data, physical examinations, vital signs, 12-lead 
ECGs and bone marrow sampling.  
Adverse event data will be descriptively evaluated. All AEs will be listed. The incidence and 
duration of TEAEs, defined as AEs occurring after the first dose of study treatment through 30 
days after the last dose of study treatment, will be tabulated by Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term and system organ class, and by severity and relationship to 
study treatment. All laboratory results, vital sign measurements, ECGs and bone marrow 
assessments will be summarized using appropriate descriptive statistics.


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10.3 Efficacy Analyses
Efficacy analyses will be performed using the Efficacy Analysis Set.  Table 4 summarizes the 
planned analysis of primary and secondary efficacy endpoints. 
Table 4.
Efficacy Analyses
Endpoint
Statistical Analysis Methods
Primary 
There is no primary efficacy endpoint for this study. 
Secondary

Assess anti-leukemic activity as follows: 
o
Overall Response rate (ORR) – the proportion of subjects
in the Efficacy Analysis Set with a best overall response of 
CR, CRi, CRh, MLFS and PR  
o
Complete Remission (CR) rate – the proportion of subjects
in the Efficacy Analysis Set with a best overall response of 
CR 
o
Complete Remission with Incomplete Hematologic 
Recovery (CRi) rate – the proportion of subjects in the 
Efficacy Analysis Set with a best overall response of CRi 
o
Complete remission with partial hematological recovery 
(CRh) – the proportion of subjects in the Efficacy Analysis 
Set with a best overall response of CRh 
o
Morphologic Leukemia Free State (MLFS) rate – the 
proportion of subjects in the Efficacy Analysis Set with a 
best overall response of MLFS 
o
Partial Remission (PR) rate – the proportion of subjects in 
the Efficacy Analysis Set with a best overall response of 
PR 
o
Event-free survival (EFS) – the interval between first 
brequinar 
blasts, reappearance of blasts in blood, or development of 
extramedullary disease), disease progression, or death 
o
Overall survival (OS) – the time from first dose of 
brequinar to date of death or last known alive date 
For ORR and other endpoints defined as proportions, estimated 
response rates and two-sided exact binomial 95% CIs will be provided.  
The distributions of EFS and other time-to-event endpoints will be 
summarized using the Kaplan-Meier method.  Time to event analyses 
will be from first dose of brequinar.  Censoring rules for time-to-event 


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endpoints will be described in the SAP. 
Exploratory
Will be described in the SAP finalized before database lock.
Disease response for participants with AML will be assessed based on Döhner et al, 2017 [10]. 
Complete remission (CR):  

Bone marrow showing less than 5% myeloblasts with normal maturation of all cell lines, 

ANC of at least 1000/µL  

Platelet count of 100,000/µL

Absence of blasts in peripheral blood

Absence of identifiable leukemic cells in the bone marrow

Absence of extramedullary disease. 
Complete Remission with Incomplete Blood Count Recovery (CRi): 

Same as for CR but without achievement of ANC at least 1000/uL (CRi) and/or platelet 
count of 100,000/uL (CRp). 
Complete Remission with Partial Hematological Recovery (CRh)

Complete remission with partial hematological recovery defined as <5% of blasts in the 
bone marrow, no evidence of disease, and partial recovery of peripheral blood counts 
(platelets >50,000/microliter and ANC >500/microliter) (Kantarjian HM et al, 2016 [14]). 
Partial Remission: 

All hematologic criteria of CR are fulfilled, and 

A decrease of bone marrow blast percentage to 5% to 25%, and 

Decrease of pretreatment bone marrow blast percentage by at least 50%.
Morphologic Leukemia Free State:

Bone marrow blasts <5%; 

Absence of blasts with Auer rods; 

Absence of extramedullary disease;

No hematologic recovery required
Stable Disease:

Failure to achieve a response

Not meeting criteria for Progressive Disease


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Progressive Disease
Evidence for an increase in bone marrow blast percentage and/or increase of absolute blast counts 
in the blood:

>50% increase in marrow blasts over baseline (a minimum 15% point increase is required 
in cases with <30% blasts at baseline; or persistent marrow blast percentage of >70% over 
at least 3 months; without at least a 100% improvement in absolute neutrophil count (ANC) 
to an absolute level 
 platelet count to >50 x 109/L
-transfused]; or

>50% increase in peripheral blasts (WBC x % blasts) to >25 x 109/L 
absence of differentiation syndrome); or

New extramedullary disease 
Duration of Response  

The duration of response is defined as the number of days from the time response criteria 
are initially met for CR, CRi, CRh, PR, or MLFS (whichever is first recorded) until the 
first date that recurrent or progressive disease is objectively documented, or death due to 
any cause. Participants without events reported are censored at the last disease evaluation.
Clinical Benefit
Requires one of the following in the absence of progression or CR/partial response and 
independent of marrow response to be considered a clinical benefit: 

Erythroid response 
o
Transfusion Independence
units 
of packed red blood cell transfusions in the previous 8 weeks. Only red blood cell 
g/dL will count in the red blood cell TI response evaluation. 

Platelet response 
o
Transfusion independence when previously requiring platelet transfusions of at 
least a rate of 4 platelet transfusions in the previous 8 weeks.
 
10.4 Other Endpoints
Brequinar Pharmacokinetics (PK)
Blood samples for PK analysis will be obtained at pre-specified times. Plasma PK parameters of 
brequinar including steady-state plasma concentration (Css); elimination half-life (T1/2); Area 
under the concentration curve (AUC); systemic clearance (CL) and volume of distribution at 
steady state (Vss) will be estimated by compartmental and non-compartmental analysis 
(WinNonlin or similar). 
Concentration data and PK parameters will be tabulated and summarized using descriptive 


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statistics.  Relationships between brequinar PK parameters and clinical outcomes (e.g., efficacy, 
toxicity) may be explored.  PK analyses will be performed on the PK Analysis Set.
Blood samples for DHO analysis will be obtained at pre-specified times and will be summarized.  
Relationships between DHO levels and PK and clinical outcomes (e.g., efficacy, toxicity) will be 
explored. 
Changes in myeloid markers per serial flow cytometry will be studied to look for evidence of 
myeloid differentiation.
10.5 Sample Size Considerations
Formal sample size calculations are not applicable for this phase 1b/2a, open label study. Up to 27 
subjects are planned to be entered in this trial: Cohort 1 will have 6 subjects; two additional cohorts 
of 3 subjects each will be added if adjustments are required to the cohort starting dose. The cohorts 
with 3 subjects may be expanded to 6 subjects depending on safety outcomes within the cohort. 
An expansion cohort of approximately 15 subjects will be enrolled with a starting dose of the 
highest tolerated starting dose from Cohorts 1 to 3.  
10.6 Randomization
No randomization scheme is needed for this open label study. 
10.7 Pooling of Study Centers
Not applicable to this small, early phase study. 
10.8 Interim Analysis
No interim analysis is planned for this trial. 


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11
INVESTIGATOR RESPONSIBILITIES
11.1 Investigator’s Performance
The Investigator will ensure that all those concerned with conducting the trial are:
provided with copies of the protocol and all safety information prior to the start of the trial;
trained regarding the conduct of the study and the training has been documented.
The Investigator will sign the Investigator’s Statement and Agreement (Appendix 14.6) to indicate 
commitment to comply with the contents. 
11.2 Confidentiality
The Investigator shall assure the subject that his/her identity will be protected and confidentiality 
will be maintained during all audits and inspections of the trial site and documentation. A unique 
number will be assigned to each subject at the start of the trial and this, with the subject’s initials, 
will be used to identify the subject. In some cases, a further step may be taken to assign “fake 
initials” to the subject, per individual site requirements. The subject’s number will be the site 
number followed by the number of this subject at this site and will be used as the unique identifier 
in the source records and on the CRF, on all trial correspondence and in the trial database. The 
Investigator will keep a list of identification codes or initials used for each subject along with the 
unique number assigned. 
All information provided to the Investigator relevant to the investigational medicinal product 
(IMP), as well as information obtained during the course of the trial will be regarded as 
confidential. The Investigator and members of his/her research team agree not to disclose or 
publish such information in any way to any third-party without prior written permission from the 
Sponsor which will not be unreasonably withheld, except as required by law, or as permitted by 
the Publications section of this protocol, Section 11.7.
The Investigator will take all measures to ensure subject’s confidentiality will be maintained at all 
times. 
11.3 Source Documentation
Investigators are to maintain adequate source documentation of the original study data, for 
example medication records, laboratory reports and pharmacy records as appropriate. The 
Investigator will allow inspections of the trial site and documentation by clinical research and audit 
personnel from the Sponsor, external auditors or representatives of regulatory authorities. The 
purpose of these inspections is to verify and corroborate the data collected on the CRFs. In order 
to do this, direct access to the subjects' medical or clinic records is necessary. The Investigator will 
ensure that certain information is contained in the medical or clinic records of the subject and that 
the entries are signed and dated, as follows:

sufficient data to allow verification of the entry criteria in terms of past and present medical 
and medication histories;

a note on the day the subject entered the trial describing the trial number, the IMP being 
evaluated, the trial number assigned to that subject and a statement that consent was obtained;


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
a note of each subsequent trial visit including any concerns about AEs and their resolution;

notes of all concomitant medication taken by the subject, including start and stop dates; 

a note of when the subject terminated from the trial, the reason for termination and the subject’s 
general condition at termination; 

a copy of the signed informed consent form should be kept in the medical records of each 
subject during the clinical phase of the study. A signed copy should also be filed in the 
investigator file. 
11.4 Data Collection
Suitably qualified and trained personnel at the trial site will ensure compliance with the protocol, 
adherence to ICH GCP obligations, proper maintenance of trial records including IMP 
accountability records, correct administration of IMP including storage conditions and accurate 
reporting of AEs. In addition, suitably qualified and trained clinical research personnel of the 
Sponsor will visit the trial site at regular intervals during the trial for monitoring purposes and to 
assist the research staff with any queries. All queries and discrepancies relating to the data 
collection are to be resolved at the completion of the trial. 
11.5 Case Report Forms, Investigator’s Site File and Record Retention
The Sponsor may provide the CRFs in paper, electronic (eCRF), or other media. The forms will 
be reviewed against source documentation at each monitoring visit. All CRFs and supporting 
source documentation must be completed and available to the Sponsor in a timely manner. 
Changes or corrections due to data clarification and resolutions will be tracked by paper or 
electronically with an audit trail. 
Prior to review of the case report forms by the Sponsor’s representative, they should be reviewed 
for completeness and accuracy by the Investigator or a member of the research team.
The Investigator must maintain an Investigator Site File which includes, but is not limited to, the 
Investigator’s Brochure, the protocol plus any amendments, all correspondence with the IRB 
including the approval for the trial to proceed, Regulatory Authority approval/ notification (if 
applicable) including a sample of an approved informed consent, IMP accountability, Source 
Documents, investigator and staff curricula vitae (CVs,) trial documentation, and all trial 
correspondence. The original signed informed consent forms and the final report will be kept in 
the Investigator Site File. 
The Investigator will archive all essential documents. The medical files of trial subjects shall be 
retained in accordance with national legislation and in accordance with the maximum period of 
time permitted by the hospital, institution or private practice. The Investigator has a responsibility 
to retain essential documents for as long as is required by the Sponsor and applicable regulatory 
authorities.  It is the responsibility of the Sponsor to inform the Investigator as to when these 
documents no longer need to be retained. Investigators will be asked to contact the Sponsor prior 
to the destruction of any data or removal to another site if this occurs prior to the Sponsor 
notification that the documentation is no longer required. Any transfer of ownership of the data or 


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of documents will be documented in writing.  The new owner will assume responsibility for data 
retention and archiving.
Should the Investigator retire, relocate, or for other reasons withdraw from the responsibility of 
keeping the trial essential documents, custody must be transferred to a person who will accept that 
responsibility, and the Sponsor must be notified in writing of the name and address of said person.
11.6 Non-Protocol Research
No investigational procedures other than those outlined in this protocol may be undertaken on the 
subjects in this trial without the prior written permission of the subject, the Sponsor, the IRB and, 
when appropriate, the regulatory authority. 
11.7 Publication
The Sponsor acknowledges the benefit of making widely available the results of all clinical trials 
and intends to publish the results of this trial. All publications resulting from the clinical trial must 
be in a form that does not reveal technical information that the Sponsor considers confidential or 
proprietary.  A copy of any abstract, presentation or manuscript proposed for publication must be 
submitted to the Sponsor for review at least 30 days before its submission for any meeting or 
journal. In addition, if deemed necessary by the Sponsor for protection of proprietary information 
prior to patent filing, the Investigator agrees to a further delay of 60 days before any presentation 
or publication is submitted. The Sponsor reserves the right to include the report of this trial in any 
regulatory documentation or submission or in any informational materials prepared for the medical 
profession. 
Authorship determination will be at the discretion of the Sponsor and will include evaluation of 
the following criteria: Investigator must participate in the review of and content of the protocol; 
review and comment on the study results; participate in the writing, reviewing and commenting of 
the manuscript; and approve the final manuscript for submission. 
 
 
 
 
 
 
 
 
 
 


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12
SPONSOR RESPONSIBILITIES
12.1 General
The Sponsor agrees to adhere to the ICH Note for Guidance on Good Clinical Practice 
(CPMP/ICH/135/95, Jan.97) and US FDA Regulations. It is the Sponsor's responsibility to obtain 
appropriate regulatory approval to perform the trial (if applicable). The Sponsor should notify 
promptly all concerned investigator(s), IRB(s) and the Regulatory Authority of findings that could 
adversely affect the health of the patients/ subjects, impact on the conduct of the trial or alter the 
Regulatory Authority’s authorization to continue the trial. If it is necessary to change or deviate 
from the protocol to eliminate an immediate hazard to the subjects the Sponsor will notify the 
relevant regulatory authority and relevant IRB of the new events, the measures taken and the plan 
for further action as soon as possible.  This will be by telephone in the first instance followed by a 
written report.   
On completion of the trial, the Sponsor will inform the regulatory authority that the trial has ended.  
If the study is terminated for any reason the Sponsor will provide a written statement to the relevant 
regulatory authority and the IRB with the reasons for termination of the trial. This will be 
conducted within 15 days of the decision to terminate the trial.  The Sponsor will report in an 
expeditious manner all suspected unexpected serious adverse reactions (SUSARs) to the relevant 
regulatory authority and IRBs.   
12.2
Indemnity
The Sponsor will provide compensation insurance against any risk incurred by a subject as a result 
of participation in this trial. The Sponsor will indemnify the Investigators as detailed in a separate 
document.
12.3
Data Monitoring
Suitably qualified and trained clinical research personnel of the Sponsor will visit the trial site at 
regular intervals during the trial for monitoring purposes and to assist the research staff with any 
queries. CRFs and source documentation will be available for review during monitoring visits to 
the trial site. The function of this monitoring is to ensure compliance with the protocol, adherence 
to regulatory and Good Clinical Practice obligations, proper maintenance of records including IMP 
accountability records, correct administration of IMP including storage conditions and accurate 
reporting of AEs.  
Once the data from the case report forms have been entered onto the database, they will be 
reviewed and the data verified against the subject’s source data. Any discrepancies will be tracked 
by paper or electronically with an electronic audit trail. 
12.4
Audit
The Sponsor has an obligation to audit a proportion of studies.  A department other than the clinical 
department will undertake this obligation. Therefore, the Sponsor, an independent auditor or a 
regulatory authority may audit the trial site and trial documentation. These audits may take place 
while the trial is being conducted or up to several years later.  


PROTOCOL NUMBER:  CCB-01
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CONFIDENTIAL:  Clear Creek Bio, Inc. 
12.5
Confidentiality
The Sponsor will not keep any material on file bearing any subject’s name, and subjects’
confidentiality will be maintained at all times. 
12.6
Finance
This will be the subject of a separate agreement between the Investigator/Institution and Sponsor.


PROTOCOL NUMBER:  CCB-01
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DATE:  16 October 2018 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
13
REFERENCES
1. Surveillance, Epidemiology, and End Results (SEER) Program, 1973-2015.
www.seer.cancer.gov.
2. Ng SB, Buckingham KJ, Lee C, et al. Exome sequencing identifies the cause of a 
mendelian disorder. Nature 2010; 42: 30-35.
3. Huang M, Wang Y, Collins M, et al. A77 1726 induces differentiation of human myeloid 
leukemia K562 cells by depletion of intracellular CTP pools. Mol Pharmacol 2002; 
62(3):463-472.
4. Sykes DB, Kfoury YS, Mercier FE, et al. Inhibition of dihydroorotate dehydrogenase 
overcomes differentiation blockade in acute myeloid leukemia. Cell 2016; 167(1): 
171-186.
5. Arteaga CL, Brown TD, Kuhn JG, et al. Phase I clinical and pharmacokinetic trial of 
Brequinar sodium (DuP 785: NSC 368390). Cancer Res 1989; 49(16): 4648-4653.
6. Burris HA 3rd, Raymond E, Awada A, et al. Pharmaocokinetic and phase I studies of 
brequinar (DUP 785; NSC 368390) in combination with cisplatin in patients with advanced 
malignancies. Invest New Drugs 1998; 16(1): 19-27.
7. Noe DA, Rowinsky EK, Shen HS, et al. Phase I and pharmacokinetic study of brequinar 
sodium (NSC 368390). Cancer Res 1990; 50(15): 4595 – 4599.
8. Schwartsmann G, Dodion P, Vermorken JB, et al. Phase I study of Brequinar sodium (NSC 
368390) in patients with solid malignancies. Cancer Chemother Pharmacol. 1990; 25(5):
345-351.
9. Brequinar Investigator’s Brochure
10. Döhner H, Estey E, Grimwade D, Amadori S, Applebaum FR, Büchner T, et al. Diagnosis 
and management of AML in adults: 2017 ELN recommendations from an expert 
international expert panel. Blood 2017; 129(4): 424-447.
11. Cairo MS, Coiffier B, Reiter A, et al. Recommendations for the evaluation of risk and 
prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant 
diseases: an expert TLS panel consensus. Br J Haematol 2010; 149:578.
12. Coiffer B, Altman A, Pui CH, et al. Guidelines for the management of pediatric and adult 
tumor lysis syndrome: an evidence-based review. J Clin Oncol 2008; 26:2767.
13. Howard SC, Jones, DF, Pui, C-H. The Tumor Lysis Syndrome. N Engl J Med 2011; 
364:1844-1854.
14. Kantarjian HM, Stein AS, Bargou RC, Grande Garcia C, Larson RA, Stelljes M, et al. 
Blinatumomab treatment of older adults with relapsed/refractory B-precursor acute 
lymphoblastic leukemia: Results from 2 phase 2 studies. Cancer 2016; 122(4): 2178-2185.


PROTOCOL NUMBER:  CCB-01
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CONFIDENTIAL:  Clear Creek Bio, Inc. 
14
APPENDICES
14.1 APPENDIX A:  CCB-01 Schedule of Events


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CONFIDENTIAL:  Clear Creek Bio, Inc. 
CCB-01 Schedule of Events
Proceduresa
Screenb
Cycle 1 (Study Days 1 – 14)
Dose 
Adjustment
Cycle (Cycle 2 
and beyond as 
needed)
Maintenance 
Dose Cycle (no 
dose 
adjustment)
Every 2 weeks
Final 
Visit
F/U 
Phone
Call
Survival
D1
D2
D3
D4
D8
D1
D8
D1
Final 
Visit 
+ 2 wks
Informed Consentb 
X 
 
 
 
 
 
 
 
 
 
 
 
AE/Concomitant Medications  
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Medical historyc  
X 
 
 
 
 
 
 
 
 
 
 
Demographicsd 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical Examd 
X 
X 
 
 
 
 
X 
 
X 
X 
 
 
Vital Signsd
X
X
X
X
X
X
X
Pregnancy Teste
X
X
X
ECOG Performance Status
X
Hematology/Chemistryf
X
X
X
X
X
X
X
Flow Cytometryg 
 
X 
X 
X 
 
 
 
 
 
 
 
 
Chromosomal/mutational testingh 
X 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECGb
X
X
X
MUGA/Echocardiogram 
X
Bone Marrow Samplingi
X
X
X
Brequinar/DHO Plasma Samplej
X
X
X
X
X
X
X
X
X
Biobanking samplesk
X
X
X
Ship DHO Plasma Samples
X
X
X
Dispense/Collect Study Medication 
X
X
X
X
Dispense/Collect Subject Calendar/Diary
X
X
X
X
Survival Assessment
X


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a.
Visit window of ± 1 day for dose escalation cycles; window of ± 3 days for non dose escalation cycles.
b.
Obtain informed consent prior to performing any screening or study-specific procedures. Screening procedures must be performed 
within 14 days prior to initial study drug administration.  Procedures at C1D1 that are repeats of Screening may be omitted if <72h 
since Screening assessment. ECG and pregnancy test frequency are every 4 weeks or per institutional guidelines. 
c.
Medical history is to include AML diagnosis, previous AML treatment, and standard chromosomal and mutational results per 
institutional guidelines. 
d.
Demographic information is to include date of birth, height, weight, race, and ethnic origin. Rectal examination may be deferred for 
Physical Examination. Vital signs include heart rate, respiratory rate, seated blood pressure, respiratory rate, oral/aural body 
temperature. Physical exam is to include weight. 
e.
For women of childbearing potential only, frequency is every 4 weeks or per institutional guidelines. 
f.
In addition to the already scheduled weekly chemistry assessment during Cycles 1 and 2 for each subject, subjects taking potentially 
hepatotoxic drugs are permitted to have more frequent monitoring than indicated in the schedule of events, if ordered by the study 
team. 
g.
Flow cytometry testing of peripheral blood is to be obtained at 0 (pre-dose C1D1), and post dose at 24 and 48 hours.  
h.
Testing panel is per institutional standard of care; obtain sample at Screening. 
i.
Bone marrow sampling local testing will include analysis of the aspirate on smear, core biopsy by microscopy, flow cytometry, and 
karyotype for cytogenetics. Local molecular analysis will be performed on the screening bone marrow samples only. Bone marrow 
samples will be sent for biobanking for possible further analysis from Screening, Day 43, and Final Visit (or bone marrow sample 
closest to Final Visit). Perform bone marrow sampling at screening, at study Day 22 (C2D8), at Day 43, and once every 12 weeks 
after a stable dose has been reached. Timing of this procedure may be adjusted to ensure results are available for the next clinic visit. 
Procedure window is ±7 days. 
j.
Brequinar/DHO plasma sampling schedule: Cycle 1: 0 (pre-dose), post dose 1, 2, 4, 6, 24, 48, 72 hours and C1D8 pre-dose (+84h after 
C1D4 dose); Cycle 2 and adjustment cycles: pre-dose Days 1 and 8; every 2-week Maintenance Cycle until 3-months on drug: pre-
dose Day 1 and every 2 to 4 week Maintenance Dose Cycle beyond 3-months on drug. Day 1 sample window ±15 minutes through 6h 
draw; window for additional C1 draws ±2h; window for Cycle 2 and beyond plasma brequinar/DHO draws ±4h. Ensure trough 
samples (e.g., C1D1, C2D1, C3D1) are obtained prior to dosing. Plasma samples for brequinar/DHO for expansion cohort are to be 
obtained prior to dosing on Day 1 of each 2-week cycle for the first 3 cycles, then every 12 weeks. 
k.
Biobanking samples (bone marrow) are to be collected whenever bone marrow sampling is performed. 


PROTOCOL NUMBER:  CCB-01
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CONFIDENTIAL:  Clear Creek Bio, Inc. 
14.2 APPENDIX B: ECOG Performance Status Criteria
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent 
Description
0
Normal level.  Fully active, able to 
carry 
on 
all 
pre-disease 
performance without restriction.
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal level; minor 
signs or symptoms of disease.
1
Symptoms, 
but 
ambulatory.  
Restricted in physically strenuous 
level, but ambulatory and able to 
carry out work of a light or 
sedentary 
nature 
(e.g., 
light 
housework, office work).
80 
Normal level with effort; some signs 
or symptoms of disease.
70 
Cares for self, unable to carry on 
normal level or to do active work. 
2
In 
bed 
<50% 
of 
the 
time.  
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities.  Up and about more 
than 50% of waking hours. 
60 
Requires occasional assistance but is 
able to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance.
30 
Severely disabled, hospitalization 
indicated.  Death not imminent.
4
100% bedridden.  Completely 
disabled.  Cannot carry on any self-
care.  Totally confined to bed or 
chair.
20 
Very sick, hospitalization indicated. 
Death not imminent.
10 
Moribund, 
fatal 
processes 
progressing rapidly.
5
Dead. 
0 
Dead. 
 


PROTOCOL NUMBER:  CCB-01
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CONFIDENTIAL:  Clear Creek Bio, Inc. 
14.3 APPENDIX C: Brequinar/DHO Plasma Sampling
Information is provided in a separate laboratory manual regarding collection, processing, storing, 
and shipment of samples.  
Brequinar and DHO plasma samples are to be obtained at the following time points (±30 minutes 
through 6h, then ±2h for the 24h, 48h, 72h and 84h samples:
Cycle 1
Cycle 2*
Maintenance 
Dose Cycle 
Final 
Visit 
D1 
D2 
D 3 
D 4 
D8 
D1 
D8 
D1 
 
Time 
Point 
Pre-
dose 
1h 
2h 
4h 
6h 
24h 
48h 
72h 
84h 
after 
prev. 
dose 
84h 
after 
prev. 
dose 
84h 
after 
prev. 
dose 
84h after prev. 
dose 
84h 
after 
prev. 
dose 
*Or any cycle where the brequinar dose has been adjusted from the previous 2-week dose.


PROTOCOL NUMBER:  CCB-01
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CONFIDENTIAL:  Clear Creek Bio, Inc. 
14.4 APPENDIX D: Common Terminology Criteria for Adverse Events (CTCAE)
https://evs.nci.nih.gov/ftp1/CTCAE/About.html


PROTOCOL NUMBER:  CCB-01
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14.5
APPENDIX E:
Sample Subject Consent Form 
TITLE:
A Phase 1b/IIa open-label, multi-center study to assess the safety, efficacy and 
pharmacokinetics of intrapatient dose-adjusted brequinar and inhibition of 
dihydroorotate dehydrogenase (DHODH) in adult subjects with acute myelogenous 
leukemia (AML)
PROTOCOL NO.:
CCB-01
SPONSOR: 
 
Clear Creek Bio, Inc. 
 
585 Massachusetts Avenue, 4th Floor, 
 
 
Cambridge MA 02139 
 
INVESTIGATOR: 
 
<insert PI name> 
Site(s):
<insert name> 
 
 
<insert address> 
STUDY-RELATED
PHONE NUMBER(S): <insert name(s)>
 
<insert number>
<insert alternate number (24-hour contact number)> 
VERSION and DATE: <e.g. CCB-01 Master ICF Version 2.0 04June2018>
 
You are being asked to take part in a research study. Before you decide to participate, it is important 
for you to understand why the research is being done and what it will involve. Please take time to 
read the following information carefully and discuss it with others, if you wish, before deciding 
whether or not to take part. Ask us if there is anything that is not clear or if you would like more 
information. 
WHAT IS THE PURPOSE OF THE STUDY?
The purpose of the study is to evaluate the safety, efficacy, pharmacokinetics (PK) (level of study 
medication in the blood) and the inhibition (decrease in level) of an enzyme called “dihydroorotate 
dehydrogenase” (DHODH). DHODH blocks the ability of blood cells formed in the bone marrow 
to differentiate (grow into mature white blood cells that can fight infection and platelets that help 
blood to clot). Brequinar is a drug that has been shown in animals in the laboratory to be able to 
decrease the level of DHODH and decrease leukemic cells in the bone marrow. Reducing DHODH 
level in patients with AML may help treat this type of leukemia by allowing cells in the bone 
marrow to grow into different types of mature cells.


PROTOCOL NUMBER:  CCB-01
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WHY HAVE I BEEN ASKED TO PARTICIPATE?
You have been asked to consider participating in this study because you because you have AML 
that has not responded to treatment (refractory), or the leukemia has recurred (relapsed).
HOW LONG WILL I BE IN THE STUDY?
Your participation in this study will last approximately 7 months and approximately 27 subjects 
will be participating in this study. If you respond (your leukemia improves) due to the effects of 
the study medication, you may be able to continue being treated for up to one year. You will take 
the study medication about every three-and-one-half (3.5) days, for example on Monday mornings 
and Thursday evenings. You and your study team can decide on the exact schedule for you to take 
your medication.
WHAT WILL HAPPEN TO ME IF I TAKE PART?
If you decide to take part in the study, you will have the following procedures: 
Screening Assessment
The Screening period is defined as the period prior to the administration of study drug. During this 
period, the investigator or designee will obtain/perform the following: 

Written, informed consent; 

Demographic details (height, weight, date of birth, race, ethnicity). 

Pertinent medical/surgical history, medications you are currently taking or have taken 
recently. 

Physical examination.  

Vital signs (heart rate, respiratory rate, blood pressure, body temperature).  

Pregnancy test for women of childbearing potential (WOCBP).  

ECOG performance assessment (a measure of your ability to perform activities of daily 
living).  

Blood samples for hematology/chemistry. 

Standard chromosomal and mutational testing (blood samples) if not already done. 

Bone marrow sampling (aspiration and biopsy). 

12-lead ECG with QTcF to assess cardiac function.  
If you qualify for the study, the treatment period begins with Cycle 1, Day 1 of the first 2-week 
dosing cycle. 
Cycle 1 Day 1:
At this visit you will: 

Be asked about any new medical events or new or changed medications since your last 
visit. 

Have blood samples taken for baseline brequinar/DHO, flow cytometry, and 
hematology/chemistry.  

Have a physical examination (including weight) (unless within one week of Screening), 
vital signs, urine pregnancy test for women able to bear children, and 12-lead ECG. 


PROTOCOL NUMBER:  CCB-01
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
If you qualify for the study and still choose to participate, you will be given adequate 
study medication for 2 weeks (4 doses). 

You will take the first dose at the clinic and remain at the clinic for pharmacokinetic 
(PK) and dihydroorotate (DHO) blood sampling at 1, 2, 4, and 6 hours after this first
dose. Each dose of study medication will be made up of several capsules, depending 
on what dose you will be taking. Take the medication with about 8 ounces of plain 
water. You can take more water than 8 ounces if needed. 

Be given a calendar/diary you will use to write down the dates/times of study 
medication administration and any new medical events, new medications or a change 
in dose of any medications. Please bring your study medication and diary to every visit. 
Cycle 1 Day 2: You will come back to the clinic approximately 24 hours (the next day) after 
your first dose to have blood samples taken for brequinar/DHO and flow cytometry. Your diary 
will be checked for any new medical events, new medications or a change in dose of any 
medications since the last visit.
Cycle 1 Day 3: You will come back to the clinic approximately 48 hours (2 days) after your 
first dose to have blood samples taken for brequinar/DHO and flow cytometry. Your diary will 
be checked for any new medical events, new medications or a change in dose of any 
medications since the last visit. 
Cycle 1 Day 4: You will come back to the clinic approximately 72 hours (3 days) after your 
first dose to have blood samples taken for brequinar/DHO. Your diary will be checked for any 
new medical events, new medications or a change in dose of any medications since the last 
visit. You will take your second dose of study medication this evening. 
Cycle 1 Day 8:  
At this visit, you will: 
-
Have your vital signs checked. 
-
Before you take your morning dose, you will have blood samples taken for brequinar/DHO 
and hematology/chemistry.  
-
Take your next dose of study medication in the clinic. 
-
Your diary will be checked for any new medical events, new medications or a change in 
dose of any medications since the last visit. 
Cycle 2 
You will return to the clinic 2 weeks after starting the study medication. The study team may adjust 
your dose of study medication (you may be given more or less of the drug) depending on your
safety results, laboratory, and DHO levels. This visit may be repeated as needed if your dose 
adjustment continues. 
Day 1:  
-
Your unused study medication will be collected (if you have any), and your diary will be 
checked for any new medical events, new medications or a change in dose of any 
medications since the last visit.
-
Your vital signs will be checked and a physical examination performed.
-
Before you take your morning dose, you will have blood samples taken for brequinar/DHO
and hematology/chemistry.


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-
If you are not having any side effects that may indicate it is not safe for you to continue 
taking the study medication, you will be given adequate medication for another 2 weeks (4 
doses). Take your next dose of study medication in the clinic. 
Day 8: 
At this visit, you will: 
-
Have your vital signs checked.
-
Have a bone marrow sample (window ±7 days). 
-
Before you take your morning dose, you will have blood samples taken for brequinar/DHO
and hematology/chemistry.  
-
Your diary will be checked for any new medical events, new medications or a change in 
dose of any medications since the last visit.
-
If you are not having any side effects that may indicate it is not safe for you to continue 
taking the study medication, you will continue to take the medication dispensed to you.
 
Maintenance Dose Cycle (visit every 2 - 4 weeks)
Once you have reached a “stable dose” where no more dose adjustments seem to be needed, you 
will return to the clinic every 2 weeks and have the procedures below. After you've been taking 
the study medication for 3 months, your study doctor may space your visits out to every 4 weeks.
Day 1:
At this visit, you will: 
-
Be asked about any new medical events or new or changed medications since your last visit.  
-
Have blood samples taken for pre-dose brequinar/DHO and hematology/chemistry.  
-
Have a physical examination, vital signs, urine pregnancy test for women able to bear 
children, 12-lead ECG. 
-
Have a bone marrow sampling (the bone marrow aspiration sampling is performed at study 
Day 22 ±7 days, at study Day 43 and repeated every 12 weeks or more often if there is a 
safety concern).  
-
Your study team will review the laboratory results/safety information and determine 
whether you should stay at the same dose or whether you should temporarily stop taking 
the study medication or whether the dose should be changed.  
-
If you are not having any side effects that may indicate it is not safe for you to continue 
taking the study medication, you will be given additional medication and continue to take 
the medication dispensed to you as directed by the study team. 
-
Your diary/calendar will be collected and a new one provided to you.  
Final Visit
This visit is to take place if you or your study team decide you should stop participation in the 
study or you have reached 12 months of study participation. At this visit, you will: 
-
Be asked about any new medical events or new or changed medications since your last visit. 
-
Have blood samples taken for brequinar/DHO, and hematology/chemistry. 


PROTOCOL NUMBER:  CCB-01
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-
Have a physical examination (including weight), vital signs, urine pregnancy test for women 
able to bear children, 12-lead ECG and bone marrow sampling (unless it has been less than 
4 weeks since the previous bone marrow sampling).  
-
Turn in any unused study medication. 
-
Turn in your calendar/diary. 
Follow Up Visit (2 weeks after Final Visit)
-
You will be contacted by phone to be asked about any new medical events or new or 
changed medications since your last clinic visit.  
WHAT ARE THE POSSIBLE DISADVANTAGES AND RISKS OF TAKING PART IN 
THIS RESEARCH?
Risks from brequinar:
While participating in this study, you are at risk for side effects. These side effects will vary from 
person to person. The more commonly occurring side effects are listed in this form, as are rare but 
serious side effects. You should discuss these with the study doctor. You may also want to ask 
about uncommon side effects that have been observed in small numbers of patients but are not 
listed in this form.  
Brequinar has been given to more than 800 patients with various forms of cancer in more than 20 
clinical trials and has also been tested in patient with psoriasis (a skin condition) and those who 
have had a kidney or liver transplant. The most common side effects have been: 

Thrombocytopenia (low platelet count, platelets are a part of the blood that help your blood 
clot, they may need to be replaced) 

Stomatitis/mucositis (the inside of your mouth and intestines may develop ulcers which 
make eating and drinking difficult)

Skin rash

Nausea

Vomiting 

Diarrhea

Neutropenia (low white blood cell count, which may reduce the body’s ability to fight 
infections) 

Anemia (low red blood cell count, red cells carry oxygen) 

Fatigue  
In most cases, these side effects went away within about 2 weeks after patients stopped taking 
brequinar, but that cannot be guaranteed as the drug may work differently for you. If you develop 
these side effects during the study, your study team may decide to have you temporarily stop taking 
brequinar to see if the side effects get better. You and your study team may also decide to either 
stop your study participation or reduce the dose of the study medication to see if you can tolerate 
a lower dose. 


PROTOCOL NUMBER:  CCB-01
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Brequinar may cause differentiation syndrome. This is a condition that affects your blood cells 
which may be life-threatening or lead to death if not treated. Differentiation syndrome has not been 
previously seen with brequinar. Call your healthcare provider or go to the nearest hospital 
emergency room right away if you develop any of the following symptoms of differentiation 
syndrome: 

Fever

Cough

Shortness of breath

Swelling of arms and legs, around the neck, groin, or underarm area

Fast weight gain (more than 10 pounds within a week)

Bone pain
If you develop differentiation syndrome, your healthcare provider may start you on corticosteroids 
which you will either take by mouth or receive by vein. You may be monitored in the hospital.
You may also develop Tumor Lysis Syndrome (TLS). TLS is characterized by nausea, vomiting, 
diarrhea, anorexia, lethargy, irregular heart rhythms, heart failure, hematuria, seizures, muscle 
cramps, syncope, tetany and possible sudden death due to the acute metabolic irregularities of 
low blood levels of potassium, phosphorous, and calcium associated with the breakdown of 
tumor cells secondary to cytotoxic therapy.  
While TLS was not observed in the previous subjects who took brequinar in a clinical trial, the 
experience with brequinar in AML is limited. Signs and symptoms of TLS will therefore be 
carefully monitored particularly in the period that tumor lysis is most likely to occur (24-48 hours 
after first dose). If you develop this condition, you will be carefully monitored and may need to be 
treated in the hospital.
Risks from Study Procedures: 
Blood draws may cause pain, bleeding, and/or bruising. You may faint and/or develop an infection 
with redness and irritation of the vein at the site where blood is drawn. Frequent blood collection 
may cause anemia (low red blood cell count), which may create a need for blood transfusions.
Having bone marrow sampling (biopsies and aspirations) performed may cause pain, bruising, 
bleeding, redness, low blood pressure, swelling, and/or infection at the site of the biopsies. An 
allergic reaction to the anesthetic may occur. A scar may form at the biopsy site. 
Bone marrow sampling will include analysis of the aspirate on smear, core biopsy by microscopy, 
flow cytometry, and karyotype for cytogenetics. You can talk with the study team about this 
testing. The type of genetic testing being performed for this study will not provide you or your 
doctor information about diseases that are passed down in families. It will not tell the study 
researchers anything that will prevent you from getting health insurance, and it will not tell the 
study researchers anything about any diseases or conditions you may get in the future. 
There may be risks or side effects that are unknown at this time. 


PROTOCOL NUMBER:  CCB-01
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If a condition of which you were unaware is discovered during the study, a full report will be sent 
to your doctor if you request this.  You will be advised of the appropriate action to take for 
treatment. 
Pregnancy-Related Risks
Taking part in this study can result in risks to an unborn or breastfeeding baby, so you should not 
become pregnant, breastfeed a baby, or father a child while participating in this study. If you are 
able to become pregnant or father a child, you must use birth control during the study and for at 
least 3 months after your last dose of study drug if you are sexually active. 
Birth control specifications: Female participants who are able to become pregnant must use 2 
methods of birth control while on this study. Male participants must use an effective barrier method 
(such as a condom) while on this study. 
Talk with the study team about acceptable methods of birth control to use while taking part in this 
study. 
Males: Tell the study team right away if your partner becomes pregnant or suspects pregnancy. 
Females: If you are pregnant, you will not be enrolled into this study. If you become pregnant or 
suspect that you are pregnant during the study, you must tell your doctor right away. 
Getting pregnant may result in your removal from this study.  
WHAT ARE THE POSSIBLE BENEFITS?
The study drug may help to control the disease. Future patients may benefit from what is learned. 
There may be no benefits for you in this study. 
WILL IT COST ANYTHING TO BE IN THE STUDY?
If you participate in this study, you will not have to pay for the cost of the study drug used in the 
study. 
You or your insurer will be responsible for the cost of your usual ongoing medical care, including 
procedures and non-study medications that the doctor or your regular doctor requires during this 
study as part of your usual medical care. If you have any questions, please ask the doctor and/or a 
member of the study staff about the costs that will or will not be covered by the sponsor.
IS THERE PAYMENT FOR PARTICIPATION?
You will not receive any payment for participation in this study. 


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WHAT ARE THE ALTERNATIVES FOR TREATMENT?
You do not have to participate in this research study to receive treatment. Instead, you may be 
eligible for recently approved therapies, and may be able to have a bone marrow transplant outside 
of this study. You may choose to receive other investigational therapies, if available. You may 
also choose not to have treatment for cancer at all. Regardless of your choices, you will receive 
appropriate medical care, including treatment for pain and other symptoms of cancer. Please note 
that you will be informed in a timely manner if new information becomes available that is relevant 
during your participation in this study. 
WHAT IF SOMETHING GOES WRONG?
An important part of this study is to see if the investigational product causes side effects. You must 
inform the staff if you feel unwell or have any unusual symptoms at any time during the study, no 
matter how minor you think they are. If you experience such events, treatment will be made 
available by the doctor. 
You will be provided any reasonably necessary medical treatment for any injuries sustained as a 
result of participating in this study, except to the extent such costs are covered by your medical or 
hospital insurance or by governmental programs providing such coverage. You must follow the 
directions of the doctor to be eligible for this coverage. Neither the sponsor nor the doctor have 
plans to provide other compensation in the event of an injury. You are not giving up any of your 
legal rights by signing this consent form. 
Certain tests, procedures, and/or drugs that you may receive as part of this study may be without 
cost to you because they are for research purposes only. However, your insurance provider and/or 
you may be financially responsible for the cost of care and treatment of any complications resulting 
from the research tests, procedures, and/or drugs. Standard medical care that you receive under 
this research study will be billed to your insurance provider and/or you in the ordinary manner. 
Before taking part in this study, you may ask about which parts of the research-related care may 
be provided without charge, which costs your insurance provider may pay for, and which costs 
may be your responsibility. You may ask that a financial counselor be made available to you to 
talk about the costs of this study. 
WILL ALL THE DOCUMENTS CONCERNING ME REMAIN CONFIDENTIAL?
Yes. The company that is conducting this study will not keep any document on file that contains 
your name; you will only be identified by your initials and a subject number. It will be necessary 
for the sponsor, its representatives, the regulatory authorities, other institutions participating in the 
study, and possibly the Institutional Review Board (an IRB is a group of people who review the 
risks and benefits of a study) to review your medical records, but these will be treated in the 
strictest confidence permitted by law. If the results of the study are published, you will not be 
identified by name. Your personal health information (PHI) will be kept as confidentially as 
possible according to state and federal laws. However, in some situations, the Food and Drug 
Administration (FDA) could be required to reveal the names of participants. 


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The permission to use your PHI will continue indefinitely unless you withdraw your authorization 
in writing. 
WILL INFORMATION ABOUT ME BEING IN THIS STUDY BE USED AND SHARED?
This section explains how your medical and health records might be used and shared if you agree 
to participate in this study. If you do not sign this consent form, you cannot participate in the study.
During the study, the doctor and/or a member of the study staff will record health information 
about you (your “records”).  Your records include the data collected or reviewed during the study, 
including data about the physical examination, tests, and other procedures described above. Your 
records also will include identifying information, such as your name and address. 
By signing this consent form, you:

Allow the doctor and/or a member of the study staff to use your records to carry out this 
study.

Allow the doctor and/or a member of the study staff to share your records with the company 
paying for this study, Clear Creek Bio, Inc., their representatives, and other researchers 
involved in this study. These people will use these records to review the study and to check 
the safety of the study. 

Allow the doctor or sponsor to publish results of the study in medical journals or to present 
results at meetings. If this happens, your name will not be used. The doctor also may share 
all of your records and this signed consent form with government agencies, including the 
U.S. Food and Drug Administration (FDA), and government agencies in other countries. 
They may also share your records with regulatory agencies. These agencies may use these 
records to check the information collected in this study, to check how the study is carried 
out, and to check subjects’ safety. 
There are national and state laws that state that the doctor must protect the privacy of your records.  
However, you do not have a guarantee of absolute privacy because of the need to share your 
information as described above. After the doctor shares your records with the sponsor and others, 
the laws may no longer protect the privacy of your records. These records might be shared with 
other people who do not have to protect the privacy of your records. 
If you get hurt or sick possibly because of being in the study, and you seek medical treatment:

The doctor and sponsor may obtain study-related records from your or other health care 
providers to learn more about the effects of the study and your condition. 

Information about this study might be given to your insurance company or health care 
payer for the purpose of resolving your claim. 

The sponsor might give information that identifies you to its insurance carrier for the 
purpose of resolving your insurance claim. 
You have the right to see and copy your records in the doctor’s possession. However, by signing 
this consent form, you agree that you might not be able to review some of these records related to 


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the study until after the study is complete. At that time, your right to see these records will be 
restored.
This consent form has no expiration date.  If you do not cancel this consent form, then it will 
remain valid indefinitely.
You will receive a signed and dated copy of this consent for your records. 
WHAT WILL HAPPEN TO THE RESULTS OF THE RESEARCH STUDY?
The results of the study will be reported in a Clinical Study Report and may be published in 
scientific journals or presented in scientific meetings. The results of this study may also be used to 
support regulatory filings by the sponsor in support of the use of this medication for treating AML 
or other blood cancers or diseases. A description of this clinical trial will be available on 
http://www.ClinicalTrials.gov, as required by U.S. law. This web site will not include information 
that can identify you. At most, the web site will include a summary of the results. You can search 
this web site at any time.
WHO IS ORGANIZING AND FUNDING THE RESEARCH?
The study has been organized and funded by Clear Creek Bio, Inc. The investigational medicinal 
product (study drug) is being provided by Clear Creek Bio, Inc. 
DO I HAVE TO TAKE PART?
Your participation in this study is voluntary. You may decide not to participate, or you may leave 
the study at any time. Your decision will not result in any penalty or loss of benefits to which you 
are entitled. If you decide to take part, you will be asked to sign and date this consent form and 
given a copy to keep.   
Your participation in this study may be ended by the doctor, sponsor, the regulatory agencies or 
the Institutional Review Board (an IRB is a group of people who review the risks and benefits of 
a study).  They can end your participation for any of the following reasons without your consent:

if it is in your best interest;

you do not later consent to any future changes that may be made in the study plan; or

for any other reason. 
If this is the case, you will be given further instructions by the doctor for any final evaluations that 
may be needed. 
CONTACT FOR FURTHER INFORMATION
Any questions, concerns, or complaints about this study or if you feel you have had a 
research-related injury or reaction to the study drug should be directed to <insert PI name and 
contact information [24-hour contact]>.
If you have questions about your rights as a research subject or for questions, concerns or 
complaints about the research, you may contact: 


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<Insert IRB name >
<Insert address>
<Insert telephone number> 
<Insert email if applicable> 
The IRB will not be able to answer some study-specific questions however, you may contact the 
IRB if the research staff cannot be reached or if you wish to talk to someone other than the research 
staff. 
Do not sign this consent form unless you have had a chance to ask questions and have received 
satisfactory answers to all of your questions. 
You will be given a signed and dated copy of this consent form to keep.
Thank you for taking the time to read this consent form. 


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Consent Form Signature Page
SUBJECT’S DATE OF BIRTH:  ______/______/______ 
mmm / dd
/ yyyy
Print Name of Investigator:
Please initial 
box:
1.
I confirm that I have read this consent form for the above study and have 
had the opportunity to ask questions. 
 
2.
I understand my participation is voluntary and I am free to withdraw at any 
time, without giving any reason, without my medical care or legal rights 
being affected. 
 
3.
I understand that sections of any of my medical records may be looked at 
by responsible individuals from Clear Creek Bio, Inc. and/or its 
representatives or from regulatory authorities and the IRB where it is 
relevant to my taking part in research. I give permission for these individuals 
to have access to my records. 
 
4.
I understand that my data may be transmitted outside the country to 
countries with less strict data protection laws.
 
5.
I agree to take part in the above study. 
 
By signing this consent form, I have not given up any of my legal rights. 
Printed Name of Subject                       Signature of Subject 
Date 
Time
 
 
                                                                      
Printed Name of person conducting      Sign  
Date 
Time
informed consent discussion 
Original with Investigator File
1 copy for subject
1 copy for Subject’s Medical Records
 
 


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Addendum to Informed Consent for Short Messaging Service (SMS/text)
Reminders for Protocol CCB-01
 
 
TITLE:
A Phase 1b/IIa open-label, multi-center study to assess the safety, efficacy and 
pharmacokinetics of intrapatient dose-adjusted brequinar and inhibition of 
dihydroorotate dehydrogenase (DHODH) in adult subjects with acute myelogenous 
leukemia (AML)
PROTOCOL NO.: 
CCB-01 
SPONSOR: 
 
Clear Creek Bio, Inc. 
 
585 Massachusetts Avenue, 4th Floor, 
 
 
Cambridge MA 02139 
 
INVESTIGATOR: 
 
<insert PI name> 
Site(s):
<insert name> 
 
 
<insert address> 
STUDY-RELATED
PHONE NUMBER(S): <insert name(s)>
 
<insert number>
<insert alternate number (24-hour contact number)> 
VERSION and DATE: <e.g. CCB-01 Addendum ICF Version 1.0 31May2018> 
 
WHY AM I BEING ASKED TO SIGN THIS ADDENDUM TO THE CONSENT?
You are being asked to sign this addendum to the consent because you have agreed to participant 
in study CCB-01 and because it is very important for you to take your study medication at the 
correct times (e.g., Monday mornings and Thursdays evenings). One effective way to help you 
remember to take your medication on time is for you to receive a text reminder on your phone. 
The sponsor of the study (Clear Creek Bio, Inc.) is using an external vendor to generate a text 
message reminder that will be sent to your mobile device when it is time for you to take your study 
medication.  
 
VOLUNTARY NATURE OF THIS SERVICE
It is entirely optional for you to receive this service. Your decision to receive text message 
reminders for your medications will not in any way affect your ability to enroll in the study. You 
may also "opt out" at any time by responding "STOP" to the messages, or by contacting your study 
team. 


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DESCRIPTION OF THE NATURE OF THE DATA YOU WILL PROVIDE
You will provide your mobile device number to the study team who will then enter the number 
into the third-party vendor's system for sending out the text reminders.  
 
DESCRIPTION OF HOW THE DATA WILL BE USED
The only information that will be shared with the third-party vendor is your mobile device number 
and your study participant identification number. The system is set up so that one-way messages 
are sent from the service to you. You should not reply to the messages you receive except to "opt 
out". If you do send a message, the texting service will reply with a message indicating that the 
messages you may send are not being monitored. 
 
WHAT WILL THE MESSAGE SAY?
On the twice-weekly schedule (i.e., Monday mornings and Thursday evenings), you will receive a 
text with the following information: “It is time for you to take your CCB-01 study medication. 
Thank you for participating in this study.” You may delete this message after reading. 
 
DESCRIPTION OF HOW THIS DATA WILL BE SECURELY MANAGED
The mobile device number you provide to be used for these reminders will be managed in a manner 
that ensures the best possible security. The mobile device number will not be shared with any other 
third-party vendor or the sponsor of this study (Clear Creek Bio, Inc.). 
 
WHAT IF I DON’T HAVE A PHONE THAT CAN RECEIVE TEXT MESSAGES?
If you do not have a mobile phone or cannot receive text messages, you cannot participate in 
receiving these text message reminders. 
DISCLOSURES OF RISKS AND VULNERABILITIES
Although unlikely, it is possible that the unencrypted text messages you receive could 
inadvertently be seen by someone else. Because the messages are de-identified (your name will 
not appear), the most information that could be seen would be that you are participating in a study. 
You are not sending any information back to the third-party vendor, so nothing you send could be 
seen by mistake. 
 
The study team members are not responsible for any loss or breach of data that results from 
something beyond their control, e.g., you lose your mobile device containing text messages 
reminders, or a third-party vendor or host experiences a server/data breach.  
 
Standard text/data messaging rates apply to these messages, and because some mobile phone 
providers charge an additional fee for the sending and receiving of text messages, you might be 
charged additionally by your mobile phone provider if you choose to receive the text message 
reminders.  
 


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PROCESS FOR NOTIFYING PARTICIPANT IN CASE OF AN ACTUAL OR 
POTENTIAL SECURITY BREACH
If the third-party vendor that has your mobile device number experiences a breach or a potential 
breach, the third-party vendor will notify the sponsor of this study, Clear Creek Bio, Inc. The 
sponsor will notify the study team at each participating institution, and the study team will contact 
you regarding the possible risks associated with the breach/potential breach regarding your mobile 
device number.  
 
Consent Form SMS/Text Addendum Signature 
SUBJECT’S DATE OF BIRTH:  ______/______/_____
mmm / dd
/ yyyy
Print Name of Investigator: 
Please initial 
box:
1. I confirm that I have read this consent form for receiving text message 
medication reminders for the above study and have had the opportunity to 
ask questions. 
 
2. I understand my participation is voluntary in this text messaging service and 
I am free to withdraw at any time, without giving any reason, without my 
medical care or legal rights being affected. 
 
3. I give permission for the study team and third-party vendor to have access 
to my mobile device number. 
 
4. I agree to take part in the mobile device text message reminder for the above 
study.
 
By signing this consent form, I have not given up any of my legal rights. 
Printed Name of Subject                       Signature of Subject 
Date 
Time
 
                                                                      
Printed Name of person conducting      Sign 
Date 
Time
informed consent discussion
Original with Investigator File
1 copy for subject
1 copy for Subject’s Medical Records


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


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


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


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


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32. The benefits, risks, burdens and effectiveness of a new intervention must be tested against 
those of the best current proven intervention, except in the following circumstances:
The use of placebo, or no treatment, is acceptable in studies where no current proven 
intervention exists; or 
Where for compelling and scientifically sound methodological reasons the use of placebo 
is necessary to determine the efficacy or safety of an intervention and the patients who 
receive placebo or no treatment will not be subject to any risk of serious or irreversible 
harm. Extreme care must be taken to avoid abuse of this option. 
33. At the conclusion of the study, patients entered into the study are entitled to be informed about 
the outcome of the study and to share any benefits that result from it, for example, access to 
interventions identified as beneficial in the study or to other appropriate care or benefits. 
34. The physician must fully inform the patient which aspects of the care are related to the 
research. The refusal of a patient to participate in a study or the patient's decision to withdraw 
from the study must never interfere with the patient-physician relationship. 
35. In the treatment of a patient, where proven interventions do not exist or have been ineffective, 
the physician, after seeking expert advice, with informed consent from the patient or a legally 
authorized representative, may use an unproven intervention if in the physician's judgment it 
offers hope of saving life, re-establishing health or alleviating suffering. Where possible, this 
intervention should be made the object of research, designed to evaluate its safety and efficacy. 
In all cases, new information should be recorded and, where appropriate, made publicly 
available. 
22.10.2008 
 
 
 


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14.6 Appendix G: Investigator’s Statement and Agreement
STUDY NUMBER: CCB-01
STUDY TITLE:  A Phase 1b/2a open-label, multi-center study to assess the safety, efficacy and 
pharmacokinetics of intrapatient dose-adjusted brequinar and inhibition of dihydroorotate 
dehydrogenase (DHODH) in adult subjects with acute myelogenous leukemia (AML)
 
INVESTIGATOR’S STATEMENT AND AGREEMENT
I (the Investigator) have read this protocol and hereby agree to conduct the trial in accord with all 
of its provisions.  It is further agreed that the details of this trial and all information provided to 
me by Clear Creek Bio, Inc. (the Sponsor) will be held in the strictest confidence and will not be 
revealed for any reason without written authorization from Clear Creek Bio, Inc. except to those 
who are to participate in the conduct of the trial. 
I agree that all data, the case report forms and all materials provided for the conduct of the trial are 
the property of Clear Creek Bio, Inc. unless specified otherwise in writing. It is understood that 
Clear Creek Bio, Inc. will utilize the information derived from this trial in various ways, such as 
for submission to government regulatory agencies, required internal reports, and presentations 
without violating patient/ subject confidentiality in any way. 
I further agree that Clear Creek Bio, Inc. or its representatives will be permitted access, in 
accordance with current Good Clinical Practice Guidelines, to all data generated by this trial and 
the source documents from which case report form data were generated.
PRINCIPAL INVESTIGATOR
Printed Name:
Signature:                                                                                           Date:
Site Address:        
 


PROTOCOL !\UMBER: CCB-01 
PROTOCOL VERSION: FINAL v 6.0 
DATE: 30 April 2019 
Page 0 of 103 
CCB-01 Approvals and Revision History 
Protocol agreed by: 
Clinical Development 
Date: 06 May 2019 
Digitally signed by Barbara L. Powers, MSN, PhD 
(JOAJJ4 
DN: cn=Barbara L. Powers, MSN, PhD, o=Clear 
Creek Bio, Inc., ou=Chnlul Operations, 
emall=bpowers@Clearcreekblo.com. c=<US 
Date: 2019.05.06 15:09:40 -04'00' 
PRINT NAME: Barbara Powers, MSN, Ph.D. 
Research & Development 
Date: 06 May 2019 
David P 
Digitally signed by David P 
Hesson, PhD 
Hesson, PhD 
Date: 2019.05.06 16:29:11 
-04'00'
PRINT NAME: David P. Hesson, Ph.D. 
Chemistry and Manufacturing/Quality 
Date: 06 May 2019 
David P. 
Digitally signed by David P. 
Hesson, PhD 
Hesson, PhD 
Date: 2019.05.06 16:29:44 
-04'00'
PRINT NAME: David P. Hesson, Ph.D. 
Sponsor Representative 
Date: 06 May 2019 
?;;/CwA- fluJ  
PRINT NAME: Vikram Sheel Kumar, MD 
Revision History/ Amendments: 
Version Number 
Date 
1.0 
31 May2018 
2.0 
04 June 2018 
3.0 
04 October 2018 
4.0 
. 
11 October 20 I 8 
5.0 
16 October 20 I 8 
6.0 
30 April 2019 
CONFIDENTIAL: Clear Creek Bio, Inc. 


PROTOCOL NUMBER:  CCB-01  
Page 1 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
STUDY PROTOCOL 
A Phase 1b/2a open-label, multi-center study to assess the safety, 
efficacy and pharmacokinetics of intrapatient dose-adjusted 
brequinar and inhibition of dihydroorotate dehydrogenase 
(DHODH) in adult subjects with acute myelogenous leukemia 
(AML)
Study No: CCB-01 
Version Date:  30 April 2019 
Sponsor: 
Clear Creek Bio, Inc. 
585 Massachusetts Avenue, 4th Floor, 
Cambridge MA 02139 
Sponsor Telephone: (617) 765-2252 
Sponsor Facsimile: (617) 863-2082 
IND Number: 138335 
This confidential document is the property of Clear Creek Bio, Inc.  No unpublished information contained herein 
may be disclosed without the prior written approval of Clear Creek Bio, Inc. This trial will be conducted in 
accordance with the ICH Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95, Jan.97), the Declaration 
of Helsinki (1964, 1975, 1983, 1989, 1996, 2000 (Note for Clarification 2002 & 2004) and 2008), FDA Regulations 
and locally applicable regulations. 


PROTOCOL NUMBER:  CCB-01  
Page 2 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
TABLE OF CONTENTS 
2 SYNOPSIS .......................................................................................................................... 11 
3 INTRODUCTION .............................................................................................................. 25 
3.1 Background: Acute Myeloid Leukemia ..................................................................... 25 
3.2 Dihydroorotate dehydrogenase (DHODH) ................................................................ 25 
3.3 Brequinar .................................................................................................................... 25 
3.4 Rationale for the Planned Trial .................................................................................. 27 
3.4.1 Brequinar Starting Dose Selection ............................................................................... 27 
3.5 Risk/Benefit of Brequinar .......................................................................................... 28 
3.6 Risks Associated with Participation in the Clinical Study ......................................... 28 
3.7 Possible Interactions with Concomitant Medical Treatments .................................... 29 
3.7.1 CYP Interactions .......................................................................................................... 29 
3.8 Steps to be Taken to Control or Mitigate Risks ......................................................... 29 
4 TRIAL OBJECTIVES ........................................................................................................ 30 
4.1 Primary Objective ...................................................................................................... 30 
4.2 Secondary Objectives ................................................................................................. 30 
4.3 Exploratory Objectives ............................................................................................... 30 
5 TRIAL DESIGN ................................................................................................................. 31 
6 TRIAL ENDPOINTS.......................................................................................................... 32 
6.1 Primary Endpoint ....................................................................................................... 32 
6.2 Secondary Endpoints .................................................................................................. 32 
6.3 Exploratory Endpoints................................................................................................ 32 
7 TRIAL POPULATION ....................................................................................................... 33 
7.1 Number of Subjects .................................................................................................... 33 
7.2 Inclusion criteria ......................................................................................................... 33 
7.3 Exclusion Criteria ....................................................................................................... 33 
7.4 Inclusion of Women and Minorities........................................................................... 34 
8 STUDY TREATMENTS .................................................................................................... 35 


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CONFIDENTIAL:  Clear Creek Bio, Inc. 
8.1 Description of Brequinar ............................................................................................ 35 
8.2 Treatment Administration .......................................................................................... 35 
8.3 Safety/Tolerability ...................................................................................................... 36 
8.3.1 Safety/Tolerability – Subject Level .............................................................................. 37 
8.3.2 Hematologic Toxicity ................................................................................................... 37 
8.4 Cohort Starting Doses ................................................................................................ 38 
8.5 Individual Dose Adjustment Guidelines .................................................................... 38 
8.5.1 Brequinar Exposure (BRQ PK) and 72h DHO Criteria to Set Twice-Weekly Dosing 38 
8.5.2 Dose Adjustment Using 84h DHO ............................................................................... 40 
8.6 Medication/AE Diary ................................................................................................. 42 
8.7 Bone Marrow Biopsy ................................................................................................. 42 
8.8 Expansion Cohort ....................................................................................................... 42 
8.9 Study Drug Discontinuation ....................................................................................... 42 
8.10 Brequinar Pharmacokinetics (PK)/Dihydroorotate (DHO) Plasma Levels/Flow 
Cytometry .......................................................................................................................... 43 
8.11 Concomitant Medication/Treatment .......................................................................... 43 
8.11.1 
Gastric pH ............................................................................................................... 43 
8.12 Treatment Compliance ............................................................................................... 43 
8.13 Storage, Stability, Labeling and Packaging ............................................................... 44 
8.13.1 
Storage and Stability ............................................................................................... 44 
8.13.2 
Labeling and Packaging .......................................................................................... 44 
8.13.3 
Blinding and Randomization .................................................................................. 44 
8.13.4 
Unblinding/Expectedness ....................................................................................... 44 
8.13.5 
Study Drug Accountability ..................................................................................... 45 
9 CONDUCT OF THE TRIAL.............................................................................................. 46 
9.1 Ethical and Regulatory Considerations ...................................................................... 46 
9.2 Informed Consent ....................................................................................................... 46 
9.3 Institutional Review Board / Ethics Committees ....................................................... 47 


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9.4 Schedule of Events ..................................................................................................... 47 
9.5 Study Conduct ............................................................................................................ 48 
9.5.1 Screening Visit (Study Days -14 to -1) ........................................................................ 48 
9.5.2 Treatment...................................................................................................................... 48 
9.5.3 Dose Adjustment: Cycle 1 Week 1 .............................................................................. 48 
9.5.4 Dose Adjustment: Cycle 1 Week 2 .............................................................................. 49 
9.5.5 Maintenance Dose Cycle .............................................................................................. 50 
9.5.6 Final Visit ..................................................................................................................... 50 
9.5.7 Telephone Follow Up Visit (2 weeks after Final Visit) ............................................... 51 
9.5.8 Unscheduled Visits ....................................................................................................... 51 
9.6 Compliance with Study Procedures ........................................................................... 51 
9.7 Early Withdrawal from the Study .............................................................................. 51 
9.8 Early Termination of the Study .................................................................................. 52 
9.9 Short Messaging Service (SMS) Medication Reminders ........................................... 52 
10 ADVERSE EVENT REPORTING..................................................................................... 54 
10.1 Classification of Causality ......................................................................................... 56 
10.2 Classification of Severity ........................................................................................... 56 
10.3 Serious Adverse Event (SAE) Reporting ................................................................... 56 
10.4 Suspected Unexpected Serious Adverse Reactions (SUSARs) ................................. 58 
10.5 Pregnancies................................................................................................................. 58 
10.6 Hematologic Adverse Events ..................................................................................... 59 
10.7 Management of Myelosuppression ............................................................................ 60 
10.8 Differentiation Syndrome ........................................................................................... 60 
10.9 Tumor Lysis Syndrome (TLS) ................................................................................... 61 
10.10 Infection Prophylaxis ............................................................................................... 63 
10.11 Growth Factor Support ............................................................................................. 63 
10.12 Management of Nausea, Vomiting, and Diarrhea .................................................... 63 
11 STATISTICAL CONSIDERATIONS................................................................................ 64 


PROTOCOL NUMBER:  CCB-01  
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DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
11.1 Study Populations for Analysis .................................................................................. 64 
11.2 Safety Analyses .......................................................................................................... 64 
11.3 Efficacy Analyses ....................................................................................................... 65 
11.4 Other Endpoints.......................................................................................................... 67 
11.5 Sample Size Considerations ....................................................................................... 68 
11.6 Randomization ........................................................................................................... 68 
11.7 Pooling of Study Centers............................................................................................ 68 
11.8 Interim Analysis ......................................................................................................... 68 
12 INVESTIGATOR RESPONSIBILITIES ........................................................................... 69 
12.1 Investigator’s Performance ........................................................................................ 69 
12.2 Confidentiality ............................................................................................................ 69 
12.3 Source Documentation ............................................................................................... 69 
12.4 Data Collection ........................................................................................................... 70 
12.5 Case Report Forms, Investigator’s Site File and Record Retention ........................... 70 
12.6 Non-Protocol Research .............................................................................................. 71 
12.7 Publication .................................................................................................................. 71 
13 SPONSOR RESPONSIBILITIES ...................................................................................... 72 
13.1 General ....................................................................................................................... 72 
13.2 Indemnity ................................................................................................................... 72 
13.3 Data Monitoring ......................................................................................................... 72 
13.4 Audit ........................................................................................................................... 72 
13.5 Confidentiality ............................................................................................................ 73 
13.6 Finance ....................................................................................................................... 73 
14 REFERENCES ................................................................................................................... 74 
15 APPENDICES .................................................................................................................... 75 
15.1 APPENDIX A:  CCB-01 Schedule of Events ............................................................ 75 
15.2 APPENDIX B: ECOG Performance Status Criteria .................................................. 78 
15.3 APPENDIX C: Brequinar/DHO/Flow Cytometry Sampling ..................................... 79 


PROTOCOL NUMBER:  CCB-01  
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15.4 APPENDIX D: Common Terminology Criteria for Adverse Events (CTCAE) ....... 80 
15.5 APPENDIX E:  Sample Subject Consent Form ......................................................... 81 
15.6 APPENDIX F:  WMA Declaration of Helsinki ......................................................... 97 
15.7 APPENDIX G: Investigator’s Statement and Agreement........................................ 102 


PROTOCOL NUMBER:  CCB-01  
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LIST OF TABLES 
Table 8-1. 
Exceptions to Grade 3 Nonhematologic AEs ......................................................... 37 
Table 8-2. 
Algorithm to Set Twice-Weekly Dose ................................................................... 39 
Table 8-3. 
Algorithm to Adjust Twice-Weekly Dose using 84h DHO (Trough) .................... 41 
Table 11-1. Analysis Sets........................................................................................................... 64 
Table 11-2. Efficacy Analyses ................................................................................................... 65 


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LIST OF FIGURES 
Figure 8-1. 
CCB-01: Algorithm to Set Twice-Weekly Dose .................................................... 40 
Figure 8-2. 
Algorithm to Adjust Dose Using 84h DHO ........................................................... 41 
Figure 10-1. 
Monitoring of Tumor Lysis Syndrome ............................................................... 62 


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ABBREVIATIONS 
Abbreviation 
Definition 
µg 
Microgram 
5-FU
5-Fluorouracil
AUC 
Area Under Curve 
BID 
Bis in die (two times a day) 
C6min 
Concentration at 6 minutes 
CHO/HGPRT 
Chinese hamster ovary cell/hypoxanthine-guanine phosphoribosyl-transferase 
CL 
Clearance 
ClR
Low Renal Clearance 
ClT
Low Plasma Total Clearance 
CRh 
Partial hematological response 
CRi 
Incomplete hematological response 
CT 
Computerized Tomography 
CYP 
Cytochrome P450 
DHO 
Dihydroorotate 
DHODH 
Dihydroorotate dehydrogenase 
DLT(s) 
Dose-Limiting Toxicity(ies) 
DNA 
Deoxyribonucleic Acid 
ECGs 
Electrocardiograms 
ECOG 
Eastern Cooperative Oncology Group 
ED50 
Median Effective Dose 
EORTC 
European Organisation for the Research and Treatment of Cancer 
ESR 
Erythrocyte Sedimentation Rate 
F 
Bioavailability 
FDA 
United States Food and Drug Administration 
g 
Grams 
GI 
Gastrointestinal 
G-R
Good Risk Patients 
HPLC 
High-Performance Liquid Chromatography 
HIPAA 
Health Insurance Privacy and Portability Act 
Hr 
Hour 
IB 
Investigator Brochure 
IP 
Intraperitoneal 
IV 
Intravenous 
kg 
Kilograms 
l 
Liters 
LD(10, 50, 90)
Lethal Dose(10%, 50%, 90%)
LPS 
Lipopolysaccharide 
M 
Molar 
Mg 
Milligram 
mL 
Milliliters 
MLED10 
Mouse Equivalent Lethal Dose for 10% of population 
mM 
Micromolar 


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CONFIDENTIAL:  Clear Creek Bio, Inc. 
Mm 
Millimeters 
MRD 
Minimal Residual Disease 
MRT 
Long Median Residence Time 
MS 
Mucositis/stomatitis 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
NCI 
United States National Cancer Institute 
NMR 
Nuclear Magnetic Resonance Spectroscopy 
NSC 
National Service Center 
ORR 
Overall Response Rate 
PK 
Pharmacokinetic(s) 
PO 
Per Orem 
P-R
Poor Risk Patients 
PR 
Partial Response 
PS 
Performance Status 
Pts. 
Patients 
QTcF 
Corrected QT interval by Fredericia 
RDP2 
Recommended Dose for Phase II 
RNA 
Ribonucleic Acid 
SC 
Subcutaneous 
SD 
Standard Deviation 
SE 
Standard Error 
SEM 
Standard error of the means 
SI 
Simulation Index 
t½ 
Half-Life 
TEAE 
Treatment-emergent adverse event 
USP 
United States Pharmacopeia 
UV 
Ultraviolet 
V 
Volume 
Vd 
Volume of Distribution 
VdSS 
Steady-State Volume of Distribution 
WBC 
White Blood Cell 
WHO 
World Health Organization 


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2 
SYNOPSIS 
IND 
138,335 
Title 
A Phase 1b/2a open-label, multi-center study to assess the safety, efficacy and 
pharmacokinetics of intrapatient dose-adjusted brequinar and inhibition of 
dihydroorotate dehydrogenase (DHODH) in adult subjects with acute 
myelogenous leukemia (AML) 
Protocol 
CCB-01 
Investigational 
Medicinal 
Product and 
Dosage 
Brequinar is available as 100 and 250 mg oral capsules to be taken every 3.5 days 
with approximately 240 mL of water. Each subject’s mg/m2 dose will be calculated 
based on body surface area at study entry; actual dose will be rounded down to the 
nearest mg based on available oral capsule doses.  
Primary 
Objective 
●
To determine the safety and tolerability of brequinar and the DHODH
inhibitory level of brequinar in adult patients with AML.
Secondary 
Objectives 
●
To determine the overall response rate (ORR) including complete remission
(CR), CR with incomplete hematologic recovery (CRi), morphologic
leukemia-free state (MLFS), and partial remission (PR) (criteria as defined in
the ELN Guidelines, Döhner et al., 2017) and complete remission with partial
hematological recovery (CRh).
●
To assess the rate of overall survival (OS) and event-free survival (EFS).
●
To evaluate duration of response.
●
To characterize the pharmacokinetic (PK) profile of brequinar.
●
To characterize the dihydroorotate (DHO) plasma levels of brequinar after oral
dosing.
Exploratory 
Objectives 
●
To assess the relationship between DHODH inhibition and the efficacy and
safety of brequinar.
●
To evaluate molecular and cellular biomarkers that may be predictive of
antitumor level and/or treatment resistance including cytogenetics, molecular
profiling, and flow cytometry during and after treatment.
●
To evaluate global gene expression profiles, DNA methylation profiles, and
other potential prognostic markers to explore predictors of antitumor activity
and/or resistance to treatment.
Design 
This will be a Phase 1b/2a multi-center, open-label, non-randomized clinical trial 
to assess the safety, tolerability and efficacy of dose-adjusted brequinar in adult 
subjects with AML. The study will also assess the inhibition of DHODH and the 


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PK profile of brequinar in plasma. Subject dosing will be adjusted based on 
safety/tolerability, brequinar pharmacokinetics, and DHO levels. 
Up to 27 subjects are planned to be entered in this trial. Although Cohort 1 was 
planned to have 6 subjects, enrollment in this cohort was stopped after 5 subjects 
when brequinar PK and DHO results became available; these results led to changes 
in study design as described in this section. The sixth subject will not be enrolled in 
Cohort 1. 
Cohort 2 will enroll approximately 6 subjects followed by an expansion cohort of 
approximately 15 subjects. Subjects in Cohort 2 will be dosed starting with 500 
mg/m2 once-weekly. Brequinar PK and DHO samples will be obtained during Week 
1. The results from Week 1 will be used to make decisions about the Week 2 once-
weekly dose. Brequinar PK and DHO samples will also be obtained during Week 2,
and the Week 2 results will be used to make decisions about the Week 3 dose
frequency (once- or twice-weekly) and dose. The dose is to be adjusted for each
subject to meet the twice-weekly brequinar PK and 72h DHO criteria, and the Week
2 procedures may be repeated if needed until the twice-weekly dose is found.
After both the brequinar PK and 72h DHO level meet criteria described in the 
Individual Dose Adjustment Guidelines (below), the subject may move to twice-
weekly dosing on a continuing basis as tolerated. The twice-weekly dose may be 
further adjusted using 84h DHO (trough ~84 hours after dosing) criteria also 
described in the Guidelines for Individual Dose Adjustment.  
Safety will be assessed utilizing physical examination, vital sign measurements, 
safety laboratory testing, 12-lead ECGs and bone marrow sampling. Bone marrow 
sampling will also be utilized to measure response. Tolerability will be assessed by 
spontaneously reported and elicited adverse events. DHO level will be measured 
using a validated assay. Brequinar PK will be analyzed using standard PK 
parameters.  
Dosing will continue for up to 12 months in the absence of unacceptable toxicity 
or disease progression.  
Primary 
endpoints: 
●
Safety/tolerability and DHO level relationship with safety and therapeutic
brequinar levels
Secondary 
endpoints: 
●
Rates of treatment-emergent adverse events.
●
Overall Response Rate (ORR) including CR, CRi, CRh, MLFS, or PR.
●
Event free survival (EFS).
●
Duration of response.
●
PK profile of brequinar.
●
DHO plasma profile.


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Exploratory 
endpoints: 
●
Relationship between DHODH inhibition and the efficacy and safety of
brequinar.
●
Antitumor level based on molecular and cellular biomarkers including
cytogenetics, molecular profiling, and flow cytometry during and after
treatment.
●
Global gene expression profiles, DNA methylation profiles, and other potential
prognostic markers to explore predictors of antitumor activity and/or resistance
to treatment
Sample Size: 
Up to 27 subjects 
Number of 
Sites: 
3 – 6 
Study Period: 
An enrollment period of 18 - 24 months is expected. 
Inclusion 
Criteria: 
1. Willing and able to provide written informed consent for the trial.
2. Patients 18 years of age or older, with relapsed/refractory AML by World
Health Organization classification who have exhausted available therapy.
3. ECOG Performance Status 0 to 2.
4. 12-lead ECG with no clinically unacceptable findings; adequate cardiac
function/NYHA Class 0 to 2.
5. Adequate hepatic function (unless deemed to be related to underlying
leukemia).
1. Direct bilirubin ≤ 2 x ULN
2. ALT ≤ 3 x ULN
3. AST ≤ 3 x ULN
6. Adequate renal function as documented by creatinine clearance ≥ 30
mL/min based on the Cockcroft-Gault equation.
7. In the absence of rapidly proliferative disease, the interval from prior
leukemia-directed therapy to first dose of study drug will be at least 7 days
for cytotoxic or non-cytotoxic (immunotherapy) agents. Use of supportive
care measures per institution’s standard of care is permitted at any time.
8. The effects of brequinar on the developing human fetus are unknown. For
this reason, women of child-bearing potential and men must agree to use
adequate contraception (hormonal or barrier method of birth control;
abstinence) prior to study entry and for the duration of study participation.
Should a woman become pregnant or suspect she is pregnant while she or
her partner is participating in this study, she should inform her treating


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physician immediately. Men treated or enrolled on this protocol must also 
agree to use adequate contraception prior to the study, for the duration of 
study participation, and for 90 days after completion of brequinar 
administration. 
9. Male subjects must agree to refrain from sperm donation from initial study
drug administration until 90 days after the last dose of study drug.
Exclusion 
Criteria: 
1. Patients in need of immediate leukapheresis.
2. Any concurrent uncontrolled clinically significant medical condition,
laboratory abnormality, or psychiatric illness that could place the
participant at unacceptable risk of study treatment.
3. QTc interval using Fridericia’s formula (QTcF) ≥ 470 msec. Participants
with a bundle branch block and prolonged QTc interval may be eligible
after discussion with the medical monitor.
4. Pre-existing liver disease.
5. The use of other chemotherapeutic agents or anti-leukemic agents is not
permitted during study with the following exceptions:
a.
Intrathecal chemotherapy for prophylactic use or maintenance of
controlled CNS leukemia.
6. Presence of graft versus host disease (GVHD) which requires an equivalent
dose of ≥ 0.5 mg/kg/day of prednisone or therapy beyond systemic
corticosteroids (e.g. cyclosporine or other calcineurin inhibitors or other
immunosuppressive agents used for GVHD).
7. Active cerebrospinal involvement of AML.
8. Diagnosis of acute promyelocytic leukemia (APL)
9. Clinically active hepatitis B (HBV) or hepatitis C (HCV) infection.
10. Severe gastrointestinal or metabolic condition that could interfere with the
absorption of oral study medication.
11. Prior malignancy, unless it has not been active or has remained stable for at
least 2 years. Participants with treated non-melanoma skin cancer, in situ
carcinoma or cervical intraepithelial neoplasia, regardless of the disease-
free duration, are eligible if definitive treatment for the condition has been
completed. Participants with organ-confined prostate cancer with no
evidence of recurrent or progressive disease are eligible if at the active
surveillance stage, hormonal therapy has been initiated, or the malignancy
has been surgically removed or treated with definitive radiotherapy.
12. Nursing women or women of childbearing potential (WOCBP) with a
positive urine pregnancy test.


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PROTOCOL NUMBER:  CCB-01  
Page 19 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
Diarrhea 
Grade 3 diarrhea resolving to less than or equal to Grade 1 or 
baseline within 1 week after receiving the maximal 
supportive therapy based on standard practice. 
Laboratory 
abnormalities 
Asymptomatic Grade 3 laboratory abnormalities that are not 
considered to be clinically significant. 
Mucositis 
Grade 3 with duration < 1 week 
Fatigue 
Grade 3 with duration < 2 weeks 
For the expansion cohort, the definition of unacceptable safety is expanded to 
include signs of hepatotoxicity (≥ Grade 2 toxicity for ALT and AST). Dosing is 
to be held for subjects who experience hepatotoxicity; dosing may resume only if 
the hepatotoxicity AE resolves to ≤ Grade 1 within two weeks. If the subject 
experiences a second episode of ≥ Grade 2 hepatotoxicity after resuming dosing, 
dosing is to be discontinued for that subject. 
Hematologic Toxicity 
After the subject has completed the first 42 days of treatment, the definition of 
unacceptable safety expands to include hematologic AEs defined as prolonged 
neutropenia with ANC < 500 from the start of therapy in the absence of disease, ≥ 
Grade 4 neutropenia, and/or ≥ Grade 4 thrombocytopenia, with a hypocellular bone 
marrow and no greater than 5% marrow blasts lasting for ≥ 2 weeks. Anemia will 
not be considered a hematologic AE for the definition of unacceptable safety. 
Febrile neutropenia is also excluded from the DLT definition for this population. 
For clinic visits when bone marrow sampling is scheduled, the timing of the bone 
marrow sampling can be adjusted to ensure that the results are available at the time 
of the clinic visit. 
Cohort Starting 
Doses 
Cohort 1 enrollment was stopped after treating 5 subjects at 500 mg/m2 twice weekly 
to allow data review and analysis. No dose escalation was permitted for Cohort 1 
subjects. Due to extensive study design changes a sixth subject will not be enrolled 
into Cohort 1. 
All subjects will have a starting dose of 500 mg/m2 once-weekly. Cohort 2 will treat 
approximately 6 subjects with this starting dose once-weekly, which may be 
adjusted to twice-weekly with an adjusted dose (if needed) based on brequinar PK 
and DHO levels. Each subject’s dosing frequency and dose may be adjusted as 
shown below. 
Expansion 
Cohort 
An expansion cohort of up to 15 subjects will be added to obtain further 
information on safety, brequinar exposure, and DHO levels. 
Guidelines for 
Individual Dose 
Adjustment  
Cohort 1 is now complete; all subjects were dosed with 500 mg/m2 twice-weekly. 
Starting with Cohort 2, subjects will have a starting dose of 500 mg/m2 and initially 
take oral brequinar once-weekly for at least two weeks (two total doses). Brequinar 
pharmacokinetics (BRQ PK) and dihydroorotate (DHO) levels from each week will 
be used to determine the next week’s dose using the algorithm shown in the table 


PROTOCOL NUMBER:  CCB-01  
Page 20 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
below. Additional weeks of once-weekly dosing are permitted as needed to adjust 
the dose until the criteria have been met or the dosing limits have been reached 
(minimum 200 mg/m2, maximum 800 mg/m2). If BRQ PK adjustments lead to a 
previously tested dose, accept the highest previously tested dose with 24h BRQ PK 
< 5 mcg/mL and move to the 72h DHO assessment. Do not reassess BRQ PK criteria 
after moving to the 72h DHO assessment. After the dose has been adjusted (if 
necessary) to meet BRQ PK and 72h DHO criteria, subjects may move to twice-
weekly dosing (approximately every 3.5 days, e.g., Monday morning and Thursday 
evening) on a continuing basis.   
Algorithm to Set Twice-Weekly Dose 
Brequinar PK* 
72h DHO** 
Action 
24h BRQ PK 
< 5 mcg/mL 
NA 
Increase dose 150 mg/m2 and continue 
weekly dosing, reassess BRQ PK 
48h BRQ PK 
> 5 mcg/mL
NA 
Decrease dose 150 mg/m2 and continue 
weekly dosing, reassess BRQ PK 
BRQ PK 
Criteria Met* 
72h DHO Criteria 
NOT MET** 
Decrease dose 75 mg/m2 and continue 
weekly dosing, reassess 72h DHO criteria 
BRQ PK 
Criteria Met* 
72h DHO Criteria 
MET** 
Begin twice-weekly dosing Week 3 or after 
* Brequinar PK (BRQ PK) Criteria: 24h BRQ PK ≥ 5 mcg/mL AND 48h BRQ ≤ 5
mcg/mL; if BRQ PK adjustments lead to a previously tested dose, accept the highest
previously tested dose with 24h BRQ PK < 5 mcg/mL and move to the 72h DHO 
assessment. 
**72h DHO Criteria: 72h DHO < 48h DHO (on a downward slope) AND 72h DHO 
<5000 ng/mL 
After the twice-weekly dose has been determined using the above criteria, the twice-
weekly dose may be further adjusted using the 84h DHO (trough) algorithm shown 
below. The 84h DHO level obtained at the beginning of each week will be used to 
adjust the next week’s dose as needed. This dose adjustment may be made each 
week through Week 12 and every two weeks after Week 12, if necessary. 
Algorithm to Adjust Twice-Weekly Dose using 84h DHO 
84h DHO (Trough) 
Action 
84h DHO < 1500 ng/mL 
Increase next week's dose by 75 mg/m2 
84h DHO ≥ 1500 ng/mL and < 5000 ng/mL 
Stable Dose. Check 84h DHO weekly 
through Week 12 then every 2 weeks. 
Adjust dose prn per 84h DHO criteria. 
84h DHO ≥ 5000 ng/mL 
HOLD. Notify subject not to take next dose. 
Hold dosing for one week. Decrease next 
week's dose by 75 mg/m2. Resume twice-
weekly dosing. 


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PROTOCOL NUMBER:  CCB-01  
Page 23 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
STUDY PERSONNEL 
SPONSOR CONTACT 
Name: 
Barbara Powers, MSN, Ph.D. 
Title: 
Clinical Operations 
Address: 
Clear Creek Bio, Inc. 
585 Massachusetts Avenue, 4th Floor, 
Cambridge, MA 02139 
Telephone No.: 
484-686-0545
Fax No.: 
617-863-2082
E-mail:
bpowers@clearcreekbio.com
SPONSOR MEDICAL CONTACT 
Name:  
Robert Sims, MD 
Title: 
Senior Medical Director / Medical Monitor 
Address: 
IQVIA 
1700 Perimeter Park Drive 
Morrisville, NC 27560   
Telephone No.: 
614-721-2630
24-hour Safety No.:
1-866-758-2798 or 919-313-7111
E-mail:
robert.sims@iqvia.com
YYA36071medmon.iqvia.com
Medical Monitor Fax No.: 
206-826-0483
SAE Reporting Fax:    
       919.313.1412 (US Toll-free:  1-866-761-1274) 
SAE Reporting email: 
   safety-inbox.biotech@iqvia.com 
LEAD INVESTIGATOR 
Name: 
Amir Fathi, MD 
Title: 
Assistant Professor of Medicine 
Affiliation: 
Massachusetts General Hospital 
Telephone No.: 
617-724-1124
E-mail:
afathi@mgh.harvard.edu


PROTOCOL NUMBER:  CCB-01  
Page 24 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
SUPPORT SERVICES 
CRO Project Manager 
Name: 
Mary Armstrong or current PM 
Company: 
IQVIA 
Address: 
1700 Perimeter Park Drive 
Morrisville, NC 27560 
E-mail:
mary.armstrong@iqvia.com 
Data Management/eCRF PROVIDER 
Company: 
Address: 
Telephone No.: 
IQVIA 
1700 Perimeter Park Drive 
Morrisville, NC 27560 
919-972-2397
Help Desk: 
1-866-342-0693
Help Desk E-mail: 
sitesupport@iqvia.com
STATISTICAL ANALYSIS 
Company: 
IQVIA 
Address: 
1700 Perimeter Park Drive 
Morrisville, NC 27560 
STUDY DRUG HOLDING COMPANY 
Name: 
Almac Clinical Services 
Address: 
25 Fretz Road 
Souderton, PA 18964 
Telephone No.: 
215-660-8500
Email:  
clinicalservices@almacgroup.com


PROTOCOL NUMBER:  CCB-01  
Page 25 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
3 
INTRODUCTION 
3.1 BACKGROUND: ACUTE MYELOID LEUKEMIA 
Acute myeloid leukemia (AML) is a malignant disorder of immature hematopoietic cells, 
characterized by differentiation arrest and rapid proliferation of abnormal myeloid precursors. 
These abnormal cells accumulate in the bone marrow and interfere with the production of normal 
blood cells. More than 20,000 people are diagnosed with AML per year in the United States (US) 
(SEER, 2015 [1]). The median age at diagnosis is 67 years. 
Although there have been recent advances including midostaurin, enasidenib, CPX-351, 
gemtuzumab ozogomycin and venetoclax, outcomes for patients with AML remain poor. With 
modern treatment regimens, expected complete remission (CR) rates are 60-70%, but long-term 
cure rates are 15-25%. Younger patients (i.e. those 50 years of age or younger) with diploid 
karyotypes have a CR rate of 70-80% and cure rates of 20-25%, while older patients and/or those 
with adverse cytogenetics have CR rates of 35-50% and cure rates of < 10% (SEER, 2015 [1]).  It 
is therefore critical to improve both the remission rate and the durability of remission in AML 
patients of all ages. 
3.2 DIHYDROOROTATE DEHYDROGENASE (DHODH) 
Dihydroorotate dehydrogenase (DHODH) catalyzes the fourth step in pyrimidine synthesis, the 
conversion of dihydroorotate (DHO) to orotate. The enzyme is located on the inner mitochondrial 
membrane and transfers electrons between DHO and complex III of the electron-transport chain 
via the reduction of its ubiquinone (coenzyme Q10) cofactor.  
DHODH is a ubiquitous, essential enzyme. The Miller syndrome, a rare autosomal recessive 
disorder in which patients have inherited hypomorphic mutations in both alleles of DHODH, 
results in multi-organ dysfunction (Ng et al., 2010 [2]). Two weak inhibitors of human DHODH 
are approved for clinical use. Leflunomide, a pro-drug, is used in the treatment of patients with 
rheumatoid arthritis. Its active form, teriflunomide, is marketed for multiple sclerosis. Leflunomide 
is known to affect erythroid differentiation of K562 cells in vitro, via the depletion of uridine 
triphosphate (UTP) and cytidine triphosphate (CTP) ribonucleotides (Huang et al., 2002 [3]). 
Despite the connection between bone marrow level, blood cell differentiation and DHODH, 
leukemia models of leflunomide have not been very promising. Leukemic mice treated with 
leflunomide demonstrated no reduction in leukemic burden and experienced significant weight 
loss and lethargy. 
Recent nonclinical studies have demonstrated that inhibition of DHODH can overcome myeloid 
differentiation arrest (Sykes et al., 2016 [4]). The mechanism through which a reduction in de novo 
pyrimidine biosynthesis modulates myeloid differentiation is not clear. The differentiation effect 
of DHODH inhibitors appears to involve a combination of inhibition of nucleic acid synthesis, 
cell-cycle arrest, and changes in the post-translational glycosylation of important protein targets.  
3.3 BREQUINAR 
It is well known that brequinar is a potent inhibitor of DHODH. Brequinar is one of more than 300 
quinoline-carboxylic acid derivatives prepared in an analog synthesis program in the 1980s, which 
was started after it was found that a compound of this class had antitumor activity. Brequinar was 


PROTOCOL NUMBER:  CCB-01  
Page 26 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
selected by DuPont for further development as a potential clinical drug because of its activity 
against experimental tumors and because its water solubility made it relatively straightforward to 
formulate. Ultimately, the rationale to use brequinar for the treatment of multiple solid tumors did 
not translate into efficacy after extensive clinical development and the project was terminated by 
DuPont in 1994. Clear Creek Bio exclusively licensed the historic data from Bristol Myers Squibb 
(that acquired DuPont in 2001). 
Sykes et al. showed that brequinar’s pro-myeloid differentiation activity might be useful for the 
treatment of AML. Utilizing a high throughput screening technique, brequinar was identified as a 
compound that overcame arrest of myeloid differentiation. Brequinar triggers myeloid 
differentiation in vitro and in vivo. Brequinar was highly active in vivo, as demonstrated in 
syngeneic murine AML models (HoxA9+Meis1 and MLL/AF9) as well as xenotransplant AML 
models (THP1, HL60, MOLM13, OCI/AML3). In an aggressive MLL/AF9 murine model of 
AML, treatment with brequinar promoted myeloid differentiation, reduced leukemic cell burden, 
and improved overall survival. Brequinar also led to a reduction in the number of leukemia stem 
cells, reduced colony-formation level, and depleted the number of leukemia-initiating cell level.  
In addition, Sykes and colleagues demonstrated that treatment with brequinar was better-tolerated 
and more effective than treatment with cytotoxic chemotherapy in animal models. Brequinar was 
given for many weeks without cumulative toxicity. The effect of brequinar and DHODH inhibition 
on normal cells was also assessed through study of competitive bone marrow transplantation 
assays. Mice were treated with brequinar, 5-fluorouracil (5-FU), or induction chemotherapy, and 
their bone marrow was transplanted in competition (1:1) with normal (untreated) bone marrow to 
gauge the effect of therapy on hematopoietic stem cell (HSC) function. The fitness of HSCs from 
mice treated with brequinar were functionally equivalent to those of untreated mice when 
compared to that of HSCs exposed to 5-FU and induction chemotherapy, which promoted a 
marked decrease in fitness.  
Sykes et al. administered brequinar at a dose and schedule (every 72 hours) that was non-toxic to 
the animals yet led to eradication of the leukemia cells. This schedule of administration was based 
on data demonstrating that the pro-differentiation effect of brequinar required a period of sustained 
DHODH-inhibition of approximately three days. This observation suggests that brequinar’s 
efficacy depends on producing approximately 72-hours “time-above-threshold” to maintain 
sustained DHODH inhibition. The hypothesis is that pyrimidine starvation via inhibition of 
DHODH for approximately 72 hours elicits pro-myeloid differentiation and leads to the anti-
leukemia efficacy of brequinar.  
Sykes et al. also showed that normal cells could tolerate longer periods of pyrimidine starvation 
than their leukemic counterparts. The proposed dosing regimen of brequinar in this clinical trial, 
CCB-01, is intended to take advantage of the different sensitivity of normal and leukemic cells 
and thus spare normal cells while eradicating leukemic cells.  
A pharmacodynamic marker of enzyme inhibition (i.e. target engagement) is required to 
accomplish this type of rational dosing approach. Sykes and colleagues demonstrated how 
DHODH inhibition could be monitored by the accumulation of the substrate DHO. Indeed, 
inhibition of the DHODH enzyme led to the rapid accumulation of intracellular DHO, which was 


PROTOCOL NUMBER:  CCB-01  
Page 27 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
reflected by accumulation of DHO in plasma hence the rationale for measuring plasma DHO as 
the pharmacodynamic marker in CCB-01.  
Given this new information, real-time monitoring of target engagement via plasma DHO of 
DHODH inhibition in each patient should permit identification of a brequinar dose that is both 
efficacious and well-tolerated. Maintaining intermittent DHODH inhibition for prolonged 
treatment cycles may be efficacious compared to previous studies using short periods and high 
doses followed by long periods of recovery.  
The prior data on the clinical evaluation of brequinar in patients with multiple solid tumors 
provides valuable safety data that supports the safety of the proposed dosage regimen. Brequinar 
has not been studied clinically in myeloid malignancies in the past. Given encouraging pre-clinical 
results, brequinar has been evaluated in phase 1 and phase 2 trials of more than 800 patients with 
advanced solid tumor malignancies (Arteaga 1989 [5], Burris 1998 [6], Noe 1990 [7], 
Schwartsmann 1990 [8]). These studies indicated a lack of efficacy for brequinar at the doses and 
schedules evaluated. However, many of these trials studied brequinar administered as a single, 
high dose infusion given weekly or daily x 5 days every 3-4 weeks or every day for 21 days. The 
lack of efficacy in the previous trials may have been due to the narrow therapeutic window with 
the high doses studied, and to the inability, or lack of knowledge, to use a pharmacodynamic 
marker such as plasma DHO to fine-tune a therapeutic window based on differential pyrimidine 
starvation of myeloid precursors versus normal cells.  
3.4 RATIONALE FOR THE PLANNED TRIAL 
This study is designed to obtain safety and efficacy data for brequinar in patients with AML. 
Subject Population 
The population for this study is patients 18 years of age or older, with relapsed/refractory AML by 
World Health Organization classification that have failed prior standard therapy and for which no 
standard therapies are available that result in a durable remission. 
Study Treatments 
This is an open label study of oral brequinar using intra-subject dose adjustment. The dose-
adjustment scheme is presented in detail in Section 8.5.  
3.4.1 Brequinar Starting Dose Selection 
The rationale underlying the proposed dosage regimen for brequinar and the use of plasma DHO 
to guide dosing is the prior demonstration using nonclinical models by Sykes et al. (2016) [4] that 
malignant cells are more sensitive than normal cells to periods of DHODH inhibition. The 
objective is to identify a dose and regimen of brequinar that maintains suppression of DHODH 
adequate to induce differentiation and stop myeloid proliferation but avoid harming normal cells. 
These features have been realized in vivo in animal models. Specifically, intermittent dosing that 
preserved elevated levels of the metabolite DHO markedly reduced AML cells, preserved normal 
hematopoietic stem cells, and improved animal survival. These recent findings and historic 
pharmacokinetic (PK) and safety data from humans support the planned approach.  


PROTOCOL NUMBER:  CCB-01  
Page 28 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
Rather than intermittent high doses as were given by DuPont, Clear Creek will use relatively low 
doses and prolonged exposure to brequinar. There will not be a lengthy conventional rest period 
as is generally required between infrequent high doses. There will instead be twice-weekly 
administration of lower doses with a dosing interval that allows enough time for normal cells to 
recover from or avoid pyrimidine starvation in between the periods of DHODH inhibition. Based 
on its average half-life of 10.5 hours and what has been observed in the clinical PK data (see the 
Brequinar IB [9]), brequinar plasma levels return to baseline at about 3.5 days or 84 hours after an 
oral dose. For this reason, the proposed clinical study includes a twice-weekly schedule of 
brequinar dosed approximately every 84 hours, while measuring brequinar PK and plasma DHO 
to fine-tune the dose that ensures sustained DHODH inhibition while avoiding adverse effects to 
normal cells. 
Safety data from previous oncology clinical studies of brequinar (see Brequinar IB, Section 5) with 
maximum tolerated doses as high as 2250 mg/m2 repeated every 3 weeks suggest that a starting 
dose for Cohort 1 of 500 mg/m2 p.o. will be safe and well-tolerated in subjects with AML. Each 
subject’s subsequent dosing may be adjusted depending on the safety, tolerability, brequinar PK, 
and DHO level obtained during the period following dose adjustment. See Section 8.4. 
3.5 RISK/BENEFIT OF BREQUINAR 
As presented in the brequinar IB, more than 800 patients have been exposed to this compound for 
treatment of a variety of solid tumors at various treatment regimens, doses, and routes including a 
single dose, once weekly, twice weekly, single dose every 3 weeks, daily times 5 every 4 weeks, 
and daily times 21 days for multiple courses. The maximum intravenous dose given was 2,250 
mg/m2 every 3 weeks, and the maximum oral dose was 100 mg/m2 daily for 21 days. Study results 
have not shown evidence of efficacy in solid tumors at the doses and regimens studied. However, 
the preclinical work of Sykes et al (2016) [4] have demonstrated the efficacy of brequinar in a 
mouse model of leukemia, indicating that brequinar may be effective in patients with this type of 
leukemia. It is for this reason that study CCB-01 will study patients with AML.   
A universal hallmark of AML is the arrest of leukemic myeloblasts at an immature and self-
renewing stage of development. Therapies that can overcome differentiation arrest caused by 
DHODH represent a powerful treatment strategy. A potential benefit of brequinar treatment in 
patients with AML is that brequinar has been identified as a compound that can inhibit DHODH.  
The major risk associated with brequinar is myelosuppression, particularly a decrease in platelet 
count. Patients with AML typically have a low platelet count due to their disease, and there is a 
risk that treatment with brequinar may worsen existing thrombocytopenia. 
3.6 RISKS ASSOCIATED WITH PARTICIPATION IN THE CLINICAL STUDY 
In studies utilizing the weekly schedule of administration in patients with refractory solid tumors, 
reversible myelosuppression, in particular thrombocytopenia, and mucositis have been the primary 
dose-limiting toxicities. In addition, skin rash, nausea/vomiting, fatigue, and leukopenia have been 
dose-limiting in trials utilizing other schedules of drug administration. The majority of these 
adverse effects have been less than grade IV in severity and resolve following discontinuation of 
dosing. Symptoms of tumor lysis syndrome have not previously been reported following exposure 
to brequinar, however clinicians will monitor for and treat this condition should it arise per the 


PROTOCOL NUMBER:  CCB-01  
Page 29 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
guidelines presented in Section 10.9. An increased risk of infection may occur due to the 
myelosuppressive effects of brequinar (particularly neutropenia); infection prophylaxis and 
treatment are described in Sections 10.10 and 10.11. Differentiation syndrome has been seen in 
other pro-differentiating agents and will be closely followed as described in Section 10.7. 
3.7 POSSIBLE INTERACTIONS WITH CONCOMITANT MEDICAL TREATMENTS 
Brequinar has been administered to subjects taking a variety of concomitant medications that are 
typical in cancer patients. No formal interaction studies have been conducted for these 
medications, however, there have not been any reports of interactions with any medications during 
the clinical trials with more than 800 cancer patients.  
3.7.1 CYP Interactions 
No formal drug-drug interaction studies have been performed with medications commonly used 
in treating AML, however nonclinical in vitro studies have confirmed there is no CYP interaction 
or CYP induction associated with brequinar use. The nonclinical studies have demonstrated there 
is no first-pass metabolism and there have been no apparent hepatotoxic effects in the clinical 
studies performed to date.  
3.8 STEPS TO BE TAKEN TO CONTROL OR MITIGATE RISKS 
Guidelines for the prevention, monitoring and treatment of differentiation syndrome, tumor lysis 
syndrome, infection prophylaxis and growth factor support are provided in Section 10. 


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PROTOCOL NUMBER:  CCB-01  
Page 31 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
5 
TRIAL DESIGN 
This will be a Phase 1b/2a multi-center, open-label, non-randomized clinical trial to assess the 
safety, tolerability and efficacy of dose-adjusted brequinar in adult subjects with AML. The study 
will also assess the inhibition of DHODH and the PK profile of brequinar in plasma. Intra-subject 
dosing may be adjusted based on safety/tolerability, brequinar pharmacokinetics (PK), and DHO 
levels.  
Up to 27 subjects are planned to be entered in this trial. Although Cohort 1 was planned to have 6 
subjects, enrollment in this cohort was stopped after 5 subjects when brequinar PK and DHO 
results became available; these results led to changes in study design as described in this section. 
The sixth subject will not be enrolled in Cohort 1. 
All subjects will now start with 500 mg/m2 once weekly. Cohort 2 will enroll approximately 6 
subjects followed by an expansion cohort of approximately 15 subjects. Brequinar PK and DHO 
samples will be obtained during Week 1. The results from Week 1 will be used to make decisions 
about the Week 2 once-weekly dose. Brequinar PK and DHO samples will also be obtained during 
Week 2, and the Week 2 results will be used to make decisions about the Week 3 dose frequency 
(once- or twice-weekly) and dose. The dose is to be adjusted for each subject to meet the twice-
weekly brequinar PK and 72h DHO criteria, and the Week 2 procedures may be repeated if needed 
until the twice-weekly dose is found. 
After both the brequinar PK and 72h DHO level meet criteria described in Section 8.5.1, the subject 
may move to twice-weekly dosing as tolerated. The twice-weekly dose may be further adjusted 
using 84h DHO (trough ~84 hours after dosing) criteria described in Section 8.5.2.  
Safety will be assessed utilizing physical examination, vital sign measurements, safety laboratory 
testing, 12-lead ECGs and bone marrow sampling. Bone marrow sampling will also be utilized to 
measure response. Tolerability will be assessed by spontaneously reported and elicited adverse 
events. DHO level will be measured using a validated assay. Brequinar PK will be analyzed using 
standard PK parameters.  
Dosing will continue for up to 12 months in the absence of unacceptable toxicity or disease 
progression. 
Study procedures are presented in detail in Section 8. 


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PROTOCOL NUMBER:  CCB-01  
Page 33 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
7 
TRIAL POPULATION 
7.1 NUMBER OF SUBJECTS 
Subjects who meet all the inclusion and none of the exclusion criteria will be enrolled in the study 
until approximately 27 subjects have completed the study.     
7.2 INCLUSION CRITERIA 
1. Willing and able to provide written informed consent for the trial.
2. Patients 18 years of age or older, with relapsed/refractory AML by World Health
Organization (WHO) classification who have exhausted available therapy.
3. ECOG Performance Status 0 to 2.
4. 12-lead ECG with no clinically unacceptable findings; adequate cardiac function/NYHA
Class 0 to 2.
5. Adequate hepatic function (unless deemed to be related to underlying leukemia).
a.
Direct bilirubin ≤ 2 x ULN
b. ALT ≤ 3 x ULN
c.
AST ≤ 3 x ULN
6. Adequate renal function as documented by creatinine clearance ≥ 30 mL/min based on the
Cockcroft-Gault equation.
7. In the absence of rapidly proliferative disease, the interval from prior leukemia-directed
therapy to time of first dose of study drug will be at least 7 days for cytotoxic or non-
cytotoxic (immunotherapy) agents. Use of supportive care measures per institution’s
standard of care is permitted at any time.
8. The effects of brequinar on the developing human fetus are unknown.  For this reason,
women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and for the
duration of study participation.  Should a woman become pregnant or suspect she is
pregnant while she or her partner is participating in this study, she should inform her
treating physician immediately.  Men treated or enrolled on this protocol must also agree
to use adequate contraception prior to the study, for the duration of study participation, and
for 90 days after completion of brequinar administration.
9. Male subjects must agree to refrain from sperm donation from initial study drug
administration until 90 days after the last dose of study drug.
7.3 EXCLUSION CRITERIA 
1. Patients in need of immediate leukapheresis.
2. Any concurrent uncontrolled clinically significant medical condition, laboratory
abnormality, or psychiatric illness that could place the participant at unacceptable risk of
study treatment.


PROTOCOL NUMBER:  CCB-01  
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DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
3. QTc interval using Fridericia’s formula (QTcF) ≥ 470 msec. Participants with a bundle
branch block and prolonged QTc interval may be eligible after discussion with the medical
monitor.
4. Pre-existing liver disease.
5. The use of other chemotherapeutic agents or anti-leukemic agents is not permitted during
study with the following exceptions:
a.
Intrathecal chemotherapy for prophylactic use or maintenance of controlled CNS
leukemia.
6. Presence of graft versus host disease (GVHD) which requires an equivalent dose of ≥
0.5mg/kg/day of prednisone or therapy beyond systemic corticosteroids (e.g. cyclosporine
or other calcineurin inhibitors or other immunosuppressive agents used for GVHD).
7. Active cerebrospinal involvement of AML.
8. Diagnosis of acute promyelocytic leukemia (APL).
9. Clinically active hepatitis B (HBV) or hepatitis C (HCV) infection.
10. Severe gastrointestinal or metabolic condition that could interfere with the absorption of
oral study medication.
11. Prior malignancy, unless it has not been active or has remained stable for at least 2 years.
Participants with treated non-melanoma skin cancer, in situ carcinoma or cervical
intraepithelial neoplasia, regardless of the disease-free duration, are eligible if definitive
treatment for the condition has been completed. Participants with organ-confined prostate
cancer with no evidence of recurrent or progressive disease are eligible if at the active
surveillance stage, if hormonal therapy has been initiated or the malignancy has been
surgically removed or treated with definitive radiotherapy.
12. Nursing women or women of childbearing potential (WOCBP) with a positive urine
pregnancy test.
7.4 INCLUSION OF WOMEN AND MINORITIES 
Both men and women of all races and ethnic groups are eligible for this trial. 


PROTOCOL NUMBER:  CCB-01  
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DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
8 
STUDY TREATMENTS 
Up to 27 subjects are planned to be entered in this trial. Although Cohort 1 was planned to have 6 
subjects, enrollment in this cohort was stopped after 5 subjects when brequinar PK and DHO 
results became available; these results led to changes in study design as described in this section. 
The sixth subject will not be enrolled in Cohort 1. 
All subjects will start with 500 mg/m2 once weekly. Cohort 2 will enroll approximately 6 subjects 
followed by an expansion cohort of approximately 15 subjects. Brequinar PK and DHO samples 
will be obtained during Week 1. The results from Week 1 will be used to make decisions about 
the Week 2 once-weekly dose. Brequinar PK and DHO samples will also be obtained during Week 
2, and the Week 2 results will be used to make decisions about the Week 3 dose frequency (once- 
or twice-weekly) and dose. The dose is to be adjusted for each subject to meet the twice-weekly 
brequinar PK and 72h DHO criteria, and the Week 2 procedures may be repeated if needed until 
the twice-weekly dose is found.   
After both the brequinar PK and 72h DHO level meet criteria described in Section 8.5.1, the subject 
may move to twice-weekly dosing as tolerated. The twice-weekly dose may be further adjusted 
using 84h DHO (trough ~84 hours after dosing) criteria described in Section 8.5.2.  
Safety will be assessed utilizing physical examination, vital sign measurements, safety laboratory 
testing, 12-lead ECGs and bone marrow sampling. Bone marrow sampling will also be utilized to 
measure response. Tolerability will be assessed by spontaneously reported and elicited adverse 
events. DHO level will be measured using a validated assay. Brequinar PK will be analyzed using 
standard PK parameters.  
Dosing will continue for up to 12 months in the absence of unacceptable toxicity or disease 
progression or may be discontinued with Sponsor consent after completing at least 6 weeks of 
dosing. 
8.1 DESCRIPTION OF BREQUINAR 
Brequinar will be supplied as 100 and 250 mg capsules. Dosing will be determined on a mg/m2 
basis and will be adjusted based on tolerability, safety, brequinar PK, and DHO levels. Brequinar 
capsules should be taken whole; they should not be crushed or chewed. If the participant forgets 
to take the daily dose, he/she should make up the dose within 24 hours. Any medication remaining 
from extra supplies or missed doses should not be taken beyond the last scheduled day of brequinar 
administration but should be documented in the subject diary and returned by the participant for 
drug accountability purposes.  
8.2 TREATMENT ADMINISTRATION 
Five subjects were enrolled in the now-completed Cohort 1. All subjects were dosed with twice 
weekly brequinar 500 mg/m2 for a range of 2 to 16 doses (one to 8 weeks). No additional subjects 
will be enrolled into Cohort 1.  
Starting with Cohort 2, subjects will initially take oral brequinar once weekly for at least two weeks 
(two total doses). Brequinar exposure and DHO levels will be used to adjust the brequinar dose (if 
necessary) to meet brequinar PK and 72h DHO criteria described in Section 8.5.1. Subjects may 


PROTOCOL NUMBER:  CCB-01  
Page 36 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
then move to twice-weekly dosing (approximately every 3.5 days, e.g., Monday morning and 
Thursday evening) on a continuing basis. The brequinar dose may be further adjusted if needed 
using the 84h DHO (trough) Criteria shown in Section 8.5.2. Each dose is to be taken with 
approximately 240 mL of water. The subject does not need to be fasting. Each dose will generally 
consist of multiple capsules; the capsules do not need to be swallowed all at once but can be spread 
over up to 15 minutes as needed. The chosen dosing schedule needs to accommodate clinic visits 
as well as shipping and receipt of the brequinar/DHO samples and results needed for dosing 
adjustments. Sample processing and shipping procedures will be addressed in a separate laboratory 
manual.  
8.3 SAFETY/TOLERABILITY 
Safety/tolerability is assessed for each subject at each study visit using the Common Terminology 
Criteria for Adverse Events v4.03 (CTCAE). Cohort 1 had a fixed starting dose of 500 mg/m2 with 
no dose escalation permitted. Cohort 2 and the expansion cohort will start with 500 mg/m2 once-
weekly and have adjustments made to dose and dose frequency using safety/tolerability, brequinar 
exposure (PK), and DHO levels. Safety at the subject level is defined in Section 8.3.1; hematologic 
toxicity is defined in Section 8.3.2. 
The following adverse events are commonly observed in patients with AML and should be 
differentiated from possible adverse effects of brequinar: fatigue, fever, thrombocytopenia and 
other cytopenias, infection, pallor, shortness of breath, weight loss, night sweats, and anorexia. 
Any of these events can be serious in nature and may result in death. Disease progression of AML 
is considered a lack of efficacy rather than an adverse event. Death from disease progression is to 
be reported as presented in Section 10. 
Adverse events commonly observed in patients treated with brequinar are provided in the 
Investigator’s Brochure and include thrombocytopenia, nausea, anemia, diarrhea, vomiting, 
leukopenia, stomatitis, rash, granulocytopenia, fatigue, and infection. In a study of 209 subjects 
treated once-weekly (DuP 785-012), the deaths of three patients were attributed to study drug 
toxicity (two to hemorrhage, one following acute renal failure). Severe toxicities grades (Grades 3 
to 4) which typically led to discontinuation in this study included hematologic toxicities (anemia, 
thrombocytopenia, leukopenia, granulocytopenia), digestive system toxicity (nausea, vomiting, 
stomatitis, others including gastric hemorrhage) and mucositis. 
In most instances, drug related toxicities were clinically manageable and reversible upon 
discontinuation of brequinar treatment. In a study where brequinar was dosed twice-weekly to 
solid tumor subjects, no drug-related deaths occurred. Stomatitis/mucositis was observed in 13 of 
the 19 (68%) patients across all doses. Mild to moderate (Grades 1 and 2) stomatitis was observed 
in 10 patients with a more severe (Grade 3) stomatitis seen in 3 patients at doses over 600 mg/m2. 
One patient at 600 mg/m2 had drug discontinuation due to drug-related stomatitis. 
Myelosuppression was the main dose-limiting toxicity (DLT) with thrombocytopenia (Grades 1-
4), observed after 2 to 9 doses above 600 mg/m2. Any of these events reported with brequinar use 
can be serious in nature and may result in death. 
Prescriptions can be provided in advance for supportive care for common brequinar-related AEs 
such as mucositis. 


PROTOCOL NUMBER:  CCB-01  
Page 37 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
8.3.1 Safety/Tolerability – Subject Level 
Safety/tolerability is assessed for each subject at each study visit using the Common Terminology 
Criteria for Adverse Events v4.03 (CTCAE). Acceptable safety/tolerability for a subject through 
Day 42 is defined as no ≥ Grade 3, treatment-emergent, study-drug-related, non-hematologic 
adverse events. Due to the expected hematologic profile associated with AML, hematologic AEs 
of any grade will not be considered a DLT during the first 42 days of dosing (i.e., assessed at the 
visit conducted on Day 43). Exceptions to the non-hematologic Grade 3 criterion are provided in 
Table 8-1.  
If a dose is held due to safety/tolerability issues, the subject should continue to have scheduled 
visits and assessments. 
If AEs have not resolved to ≤ Grade 2 after two weeks without dosing, dosing is to be discontinued 
for this subject. 
Table 8-1. 
Exceptions to Grade 3 Nonhematologic AEs 
Condition 
Exception Description 
Nausea/ 
Emesis 
Grade 3 nausea and/or emesis resolving to less than or equal to Grade 2 or baseline within 
1 week after the use of an optimal antiemetic regimen based on standard practice. 
Diarrhea 
Grade 3 diarrhea resolving to less than or equal to Grade 1 or baseline within 1 week after 
receiving the maximal supportive therapy based on standard practice. 
Laboratory 
abnormalities 
Asymptomatic Grade 3 laboratory abnormalities that are not considered to be clinically 
significant. 
Mucositis 
Grade 3 with duration < 1 week 
Fatigue 
Grade 3 with duration < 2 weeks 
After completion of the first 42 days of treatment, the definition of unacceptable safety is expanded 
to include signs of hepatotoxicity (≥ Grade 2 toxicity for ALT and AST). Dosing is to be held for 
at least one week (i.e., two doses if twice-weekly) for subjects who experience hepatotoxicity; 
dosing may resume only if the hepatotoxicity AE resolves to ≤ Grade 1 within two weeks. If the 
subject experiences a second episode of ≥ Grade 2 hepatotoxicity after resuming dosing, dosing is 
to be discontinued for that subject. 
8.3.2 Hematologic Toxicity 
After the subject has completed the first 42 days of treatment, the definition of unacceptable safety 
expands to include hematologic AEs defined as prolonged neutropenia with ANC < 500 from the 
start of therapy in the absence of disease, ≥ Grade 4 neutropenia, and/or ≥ Grade 4 
thrombocytopenia, with a hypocellular bone marrow and no greater than 5% marrow blasts lasting 
for 2 weeks or more. Anemia will not be considered a hematologic AE for the definition of 
unacceptable safety. Febrile neutropenia is also excluded from the DLT definition for this 
population. For clinic visits when bone marrow sampling is scheduled, the timing of the bone 
marrow sampling can be adjusted to ensure that the results are available at the time of the clinic 
visit. 


PROTOCOL NUMBER:  CCB-01  
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8.4 COHORT STARTING DOSES 
Cohort 1 enrollment was stopped after treating 5 subjects at 500 mg/m2 twice weekly to allow data 
review and analysis. No dose escalation was permitted for Cohort 1 subjects. Due to extensive 
study design changes a sixth subject will not be enrolled into Cohort 1. 
All subjects will have a starting dose of 500 mg/m2 once-weekly. Cohort 2 will treat approximately 
6 subjects with this starting dose once-weekly, which may be adjusted to twice-weekly with an 
adjusted dose (if needed) based on brequinar PK and DHO levels. Each subject’s dosing frequency 
and dose may be adjusted as shown in the following sections. 
8.5 INDIVIDUAL DOSE ADJUSTMENT GUIDELINES 
Cohort 1 is now complete; all subjects were dosed with 500 mg/m2 twice weekly. 
Starting with Cohort 2, subjects will have a starting dose of 500 mg/m2 and initially take oral 
brequinar once weekly for at least two weeks (two total doses). Brequinar pharmacokinetics (BRQ 
PK) and dihydroorotate (DHO) levels from each week will be used to determine the next week’s 
dose using the algorithm shown in the tables below. Additional weeks of once-weekly dosing are 
permitted as needed to adjust the dose until the criteria have been met or the dosing limits have 
been reached (minimum 200 mg/m2, maximum 800 mg/m2). If BRQ PK adjustments lead to a 
previously tested dose, accept the highest previously tested dose with 24h BRQ PK < 5 mcg/mL 
and move to the 72h DHO assessment. Do not reassess BRQ PK criteria after moving to the 72h 
DHO assessment. After the dose has been adjusted (if necessary) to meet BRQ PK and 72h DHO 
criteria, subjects may move to twice-weekly dosing (approximately every 3.5 days, e.g., Monday 
morning and Thursday evening) on a continuing basis. 
The dose adjustment procedures may be revised after each preceding cohort’s safety, brequinar 
PK, DHO plasma levels, and bone marrow results have been reviewed.  
8.5.1 Brequinar Exposure (BRQ PK) and 72h DHO Criteria to Set Twice-Weekly Dosing 
All subjects in Cohort 2 will begin with 500 mg/m2 dosed once weekly. A second weekly dose is 
administered at either 500 mg/m2 or an adjusted dose. Additional weekly doses may be 
administered if dose adjustment is needed to meet the twice-weekly criteria. Pre-clinical evidence 
(Sykes et al., 2016 [4]) suggests that a twice-weekly dose is most likely to lead to efficacy, 
therefore the goal is to adjust the dose to allow all subjects to dose on a twice-weekly basis. In 
order to move to twice-weekly dosing both the brequinar exposure (BRQ PK) and 72h DHO 
criteria as described below must be met. The maximum allowable dose is 800 mg/m2; the minimum 
allowable dose is 200 mg/m2. If BRQ PK adjustments shown in Table 8-2 and Figure 8-1 below 
lead to a dose previously tested in this subject, accept the highest previously tested dose for this 
subject that resulted in 24h BRQ PK < 5 mcg/mL and move to the 72h DHO assessment. 
Dose increases must first meet acceptable safety requirements as described in Section 8.3.1. If 
unacceptable safety occurs, hold dosing until AE resolves to ≤ grade 2, reduce dose by 150 mg/m2 
and resume dosing. If brequinar PK or DHO levels are not available for dose adjustment decisions, 
confirm safety is acceptable and continue to dose using the subject’s current dosing frequency and 
current dose until results are available. 


PROTOCOL NUMBER:  CCB-01  
Page 39 of 103 
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DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
Table 8-2. 
Algorithm to Set Twice-Weekly Dose 
Brequinar PK* 
72h DHO** 
Action 
24h BRQ PK 
< 5 mcg/mL 
NA 
Increase dose 150 mg/m2 and continue weekly dosing, reassess 
BRQ PK 
48h BRQ PK 
> 5 mcg/mL
NA 
Decrease dose 150 mg/m2 and continue weekly dosing, reassess 
BRQ PK 
BRQ PK 
Criteria Met* 
72h DHO Criteria 
NOT MET** 
Decrease dose 75 mg/m2 and continue weekly dosing, reassess 
72h DHO criteria 
BRQ PK 
Criteria Met* 
72h DHO Criteria 
MET** 
Begin twice-weekly dosing Week 3 or after 
* Brequinar PK (BRQ PK) Criteria: 24h BRQ PK ≥ 5 mcg/mL AND 48h BRQ ≤ 5 mcg/mL; if BRQ PK adjustments
lead to a previously tested dose, accept the highest previously tested dose with 24h BRQ PK < 5 mcg/mL and 
move to the 72h DHO assessment. 
**72h DHO Criteria: 72h DHO < 48h DHO (on a downward slope) AND 72h DHO <5000 ng/mL 


PROTOCOL NUMBER:  CCB-01  
Page 40 of 103 
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Figure 8-1. 
Algorithm to Set Twice-Weekly Dose 
8.5.2 Dose Adjustment Using 84h DHO 
After the twice-weekly dose has been determined using the above criteria, the twice-weekly dose 
may be further adjusted using the 84h DHO (trough) algorithm shown below. The 84h DHO level 
obtained prior to the first dose of each week will be used to adjust the next week’s dose as needed. 
This dose adjustment may be made each week through Week 12 and every two weeks after Week 
12, if necessary. If DHO levels are not available for dose adjustment decisions, confirm safety is 
acceptable and continue to dose using the subject’s current dosing frequency and current dose until 
results are available. 


PROTOCOL NUMBER:  CCB-01  
Page 41 of 103 
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DATE:  30 April 2019 
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Table 8-3. 
Algorithm to Adjust Twice-Weekly Dose using 84h DHO (Trough) 
84h DHO Criteria 
Action 
84h DHO < 1500 ng/mL 
Increase next week's dose by 75 mg/m2 
84h DHO ≥ 1500 ng/mL and < 5000 ng/mL 
Stable Dose. Check 84h DHO weekly x 12 weeks then 
every 2 weeks. Adjust dose PRN per 84h DHO criteria. 
84h DHO ≥ 5000 ng/mL 
HOLD. Notify subject not to take next dose. Hold dosing 
for one week. Decrease next week's dose by 75 mg/m2. 
Resume twice-weekly dosing. 
Figure 8-2. 
Algorithm to Adjust Dose Using 84h DHO 
Each subject will continue twice-weekly dosing at the individually adjusted dose for up to 12 
months (total time from first dose) in the absence of unacceptable toxicity or disease progression. 
Additional intra-subject dose adjustment is permitted at any time throughout the study based on 
safety/tolerability and 84h DHO levels. Subjects who discontinue due to unacceptable 
safety/tolerability or die due to disease progression prior to the Week 7 (Day 43) visit may be 
replaced.  


PROTOCOL NUMBER:  CCB-01  
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DATE:  30 April 2019 
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8.6 MEDICATION/AE DIARY 
The participant will be provided with a study calendar of events and will be required to maintain 
a medication diary of each dose of medication. Subjects will be instructed to record the date and 
time each dose of brequinar is taken, indicating if any doses are missed. Subjects will be instructed 
to record adverse events and changes in concomitant medications in the subject calendars/diaries. 
Subjects will be instructed and reminded to bring the medication diary to each clinic visit for 
review. The diary will be returned to clinic staff at the end of each cycle and a new diary dispensed. 
8.7 BONE MARROW BIOPSY 
The participant will have a bone marrow sampling (aspiration and core biopsy) at baseline (prior 
to dosing), one for research purposes at the Week 4 visit (Day 22 ± 7 days), and one at the Week 
7 visit (Day 43 ± 7 days); thereafter, bone marrow sampling will be obtained every 12 weeks  ± 7 
days (or per institutional standard of care) and at the Final Visit. If a participant develops frank 
evidence of progression of AML during the course of treatment based on laboratory or clinical 
assessment, he/she will be discontinued from study treatment and can proceed with additional 
management off-study per discretion of the treating oncologist. If the results of the bone marrow 
sampling reveal disease progression at Visit 7 (Day 43) (defined as 43 days after initiating 
treatment or after 6 complete weeks after initiating study drug treatment regardless of number of 
doses), then the participant will be taken off treatment. Timing of the bone marrow biopsy 
procedure may be adjusted to ensure that results are available for any visit. Bone marrow sampling 
will include analysis of the aspirate on smear, core biopsy by microscopy, flow cytometry, and 
karyotype for cytogenetics. Molecular analysis will be performed on the screening bone marrow 
samples. 
8.8 EXPANSION COHORT 
Following completion of Cohort 2, an expansion cohort of up to 15 subjects will be added to further 
define the dosing, BRQ PK and DHO criteria and assess the safety, tolerability, and biological 
activity of the dosing scheme.  
The expansion cohort will follow the same visit procedures as Cohort 2. 
8.9 STUDY DRUG DISCONTINUATION 
If there is evidence of stable disease, partial response, or complete remission (CR, CRi, or CRh) 
at or prior to Visit 7 (43 days), the participant may continue with brequinar treatment until there is 
evidence of disease progression, intolerable toxicity, or for a maximum of one year. Study drug 
will be discontinued for an individual subject if there is evidence of unacceptable safety/tolerability 
that does not resolve to ≤ Grade 2 within 2 weeks after stopping brequinar dosing.  
After treatment discontinuation, participants will be monitored for a minimum of 14 days after the 
last dose of brequinar or until they receive another treatment for their AML. Participants may 
discontinue treatment to receive a stem cell transplantation upon remission, if indicated. 
The reason for study drug discontinuation will be recorded in the source document and the eCRF. 


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PROTOCOL NUMBER:  CCB-01  
Page 44 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
8.13 STORAGE, STABILITY, LABELING AND PACKAGING 
8.13.1 Storage and Stability 
The study drug is stored at room temperature. Stability testing is ongoing. 
8.13.2 Labeling and Packaging  
Each bottle for subject use will be labeled with at least the following information: 
For Clinical Trial Use Only 
Study Number: 
CCB-01 
Contents: 100 or 250 mg Brequinar capsules 
For oral use only. Take with approximately 8 ounces water every 3.5 days. 
Subject Number: XX-XXXX 
Treatment Duration: As directed 
IND: 138355             Clinical Batch Number: XXXXXXX  
Expiration Date: 
TBD 
Storage: Store at controlled room temperature  
Study Sponsor:  Clear Creek Bio, Inc., 585 Massachusetts Avenue, 4th 
Floor, Cambridge MA 02139 
Caution: New Drug – Limited by US Federal Law to Investigational Use
Only. To be used by Qualified Investigators only. 
8.13.3 Blinding and Randomization 
The trial will be conducted in an open-label manner. The brequinar capsules will be provided to 
each participating institution in bulk to be dispensed by the institution’s pharmacist per the 
designated mg/m2 dose for each subject. No randomization codes are necessary for this open-label 
study. 
8.13.4 Unblinding/Expectedness 
It is not necessary to break the blind for this open label study as the treatment is known for each 
subject. 
Expectedness will be determined by establishing whether the adverse event is among those 
identified in the protocol and the Investigator’s Brochure or are commonly associated with AML.  
The event will be considered expected if commonly associated with AML in the opinion of the 
investigator or Medical Monitor even if not specifically listed in these documents.  


PROTOCOL NUMBER:  CCB-01  
Page 45 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
8.13.5 Study Drug Accountability 
The study drug provided is for use only as directed in this protocol. 
The Investigator must keep a record of all study medication received, used and discarded.  It must 
be clear from the records which subject received which medication. Adequate drug is to be 
dispensed for each dosing period to allow for dosing every 3.5 days during the period until the 
next clinic visit, plus one additional dose to act as a spare in the event medication is unable to be 
used.  
The pharmacist/staff member responsible for drug accountability is to document the date and time 
of dispensing and for what subject the study drug was intended (i.e., record subject initials and 
birth date or other unique identifier). A pharmacy manual will be provided by the Sponsor detailing 
how to calculate the mg/m2 dose together with examples of combinations of the 100 and 250 mg 
capsules to provide the most efficient use of the clinical supplies. 
At the end of the study, any unused study drug will be returned to the Sponsor for destruction or 
destroyed locally; disposition of study drug will be documented.   
The Sponsor will be permitted access to the trial supplies at any time within usual business hours 
and with appropriate notice during or after completion of the study to perform drug accountability 
reconciliation. 


PROTOCOL NUMBER:  CCB-01  
Page 46 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
9 
CONDUCT OF THE TRIAL 
9.1 ETHICAL AND REGULATORY CONSIDERATIONS 
The trial will be performed in accordance with the Declaration of Helsinki (1964) (Appendix F) 
as revised in Tokyo (1975), Venice (1983), Hong Kong (1989), South Africa (1996), Scotland 
(2000, Note of Clarification 2002 & 2004) and Seoul 2008 (Appendix A), and Fortaleza (Brazil) 
(2013), and with the ICH Tripartite Guideline on Good Clinical Practice (CPMP/ICH/135/95, 
Jan.97) and US FDA Regulations. 
9.2 INFORMED CONSENT 
The principles of informed consent in the current edition of the Declaration of Helsinki must be 
implemented in each clinical study before protocol-specified procedures are carried out.  Informed 
consent must be obtained in accordance with US Code of Federal Regulations (21 CFR Part 50) 
as well as local and national regulations. Information should be given in both oral and written form 
whenever possible and deemed appropriate by the Institutional Review Board (IRB). Subjects and 
their relatives, if necessary, must be given ample opportunity to inquire about details of the study. 
The Investigator or qualified designated person will verbally inform subjects as to the nature, 
expected duration and purpose of the trial, the administration of the Investigational Medicinal 
Product (IMP), and the hazards involved, as well as the potential benefits that may come from 
treatment with this IMP. The trial procedures will be explained in lay language and any questions 
will be answered. The subjects will be given an IRB-approved consent form. The subjects will be 
given appropriate time to consider their participation in the trial and have any questions answered 
prior to signing the consent form. If a subject agrees to participate, he/she will sign and date an 
informed consent form and be provided with a copy of the signed consent. All subjects who sign 
an informed consent form are to be recorded on the applicable screening log.   
The subject will be informed that his/her medical records will be subject to review by the Sponsor, 
Sponsor’s representatives, and possibly by a representative of the Food and Drug Administration 
and other relevant regulatory authorities. Subjects will be informed that they are free to refuse 
participation in this clinical investigation, and if they should participate, it will be made clear to 
them that they may withdraw from the trial at any time without prejudicing further medical care 
they may require. The subject will receive a copy of the consent form as well as an information 
sheet about the trial.  
Signed written informed consent must be obtained from every subject prior to any study-specific 
procedures.  Standard procedures carried out prior to signing the informed consent but within the 
time constraints of the protocol may be used for baseline evaluation; they need not be repeated. 
An original signed informed consent form will be filed in the Investigator Site File and will be 
subject to review by the Sponsor; a copy will be given to the subject and a copy will be filed with 
the subject’s medical notes. 
The study should be discussed with the potential participant only after an initial review of his/her 
clinical status and appropriateness for participation have been evaluated to determine if he/she 
meets the subject selection criteria. 


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PROTOCOL NUMBER:  CCB-01  
Page 48 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
Hematology tests include hemoglobin, hematocrit, complete blood count with full differential and 
platelet count, and peripheral blast count.  
In addition to the already scheduled chemistry assessments, subjects taking potentially hepatotoxic 
drugs are permitted to have more frequent monitoring than indicated in the schedule of events, if 
ordered by the study team. 
9.5 STUDY CONDUCT 
9.5.1 Screening Visit (Study Days -14 to -1) 
These procedures must be completed within the 14 days prior to starting dosing. Obtain the 
subject’s written informed consent, then collect baseline information: 
-
Demographics (height, weight, date of birth, gender, race, ethnicity); body surface area
(BSA) determined at Screening will be utilized for all BSA-driven mg/m2 dosing
calculations throughout the study.
-
Pertinent medical/surgical history (including AML diagnosis and laboratory and clinical
evidence of progression, previous AML treatment, and any available chromosomal and
mutational testing results per institutional guidelines) and concomitant medications.
-
Physical examination (including weight).
-
Vital signs (heart rate, respiratory rate, seated blood pressure, body temperature).
-
Pregnancy test for women of childbearing potential (WOCBP).
-
ECOG performance assessment.
-
Hematology/chemistry.
-
12-lead ECG with QTcF.
-
Standard chromosomal and mutational testing per institutional guidelines.
-
Bone marrow sampling.
-
Confirm subject meets all inclusion and no exclusion criteria.
9.5.2 Treatment 
The treatment period begins with Cycle 1, Day 1 of the first 2-week dosing cycle. The laboratory 
manual provides procedures for processing, storage, and shipment of brequinar PK, DHO, and 
flow cytometry samples. If brequinar PK or DHO levels are not available for dose adjustment 
decisions, confirm safety is acceptable and continue to dose using the subject’s current dosing 
frequency and current dose until results are available. 
9.5.3 Dose Adjustment: Cycle 1 Week 1 
Week 1 Day 1  
-
Collect any adverse events or new concomitant medications since Screening.
-
Collect samples for baseline (pre-dose) brequinar/DHO, flow cytometry, and
hematology/chemistry.
-
Conduct physical examination (including weight), vital signs, urine pregnancy test for
WOCBP if >4 weeks since last test and 12-lead ECG if >4 weeks since last test.
-
Review results and confirm subject remains eligible for the study.


PROTOCOL NUMBER:  CCB-01  
Page 49 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
-
Dispense study medication.
-
Subject is to take the first dose at the clinic and remain for brequinar/DHO/flow cytometry
sampling. Collect samples at 1, 2, 4, and 6 hours post dose.
-
Dispense the subject’s calendar/diary. The diary will collect dates/times of study medication
administration and AEs/new concomitant medications.
-
Enroll subject for text message reminders if the subject consents to that service; initiate
when subject reaches twice-weekly dosing.
Week 1 Day 2: 
-
Collect 24h post dose brequinar/DHO and flow cytometry samples.
Week 1 Day 3: 
-
Collect 48h post dose brequinar/DHO and flow cytometry samples.
Week 1 Day 4: 
-
Collect 72h post dose brequinar/DHO samples and flow cytometry samples.
Week 1 Day 5: 
-
Collect 96h post dose brequinar/DHO/flow cytometry samples.
Week 1 Day 6: 
-
Collect 120h post dose brequinar/DHO samples and flow cytometry samples.
9.5.4 Dose Adjustment: Cycle 1 Week 2 
The Cycle 1 Week 2 procedures are to be followed to move to twice-weekly dosing using brequinar 
exposure and 72h DHO. This week’s procedures may be repeated weekly as necessary until the 
twice-weekly dose is determined. 
Week 2 Day 1: 
-
Vital signs.
-
Check the diary/elicit information about AEs/new concomitant medications since the last
visit.
-
Check results of previous week’s brequinar PK and DHO levels to determine if dose
adjustment is needed to move to twice-weekly dosing.
-
Prior to the morning dose, collect brequinar/DHO/flow cytometry samples  and
hematology/chemistry samples, then have subject take study medication.
Week 2 Day 2: 
-
Collect 24h post dose brequinar/DHO and flow cytometry samples.
Week 2 Day 3: 
-
Collect 48h post dose brequinar/DHO and flow cytometry samples.


PROTOCOL NUMBER:  CCB-01  
Page 50 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
Week 2 Day 4: 
-
Collect 72h post dose brequinar/DHO samples and flow cytometry samples.
9.5.5 Maintenance Dose Cycle 
Once a subject reaches a twice-weekly dose (see Table 8-2 and Figure 8-2), the subject will be in 
the Maintenance Dose Cycle phase. Each Maintenance Dose Cycle is 2 weeks. The Maintenance 
Dose Cycle dose may be adjusted at any time using the 84h DHO criteria. 
Maintenance Dose Cycle procedures will occur on Day 1 and Day 8 through Week 12 as shown 
below.  After Week 12, the Maintenance Dose Cycle visit is once every 2 weeks (i.e., Day 1 only). 
Maintenance Dose Cycle Day 1: 
-
Collect unused study medication and check the diary/elicit information about AEs/new
concomitant medications since the last visit.
-
Collect pre-dose brequinar/DHO, hematology/chemistry samples, and flow cytometry
sample.
-
Obtain vital signs; urine pregnancy test for WOCBP (every 4 weeks), 12-lead ECG (every
4 weeks), and bone marrow sample (note that bone marrow is collected at the Week 4 visit
(Day 22 ±7 days), at the Week 7 visit (Day 43 ±7 days), then every 12 weeks ±7 days or
per institutional standard of care; the Day 43 sample will be assessed for hematological
toxicity).
-
If subject is beginning or continuing twice-weekly dosing, review most recent 84h DHO
level, review the laboratory results and safety information and determine whether the
subject should maintain current dose (acceptable safety and 84h DHO meets criteria),
increase dose (acceptable safety and 84h DHO < 1500 ng/mL) or hold study medication
(unacceptable safety or 84h DHO ≥ 5000 ng/mL).
-
Dispense study medication.
-
Dispense calendar/diary.
-
Begin text message reminders.
Maintenance Dose Cycle Day 8 (up to Week 12) 
-
Collect pre-dose brequinar/DHO, and flow cytometry sample.
-
Review most recent 84h DHO level, review the laboratory results and safety information
and determine whether the subject should maintain current dose (acceptable safety and 84h
DHO meets criteria), increase dose (acceptable safety and DHO <1500 ng/mL) or hold
study medication (unacceptable safety or 84h DHO ≥ 5000 ng/mL).
9.5.6 Final Visit 
This visit is to take place when a subject is discontinuing from the study. 


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PROTOCOL NUMBER:  CCB-01  
Page 53 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
the texting service will reply with a message indicating that messages sent by participants are not 
being monitored. Study participants must agree to “opt in” for this service and can "opt out" at any 
time even if they initially agreed. Study participants will need to sign an addendum to the informed 
consent document documenting their decision prior to enrollment in the system (see Appendix 
15.5).   
The third-party vendor will sign an agreement with the Sponsor to use participant data only for the 
purposes of this study. Data will be purged from the vendor's servers at the conclusion of the trial 
upon written request by the Sponsor. Data will remain in the vendor's encrypted back-up files that 
will be maintained per HIPAA-compliant standards. 
If requested by the subject and permitted by the institution’s IRB, a designated caregiver may be 
texted instead of the subject. 


PROTOCOL NUMBER:  CCB-01  
Page 54 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
10 ADVERSE EVENT REPORTING 
An adverse event is any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal relationship with 
this treatment.  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of the 
medicinal product, whether or not considered related to the medicinal product.  
Events that occur prior to dosing will be entered as medical history; AEs that occur after dosing 
will be entered on the AE form. 
Subjects will be questioned and observed for evidence of AEs, whether or not related to study 
drug. All AEs will be documented in the subject's medical record and CRF.  For any pre-existing 
condition or abnormal laboratory finding that changes in severity after dosing, this change should 
be recorded as an AE. New abnormal laboratory findings that are clinically significant are 
considered AEs. 
AEs will be collected beginning from the time of informed consent through at least 14 days after 
the final dose of study medication. AEs will be specified as pre-treatment or treatment-emergent. 
AE details are to be documented including start and stop date and times, whether continuous or 
intermittent, severity, any intervention utilized to correct the event (e.g., medication, surgery or 
other therapy), outcome and the relationship to the study drug.   
AEs identified in the protocol as critical to the evaluation of safety must be reported to the Sponsor 
by the Investigator according to the reporting requirements within the time periods specified in the 
protocol. 
AEs determined by the Investigator to be related to study drug must be followed until resolution 
or until they are considered stable or for at least 30 days after discontinuation of study drug, or 
until new treatment for AML is initiated, whichever occurs first.   
Any SAEs experienced after 30 days post the last dose of study drug should only be reported to 
the sponsor if the investigator suspects a causal relationship to the study drug.   
Abnormal laboratory values or test results occurring after study enrollment constitute AEs only if 
they induce clinical signs or symptoms, are considered clinically significant, require therapy (e.g., 
hematologic abnormality that requires transfusion or hematological stem cell support), or require 
changes in study drug (e.g., discontinuation of study drug). 
Death due to disease progression should not be reported as an SAE. Report death from disease 
progression on the End of Study and Death forms.  
If a death occurs during the SAE reporting period, the cause of death is considered as the AE and 
the death is considered its outcome. Death should be considered an outcome, not an event. The 
event or condition leading to death should be recorded and reported as a single medical concept 
on the Adverse Event eCRF. Generally, only one such event should be reported. “Fatal” will be 
recorded as the outcome of this respective event; death due to an outcome of an AE will not be 
recorded as separate event. If the primary cause of death is disease progression, the cause of death 
should be clearly identified as progression of cancer under study. 


PROTOCOL NUMBER:  CCB-01  
Page 55 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
In cases of surgical or diagnostic procedures, the condition leading to the procedure is considered 
as the AE instead of the procedure itself. Each AE will be coded by the Sponsor from the verbatim 
text to a preferred term using a thesaurus based on the Medical Dictionary for Regulatory Activities 
(MedDRA).  
The following guidelines will be followed for the recording and reporting of adverse and serious 
adverse events. 
1. Baseline events will be recorded in the medical history section of the case report form and
will include the terminology event name, grade, and start date of the event.  The medical
history section of the case report form will serve as the source document for baseline events
once signed and dated by the principal investigator.
a.
Baseline events are any medical condition, symptom, or clinically significant lab
abnormality present before the informed consent is signed.
i. Hematologic laboratory abnormalities will not be recorded as baseline events
for patients with acute leukemia, myelodysplastic syndrome, chronic
lymphocytic leukemia, or chronic myeloid leukemia in blast phase.
ii. If exact start date is unknown, month and year or year may be used as the start
date of the baseline event.
2. The maximum grade of the adverse event will be captured per course or protocol-defined
visit date.
3. These adverse events will be recorded in the case report form:
a.
Any grade adverse event that is possibly, probably, or definitely related to the study
drug.
b. All serious adverse events regardless of attribution to the study drug.
c.
Any grade adverse event regardless of attribution to the study drug that results in any
dose modification.
4. Hematologic adverse events will not be recorded or reported for studies in patients with acute
leukemia, myelodysplastic syndrome, chronic lymphocytic leukemia, or chronic myeloid
leukemia in blast phase except for:
a.
Prolonged myelosuppression as defined by the NCI-CTCAE criteria specific for
leukemia, e.g. marrow hypocellularity on day 42 or later (6 weeks) from start of
therapy without evidence of leukemia (< 5% blasts), or that results in dose
modifications, interruptions or meets the protocol definition of DLT or SAE.
5. Serious adverse events will be reported according to institutional policy.
6. Protocol specific language regarding the recording and reporting of adverse and serious
adverse events will be followed in the event of discordance between the protocol and
Leukemia-specific adverse event recording and reporting guidelines.
(MD Anderson Cancer Center Leukemia-specific Adverse Event Recording and Reporting 
Guidelines) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html).   


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PROTOCOL NUMBER:  CCB-01  
Page 58 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
YYA36071medmon@iqvia.com 
Telephone: 
614-721-2630
24-hour safety line: 1-866-758-2798 or 919-313-7111
Fax: 
 
 
206-826-0483
Sponsor Representative: 
Barbara Powers, MSN, Ph.D. 
E-mail:
bpowers@clearcreekbio.com  
Telephone:
484-686-0545
All SAEs will be reported to the IRB periodically, at the end of the study or per local institutional 
guidelines.   
10.4 SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTIONS (SUSARS) 
Suspected, unexpected, serious adverse reactions (SUSARs) are SAEs that are both related to the 
study drug (Relationship = Related) and unexpected (not previously described in the investigator’s 
brochure). All SUSARs will be reported in an expedited manner to the Sponsor or designee and 
IRB by the Investigators and to all relevant regulatory authorities by the Sponsor. Expectedness 
will be judged by the Medical Monitor and site PI. It is critical that all SAEs are reported within 
the 24-hour guideline so that the expectedness determination can be made. SUSARs require 
immediate attention and expedited reporting to relevant regulatory authorities. 
The Sponsor is to ensure that all relevant information about fatal or life-threatening SUSARs are 
appropriately recorded and reported to the concerned Regulatory Authority and to the concerned 
IRB(s) within seven (7) calendar days of the date of first report to the Medical Monitor/Sponsor. 
Follow-up information is to be subsequently communicated to the relevant Regulatory Authority 
within an additional eight calendar days. 
All other SUSARs are to be reported to the Regulatory Authority and to the IRB(s) concerned as 
soon as possible within a maximum of fifteen calendar days of first knowledge by the Medical 
Monitor/Sponsor. 
The Medical Monitor/Sponsor or designee must also inform all Investigators studying the 
investigational medicinal product about SUSARs and ensure that all IRBs have been notified. 
For reported deaths of a subject, the Investigator shall supply the Sponsor and the IRB(s) with 
additional information requested on an expedited basis.   
10.5 PREGNANCIES 
Pregnancy occurring in a female subject or a subject’s partner during the study period will be 
documented in the subject’s source documents and reported on a Pregnancy Form to the Sponsor 
Contact and to the IRB/IEC by the investigational staff within 1 working day of their knowledge 
of the event. The pregnancy information should be submitted using a Pregnancy Report Form. The 
collection period for a pregnancy occurring in a subject or a subject’s partner will begin at the first 
dose of study drug and will continue through 90 days after the last dose of study drug. Monitoring 
of the subject or partner should continue until the conclusion of the pregnancy, if the subject or 


PROTOCOL NUMBER:  CCB-01  
Page 59 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
subject’s partner has consented to this. Monitoring of the baby should continue for 3 months after 
birth, if the subject or subject’s partner has consented to this.  
Pregnancy itself is not an AE; it should be reported for tracking purposes. The Investigator or 
designee will discontinue the pregnant subject from the treatment aspects of the study, continue to 
follow her per protocol for safety outcomes only, and advise her to seek prenatal care and 
counseling from her primary care provider. Data on fetal outcome and breast-feeding will be 
collected for regulatory reporting and drug safety evaluation. 
If the pregnancy is due to a subject’s failure to comply with the contraceptive requirements of this 
protocol, this should also be documented as a protocol deviation.  
Complications of pregnancy or congenital abnormalities in the newborn child will be reported 
appropriately as AEs.  
The site clinical staff will request the pregnant subject to notify the site of the outcome of the 
pregnancy (i.e., birth, loss, or termination). To help ensure this, the site clinical staff will follow-
up with the subject until the end of pregnancy, with the subject’s consent. This request and the 
subject’s response will be documented in the subject’s source document. 
10.6 HEMATOLOGIC ADVERSE EVENTS 
It is recognized that laboratory value variability is a frequent and expected and may be present at 
Baseline when a subject enrolls in the study. In general, mild day to day fluctuation of laboratory 
values should not be classified as AEs. Fluctuations in laboratory values resulting from adverse 
changes in the patient’s medical condition should be reported as AEs. Laboratory abnormalities 
that constitute an AE in their own right as per CTCAE V4.03 criteria if applicable (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study drug), should be recorded on the AE eCRF. 
Whenever possible, a diagnosis, rather than a symptom should be provided (e.g., anemia instead 
of low hemoglobin). Laboratory abnormalities that meet the criteria for AEs should be followed 
until they have returned to normal or an adequate explanation of the abnormality is found. When 
an abnormal laboratory or test result corresponds to a sign/symptom of an already reported AE, it 
is not necessary to separately record the lab/test result as an additional event.  
Laboratory abnormalities that do not meet the definition of an AE should not be reported as AEs. 
A laboratory abnormality designated a Grade 3 or 4 event (severe) as per CTCAE does not 
automatically indicate a SAE unless it meets the definition of serious as defined below and/or as 
per Investigator’s discretion.  
For laboratory abnormalities and any AEs, it should be noted that the terms serious and severe are 
not symptoms. The term severe describes the intensity of the specific event (e.g., Grade 3 or 4). 
The term serious is based on patient and event outcomes or actions required as described in the 
protocol definition of SAEs and is usually associated with events posing a threat to the subject’s 
life or ability to function. A severe AE (Grade 3 or 4) does not necessarily need to be considered 
serious; laboratory abnormalities (such as WBC or platelet count) may be severe but not serious. 


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PROTOCOL NUMBER:  CCB-01  
Page 62 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
Figure 10-1. Monitoring of Tumor Lysis Syndrome 
TLS Treatment 
TLS requires urgent inpatient management including intense nursing care, cardiac monitoring, 
nephrology consultation, and measurements of uric acid, creatinine, and electrolytes every four 
to six hours. Treat any electrolyte abnormalities and any acute renal injury.  


PROTOCOL NUMBER:  CCB-01  
Page 63 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
10.10 INFECTION PROPHYLAXIS 
Supportive care, including prophylactic antibiotics, antifungal and/or antiviral agents, are 
frequently used in neutropenic patients, and may be used per standard institutional practice and as 
deemed necessary by the investigator. 
10.11 GROWTH FACTOR SUPPORT 
The use of myeloid growth factors (granulocyte-colony stimulating factor [G-CSF] and 
granulocyte-macrophage colony-stimulating factor [GM-CSF]) may be given to support subjects 
who have developed Grade 4 neutropenia or Grade 3 neutropenia with fever and/or infection, per 
institutional guidelines. 
10.12 MANAGEMENT OF NAUSEA, VOMITING, AND DIARRHEA 
Recommended management of nausea and vomiting is to administer antiemetics. The 
recommended treatment for managing diarrhea is loperamide antidiarrheal therapy, 4 mg at first 
onset, followed by 2 mg with each loose movement until diarrhea-free for 12 hours (maximum 
dosage: 16 mg/24 hours). Adjunct anti-diarrheal therapy is permitted. 


PROTOCOL NUMBER:  CCB-01  
Page 64 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
11 STATISTICAL CONSIDERATIONS 
A separate, detailed statistical analysis plan (SAP) will be finalized prior to locking the database. 
All analyses of safety and anti-leukemic activity for this open-label early Phase study will be 
descriptive in nature and presented by dose group and overall, as appropriate, for the dose-
adjustment phase and the expansion phase. Procedures for accounting for missing, unused and 
spurious data will be described in the SAP.   
Summaries for quantitative variables will include the mean, median, quartiles, standard deviation 
and error, minimum, and maximum. For qualitative variables, the summaries will include the 
number and percentage of subjects for each outcome, and the exact 95% CI, when appropriate. No 
hypothesis testing will be performed. Any statistical testing will be considered exploratory and 
descriptive. All computations will be performed using SAS® (Version 9.3 or higher). 
Subject disposition, subject demographics and baseline characteristics will be summarized. 
Subject data listings will also be provided. The following sections will briefly summarize of the 
planned statistical analyses and analysis sets for the primary and secondary endpoints. 
11.1 STUDY POPULATIONS FOR ANALYSIS 
The analysis sets are defined in Table 11-1. 
Table 11-1. 
Analysis Sets 
Analysis Set 
Description 
Enrolled Analysis Set 
All subjects who have been enrolled in the study. 
Safety Analysis Set 
All subjects who were administered brequinar. 
Efficacy Analysis Set 
All subjects with AML disease at baseline and who were administered 
brequinar. 
Pharmacokinetic Analysis Set 
All subjects who take at least 1 dose of brequinar and have at least 1 
quantifiable plasma concentration collected post-dose without important 
protocol deviations/violations or events thought to significantly affect the 
PK. 
The Efficacy Analysis Set will be used for efficacy analyses. The Safety Analysis Set will be used 
for safety analyses.   
11.2 SAFETY ANALYSES 
All safety analyses will be performed on the Safety Analysis Set.  Safety and tolerability will be 
assessed in terms of AEs, SAEs, safety laboratory data, physical examinations, vital signs, 12-lead 
ECGs and bone marrow sampling.  
Adverse event data will be descriptively evaluated. All AEs will be listed. The incidence and 
duration of TEAEs, defined as AEs occurring after the first dose of study treatment through 30 
days after the last dose of study treatment, will be tabulated by Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term and system organ class, and by severity and relationship to 
study treatment. All laboratory results, vital sign measurements, ECGs and bone marrow 
assessments will be summarized using appropriate descriptive statistics. 


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PROTOCOL NUMBER:  CCB-01  
Page 68 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
statistics.  Relationships between brequinar PK parameters and clinical outcomes (e.g., efficacy, 
toxicity) may be explored.  PK analyses will be performed on the PK Analysis Set. 
Relationships between DHO levels and PK and clinical outcomes (e.g., efficacy, toxicity) will be 
explored. 
Changes in myeloid markers per serial flow cytometry will be studied to look for evidence of 
myeloid differentiation. 
11.5 SAMPLE SIZE CONSIDERATIONS 
Formal sample size calculations are not applicable for this phase 1b/2a, open label study. Up to 27 
subjects are planned to be entered in this trial: Cohort 1 will had up to 6 subjects; Cohort 2 will 
have approximately 6 subjects. An expansion cohort of approximately 15 subjects will be enrolled 
to further refine brequinar PK and DHO criteria and to further assess the safety, tolerability, and 
biological activity of this dosing scheme.   
11.6 RANDOMIZATION 
No randomization scheme is needed for this open label study. 
11.7 POOLING OF STUDY CENTERS 
Not applicable to this small, early phase study. 
11.8 INTERIM ANALYSIS 
No interim analysis is planned for this trial. 


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PROTOCOL NUMBER:  CCB-01  
Page 71 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
of documents will be documented in writing.  The new owner will assume responsibility for data 
retention and archiving. 
Should the Investigator retire, relocate, or for other reasons withdraw from the responsibility of 
keeping the trial essential documents, custody must be transferred to a person who will accept that 
responsibility, and the Sponsor must be notified in writing of the name and address of said person. 
12.6 NON-PROTOCOL RESEARCH 
No investigational procedures other than those outlined in this protocol may be undertaken on the 
subjects in this trial without the prior written permission of the subject, the Sponsor, the IRB and, 
when appropriate, the regulatory authority. 
12.7 PUBLICATION 
The Sponsor acknowledges the benefit of making widely available the results of all clinical trials 
and intends to publish the results of this trial. All publications resulting from the clinical trial must 
be in a form that does not reveal technical information that the Sponsor considers confidential or 
proprietary.  A copy of any abstract, presentation or manuscript proposed for publication must be 
submitted to the Sponsor for review at least 30 days before its submission for any meeting or 
journal. In addition, if deemed necessary by the Sponsor for protection of proprietary information 
prior to patent filing, the Investigator agrees to a further delay of 60 days before any presentation 
or publication is submitted. The Sponsor reserves the right to include the report of this trial in any 
regulatory documentation or submission or in any informational materials prepared for the medical 
profession. 
Authorship determination will be at the discretion of the Sponsor and will include evaluation of 
the following criteria: Investigator must participate in the review of and content of the protocol; 
review and comment on the study results; participate in the writing, reviewing and commenting of 
the manuscript; and approve the final manuscript for submission. 


PROTOCOL NUMBER:  CCB-01  
Page 72 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
13 SPONSOR RESPONSIBILITIES 
13.1 GENERAL 
The Sponsor agrees to adhere to the ICH Note for Guidance on Good Clinical Practice 
(CPMP/ICH/135/95, Jan.97) and US FDA Regulations. It is the Sponsor's responsibility to obtain 
appropriate regulatory approval to perform the trial (if applicable). The Sponsor should notify 
promptly all concerned investigator(s), IRB(s) and the Regulatory Authority of findings that could 
adversely affect the health of the patients/ subjects, impact on the conduct of the trial or alter the 
Regulatory Authority’s authorization to continue the trial. If it is necessary to change or deviate 
from the protocol to eliminate an immediate hazard to the subjects the Sponsor will notify the 
relevant regulatory authority and relevant IRB of the new events, the measures taken and the plan 
for further action as soon as possible.  This will be by telephone in the first instance followed by a 
written report.   
On completion of the trial, the Sponsor will inform the regulatory authority that the trial has ended. 
If the study is terminated for any reason the Sponsor will provide a written statement to the relevant 
regulatory authority and the IRB with the reasons for termination of the trial. This will be 
conducted within 15 days of the decision to terminate the trial.  The Sponsor will report in an 
expeditious manner all suspected unexpected serious adverse reactions (SUSARs) to the relevant 
regulatory authority and IRBs.   
13.2  INDEMNITY 
The Sponsor will provide compensation insurance against any risk incurred by a subject as a result 
of participation in this trial. The Sponsor will indemnify the Investigators as detailed in a separate 
document. 
13.3  DATA MONITORING 
Suitably qualified and trained clinical research personnel of the Sponsor will visit the trial site at 
regular intervals during the trial for monitoring purposes and to assist the research staff with any 
queries. CRFs and source documentation will be available for review during monitoring visits to 
the trial site. The function of this monitoring is to ensure compliance with the protocol, adherence 
to regulatory and Good Clinical Practice obligations, proper maintenance of records including IMP 
accountability records, correct administration of IMP including storage conditions and accurate 
reporting of AEs.   
Once the data from the case report forms have been entered onto the database, they will be 
reviewed and the data verified against the subject’s source data. Any discrepancies will be tracked 
by paper or electronically with an electronic audit trail. 
13.4  AUDIT 
The Sponsor has an obligation to audit a proportion of studies.  A department other than the clinical 
department will undertake this obligation. Therefore, the Sponsor, an independent auditor or a 
regulatory authority may audit the trial site and trial documentation. These audits may take place 
while the trial is being conducted or up to several years later.   


PROTOCOL NUMBER:  CCB-01  
Page 73 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
13.5  CONFIDENTIALITY 
The Sponsor will not keep any material on file bearing any subject’s name, and subjects’ 
confidentiality will be maintained at all times. 
13.6  FINANCE 
This will be the subject of a separate agreement between the Investigator/Institution and Sponsor. 


PROTOCOL NUMBER:  CCB-01  
Page 74 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
14 REFERENCES 
1. Surveillance, Epidemiology, and End Results (SEER) Program, 1973-2015.
www.seer.cancer.gov.
2. Ng SB, Buckingham KJ, Lee C, et al. Exome sequencing identifies the cause of a 
mendelian disorder. Nature 2010; 42: 30-35.
3. Huang M, Wang Y, Collins M, et al. A77 1726 induces differentiation of human myeloid 
leukemia K562 cells by depletion of intracellular CTP pools. Mol Pharmacol 2002; 
62(3):463-472.
4. Sykes DB, Kfoury YS, Mercier FE, et al. Inhibition of dihydroorotate dehydrogenase 
overcomes differentiation blockade in acute myeloid leukemia. Cell 2016; 167(1): 
171-186.
5. Arteaga CL, Brown TD, Kuhn JG, et al. Phase I clinical and pharmacokinetic trial of 
Brequinar sodium (DuP 785: NSC 368390). Cancer Res 1989; 49(16): 4648-4653.
6. Burris HA 3rd, Raymond E, Awada A, et al. Pharmaocokinetic and phase I studies of 
brequinar (DUP 785; NSC 368390) in combination with cisplatin in patients with advanced 
malignancies. Invest New Drugs 1998; 16(1): 19-27.
7. Noe DA, Rowinsky EK, Shen HS, et al. Phase I and pharmacokinetic study of brequinar 
sodium (NSC 368390). Cancer Res 1990; 50(15): 4595 – 4599.
8. Schwartsmann G, Dodion P, Vermorken JB, et al. Phase I study of Brequinar sodium (NSC 
368390) in patients with solid malignancies. Cancer Chemother Pharmacol. 1990; 25(5):
345-351.
9. Brequinar Investigator’s Brochure
10. Döhner H, Estey E, Grimwade D, Amadori S, Applebaum FR, Büchner T, et al. Diagnosis 
and management of AML in adults: 2017 ELN recommendations from an expert 
international expert panel. Blood 2017; 129(4): 424-447.
11. Cairo MS, Coiffier B, Reiter A, et al. Recommendations for the evaluation of risk and 
prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant 
diseases: an expert TLS panel consensus. Br J Haematol 2010; 149:578.
12. Coiffer B, Altman A, Pui CH, et al. Guidelines for the management of pediatric and adult 
tumor lysis syndrome: an evidence-based review. J Clin Oncol 2008; 26:2767.
13. Howard SC, Jones, DF, Pui, C-H. The Tumor Lysis Syndrome. N Engl J Med 2011; 
364:1844-1854.
14. Kantarjian HM, Stein AS, Bargou RC, Grande Garcia C, Larson RA, Stelljes M, et al. 
Blinatumomab treatment of older adults with relapsed/refractory B-precursor acute 
lymphoblastic leukemia: Results from 2 phase 2 studies. Cancer 2016; 122(4): 2178-2185.


PROTOCOL NUMBER:  CCB-01  
Page 75 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
15 APPENDICES 
15.1 APPENDIX A:  CCB-01 SCHEDULE OF EVENTS 


PROTOCOL NUMBER:  CCB-01  
Page 76 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
CCB-01 Schedule of Events 
Proceduresa 
Screenb 
Cycle 1 
Week 1 
Cycle 1 
Week 2j 
Maintenance 
Dose Cycle 
Final 
Visit 
F/U 
Phone 
Call 
Survival 
D1 
D2 -D 6 
D1 
D2 – D4 
D1 & D8 
Final Visit  
+ 2 wks
Informed Consentb 
X 
AE/Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
Medical historyc 
X 
Demographicsd 
X 
Physical Examd 
X 
X 
X 
X 
Vital Signsd 
X 
X 
X 
X 
X 
Pregnancy Test 
X 
X q 4 weeks 
X 
ECOG Performance Status 
X 
Hematology/Chemistrye 
X 
X 
X 
X (D1 only) 
X 
Chromosomal/mutational testingf 
X 
12-lead ECG
X 
X q 4 weeks 
X 
Bone Marrow Samplingg, h 
X 
X q 12 weeks 
X 
Biobanking samplesg 
X 
X 
X 
Brequinar/DHO/Flow Cytometry Sampleh 
X 
X 
X 
X 
X 
X 
Ship DHO Plasma Samplesi 
X (D4) 
X 
X (D4) 
X 
X 
Dispense/Collect Study Medication 
X 
X 
X 
X 
Dispense/Collect Subject Calendar/Diary 
X 
X 
X 
X 
Survival Assessment 
X 


PROTOCOL NUMBER:  CCB-01  
Page 77 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
a.
Visit window of ± 1 day for Cycle 1 visits; window of ± 3 days for Maintenance Dose cycles.
b.
Obtain informed consent prior to performing any screening or study-specific procedures. Screening procedures must be performed
within 14 days prior to initial study drug administration.  Procedures at C1D1 that are repeats of Screening may be omitted if <72h
since Screening assessment. ECG and pregnancy test frequency are every 4 weeks or per institutional guidelines.
c.
Medical history is to include AML diagnosis, previous AML treatment, and standard chromosomal and mutational results per
institutional guidelines.
d.
Demographic information is to include date of birth, height, weight, race, and ethnic origin. Rectal examination may be deferred for
Physical Examination. Vital signs include heart rate, respiratory rate, seated blood pressure, respiratory rate, oral/aural body
temperature. Complete physical examination and vital signs once every 4 weeks or more often if needed to assess an AE.
e.
If additional complete blood count (CBC) with differential results are available (for example, daily reports when a subject is
hospitalized), these results may be captured in the eCRF using an Unscheduled visit.
f.
Testing panel is per institutional standard of care; obtain sample at Screening.
g.
Bone marrow sampling local testing will include analysis of the aspirate on smear, core biopsy by microscopy, flow cytometry, and
karyotype for cytogenetics. Local molecular analysis will be performed on the screening bone marrow samples only.  Bone marrow
samples will be sent for biobanking for possible further analysis from Screening, Week 7 (Day 43), and Final Visit. Perform bone
marrow sampling at screening, at Visit 4 (Day 22), Visit 7 (Day 43), then once every 12 weeks. Timing of this procedure may be
adjusted to ensure results are available for the next clinic visit. Procedure window is ±7 days.
h.
Cycle 1 Day 1 sample window ±15 minutes through 6h draw; window for additional C1 draws ±2h; window for Dose Adjustment
Week plasma brequinar/DHO draws ±2h; window for Maintenance Cycle samples is ±4h. Ensure 84h DHO trough samples (~84
hours after most recent dose) are obtained prior to dosing.
i.
Process, store and ship these samples per the Laboratory Manual.
j.
Cycle 1 Week 2 procedures are to be repeated weekly until a twice-weekly dose has been determined.


PROTOCOL NUMBER:  CCB-01  
Page 78 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
15.2 APPENDIX B: ECOG PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal level.  Fully active, able to 
carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal level; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
level, but ambulatory and able to 
carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal level with effort; some signs 
or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal level or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance but is 
able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 


PROTOCOL NUMBER:  CCB-01  
Page 79 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
15.3 APPENDIX C: BREQUINAR/DHO/FLOW CYTOMETRY SAMPLING 
Information is provided in a separate laboratory manual regarding collection, processing, storing, 
and shipment of samples.  
Cycle 1 Day 1 sample window ±15 minutes through 6h draw; window for additional C1 draws 
±2h; window for Dose Adjustment Week plasma brequinar/DHO draws ±2h; window for 
Maintenance Cycle samples is ±4h. Ensure 84h DHO trough samples (~84 hours after most recent 
dose) are obtained prior to dosing.   
Brequinar and DHO plasma samples and peripheral blood for flow cytometry are to be obtained 
at the following time points:  
Cycle 1 Week 1 
D1 
D2 
D 3 
D 4 
D 5 
D 6 
Time 
Point 
Pre-
dose 
1h 
2h 
4h 
6h 
24h 
48h 
72h 
96h 
120h 
Cycle 1 Week 2  
(or week adjusting dose using Brequinar Exposure & 72h DHO Criteria) 
D1 
D2 
D 3 
D 4 
Time 
Point 
Pre-dose 
24h 
48h 
72h 
Maintenance Cycle 
(Day 8 through Week 12 only) 
D1 
D8 
Time 
Point 
Pre-dose ~84h after previous dose 
Pre-dose ~84h after previous dose 


PROTOCOL NUMBER:  CCB-01  
Page 80 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
15.4 APPENDIX D: COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS 
(CTCAE) 
https://evs.nci.nih.gov/ftp1/CTCAE/About.html 


PROTOCOL NUMBER:  CCB-01  
Page 81 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
15.5  APPENDIX E: 
SAMPLE SUBJECT CONSENT FORM 
TITLE: 
A Phase 1b/IIa open-label, multi-center study to assess the safety, efficacy and 
pharmacokinetics of intrapatient dose-adjusted brequinar and inhibition of 
dihydroorotate dehydrogenase (DHODH) in adult subjects with acute myelogenous 
leukemia (AML) 
PROTOCOL NO.: 
CCB-01 
SPONSOR: 
Clear Creek Bio, Inc. 
585 Massachusetts Avenue, 4th Floor, 
Cambridge MA 02139 
INVESTIGATOR: 
<insert PI name> 
Site(s): 
<insert name> 
<insert address> 
STUDY-RELATED 
PHONE NUMBER(S): <insert name(s)> 
<insert number> 
<insert alternate number (24-hour contact number)> 
VERSION and DATE:  <e.g. CCB-01 Master ICF Version 3.0 30 April 2019> 
You are being asked to take part in a research study. Before you decide to participate, it is important 
for you to understand why the research is being done and what it will involve. Please take time to 
read the following information carefully and discuss it with others, if you wish, before deciding 
whether or not to take part. Ask us if there is anything that is not clear or if you would like more 
information. 
WHAT IS THE PURPOSE OF THE STUDY? 
The purpose of the study is to evaluate the safety, efficacy, pharmacokinetics (PK) (level of study 
medication in the blood) and the inhibition (decrease in level) of an enzyme called “dihydroorotate 
dehydrogenase” (DHODH). DHODH blocks the ability of blood cells formed in the bone marrow 
to differentiate (grow into mature white blood cells that can fight infection and platelets that help 
blood to clot). Brequinar is a drug that has been shown in animals in the laboratory to be able to 
decrease the level of DHODH and decrease leukemic cells in the bone marrow. Reducing DHODH 
level in patients with AML may help treat this type of leukemia by allowing cells in the bone 
marrow to grow into different types of mature cells.  


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PROTOCOL NUMBER:  CCB-01  
Page 87 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
Having bone marrow sampling (biopsies and aspirations) performed may cause pain, bruising, 
bleeding, redness, low blood pressure, swelling, and/or infection at the site of the biopsies. An 
allergic reaction to the anesthetic may occur. A scar may form at the biopsy site. 
Bone marrow sampling will include analysis of the aspirate on smear, core biopsy by microscopy, 
flow cytometry, and karyotype for cytogenetics. You can talk with the study team about this 
testing. The type of genetic testing being performed for this study will not provide you or your 
doctor information about diseases that are passed down in families. It will not tell the study 
researchers anything that will prevent you from getting health insurance, and it will not tell the 
study researchers anything about any diseases or conditions you may get in the future. 
There may be risks or side effects that are unknown at this time. 
If a condition of which you were unaware is discovered during the study, a full report will be sent 
to your doctor if you request this.  You will be advised of the appropriate action to take for 
treatment. 
Pregnancy-Related Risks 
Taking part in this study can result in risks to an unborn or breastfeeding baby, so you should not 
become pregnant, breastfeed a baby, or father a child while participating in this study. If you are 
able to become pregnant or father a child, you must use birth control during the study and for at 
least 3 months after your last dose of study drug if you are sexually active. 
Birth control specifications: Female participants who are able to become pregnant must use 2 
methods of birth control while on this study. Male participants must use an effective barrier method 
(such as a condom) while on this study. 
Talk with the study team about acceptable methods of birth control to use while taking part in this 
study. 
Males: Tell the study team right away if your partner becomes pregnant or suspects pregnancy. 
Females: If you are pregnant, you will not be enrolled into this study. If you become pregnant or 
suspect that you are pregnant during the study, you must tell your doctor right away. 
Getting pregnant may result in your removal from this study. 
WHAT ARE THE POSSIBLE BENEFITS? 
The study drug may help to control the disease. Future patients may benefit from what is learned. 
There may be no benefits for you in this study.  
WILL IT COST ANYTHING TO BE IN THE STUDY? 
If you participate in this study, you will not have to pay for the cost of the study drug used in the 
study. 
You or your insurer will be responsible for the cost of your usual ongoing medical care, including 
procedures and non-study medications that the doctor or your regular doctor requires during this 
study as part of your usual medical care. If you have any questions, please ask the doctor and/or a 
member of the study staff about the costs that will or will not be covered by the sponsor. 


PROTOCOL NUMBER:  CCB-01  
Page 88 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
IS THERE PAYMENT FOR PARTICIPATION? 
You will not receive any payment for participation in this study. 
WHAT ARE THE ALTERNATIVES FOR TREATMENT? 
You do not have to participate in this research study to receive treatment. Instead, you may be 
eligible for recently approved therapies, and may be able to have a bone marrow transplant outside 
of this study. You may choose to receive other investigational therapies, if available. You may 
also choose not to have treatment for cancer at all. Regardless of your choices, you will receive 
appropriate medical care, including treatment for pain and other symptoms of cancer. Please note 
that you will be informed in a timely manner if new information becomes available that is relevant 
during your participation in this study. 
WHAT IF SOMETHING GOES WRONG? 
An important part of this study is to see if the investigational product causes side effects. You must 
inform the staff if you feel unwell or have any unusual symptoms at any time during the study, no 
matter how minor you think they are. If you experience such events, treatment will be made 
available by the doctor. 
You will be provided any reasonably necessary medical treatment for any injuries sustained as a 
result of participating in this study, except to the extent such costs are covered by your medical or 
hospital insurance or by governmental programs providing such coverage. You must follow the 
directions of the doctor to be eligible for this coverage. Neither the sponsor nor the doctor have 
plans to provide other compensation in the event of an injury. You are not giving up any of your 
legal rights by signing this consent form. 
Certain tests, procedures, and/or drugs that you may receive as part of this study may be without 
cost to you because they are for research purposes only. However, your insurance provider and/or 
you may be financially responsible for the cost of care and treatment of any complications resulting 
from the research tests, procedures, and/or drugs. Standard medical care that you receive under 
this research study will be billed to your insurance provider and/or you in the ordinary manner. 
Before taking part in this study, you may ask about which parts of the research-related care may 
be provided without charge, which costs your insurance provider may pay for, and which costs 
may be your responsibility. You may ask that a financial counselor be made available to you to 
talk about the costs of this study. 
WILL ALL THE DOCUMENTS CONCERNING ME REMAIN CONFIDENTIAL? 
Yes. The company that is conducting this study will not keep any document on file that contains 
your name; you will only be identified by your initials and a subject number. It will be necessary 
for the sponsor, its representatives, the regulatory authorities, other institutions participating in the 
study, and possibly the Institutional Review Board (an IRB is a group of people who review the 
risks and benefits of a study) to review your medical records, but these will be treated in the 
strictest confidence permitted by law. If the results of the study are published, you will not be 
identified by name. Your personal health information (PHI) will be kept as confidentially as 
possible according to state and federal laws. However, in some situations, the Food and Drug 
Administration (FDA) could be required to reveal the names of participants. 


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PROTOCOL NUMBER:  CCB-01  
Page 91 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
<Insert IRB name > 
<Insert address> 
<Insert telephone number> 
<Insert email if applicable> 
The IRB will not be able to answer some study-specific questions however, you may contact the 
IRB if the research staff cannot be reached or if you wish to talk to someone other than the research 
staff.  
Do not sign this consent form unless you have had a chance to ask questions and have received 
satisfactory answers to all of your questions. 
You will be given a signed and dated copy of this consent form to keep. 
Thank you for taking the time to read this consent form. 


PROTOCOL NUMBER:  CCB-01  
Page 92 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
Consent Form Signature Page 
SUBJECT’S DATE OF BIRTH:  ______/______/______ 
mmm /    dd    /  yyyy 
Print Name of Investigator: 
Please initial 
box: 
1.
I confirm that I have read this consent form for the above study and have
had the opportunity to ask questions.
2.
I understand my participation is voluntary and I am free to withdraw at any
time, without giving any reason, without my medical care or legal rights
being affected.
3.
I understand that sections of any of my medical records may be looked at
by responsible individuals from Clear Creek Bio, Inc. and/or its
representatives or from regulatory authorities and the IRB where it is
relevant to my taking part in research. I give permission for these individuals
to have access to my records.
4.
I understand that my data may be transmitted outside the country to
countries with less strict data protection laws.
5.
I agree to take part in the above study.
By signing this consent form, I have not given up any of my legal rights. 
Printed Name of Subject 
Signature of Subject 
Date 
Time 
Printed Name of person conducting      Sign 
Date 
Time 
informed consent discussion 
Original with Investigator File 
1 copy for subject 
1 copy for Subject’s Medical Records 


PROTOCOL NUMBER:  CCB-01  
Page 93 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
Addendum to Informed Consent for Short Messaging Service (SMS/text) 
Reminders for Protocol CCB-01 
TITLE: 
A Phase 1b/IIa open-label, multi-center study to assess the safety, efficacy and 
pharmacokinetics of intrapatient dose-adjusted brequinar and inhibition of 
dihydroorotate dehydrogenase (DHODH) in adult subjects with acute myelogenous 
leukemia (AML) 
PROTOCOL NO.: 
CCB-01 
SPONSOR: 
Clear Creek Bio, Inc. 
585 Massachusetts Avenue, 4th Floor, 
Cambridge MA 02139 
INVESTIGATOR: 
<insert PI name> 
Site(s): 
<insert name> 
<insert address> 
STUDY-RELATED 
PHONE NUMBER(S): <insert name(s)> 
<insert number> 
<insert alternate number (24-hour contact number)> 
VERSION and DATE:  <e.g. CCB-01 Addendum ICF Version 3.0 30 April 2019> 
WHY AM I BEING ASKED TO SIGN THIS ADDENDUM TO THE CONSENT? 
You are being asked to sign this addendum to the consent because you have agreed to participant 
in study CCB-01 and because it is very important for you to take your study medication at the 
correct times (e.g., Monday mornings and Thursdays evenings). One effective way to help you 
remember to take your medication on time is for you to receive a text reminder on your phone. 
The sponsor of the study (Clear Creek Bio, Inc.) is using an external vendor to generate a text 
message reminder that will be sent to your mobile device when it is time for you to take your study 
medication.  
VOLUNTARY NATURE OF THIS SERVICE 
It is entirely optional for you to receive this service. Your decision to receive text message 
reminders for your medications will not in any way affect your ability to enroll in the study. You 
may also "opt out" at any time by responding "STOP" to the messages, or by contacting your study 
team.  


PROTOCOL NUMBER:  CCB-01  
Page 94 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
DESCRIPTION OF THE NATURE OF THE DATA YOU WILL PROVIDE 
You will provide your mobile device number to the study team who will then enter the number 
into the third-party vendor's system for sending out the text reminders.  
DESCRIPTION OF HOW THE DATA WILL BE USED 
The only information that will be shared with the third-party vendor is your mobile device number 
and your study participant identification number. The system is set up so that one-way messages 
are sent from the service to you. You should not reply to the messages you receive except to "opt 
out". If you do send a message, the texting service will reply with a message indicating that the 
messages you may send are not being monitored. 
WHAT WILL THE MESSAGE SAY? 
On the twice-weekly schedule (i.e., Monday mornings and Thursday evenings), you will receive a 
text with the following information: “It is time for you to take your CCB-01 study medication. 
Thank you for participating in this study.” You may delete this message after reading. 
DESCRIPTION OF HOW THIS DATA WILL BE SECURELY MANAGED 
The mobile device number you provide to be used for these reminders will be managed in a manner 
that ensures the best possible security. The mobile device number will not be shared with any other 
third-party vendor or the sponsor of this study (Clear Creek Bio, Inc.). 
WHAT IF I DON’T HAVE A PHONE THAT CAN RECEIVE TEXT MESSAGES? 
If you do not have a mobile phone or cannot receive text messages, you cannot participate in 
receiving these text message reminders. 
MAY I DESIGNATE A CAREGIVER TO RECEIVE THESE MESSAGES? 
If you do not have a mobile phone, you may designate a caregiver to receive these messages on 
your behalf and pass them on to you. 
DISCLOSURES OF RISKS AND VULNERABILITIES 
Although unlikely, it is possible that the unencrypted text messages you receive could 
inadvertently be seen by someone else. Because the messages are de-identified (your name will 
not appear), the most information that could be seen would be that you are participating in a study. 
You are not sending any information back to the third-party vendor, so nothing you send could be 
seen by mistake. 
The study team members are not responsible for any loss or breach of data that results from 
something beyond their control, e.g., you lose your mobile device containing text messages 
reminders, or a third-party vendor or host experiences a server/data breach.  
Standard text/data messaging rates apply to these messages, and because some mobile phone 
providers charge an additional fee for the sending and receiving of text messages, you might be 
charged additionally by your mobile phone provider if you choose to receive the text message 
reminders.  


PROTOCOL NUMBER:  CCB-01  
Page 95 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
PROCESS FOR NOTIFYING PARTICIPANT IN CASE OF AN ACTUAL OR 
POTENTIAL SECURITY BREACH 
If the third-party vendor that has your mobile device number experiences a breach or a potential 
breach, the third-party vendor will notify the sponsor of this study, Clear Creek Bio, Inc. The 
sponsor will notify the study team at each participating institution, and the study team will contact 
you regarding the possible risks associated with the breach/potential breach regarding your mobile 
device number.  


PROTOCOL NUMBER:  CCB-01  
Page 96 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
Consent Form SMS/Text Addendum Signature 
SUBJECT’S DATE OF BIRTH:  ______/______/_____ 
       mmm /    dd    /  yyyy 
Print Name of Investigator: 
Please initial 
box: 
1. I confirm that I have read this consent form for receiving text message
medication reminders for the above study and have had the opportunity to
ask questions.
2. I understand my participation is voluntary in this text messaging service and
I am free to withdraw at any time, without giving any reason, without my
medical care or legal rights being affected.
3. I give permission for the study team and third-party vendor to have access
to my mobile device number.
4. I agree to take part in the mobile device text message reminder for the above
study.
By signing this consent form, I have not given up any of my legal rights. 
Printed Name of Subject 
Signature of Subject 
Date 
Time 
Printed Name of person conducting      Sign 
Date 
Time 
informed consent discussion 
Original with Investigator File 
1 copy for subject 
1 copy for Subject’s Medical Records 


PROTOCOL NUMBER:  CCB-01  
Page 97 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
15.6 APPENDIX F:  WMA DECLARATION OF HELSINKI 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by 
the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000  
53th WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 added) 
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added) 
59th WMA General Assembly, Seoul, October 2008 
A. INTRODUCTION
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a
statement of ethical principles for medical research involving human subjects, including
research on identifiable human material and data.
The Declaration is intended to be read as a whole and each of its constituent paragraphs should
not be applied without consideration of all other relevant paragraphs.
2. Although the Declaration is addressed primarily to physicians, the WMA encourages other
participants in medical research involving human subjects to adopt these principles.
3. It is the duty of the physician to promote and safeguard the health of patients, including those
who are involved in medical research. The physician's knowledge and conscience are dedicated
to the fulfillment of this duty.
4. The Declaration of Geneva of the WMA binds the physician with the words, "The health of
my patient will be my first consideration," and the International Code of Medical Ethics
declares that, "A physician shall act in the patient's best interest when providing medical care."
5. Medical progress is based on research that ultimately must include studies involving human
subjects. Populations that are underrepresented in medical research should be provided
appropriate access to participation in research.
6. In medical research involving human subjects, the well-being of the individual research subject
must take precedence over all other interests.
7. The primary purpose of medical research involving human subjects is to understand the causes,
development and effects of diseases and improve preventive, diagnostic and therapeutic
interventions (methods, procedures and treatments). Even the best current interventions must
be evaluated continually through research for their safety, effectiveness, efficiency,
accessibility and quality.
8. In medical practice and in medical research, most interventions involve risks and burdens.


PROTOCOL NUMBER:  CCB-01  
Page 98 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
9. Medical research is subject to ethical standards that promote respect for all human subjects and
protect their health and rights. Some research populations are particularly vulnerable and need
special protection. These include those who cannot give or refuse consent for themselves and
those who may be vulnerable to coercion or undue influence.
10. Physicians should consider the ethical, legal and regulatory norms and standards for research
involving human subjects in their own countries as well as applicable international norms and
standards. No national or international ethical, legal or regulatory requirement should reduce
or eliminate any of the protections for research subjects set forth in this Declaration.
B. BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH
11. It is the duty of physicians who participate in medical research to protect the life, health,
dignity, integrity, right to self-determination, privacy, and confidentiality of personal
information of research subjects.
12. Medical research involving human subjects must conform to generally accepted scientific
principles, be based on a thorough knowledge of the scientific literature, other relevant sources
of information, and adequate laboratory and, as appropriate, animal experimentation. The
welfare of animals used for research must be respected.
13. Appropriate caution must be exercised in the conduct of medical research that may harm the
environment.
14. The design and performance of each research study involving human subjects must be clearly
described in a research protocol. The protocol should contain a statement of the ethical
considerations involved and should indicate how the principles in this Declaration have been
addressed. The protocol should include information regarding funding, sponsors, institutional
affiliations, other potential conflicts of interest, incentives for subjects and provisions for
treating and/or compensating subjects who are harmed as a consequence of participation in
the research study. The protocol should describe arrangements for post-study access by study
subjects to interventions identified as beneficial in the study or access to other appropriate
care or benefits.
15. The research protocol must be submitted for consideration, comment, guidance and approval
to a research ethics committee before the study begins. This committee must be independent
of the researcher, the sponsor and any other undue influence. It must take into consideration
the laws and regulations of the country or countries in which the research is to be performed
as well as applicable international norms and standards but these must not be allowed to reduce
or eliminate any of the protections for research subjects set forth in this Declaration. The
committee must have the right to monitor ongoing studies. The researcher must provide
monitoring information to the committee, especially information about any serious adverse
events. No change to the protocol may be made without consideration and approval by the
committee.
16. Medical research involving human subjects must be conducted only by individuals with the
appropriate scientific training and qualifications. Research on patients or healthy volunteers
requires the supervision of a competent and appropriately qualified physician or other health


PROTOCOL NUMBER:  CCB-01  
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care professional. The responsibility for the protection of research subjects must always rest 
with the physician or other health care professional and never the research subjects, even 
though they have given consent. 
17. Medical research involving a disadvantaged or vulnerable population or community is only
justified if the research is responsive to the health needs and priorities of this population or
community and if there is a reasonable likelihood that this population or community stands to
benefit from the results of the research.
18. Every medical research study involving human subjects must be preceded by careful
assessment of predictable risks and burdens to the individuals and communities involved in
the research in comparison with foreseeable benefits to them and to other individuals or
communities affected by the condition under investigation.
19. Every clinical trial must be registered in a publicly accessible database before recruitment of
the first subject.
20. Physicians may not participate in a research study involving human subjects unless they are
confident that the risks involved have been adequately assessed and can be satisfactorily
managed. Physicians must immediately stop a study when the risks are found to outweigh the
potential benefits or when there is conclusive proof of positive and beneficial results.
21. Medical research involving human subjects may only be conducted if the importance of the
objective outweighs the inherent risks and burdens to the research subjects.
22. Participation by competent individuals as subjects in medical research must be voluntary.
Although it may be appropriate to consult family members or community leaders, no
competent individual may be enrolled in a research study unless he or she freely agrees.
23. Every precaution must be taken to protect the privacy of research subjects and the
confidentiality of their personal information and to minimize the impact of the study on their
physical, mental and social integrity.
24. In medical research involving competent human subjects, each potential subject must be
adequately informed of the aims, methods, sources of funding, any possible conflicts of
interest, institutional affiliations of the researcher, the anticipated benefits and potential risks
of the study and the discomfort it may entail, and any other relevant aspects of the study. The
potential subject must be informed of the right to refuse to participate in the study or to
withdraw consent to participate at any time without reprisal. Special attention should be given
to the specific information needs of individual potential subjects as well as to the methods
used to deliver the information. After ensuring that the potential subject has understood the
information, the physician or another appropriately qualified individual must then seek the
potential subject's freely-given informed consent, preferably in writing. If the consent cannot
be expressed in writing, the non-written consent must be formally documented and witnessed.
25. For medical research using identifiable human material or data, physicians must normally seek
consent for the collection, analysis, storage and/or reuse. There may be situations where
consent would be impossible or impractical to obtain for such research or would pose a threat


PROTOCOL NUMBER:  CCB-01  
Page 100 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
to the validity of the research. In such situations the research may be done only after 
consideration and approval of a research ethics committee. 
26. When seeking informed consent for participation in a research study the physician should be
particularly cautious if the potential subject is in a dependent relationship with the physician
or may consent under duress. In such situations the informed consent should be sought by an
appropriately qualified individual who is completely independent of this relationship.
27. For a potential research subject who is incompetent, the physician must seek informed consent
from the legally authorized representative. These individuals must not be included in a
research study that has no likelihood of benefit for them unless it is intended to promote the
health of the population represented by the potential subject, the research cannot instead be
performed with competent persons, and the research entails only minimal risk and minimal
burden.
28. When a potential research subject who is deemed incompetent is able to give assent to
decisions about participation in research, the physician must seek that assent in addition to the
consent of the legally authorized representative. The potential subject's dissent should be
respected.
29. Research involving subjects who are physically or mentally incapable of giving consent, for
example, unconscious patients, may be done only if the physical or mental condition that
prevents giving informed consent is a necessary characteristic of the research population. In
such circumstances the physician should seek informed consent from the legally authorized
representative. If no such representative is available and if the research cannot be delayed, the
study may proceed without informed consent provided that the specific reasons for involving
subjects with a condition that renders them unable to give informed consent have been stated
in the research protocol and the study has been approved by a research ethics committee.
Consent to remain in the research should be obtained as soon as possible from the subject or
a legally authorized representative.
30. Authors, editors and publishers all have ethical obligations with regard to the publication of
the results of research. Authors have a duty to make publicly available the results of their
research on human subjects and are accountable for the completeness and accuracy of their
reports. They should adhere to accepted guidelines for ethical reporting. Negative and
inconclusive as well as positive results should be published or otherwise made publicly
available. Sources of funding, institutional affiliations and conflicts of interest should be
declared in the publication. Reports of research not in accordance with the principles of this
Declaration should not be accepted for publication.
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH
MEDICAL CARE
31. The physician may combine medical research with medical care only to the extent that the
research is justified by its potential preventive, diagnostic or therapeutic value and if the
physician has good reason to believe that participation in the research study will not adversely
affect the health of the patients who serve as research subjects.


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PROTOCOL NUMBER:  CCB-01  
Page 102 of 103 
PROTOCOL VERSION: FINAL v 6.0 
DATE:  30 April 2019 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
15.7 APPENDIX G: INVESTIGATOR’S STATEMENT AND AGREEMENT 
STUDY NUMBER:   CCB-01 
STUDY TITLE:  A Phase 1b/2a open-label, multi-center study to assess the safety, efficacy and 
pharmacokinetics of intrapatient dose-adjusted brequinar and inhibition of dihydroorotate 
dehydrogenase (DHODH) in adult subjects with acute myelogenous leukemia (AML) 
INVESTIGATOR’S STATEMENT AND AGREEMENT 
I (the Investigator) have read this protocol and hereby agree to conduct the trial in accord with all 
of its provisions.  It is further agreed that the details of this trial and all information provided to 
me by Clear Creek Bio, Inc. (the Sponsor) will be held in the strictest confidence and will not be 
revealed for any reason without written authorization from Clear Creek Bio, Inc. except to those 
who are to participate in the conduct of the trial. 
I agree that all data, the case report forms and all materials provided for the conduct of the trial are 
the property of Clear Creek Bio, Inc. unless specified otherwise in writing. It is understood that 
Clear Creek Bio, Inc. will utilize the information derived from this trial in various ways, such as 
for submission to government regulatory agencies, required internal reports, and presentations 
without violating patient/ subject confidentiality in any way. 
I further agree that Clear Creek Bio, Inc. or its representatives will be permitted access, in 
accordance with current Good Clinical Practice Guidelines, to all data generated by this trial and 
the source documents from which case report form data were generated. 
PRINCIPAL INVESTIGATOR 
Printed Name: 
Signature:
Date: 
Site Address:       


PROTOCOL NUMBER:  CCB-01  
PROTOCOL VERSION: FINAL v 7.0 
DATE:  21FEB2020 
CCB-01 Approvals and Revision History 
Protocol agreed by: 
Clinical Development 
Date: 27FEB2020 
PRINT NAME: BARBARA L. POWERS, MSN, PH.D. 
Research & Development 
Date: 27FEB2020 
PRINT NAME: DAVID P. HESSON, PH.D. 
Chemistry and Manufacturing/Quality 
Date: 27FEB2020 
PRINT NAME: DAVID P. HESSON, PH.D. 
Sponsor Representative 
Date: 27FEB2020 
PRINT NAME: VIKRAM SHEEL KUMAR, MD 
Revision History/Amendments: 


PROTOCOL NUMBER:  CCB-01  
PROTOCOL VERSION: FINAL v 7.0 
DATE:  21FEB2020 
Version Number 
Date 
1.0 
31 May 2018 
2.0 
04 June 2018 
3.0 
04 October 2018 
4.0 
11 October 2018 
5.0 
16 October 2018 
6.0 
30 April 2019 
7.0 
21 February 2020 


PROTOCOL NUMBER:  CCB-01  
Page 1 of 104 
PROTOCOL VERSION: FINAL v 7.0 
DATE:  21FEB2020 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
STUDY PROTOCOL 
A Phase 1b/2a open-label, multi-center study to assess the safety, 
efficacy and pharmacokinetics of intrapatient dose-adjusted 
brequinar and inhibition of dihydroorotate dehydrogenase 
(DHODH) in adult subjects with acute myelogenous leukemia 
(AML)
Study No: CCB-01 
Version Date:  21 February 2020 
Sponsor: 
Clear Creek Bio, Inc. 
585 Massachusetts Avenue, 4th Floor, 
Cambridge MA 02139 
Sponsor Telephone: (617) 765-2252 
Sponsor Facsimile: (617) 863-2082 
IND Number: 138335 
This confidential document is the property of Clear Creek Bio, Inc.  No unpublished information contained herein 
may be disclosed without the prior written approval of Clear Creek Bio, Inc. This trial will be conducted in 
accordance with the ICH Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95, Jan.97), the Declaration 
of Helsinki (1964, 1975, 1983, 1989, 1996, 2000 (Note for Clarification 2002 & 2004) and 2008), FDA Regulations 
and locally applicable regulations. 


PROTOCOL NUMBER:  CCB-01  
Page 2 of 104 
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DATE:  21FEB2020 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
TABLE OF CONTENTS 
2 SYNOPSIS .......................................................................................................................... 11 
3 INTRODUCTION .............................................................................................................. 25 
3.1 Background ................................................................................................................ 25 
Acute Myeloid Leukemia .................................................................................................. 25 
3.2 Dihydroorotate dehydrogenase (DHODH) ................................................................ 25 
3.3 Brequinar .................................................................................................................... 26 
3.4 Rationale for the Planned Trial .................................................................................. 27 
3.4.1 Brequinar Starting Dose Selection ............................................................................... 28 
3.5 Risk/Benefit of Brequinar .......................................................................................... 29 
3.6 Risks Associated with Participation in the Clinical Study ......................................... 29 
3.7 Possible Interactions with Concomitant Medical Treatments .................................... 29 
3.7.1 CYP Interactions .......................................................................................................... 30 
3.8 Steps to be Taken to Control or Mitigate Risks ......................................................... 30 
4 TRIAL OBJECTIVES ........................................................................................................ 31 
4.1 Primary Objective ...................................................................................................... 31 
4.2 Secondary Objectives ................................................................................................. 31 
4.3 Exploratory Objectives ............................................................................................... 31 
5 TRIAL DESIGN ................................................................................................................. 32 
6 TRIAL ENDPOINTS.......................................................................................................... 33 
6.1 Primary Endpoint ....................................................................................................... 33 
6.2 Secondary Endpoints .................................................................................................. 33 
6.3 Exploratory Endpoints................................................................................................ 33 
7 TRIAL POPULATION ....................................................................................................... 34 
7.1 Number of Subjects .................................................................................................... 34 
7.2 Inclusion criteria ......................................................................................................... 34 
7.3 Exclusion Criteria ....................................................................................................... 35 


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CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
7.4 Inclusion of Women and Minorities........................................................................... 36 
8 STUDY TREATMENTS .................................................................................................... 37 
8.1 Description of Brequinar ............................................................................................ 37 
8.2 Treatment Administration .......................................................................................... 37 
8.3 Safety/Tolerability ...................................................................................................... 38 
8.3.1 Safety/Tolerability – Subject Level .............................................................................. 39 
8.3.2 Hematologic Toxicity ................................................................................................... 40 
8.4 Cohort Starting Doses ................................................................................................ 40 
8.5 Individual Dose Adjustment Guidelines .................................................................... 41 
8.5.1 Brequinar Exposure (BRQ PK) and 72h DHO Criteria to Set Twice-Weekly Dosing 42 
8.5.2 Dose Adjustment Using 84h DHO ............................................................................... 43 
8.6 Medication/AE Diary ................................................................................................. 45 
8.7 Bone Marrow Biopsy ................................................................................................. 45 
8.8 Expansion Cohort ....................................................................................................... 45 
8.9 Study Drug Discontinuation ....................................................................................... 45 
8.10 Brequinar Pharmacokinetics (PK)/Dihydroorotate (DHO) Plasma Levels/Flow 
Cytometry .......................................................................................................................... 46 
8.11 Concomitant Medication/Treatment .......................................................................... 46 
8.11.1 
Gastric pH ............................................................................................................... 47 
8.12 Treatment Compliance ............................................................................................... 47 
8.13 Storage, Stability, Labeling and Packaging ............................................................... 47 
8.13.1 
Storage and Stability ............................................................................................... 47 
8.13.2 
Labeling and Packaging .......................................................................................... 47 
8.13.3 
Blinding and Randomization .................................................................................. 47 
8.13.4 
Unblinding/Expectedness ....................................................................................... 48 
8.13.5 
Study Drug Accountability ..................................................................................... 48 
9 CONDUCT OF THE TRIAL.............................................................................................. 49 


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CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
9.1 Ethical and Regulatory Considerations ...................................................................... 49 
9.2 Informed Consent ....................................................................................................... 49 
9.3 Institutional Review Board / Ethics Committees ....................................................... 50 
9.4 Schedule of Events ..................................................................................................... 50 
9.5 Study Conduct ............................................................................................................ 51 
9.5.1 Screening Visit (Study Days -14 to -1) ........................................................................ 51 
9.5.2 Treatment...................................................................................................................... 52 
9.5.3 Dose Adjustment: Cycle 1 Week 1 or Cycle 1 Week 2 if dose reduced ...................... 52 
9.5.4 Maintenance Dose Cycle .............................................................................................. 52 
9.5.5 Final Visit ..................................................................................................................... 53 
9.5.6 Telephone Follow Up Visit (2 weeks after Final Visit) ............................................... 54 
9.5.7 Unscheduled Visits ....................................................................................................... 54 
9.6 Compliance with Study Procedures ........................................................................... 54 
9.7 Early Withdrawal from the Study .............................................................................. 54 
9.8 Early Termination of the Study .................................................................................. 55 
10 ADVERSE EVENT REPORTING..................................................................................... 56 
10.1 Classification of Causality ......................................................................................... 58 
10.2 Classification of Severity ........................................................................................... 58 
10.3 Serious Adverse Event (SAE) Reporting ................................................................... 59 
10.4 Suspected Unexpected Serious Adverse Reactions (SUSARs) ................................. 61 
10.5 Pregnancies................................................................................................................. 61 
10.6 Hematologic Adverse Events ..................................................................................... 62 
10.7 Management of Myelosuppression ............................................................................ 63 
10.8 Differentiation Syndrome ........................................................................................... 63 
10.9 Tumor Lysis Syndrome (TLS) ................................................................................... 64 
10.10 Infection Prophylaxis ............................................................................................... 66 
10.11 Growth Factor Support ............................................................................................. 66 


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CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
10.12 Management of Nausea, Vomiting, and Diarrhea .................................................... 66 
11 STATISTICAL CONSIDERATIONS................................................................................ 67 
11.1 Study Populations for Analysis .................................................................................. 67 
11.2 Safety Analyses .......................................................................................................... 67 
11.3 Efficacy Analyses ....................................................................................................... 68 
11.4 Other Endpoints.......................................................................................................... 71 
11.5 Sample Size Considerations ....................................................................................... 71 
11.6 Randomization ........................................................................................................... 71 
11.7 Pooling of Study Centers............................................................................................ 71 
11.8 Interim Analysis ......................................................................................................... 72 
12 INVESTIGATOR RESPONSIBILITIES ........................................................................... 73 
12.1 Investigator’s Performance ........................................................................................ 73 
12.2 Confidentiality ............................................................................................................ 73 
12.3 Source Documentation ............................................................................................... 73 
12.4 Data Collection ........................................................................................................... 74 
12.5 Case Report Forms, Investigator’s Site File and Record Retention ........................... 74 
12.6 Non-Protocol Research .............................................................................................. 75 
12.7 Publication .................................................................................................................. 75 
13 SPONSOR RESPONSIBILITIES ...................................................................................... 76 
13.1 General ....................................................................................................................... 76 
13.2 Indemnity ................................................................................................................... 76 
13.3 Data Monitoring ......................................................................................................... 76 
13.4 Audit ........................................................................................................................... 77 
13.5 Confidentiality ............................................................................................................ 77 
13.6 Finance ....................................................................................................................... 77 
14 REFERENCES ................................................................................................................... 78 
15 APPENDICES .................................................................................................................... 79 


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CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
15.1 APPENDIX A:  CCB-01 Schedule of Events ............................................................ 79 
15.2 APPENDIX B: ECOG Performance Status Criteria .................................................. 82 
15.3 APPENDIX C: Brequinar/DHO/Flow Cytometry Sampling ..................................... 83 
15.4 APPENDIX D: Common Terminology Criteria for Adverse Events (CTCAE) ....... 84 
15.5 APPENDIX E:  Sample Subject Consent Form ......................................................... 85 
15.6 APPENDIX F:  WMA Declaration of Helsinki ......................................................... 98 
15.7 APPENDIX G: Investigator’s Statement and Agreement........................................ 104 
 
 


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CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
LIST OF TABLES 
 
Table 8-1. 
Exceptions to Grade 3 Nonhematologic AEs ......................................................... 40 
Table 8-2. 
Algorithm to Set Twice-Weekly Dose for Cohort 2 Replacement/Expansion 
Subjects (Starting Dose 350 mg/m2) ..................................................................... 42 
Table 8-3. 
Algorithm or to Adjust Twice-Weekly Dose using 84h DHO for Cohort 2 
Replacements and Expansion Cohort ................................................................... 44 
Table 11-1. Analysis Sets........................................................................................................... 67 
Table 11-2. Efficacy Analyses ................................................................................................... 68 
 


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CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
LIST OF FIGURES 
 
Figure 8-1. 
Algorithm to Set Twice-Weekly Dose ................................................................... 43 
Figure 8-2. 
Algorithm to Adjust Dose Using 84h DHO ........................................................... 44 
Figure 10-1. 
Monitoring of Tumor Lysis Syndrome ............................................................... 65 
 


PROTOCOL NUMBER:  CCB-01  
Page 9 of 104 
PROTOCOL VERSION: FINAL v 7.0 
DATE:  21FEB2020 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
ABBREVIATIONS 
Abbreviation 
Definition 
µg 
Microgram 
5-FU
5-Fluorouracil
AUC 
Area Under Curve 
BID 
Bis in die (two times a day) 
BLL 
Bi-lineal leukemia 
C6min 
Concentration at 6 minutes 
CHO/HGPRT 
Chinese hamster ovary cell/hypoxanthine-guanine phosphoribosyl-transferase 
CL 
Clearance 
ClR
Low Renal Clearance 
ClT
Low Plasma Total Clearance 
CRh 
Partial hematological response 
CRi 
Incomplete hematological response 
CT 
Computerized Tomography 
CYP 
Cytochrome P450 
DHO 
Dihydroorotate 
DHODH 
Dihydroorotate dehydrogenase 
DLT(s) 
Dose-Limiting Toxicity(ies) 
DNA 
Deoxyribonucleic Acid 
ECGs 
Electrocardiograms 
ECOG 
Eastern Cooperative Oncology Group 
ED50 
Median Effective Dose 
EORTC 
European Organisation for the Research and Treatment of Cancer 
ESR 
Erythrocyte Sedimentation Rate 
F 
Bioavailability 
FDA 
United States Food and Drug Administration 
g 
Grams 
GI 
Gastrointestinal 
G-R
Good Risk Patients 
HPLC 
High-Performance Liquid Chromatography 
HIPAA 
Health Insurance Privacy and Portability Act 
Hr 
Hour 
IB 
Investigator Brochure 
IP 
Intraperitoneal 
IV 
Intravenous 
kg 
Kilograms 
l 
Liters 
LD(10, 50, 90) 
Lethal Dose(10%, 50%, 90%) 
LPS 
Lipopolysaccharide 
M 
Molar 
MPAL 
Mixed phenotypic acute leukemia 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
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CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
Mg 
Milligram 
mL 
Milliliters 
MLED10 
Mouse Equivalent Lethal Dose for 10% of population 
mM 
Micromolar 
Mm 
Millimeters 
MRD 
Minimal Residual Disease 
MRT 
Long Median Residence Time 
MS 
Mucositis/stomatitis 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
NCI 
United States National Cancer Institute 
NMR 
Nuclear Magnetic Resonance Spectroscopy 
NSC 
National Service Center 
ORR 
Overall Response Rate 
PK 
Pharmacokinetic(s) 
PO 
Per Orem 
P-R 
Poor Risk Patients 
PR 
Partial Response 
PS 
Performance Status 
Pts. 
Patients 
QTcF 
Corrected QT interval by Fredericia 
RDP2 
Recommended Dose for Phase II 
RNA 
Ribonucleic Acid 
SC 
Subcutaneous  
SD 
Standard Deviation 
SE 
Standard Error 
SEM 
Standard error of the means 
SI 
Simulation Index 
t½  
Half-Life 
T-ALL 
T-cell lymphoblastic leukemia 
TEAE 
Treatment-emergent adverse event 
USP 
United States Pharmacopeia 
UV 
Ultraviolet 
V 
Volume 
Vd 
Volume of Distribution 
VdSS 
Steady-State Volume of Distribution 
WBC 
White Blood Cell 
WHO 
World Health Organization 
 
 
 


PROTOCOL NUMBER:  CCB-01  
Page 11 of 104 
PROTOCOL VERSION: FINAL v 7.0 
DATE:  21FEB2020 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
2 
SYNOPSIS 
IND 
138,335 
Title 
A Phase 1b/2a open-label, multi-center study to assess the safety, efficacy and 
pharmacokinetics of intrapatient dose-adjusted brequinar and inhibition of 
dihydroorotate dehydrogenase (DHODH) in adult subjects with acute 
myelogenous leukemia (AML)  
Protocol 
CCB-01 
Investigational 
Medicinal 
Product and 
Dosage 
Brequinar is available as 100 and 250 mg oral capsules to be taken every 3.5 days 
with approximately 240 mL of water. Each subject’s mg/m2 dose will be 
calculated based on body surface area at study entry; actual dose will be rounded 
down to the nearest mg based on available oral capsule doses.  
Primary 
Objective 
●
To determine the safety and tolerability of brequinar and the DHODH
inhibitory level of brequinar in adult patients with AML and other
hematological malignancies.
Secondary 
Objectives 
●
To determine the overall response rate (ORR) including complete remission
(CR), CR with incomplete hematologic recovery (CRi), morphologic
leukemia-free state (MLFS), and partial remission (PR) (criteria as defined in
the ELN Guidelines, Döhner et al., 2017) and complete remission with partial
hematological recovery (CRh).
●
To assess the rate of overall survival (OS) and event-free survival (EFS).
●
To evaluate duration of response.
●
To characterize the pharmacokinetic (PK) profile of brequinar
●
To characterize the dihydroorotate (DHO) plasma levels of brequinar after
oral dosing.
Exploratory 
Objectives 
●
To assess the relationship between DHODH inhibition and the efficacy and
safety of brequinar.
●
To evaluate molecular and cellular biomarkers that may be predictive of
antitumor level and/or treatment resistance including cytogenetics, molecular
profiling, and flow cytometry during and after treatment.
●
To evaluate global gene expression profiles, DNA methylation profiles, and
other potential prognostic markers to explore predictors of antitumor activity
and/or resistance to treatment.
Design 
This will be a Phase 1b/2a multi-center, open-label, non-randomized clinical trial 
to assess the safety, tolerability and efficacy of dose-adjusted brequinar in adult 
subjects with AML and other hematological malignancies. The study will also 
assess the inhibition of DHODH and the PK profile of brequinar in plasma. 
Subject dosing will be adjusted based on safety/tolerability, brequinar 
pharmacokinetics, and DHO levels. 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 12 of 104 
PROTOCOL VERSION: FINAL v 7.0 
DATE:  21FEB2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
Up to 27 subjects are planned to be entered in this trial. Although Cohort 1 was 
planned to have 6 subjects, enrollment in this cohort was stopped after 5 subjects 
when brequinar PK and DHO results became available; these results led to changes 
in study design as described in this section. The sixth subject will not be enrolled 
in Cohort 1. Cohort 2 enrolled 6 subjects with a starting dose of 500 mg/m2 once 
weekly. 
Although the 500 mg/m2 starting dose of brequinar was well tolerated by some 
subjects, several subjects took as many as 4 to 5 weeks to achieve twice weekly 
dosing at doses lower than 500 mg/m2. In order to more quickly achieve the desired 
twice weekly dosing schedule, newly enrolled Cohort 2 subjects will now start with 
350 mg/m2 once weekly. Approximately 3 additional subjects will be enrolled into 
Cohort 2 and may be followed by an expansion cohort of approximately 6-12 
subjects. Brequinar PK and DHO samples will be obtained during Week 1. The 
results from Week 1 will be used to make decisions about the Week 2 dose and 
schedule. Subjects who meet the twice weekly brequinar PK and 72h DHO criteria 
in Week 1 may proceed to twice weekly dosing with 350 mg/m2 in Week 2. 
Subjects whose brequinar PK and DHO levels do not meet the twice weekly criteria 
will decrease the dose to 200 mg/m2 once weekly. For subjects requiring the dose 
decrease, brequinar PK and DHO samples will also be obtained daily on Days 1 – 
4 during Week 2, and the Week 2 results will be used to make decisions about the 
Week 3 dose. If a subject still does not meet the twice weekly criteria when dosed 
at 200 mg/m2 once weekly, discontinue the subject and replace. 
 After both the brequinar PK and 72h DHO level meet criteria described in the 
Individual Dose Adjustment Guidelines (below), the subject may move to twice-
weekly dosing on a continuing basis as tolerated. The twice-weekly dose may be 
further adjusted using 84h DHO (trough ~84 hours after dosing) criteria also 
described in the Guidelines for Individual Dose Adjustment.  
Safety will be assessed utilizing physical examination, vital sign measurements, 
safety laboratory testing, 12-lead ECGs and bone marrow sampling. Bone marrow 
sampling will also be utilized to measure response. Tolerability will be assessed 
by spontaneously reported and elicited adverse events. DHO level will be 
measured using a validated assay. Brequinar PK will be analyzed using standard 
PK parameters.  
Dosing will continue for up to 12 months in the absence of unacceptable toxicity 
or disease progression.  
Primary 
endpoints: 
● Safety/tolerability and DHO level relationship with safety and therapeutic 
brequinar levels   
Secondary 
endpoints: 
● Rates of treatment-emergent adverse events. 
● Overall Response Rate (ORR) including CR, CRi, CRh, MLFS, or PR. 
● Event free survival (EFS). 
● Duration of response. 
● PK profile of brequinar. 


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PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 18 of 104 
PROTOCOL VERSION: FINAL v 7.0 
DATE:  21FEB2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
Exceptions to Grade 3 Nonhematologic AEs  
Condition 
Exception Description  
Nausea/ 
Emesis 
Grade 3 nausea and/or emesis resolving to less than or equal 
to Grade 2 or baseline within 1 week after the use of an 
optimal antiemetic regimen based on standard practice. 
Diarrhea 
Grade 3 diarrhea resolving to less than or equal to Grade 1 or 
baseline within 1 week after receiving the maximal 
supportive therapy based on standard practice. 
Laboratory 
abnormalities 
Asymptomatic Grade 3 laboratory abnormalities that are not 
considered to be clinically significant. 
Mucositis 
Grade 3 with duration < 1 week 
Fatigue 
Grade 3 with duration < 2 weeks 
 
For the expansion cohort, the definition of unacceptable safety is expanded to 
include signs of hepatotoxicity (≥ Grade 2 toxicity for ALT and AST). Dosing is 
to be held for subjects who experience hepatotoxicity; dosing may resume only if 
the hepatotoxicity AE resolves to ≤ Grade 1 within two weeks. If the subject 
experiences a second episode of ≥ Grade 2 hepatotoxicity after resuming dosing, 
dosing is to be discontinued for that subject. 
 
Hematologic Toxicity 
After the subject has completed the first 42 days of treatment, the definition of 
unacceptable safety expands to include hematologic AEs defined as prolonged 
neutropenia with ANC < 500 from the start of therapy in the absence of disease, ≥ 
Grade 4 neutropenia, and/or ≥ Grade 4 thrombocytopenia, with a hypocellular bone 
marrow and no greater than 5% marrow blasts lasting for ≥ 2 weeks. Anemia will 
not be considered a hematologic AE for the definition of unacceptable safety. 
Febrile neutropenia is also excluded from the DLT definition for this population.  
For clinic visits when bone marrow sampling is scheduled, the timing of the bone 
marrow sampling can be adjusted to ensure that the results are available at the time 
of the clinic visit. 
Cohort Starting 
Doses 
Cohort 1 enrollment was stopped after treating 5 subjects at 500 mg/m2 twice 
weekly to allow data review and analysis. No dose escalation was permitted for 
Cohort 1 subjects. Due to extensive study design changes a sixth subject will not 
be enrolled into Cohort 1. Cohort 2 treated 6 subjects with this starting dose once-
weekly, which was adjusted to twice-weekly with an adjusted dose (if needed) 
based on brequinar PK and DHO levels.  
 
Cohort 2 replacement subjects will begin with one dose of 350 mg/m2. If the Week 
1 brequinar PK and DHO levels meet the criteria to move to twice weekly dosing 
the subject will be dosed in Week 2 with 350 mg/m2 twice weekly. If the subject 
does not meet the criteria to move to twice-weekly dosing in Week 1 (i.e., 48h 
BRQ PK > 5 mcg/mL and/or 72h DHO > 48h or 72h DHO ≥ 5,000 ng/mL), 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 19 of 104 
PROTOCOL VERSION: FINAL v 7.0 
DATE:  21FEB2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
decrease the dose to 200 mg/m2 for Week 2 and administer one dose. If the subject 
then meets twice weekly criteria, move to twice weekly dosing with 200 mg/m2 
beginning in Week 3. If the subject does not meet criteria to move to twice weekly 
dosing with the 200 mg/m2 single dose, discontinue the subject. 
Each subject’s dosing frequency and dose may be adjusted as shown below. 
Expansion 
Cohort 
An expansion cohort of up to 6 to 12 subjects will be added to obtain further 
information on safety, brequinar exposure, and DHO levels. 
Guidelines for 
Individual Dose 
Adjustment  
Cohort 1 is now complete; all subjects were dosed with 500 mg/m2 twice weekly.  
The six initial Cohort 2 subjects had a starting dose of 500 mg/m2 and were to take 
oral brequinar once weekly for at least two weeks (two total doses). Brequinar 
pharmacokinetics (BRQ PK) and dihydroorotate (DHO) levels from each week 
were used to determine the next week’s dose. Additional weeks of once-weekly 
dosing were permitted as needed to adjust the dose until the criteria have been met 
or the dosing limits have been reached (minimum 200 mg/m2, maximum 800 
mg/m2).  
In order to move to twice-weekly dosing as quickly as possible, the replacement 
Cohort 2 subjects will start with a once weekly dose of brequinar of 350 mg/m2. If 
the subject meets twice weekly dosing criteria with this dose, move the subject 
move to twice weekly dosing with 350 mg/m2 in Week 2. If the twice weekly 
criteria are not met in Week 1, decrease the dose for Week 2 to 200 mg/m2 and 
dose once. If the subject now meets dosing criteria with 200 mg/m2, begin twice 
weekly dosing with 200 mg/m2 in Week3. If the twice weekly dosing criteria are 
not met with 200 mg/m2, discontinue this subject. Subjects who meet twice weekly 
dosing criteria will dose twice weekly (approximately every 3.5 days, e.g., Monday 
morning and Thursday evening) on a continuing basis.  
 
After beginning twice weekly dosing, the brequinar dose is to be further adjusted 
when necessary using the DHO level obtained approximately 84 hours after a 
twice-weekly dose (84h DHO). For example, a subject dosing twice weekly on 
Monday mornings and Thursday evenings would dose on a Thursday evening and 
the 84h DHO sample would be obtained the following Monday morning. There is 
no upper or lower dose limit during twice weekly dosing. Dose increases and 
continued dosing must first meet acceptable safety requirements. If unacceptable 
safety occurs, hold dosing until AE resolves to ≤ grade 2, reduce dose by 150 
mg/m2 and resume dosing. Discontinue the subject if a dose reduction leads to a 
dose of zero or if the available capsule strengths cannot accommodate the desired 
mg/m2 dose. If brequinar PK or DHO levels are not available for dose adjustment 
decisions, hold dosing until results are available.  


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 20 of 104 
PROTOCOL VERSION: FINAL v 7.0 
DATE:  21FEB2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
 
Algorithm 
to 
Set 
Twice-Weekly 
Brequinar 
Dose 
for 
Cohort 
2 
Replacements/Expansion Cohort (Starting Dose 350 mg/m2) 
48h BRQ PK 
> 5 mcg/mL 
NA 
Decrease dose to 200 mg/m2 and continue 
weekly dosing, reassess BRQ PK 
BRQ PK  
Criteria Met* 
72h DHO Criteria  
NOT MET** 
Decrease dose to 200 mg/m2 and continue 
weekly dosing, reassess 72h DHO criteria 
BRQ PK  
Criteria Met* 
72h DHO Criteria  
MET** 
Begin twice-weekly dosing Week 2 or after 
*  Brequinar PK (BRQ PK) Criteria for Cohort 2 replacements and Expansion Cohort: 48h BRQ ≤
**72h DHO Criteria: 72h DHO < 48h DHO (on a downward slope) AND 72h DHO <5000 ng/mL
 
After the twice-weekly dose has been determined using the above criteria, the 
twice-weekly dose may be further adjusted using the 84h DHO (trough) algorithm 
shown below. The 84h DHO level obtained at the beginning of each week will be 
used to adjust the next week’s dose as needed. This dose adjustment may be made 
each week through Week 12 and every two weeks after Week 12, if necessary. 
 
Algorithm to Adjust Twice-Weekly Dose using 84h DHO for Cohort 2 
Replacements and Expansion Cohort 
84h DHO (Trough)  
Action 
84h DHO < 1500 ng/mL 
Increase next week's dose by 75 mg/m2 
84h DHO ≥ 1500 ng/mL and < 5000 ng/mL 
Stable Dose. Check 84h DHO weekly 
through Week 12 then every 2 weeks. 
Adjust dose prn per 84h DHO criteria. 
84h DHO ≥ 5000 ng/mL 
HOLD. Notify subject not to take next dose. 
Hold dosing for one week. If next Day 1 
84h DHO is < 5,000 ng/mL, decrease next 
dose by 75 mg/m2 and resume twice-weekly 
dosing. If next Day 1 84h DHO ≥ 5,000 
ng/mL, no further dosing, discontinue the 
subject. 
 
Each subject will continue twice-weekly dosing at the individually adjusted dose 
for up to 12 months (total time from first dose) in the absence of unacceptable 
toxicity or disease progression. Additional intra-subject dose adjustment is 
permitted at any time throughout the study based on safety/tolerability and 84h 
DHO levels. Subjects who discontinue for any reason prior to the Day 43 visit may 
be replaced.  
The dose adjustment procedures may be revised after safety, brequinar PK, DHO 
plasma levels, and bone marrow results have been reviewed.  


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PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 23 of 104 
PROTOCOL VERSION: FINAL v 7.0 
DATE:  21FEB2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
STUDY PERSONNEL 
SPONSOR CONTACT 
Name: 
Barbara Powers, MSN, Ph.D. 
Title: 
Clinical Operations 
Address: 
Clear Creek Bio, Inc. 
585 Massachusetts Avenue, 4th Floor, 
Cambridge, MA 02139 
Telephone No.: 
484-686-0545 
Fax No.: 
617-863-2082 
E-mail: 
bpowers@clearcreekbio.com  
 
SPONSOR MEDICAL CONTACT 
Name:  
Olga Prokopenko, MD (or other IQVIA Medical Monitor) 
Title: 
Senior Medical Director / Medical Monitor  
Address: 
IQVIA 
1700 Perimeter Park Drive 
Morrisville, NC 27560   
Telephone No.: 
O: +49 610 25790871 
M: +49 1522 8806304 
24-hour Safety No.: 
1-866-758-2798 or 919-313-7111 
E-mail: 
olga.prokopenko@iqvia.com  
YYA36071medmon.iqvia.com 
Medical Monitor Fax No.: 
206-826-0483 
 
SAE Reporting Fax:     
       919.313.1412 (US Toll-free:  1-866-761-1274) 
SAE Reporting email:  
       safety-inbox.biotech@iqvia.com 
 
LEAD INVESTIGATOR 
Name: 
Amir Fathi, MD 
Title: 
Assistant Professor of Medicine 
Affiliation: 
Massachusetts General Hospital 
Telephone No.: 
617-724-1124 
E-mail: 
afathi@mgh.harvard.edu 
 


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SUPPORT SERVICES 
 
CRO Project Manager 
Name: 
Mary Armstrong or current PM 
Company: 
IQVIA 
Address: 
1700 Perimeter Park Drive 
Morrisville, NC 27560 
E-mail: 
mary.armstrong@iqvia.com 
 
Data Management/eCRF PROVIDER 
Company: 
Address: 
 
Telephone No.: 
IQVIA 
1700 Perimeter Park Drive 
Morrisville, NC 27560  
919-972-2397 
Help Desk: 
1-866-342-0693 
Help Desk E-mail: 
sitesupport@iqvia.com 
 
STATISTICAL ANALYSIS 
Company: 
IQVIA 
Address: 
1700 Perimeter Park Drive 
Morrisville, NC 27560 
 
STUDY DRUG HOLDING COMPANY 
Name: 
Almac Clinical Services 
Address: 
25 Fretz Road 
Souderton, PA 18964 
Telephone No.: 
215-660-8500 
Email:  
clinicalservices@almacgroup.com 
 


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3 
INTRODUCTION 
3.1 BACKGROUND 
 
ACUTE MYELOID LEUKEMIA 
Acute myeloid leukemia (AML) is a malignant disorder of immature hematopoietic cells, 
characterized by differentiation arrest and rapid proliferation of abnormal myeloid precursors. 
These abnormal cells accumulate in the bone marrow and interfere with the production of normal 
blood cells. More than 20,000 people are diagnosed with AML per year in the United States (US) 
(SEER, 2015 [1]). The median age at diagnosis is 67 years. 
Although there have been recent advances including midostaurin, enasidenib, CPX-351, 
gemtuzumab ozogomycin and venetoclax, outcomes for patients with AML and many other 
hematologic malignancies remain poor. With modern treatment regimens, expected complete 
remission (CR) rates are 60-70%, but long-term cure rates are 15-25%. Younger patients (i.e. those 
50 years of age or younger) with diploid karyotypes have a CR rate of 70-80% and cure rates of 
20-25%, while older patients and/or those with adverse cytogenetics have CR rates of 35-50% and 
cure rates of < 10% (SEER, 2015 [1]).  It is therefore critical to improve both the remission rate 
and the durability of remission in AML patients of all ages. 
3.2 DIHYDROOROTATE DEHYDROGENASE (DHODH) 
Dihydroorotate dehydrogenase (DHODH) catalyzes the fourth step in pyrimidine synthesis, the 
conversion of dihydroorotate (DHO) to orotate. The enzyme is located on the inner mitochondrial 
membrane and transfers electrons between DHO and complex III of the electron-transport chain 
via the reduction of its ubiquinone (coenzyme Q10) cofactor.  
DHODH is a ubiquitous, essential enzyme. The Miller syndrome, a rare autosomal recessive 
disorder in which patients have inherited hypomorphic mutations in both alleles of DHODH, 
results in multi-organ dysfunction (Ng et al., 2010 [2]). Two weak inhibitors of human DHODH 
are approved for clinical use. Leflunomide, a pro-drug, is used in the treatment of patients with 
rheumatoid arthritis. Its active form, teriflunomide, is marketed for multiple sclerosis. Leflunomide 
is known to affect erythroid differentiation of K562 cells in vitro, via the depletion of uridine 
triphosphate (UTP) and cytidine triphosphate (CTP) ribonucleotides (Huang et al., 2002 [3]). 
Despite the connection between bone marrow level, blood cell differentiation and DHODH, 
leukemia models of leflunomide have not been very promising. Leukemic mice treated with 
leflunomide demonstrated no reduction in leukemic burden and experienced significant weight 
loss and lethargy. 
Recent nonclinical studies have demonstrated that inhibition of DHODH can overcome myeloid 
differentiation arrest (Sykes et al., 2016 [4]). The mechanism through which a reduction in de novo 
pyrimidine biosynthesis modulates myeloid differentiation is not clear. The differentiation effect 


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of DHODH inhibitors appears to involve a combination of inhibition of nucleic acid synthesis, 
cell-cycle arrest, and changes in the post-translational glycosylation of important protein targets.  
Activated and proliferating T-cells have a particular dependence on nucleotide synthesis and 
nucleotide pools (Cohen et al., 1983 [15], Quéméneur et al., 2003 [16]), thus additional leukemias 
that may also benefit from brequinar’s mechanism of action include T-cell lymphoblastic leukemia 
(T-ALL), bi-lineal leukemia (BLL), and mixed phenotypic acute leukemia (MPAL).  
3.3 BREQUINAR 
It is well known that brequinar is a potent inhibitor of DHODH. Brequinar is one of more than 300 
quinoline-carboxylic acid derivatives prepared in an analog synthesis program in the 1980s, which 
was started after it was found that a compound of this class had antitumor activity. Brequinar was 
selected by DuPont for further development as a potential clinical drug because of its activity 
against experimental tumors and because its water solubility made it relatively straightforward to 
formulate. Ultimately, the rationale to use brequinar for the treatment of multiple solid tumors did 
not translate into efficacy after extensive clinical development and the project was terminated by 
DuPont in 1994. Clear Creek Bio exclusively licensed the historic data from Bristol Myers Squibb 
(that acquired DuPont in 2001). 
Sykes et al. (Sykes et al., 2016 [4]) showed that brequinar’s pro-myeloid differentiation activity 
might be useful for the treatment of AML. Utilizing a high throughput screening technique, 
brequinar was identified as a compound that overcame arrest of myeloid differentiation. Brequinar 
triggers myeloid differentiation in vitro and in vivo. Brequinar was highly active in vivo, as 
demonstrated in syngeneic murine AML models (HoxA9+Meis1 and MLL/AF9) as well as 
xenotransplant AML models (THP1, HL60, MOLM13, OCI/AML3). In an aggressive MLL/AF9 
murine model of AML, treatment with brequinar promoted myeloid differentiation, reduced 
leukemic cell burden, and improved overall survival. Brequinar also led to a reduction in the 
number of leukemia stem cells, reduced colony-formation level, and depleted the number of 
leukemia-initiating cell level.  
In addition, Sykes and colleagues demonstrated that treatment with brequinar was better-tolerated 
and more effective than treatment with cytotoxic chemotherapy in animal models. Brequinar was 
given for many weeks without cumulative toxicity. The effect of brequinar and DHODH inhibition 
on normal cells was also assessed through study of competitive bone marrow transplantation 
assays. Mice were treated with brequinar, 5-fluorouracil (5-FU), or induction chemotherapy, and 
their bone marrow was transplanted in competition (1:1) with normal (untreated) bone marrow to 
gauge the effect of therapy on hematopoietic stem cell (HSC) function. The fitness of HSCs from 
mice treated with brequinar were functionally equivalent to those of untreated mice when 
compared to that of HSCs exposed to 5-FU and induction chemotherapy, which promoted a 
marked decrease in fitness.  
Sykes et al. administered brequinar at a dose and schedule (every 72 hours) that was non-toxic to 
the animals yet led to eradication of the leukemia cells. This schedule of administration was based 
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on data demonstrating that the pro-differentiation effect of brequinar required a period of sustained 
DHODH-inhibition of approximately three days. This observation suggests that brequinar’s 
efficacy depends on producing approximately 72-hours “time-above-threshold” to maintain 
sustained DHODH inhibition. The hypothesis is that pyrimidine starvation via inhibition of 
DHODH for approximately 72 hours elicits pro-myeloid differentiation and leads to the anti-
leukemia efficacy of brequinar.  
Sykes et al. also showed that normal cells could tolerate longer periods of pyrimidine starvation 
than their leukemic counterparts. The proposed dosing regimen of brequinar in this clinical trial, 
CCB-01, is intended to take advantage of the different sensitivity of normal and leukemic cells 
and thus spare normal cells while eradicating leukemic cells.  
A pharmacodynamic marker of enzyme inhibition (i.e. target engagement) is required to 
accomplish this type of rational dosing approach. Sykes and colleagues demonstrated how 
DHODH inhibition could be monitored by the accumulation of the substrate DHO. Indeed, 
inhibition of the DHODH enzyme led to the rapid accumulation of intracellular DHO, which was 
reflected by accumulation of DHO in plasma hence the rationale for measuring plasma DHO as 
the pharmacodynamic marker in CCB-01.  
Given this new information, real-time monitoring of target engagement via plasma DHO of 
DHODH inhibition in each patient should permit identification of a brequinar dose that is both 
efficacious and well-tolerated. Maintaining intermittent DHODH inhibition for prolonged 
treatment cycles may be efficacious compared to previous studies using short periods and high 
doses followed by long periods of recovery.  
The prior data on the clinical evaluation of brequinar in patients with multiple solid tumors 
provides valuable safety data that supports the safety of the proposed dosage regimen. Brequinar 
has not been studied clinically in myeloid malignancies in the past. Given encouraging pre-clinical 
results, brequinar has been evaluated in phase 1 and phase 2 trials of more than 800 patients with 
advanced solid tumor malignancies (Arteaga 1989 [5], Burris 1998 [6], Noe 1990 [7], 
Schwartsmann 1990 [8]). These studies indicated a lack of efficacy for brequinar at the doses and 
schedules evaluated. However, many of these trials studied brequinar administered as a single, 
high dose infusion given weekly or daily x 5 days every 3-4 weeks or every day for 21 days. The 
lack of efficacy in the previous trials may have been due to the narrow therapeutic window with 
the high doses studied, and to the inability, or lack of knowledge, to use a pharmacodynamic 
marker such as plasma DHO to fine-tune a therapeutic window based on differential pyrimidine 
starvation of myeloid precursors versus normal cells.  
3.4 RATIONALE FOR THE PLANNED TRIAL 
This study is designed to obtain safety and efficacy data for brequinar in patients with AML and 
other hematologic malignancies including T-ALL, BLL, and MPAL as these diseases  may benefit 
from brequinar.  


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Subject Population 
The population for this study is patients 18 years of age or older, with relapsed/refractory AML by 
World Health Organization classification and other hematologic malignancies including T-ALL, 
BLL, and MPAL that have failed prior standard therapy and for which no standard therapies are 
available that result in a durable remission.  
Study Treatments 
This is an open label study of oral brequinar using intra-subject dose adjustment. The dose-
adjustment scheme is presented in detail in Section 8.5.  
3.4.1 Brequinar Starting Dose Selection 
The rationale underlying the proposed dosage regimen for brequinar and the use of plasma DHO 
to guide dosing is the prior demonstration using nonclinical models by Sykes et al. (2016) [4] that 
malignant cells are more sensitive than normal cells to periods of DHODH inhibition. The 
objective is to identify a dose and regimen of brequinar that maintains suppression of DHODH 
adequate to induce differentiation and stop myeloid proliferation but avoid harming normal cells. 
These features have been realized in vivo in animal models. Specifically, intermittent dosing that 
preserved elevated levels of the metabolite DHO markedly reduced AML cells, preserved normal 
hematopoietic stem cells, and improved animal survival. These recent findings and historic 
pharmacokinetic (PK) and safety data from humans support the planned approach.  
Rather than intermittent high doses as were given by DuPont, Clear Creek will use relatively low 
doses and prolonged exposure to brequinar. There will not be a lengthy conventional rest period 
as is generally required between infrequent high doses. There will instead be twice-weekly 
administration of lower doses with a dosing interval that allows enough time for normal cells to 
recover from or avoid pyrimidine starvation in between the periods of DHODH inhibition. Based 
on its average half-life of 10.5 hours and what has been observed in the clinical PK data (see the 
Brequinar IB [9]), brequinar plasma levels return to baseline at about 3.5 days or 84 hours after an 
oral dose. For this reason, the proposed clinical study includes a twice-weekly schedule of 
brequinar dosed approximately every 84 hours, while measuring brequinar PK and plasma DHO 
to fine-tune the dose that ensures sustained DHODH inhibition while avoiding adverse effects to 
normal cells. 
Safety data from previous oncology clinical studies of brequinar (see Brequinar IB, Section 5) with 
maximum tolerated doses as high as 2250 mg/m2 repeated every 3 weeks suggested that a starting 
dose for Cohort 1 of 500 mg/m2 p.o. would be safe and well-tolerated in subjects with AML. This 
500 mg/m2 starting dose was used in Cohorts 1 and 2 in this protocol, however Cohorts 1 and 2 
results indicate that a starting dose of 350 mg/m2 should allow subjects to more rapidly progress 
to twice weekly dosing. The starting brequinar dose for the remainder of Cohort 2 will therefore 
be reduced to 350 mg/m2. Each subject’s subsequent brequinar dosing may be adjusted depending 


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on the safety, tolerability, brequinar PK, and DHO level obtained during the period following dose 
adjustment. See Section 8.4. 
3.5 RISK/BENEFIT OF BREQUINAR 
As presented in the brequinar IB, more than 800 patients have been exposed to this compound for 
treatment of a variety of solid tumors at various treatment regimens, doses, and routes including a 
single dose, once weekly, twice weekly, single dose every 3 weeks, daily times 5 every 4 weeks, 
and daily times 21 days for multiple courses. The maximum intravenous dose given was 2,250 
mg/m2 every 3 weeks, and the maximum oral dose was 100 mg/m2 daily for 21 days. Study results 
have not shown evidence of efficacy in solid tumors at the doses and regimens studied. However, 
the preclinical work of Sykes et al (2016) [4] have demonstrated the efficacy of brequinar in a 
mouse model of leukemia, indicating that brequinar may be effective in patients with this type of 
leukemia. It is for this reason that study CCB-01 will study patients with AML.   
A universal hallmark of leukemia is the arrest of leukemic myeloblasts at an immature and self-
renewing stage of development. Therapies that can overcome differentiation arrest caused by 
DHODH represent a powerful treatment strategy. A potential benefit of brequinar treatment is that 
brequinar has been identified as a compound that can inhibit DHODH.  
The major risk associated with brequinar is myelosuppression, particularly a decrease in platelet 
count. Patients with hematologic malignancies typically have a low platelet count due to their 
disease, and there is a risk that treatment with brequinar may worsen existing thrombocytopenia. 
3.6 RISKS ASSOCIATED WITH PARTICIPATION IN THE CLINICAL STUDY 
In studies utilizing the weekly schedule of administration of brequinar in patients with refractory 
solid tumors, reversible myelosuppression, in particular thrombocytopenia, and mucositis have 
been the primary dose-limiting toxicities. In addition, skin rash, nausea/vomiting, fatigue, and 
leukopenia have been dose-limiting in trials utilizing other schedules of drug administration. The 
majority of these adverse effects have been less than grade IV in severity and resolve following 
discontinuation of dosing. Symptoms of tumor lysis syndrome have not previously been reported 
following exposure to brequinar, however clinicians will monitor for and treat this condition 
should it arise per the guidelines presented in Section 10.9. An increased risk of infection may 
occur due to the myelosuppressive effects of brequinar (particularly neutropenia); infection 
prophylaxis and treatment are described in Sections 10.10 and 10.11. Differentiation syndrome 
has been seen in other pro-differentiating agents and will be closely followed as described in 
Section 10.7. 
3.7 POSSIBLE INTERACTIONS WITH CONCOMITANT MEDICAL TREATMENTS 
Brequinar has been administered to subjects taking a variety of concomitant medications that are 
typical in cancer patients. No formal interaction studies have been conducted for these 
medications, however, there have not been any reports of interactions with any medications during 
the clinical trials with more than 800 cancer patients.  


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3.7.1 CYP Interactions 
No formal clinical drug-drug interaction studies have been performed for brequinar with 
medications commonly used in treating hematologic malignancies. The nonclinical studies 
performed to date have demonstrated there is no first-pass metabolism and there have been no 
apparent hepatotoxic effects in the clinical studies. Brequinar itself does not appear to be a 
substrate for metabolism by cytochrome P450 enzymes when tested under a variety of conditions. 
(See Brequinar Investigator’s Brochure [9]; nonclinical data on file with Clear Creek). 
3.8 STEPS TO BE TAKEN TO CONTROL OR MITIGATE RISKS 
Guidelines for the prevention, monitoring and treatment of differentiation syndrome, tumor lysis 
syndrome, infection prophylaxis and growth factor support are provided in Section 10. All subjects 
will be treated by highly experience hematologic oncologists familiar with the treatment of 
pancytopenia and its side effects. 


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5 
TRIAL DESIGN 
This will be a Phase 1b/2a multi-center, open-label, non-randomized clinical trial to assess the 
safety, tolerability and efficacy of dose-adjusted brequinar in adult subjects with AML and other 
hematologic malignancies. The study will also assess the inhibition of DHODH and the PK profile 
of brequinar in plasma. Intra-subject dosing may be adjusted based on safety/tolerability, brequinar 
pharmacokinetics (PK), and DHO levels.  
Up to 27 subjects are planned to be entered in this trial. Although Cohort 1 was planned to have 6 
subjects, enrollment in this cohort was stopped after 5 subjects when brequinar PK and DHO 
results became available; these results led to changes in study design utilized in Cohort 2. Cohort 
2 enrolled 6 subjects with a starting dose of 500 mg/m2 once weekly. 
Although the 500 mg/m2 starting dose of brequinar was well tolerated by some subjects, several 
subjects took as many as 4 to 5 weeks to achieve twice weekly dosing at doses lower than 500 
mg/m2. In order to more quickly achieve the desired twice weekly dosing schedule, newly enrolled 
Cohort 2 subjects will now start with 350 mg/m2 once weekly. Approximately 3 additional subjects 
will be enrolled into Cohort 2 and may be followed by an expansion cohort of approximately 6-12 
subjects. Brequinar PK and DHO samples will be obtained during Week 1. The results from Week 
1 will be used to make decisions about the Week 2 dose and schedule. Subjects who meet the twice 
weekly brequinar PK and 72h DHO criteria in Week 1 may proceed to twice weekly dosing with 
350 mg/m2 in Week 2. Subjects whose brequinar PK and DHO levels do not meet the twice weekly 
criteria will have the dose decreased to 200 mg/m2 once weekly. For subjects requiring the dose 
decrease, brequinar PK and DHO samples will also be obtained once daily on Days 1 – 4 during 
Week 2, and the Week 2 results will be used to make decisions about the Week 3 dose. If a subject 
still does not meet the twice weekly criteria when dosed at 200 mg/m2 once weekly, discontinue 
the subject and replace if agreed by the sponsor. 
After both the brequinar PK and 72h DHO level meet criteria described in Section 8.5.1, the subject 
may move to twice-weekly dosing as tolerated. The twice-weekly dose may be further adjusted 
using 84h DHO (trough ~84 hours after dosing) criteria described in Section 8.5.2. There is no 
upper or lower limit for brequinar dose during twice weekly dosing. 
Safety will be assessed utilizing physical examination, vital sign measurements, safety laboratory 
testing, 12-lead ECGs and bone marrow sampling. Bone marrow sampling will also be utilized to 
measure response. Tolerability will be assessed by spontaneously reported and elicited adverse 
events. DHO level will be measured using a validated assay. Brequinar PK will be analyzed using 
standard PK parameters.  
Dosing will continue for up to 12 months in the absence of unacceptable toxicity or disease 
progression. 
Study procedures are presented in detail in Section 8.  


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7 
TRIAL POPULATION 
7.1 NUMBER OF SUBJECTS 
Subjects who meet all the inclusion and none of the exclusion criteria will be enrolled in the study 
until approximately 27 subjects have completed the study.     
7.2 INCLUSION CRITERIA 
1. Willing and able to provide written informed consent for the trial. 
2. Patients 18 years of age or older, with relapsed/refractory AML by World Health 
Organization (WHO) classification, T-cell leukemia (T-ALL), bi-lineal leukemia (BLL), 
or mixed phenotypic acute leukemia (MPAL) and who have exhausted available therapy.  
3. ECOG Performance Status 0 to 2. 
4. 12-lead ECG with no clinically unacceptable findings; adequate cardiac function/NYHA 
Class 0 to 2. 
5. Adequate hepatic function (unless deemed to be related to underlying leukemia). 
a. Direct bilirubin ≤ 2 x ULN 
b. ALT ≤ 3 x ULN 
c. AST ≤ 3 x ULN 
6. Adequate renal function as documented by creatinine clearance ≥ 30 mL/min based on the 
Cockcroft-Gault equation. 
7. In the absence of rapidly proliferative disease, the interval from prior leukemia-directed 
therapy to time of first dose of study drug will be at least 7 days for cytotoxic or non-
cytotoxic (immunotherapy) agents. Use of supportive care measures per institution’s 
standard of care is permitted at any time.  
8. The effects of brequinar on the developing human fetus are unknown.  For this reason, 
women of child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry and for the 
duration of study participation.  Should a woman become pregnant or suspect she is 
pregnant while she or her partner is participating in this study, she should inform her 
treating physician immediately.  Men treated or enrolled on this protocol must also agree 
to use adequate contraception prior to the study, for the duration of study participation, and 
for 90 days after completion of brequinar administration. 


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9. Male subjects must agree to refrain from sperm donation from initial study drug 
administration until 90 days after the last dose of study drug. 
7.3 EXCLUSION CRITERIA 
1. Patients in need of immediate leukapheresis. 
2. Any concurrent uncontrolled clinically significant medical condition, laboratory 
abnormality, or psychiatric illness that could place the participant at unacceptable risk of 
study treatment. 
3. QTc interval using Fridericia’s formula (QTcF) ≥ 470 msec. Participants with a bundle 
branch block and prolonged QTc interval may be eligible after discussion with the medical 
monitor. 
4. Pre-existing liver disease. 
5. The use of other chemotherapeutic agents or anti-leukemic agents is not permitted during 
study with the following exceptions: 
a. Intrathecal chemotherapy for prophylactic use or maintenance of controlled CNS 
leukemia. 
6. Presence of graft versus host disease (GVHD) which requires an equivalent dose of ≥ 
0.5mg/kg/day of prednisone or therapy beyond systemic corticosteroids (e.g. cyclosporine 
or other calcineurin inhibitors or other immunosuppressive agents used for GVHD). 
7. Active cerebrospinal involvement of AML, T-cell leukemia (T-ALL), bi-lineal leukemia 
(BLL), or mixed phenotypic acute leukemia (MPAL). 
8. Diagnosis of acute promyelocytic leukemia (APL). 
9. Clinically active hepatitis B (HBV) or hepatitis C (HCV) infection. 
10. Severe gastrointestinal or metabolic condition that could interfere with the absorption of 
oral study medication. 
11. Prior malignancy, unless it has not been active or has remained stable for at least 2 years. 
Participants with treated non-melanoma skin cancer, in situ carcinoma or cervical 
intraepithelial neoplasia, regardless of the disease-free duration, are eligible if definitive 
treatment for the condition has been completed. Participants with organ-confined prostate 
cancer with no evidence of recurrent or progressive disease are eligible if at the active 
surveillance stage, if hormonal therapy has been initiated or the malignancy has been 
surgically removed or treated with definitive radiotherapy. 


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12. Nursing women or women of childbearing potential (WOCBP) with a positive pregnancy 
test. 
7.4 INCLUSION OF WOMEN AND MINORITIES 
Both men and women of all races and ethnic groups are eligible for this trial. 
 


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8 
STUDY TREATMENTS 
Up to 27 subjects are planned to be entered in this trial. Although Cohort 1 was planned to have 6 
subjects, enrollment in this cohort was stopped after 5 subjects when brequinar PK and DHO 
results became available; these results led to changes in study design as described in this section. 
The sixth subject was not be enrolled in Cohort 1. Cohort 2 enrolled 6 subjects with a starting dose 
of 500 mg/m2 once weekly. Although the 500 mg/m2 starting dose of brequinar was well tolerated 
by some subjects, several subjects took as many as 4 to 5 weeks to achieve twice weekly dosing 
at doses below 500 mg/m2. In order to more quickly achieve the desired twice weekly dosing 
schedule, newly enrolled (replacement) Cohort 2 subjects will start with 350 mg/m2 once weekly. 
Cohort 2 will enroll approximately 3 additional subjects at this starting dose and may be followed 
by an expansion cohort of approximately 6 to 12 subjects.  
After both the brequinar PK and 72h DHO level meet criteria described in Section 8.5.1, the subject 
may move to twice-weekly dosing as tolerated. The twice-weekly dose may be further adjusted 
using 84h DHO (trough ~84 hours after dosing) criteria described in Section 8.5.2.  
Safety will be assessed utilizing physical examination, vital sign measurements, safety laboratory 
testing, 12-lead ECGs and bone marrow sampling. Bone marrow sampling will also be utilized to 
measure response. Tolerability will be assessed by spontaneously reported and elicited adverse 
events. DHO level will be measured using a validated assay. Brequinar PK will be analyzed using 
standard PK parameters.  
Dosing will continue for up to 12 months in the absence of unacceptable toxicity or disease 
progression or may be discontinued with Sponsor consent after completing at least 6 weeks of 
dosing. 
8.1 DESCRIPTION OF BREQUINAR 
Brequinar will be supplied as 100 and 250 mg capsules. Dosing will be determined on a mg/m2 
basis and will be adjusted based on tolerability, safety, brequinar PK, and DHO levels. Brequinar 
capsules should be taken whole; they should not be crushed or chewed. If the participant forgets 
to take the daily dose, he/she should make up the dose within 24 hours. Any medication remaining 
from extra supplies or missed doses should not be taken beyond the last scheduled day of brequinar 
administration but should be documented in the subject diary and returned by the participant for 
drug accountability purposes.  
8.2 TREATMENT ADMINISTRATION 
Five subjects were enrolled in the now-completed Cohort 1. All subjects were dosed with twice 
weekly brequinar 500 mg/m2 for a range of 2 to 16 doses (one to 8 weeks). No additional subjects 
will be enrolled into Cohort 1. A total of 6 subjects were treated in Cohort 2 with a starting dose 
of 500 mg/m2 once weekly. These 6 Cohort 2 subjects took brequinar once weekly for at least two 
weeks (two total doses). Brequinar exposure and DHO levels were used to adjust the brequinar 


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dose (if necessary) to meet brequinar PK and 72h DHO criteria described in Section 8.5.1. Subjects 
then moved to twice-weekly dosing (approximately every 3.5 days, e.g., Monday morning and 
Thursday evening) on a continuing basis. The brequinar dose was further adjusted if needed using 
the 84h DHO (trough) Criteria shown in Section 8.5.2.  
Three Cohort 2 were not evaluable due to early discontinuation. Approximately 3 additional 
subjects will be enrolled into Cohort 2 to replace these subjects and may be followed by an 
expansion cohort of approximately 6-12 subjects. Cohort 2 subjects will now start with 350 mg/m2 
once weekly. Brequinar PK and DHO samples will be obtained during Week 1. The results from 
Week 1 will be used to make decisions about the Week 2 dose and schedule. Subjects who meet 
the twice weekly brequinar PK and 72h DHO criteria in Week 1 may proceed to twice weekly 
dosing with 350 mg/m2 in Week 2. For subjects whose brequinar PK and DHO levels do not meet 
the twice weekly criteria, decrease the dose to 200 mg/m2 once weekly. For these subjects, 
brequinar PK and DHO samples will also be obtained once daily on Days 1 – 4 during Week 2, 
and the Week 2 results will be used to make decisions about Week 3. If a subject still does not 
meet the twice weekly criteria when dosed at 200 mg/m2 once weekly, discontinue the subject. 
Subjects who discontinue for any reason prior to 6 weeks may be replaced with sponsor 
permission. 
Each dose is to be taken with approximately 240 mL of water. The subject does not need to be 
fasting. Each dose will generally consist of multiple capsules; the capsules do not need to be 
swallowed all at once but can be spread over up to 15 minutes as needed. The chosen dosing 
schedule needs to accommodate clinic visits as well as shipping and receipt of the brequinar/DHO 
samples and results needed for dosing adjustments. Sample processing and shipping procedures 
will be addressed in a separate laboratory manual.  
8.3 SAFETY/TOLERABILITY 
Safety/tolerability is assessed for each subject at each study visit using the Common Terminology 
Criteria for Adverse Events v4.03 (CTCAE). Cohort 1 had a fixed starting dose of 500 mg/m2 with 
no dose escalation permitted. Cohort 2 and the expansion cohort started with 500 mg/m2 once 
weekly and had adjustments made to dose and dose frequency using safety/tolerability, brequinar 
exposure (PK), and DHO levels. As described above, the replacement Cohort 2 subjects (and the 
Expansion Cohort) will start at 350 mg/m2 once weekly with the goal of moving rapidly to twice 
weekly dosing. Safety at the subject level is defined in Section 8.3.1; hematologic toxicity is 
defined in Section 8.3.2. 
The following adverse events are commonly observed in patients with hematologic malignancies 
and should be differentiated from possible adverse effects of brequinar: fatigue, fever, 
thrombocytopenia and other cytopenias, infection, pallor, shortness of breath, weight loss, night 
sweats, and anorexia. Any of these events can be serious in nature and may result in death. Disease 
progression is considered a lack of efficacy rather than an adverse event. Death from disease 
progression is to be reported as presented in Section 10. 


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Adverse events commonly observed in patients treated with brequinar are provided in the 
Investigator’s Brochure and include thrombocytopenia, nausea, anemia, diarrhea, vomiting, 
leukopenia, stomatitis, rash, granulocytopenia, fatigue, and infection. In a study of 209 subjects 
treated once-weekly (DuP 785-012), the deaths of three patients were attributed to study drug 
toxicity (two to hemorrhage, one following acute renal failure). Severe toxicities grades (Grades 3 
to 4) which typically led to discontinuation in this study included hematologic toxicities (anemia, 
thrombocytopenia, leukopenia, granulocytopenia), digestive system toxicity (nausea, vomiting, 
stomatitis, others including gastric hemorrhage) and mucositis.  
In most instances, drug related toxicities were clinically manageable and reversible upon 
discontinuation of brequinar treatment. In a study where brequinar was dosed twice-weekly to 
solid tumor subjects, no drug-related deaths occurred. Stomatitis/mucositis was observed in 13 of 
the 19 (68%) patients across all doses. Mild to moderate (Grades 1 and 2) stomatitis was observed 
in 10 patients with a more severe (Grade 3) stomatitis seen in 3 patients at doses over 600 mg/m2. 
One patient at 600 mg/m2 had drug discontinuation due to drug-related stomatitis. 
Myelosuppression was the main dose-limiting toxicity (DLT) with thrombocytopenia (Grades 1-
4), observed after 2 to 9 doses above 600 mg/m2. Any of these events reported with brequinar use 
can be serious in nature and may result in death. 
Prescriptions can be provided in advance for supportive care for common brequinar-related AEs 
such as mucositis. 
8.3.1 Safety/Tolerability – Subject Level 
Safety/tolerability is assessed for each subject at each study visit using the Common Terminology 
Criteria for Adverse Events v4.03 (CTCAE). Acceptable safety/tolerability for a subject through 
Day 42 is defined as no ≥ Grade 3, treatment-emergent, study-drug-related, non-hematologic 
adverse events. Due to the expected hematologic profile associated with AML and other 
hematologic malignancies, hematologic AEs of any grade will not be considered a DLT during the 
first 42 days of dosing (i.e., assessed at the visit conducted on Day 43). Exceptions to the non-
hematologic Grade 3 criterion are provided in Table 8-1.  
If a dose is held due to safety/tolerability issues, the subject should continue to have scheduled 
visits and assessments. 
If AEs have not resolved to ≤ Grade 2 after two weeks without dosing, dosing is to be discontinued 
for this subject. 


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Table 8-1. Exceptions to Grade 3 Nonhematologic AEs  
Condition 
Exception Description  
Nausea/ 
Emesis 
Grade 3 nausea and/or emesis resolving to less than or equal to Grade 2 or baseline within 
1 week after the use of an optimal antiemetic regimen based on standard practice. 
Diarrhea 
Grade 3 diarrhea resolving to less than or equal to Grade 1 or baseline within 1 week after 
receiving the maximal supportive therapy based on standard practice. 
Laboratory 
abnormalities 
Asymptomatic Grade 3 laboratory abnormalities that are not considered to be clinically 
significant. 
Mucositis 
Grade 3 with duration < 1 week 
Fatigue 
Grade 3 with duration < 2 weeks 
After completion of the first 42 days of treatment, the definition of unacceptable safety is expanded 
to include signs of hepatotoxicity (≥ Grade 2 toxicity for ALT and AST). Dosing is to be held for 
at least one week (i.e., two doses if twice weekly) for subjects who experience hepatotoxicity; 
dosing may resume only if the hepatotoxicity AE resolves to ≤ Grade 1 within two weeks. If the 
subject experiences a second episode of ≥ Grade 2 hepatotoxicity after resuming dosing, dosing is 
to be discontinued for that subject. 
8.3.2 Hematologic Toxicity 
After the subject has completed the first 42 days of treatment, the definition of unacceptable safety 
expands to include hematologic AEs defined as prolonged neutropenia with ANC < 500 from the 
start of therapy in the absence of disease, ≥ Grade 4 neutropenia, and/or ≥ Grade 4 
thrombocytopenia, with a hypocellular bone marrow and no greater than 5% marrow blasts lasting 
for 2 weeks or more. Anemia will not be considered a hematologic AE for the definition of 
unacceptable safety. Febrile neutropenia is also excluded from the DLT definition for this 
population. For clinic visits when bone marrow sampling is scheduled, the timing of the bone 
marrow sampling can be adjusted to ensure that the results are available at the time of the clinic 
visit. 
8.4 COHORT STARTING DOSES 
Cohort 1 enrollment was stopped after treating 5 subjects at 500 mg/m2 twice weekly to allow data 
review and analysis. No dose escalation was permitted for Cohort 1 subjects. Due to extensive 
study design changes a sixth subject will not be enrolled into Cohort 1. 
The first 6 Cohort 2 subjects had a starting dose of 500 mg/m2 once-weekly which was adjusted to 
twice-weekly with an adjusted dose (if needed) based on brequinar PK and DHO levels.  
Cohort 2 replacement subjects will begin with one dose of 350 mg/m2. If the Week 1 brequinar 
PK and DHO levels meet the criteria to move to twice weekly dosing the subject will be dosed in 
Week 2 with 350 mg/m2 twice weekly. If the subject does not meet the criteria to move to twice-


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weekly dosing in Week 1 (i.e., 48h BRQ PK > 5 mg/mL and/or 72h DHO > 48h or 72h DHO ≥ 
5,000 ng/mL), decrease the dose to 200 mg/m2 for Week 2 and administer one dose. If the subject 
then meets twice weekly criteria, move to twice weekly dosing with 200 mg/m2 beginning in Week 
3. If the subject does not meet criteria to move to twice weekly dosing with the 200 mg/m2 single 
dose, discontinue the subject. 
Each subject’s dosing frequency and dose may be adjusted as shown in the following sections. 
8.5 INDIVIDUAL DOSE ADJUSTMENT GUIDELINES 
Cohort 1 is now complete; all subjects were dosed with 500 mg/m2 twice weekly.  
The six initial Cohort 2 subjects had a starting dose of 500 mg/m2 and were to take oral brequinar 
once weekly for at least two weeks (two total doses). Brequinar pharmacokinetics (BRQ PK) and 
dihydroorotate (DHO) levels from each week were used to determine the next week’s dose. 
Additional weeks of once-weekly dosing were permitted as needed to adjust the dose until the 
criteria have been met or the dosing limits have been reached (minimum 200 mg/m2, maximum 
800 mg/m2).  
Pre-clinical evidence (Sykes et al., 2016 [4]) suggests that a twice-weekly dose is most likely to 
lead to efficacy, therefore the goal is to adjust the brequinar dose to allow all subjects to dose on a 
twice-weekly basis. In order to move to twice-weekly dosing as quickly as possible, the 
replacement Cohort 2 subjects will start with a once weekly dose of brequinar of 350 mg/m2. If 
the subject meets twice weekly dosing criteria with this dose, move the subject move to twice 
weekly dosing with 350 mg/m2 in Week 2. If the twice weekly criteria are not met in Week 1, 
decrease the dose for Week 2 to 200 mg/m2 and dose once. If the subject now meets dosing criteria 
with 200 mg/m2, begin twice weekly dosing with 200 mg/m2 in week 3. If the twice weekly dosing 
criteria are not met with 200 mg/m2, discontinue this subject. Subjects who meet twice weekly 
dosing criteria will dose twice weekly (approximately every 3.5 days, e.g., Monday morning and 
Thursday evening) on a continuing basis.  
After beginning twice weekly dosing, the brequinar dose is to be further adjusted when necessary 
using the DHO level obtained approximately 84 hours after a twice-weekly dose (84h DHO). For 
example, a subject dosing twice weekly on Monday mornings and Thursday evenings would dose 
on a Thursday evening and the 84h DHO sample would be obtained the following Monday 
morning. There is no upper or lower dose limit during twice weekly dosing. 
Dose increases and continued dosing must first meet acceptable safety requirements as described 
in Section 8.3.1. If unacceptable safety occurs, hold dosing until AE resolves to ≤ grade 2, reduce 
dose by 150 mg/m2 and resume dosing. Discontinue the subject if a dose reduction leads to a dose 
of zero or the available capsule strengths cannot accommodate the designed mg/m2 dose. If 
brequinar PK or DHO levels are not available for dose adjustment decisions, hold dosing until 
results are available. 


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The dose adjustment procedures and criteria may be revised after each preceding cohort’s safety, 
brequinar PK, DHO plasma levels, and bone marrow results have been reviewed. The dose 
adjustment process and criteria are described in the following sections. 
8.5.1 Brequinar Exposure (BRQ PK) and 72h DHO Criteria to Set Twice-Weekly Dosing 
Both brequinar exposure (pharmacokinetics, PK) and dihydroorotate (DHO) levels are utilized to 
set the twice weekly dose. For Cohort 3, the initial goal is to identify a dose that results in brequinar 
PK approximately 48 hours after dosing of less than or equal to 5 mcg/mL (48h BRQ PK ≤ 5 
mcg/mL). Next check the DHO results obtained 48 and 72 hours after dosing. The twice weekly 
DHO criteria are that the DHO obtained 72 hours after dosing must be less than the DHO obtained 
48 hours after dosing (i.e., on a downward slope). In addition, the DHO level at 72 hours must be 
less than 5,000 ng/mL. To summarize, 72h DHO < 48h DHO (on a downward slope) AND 72h 
DHO <5000 ng/mL. See the algorithm to set the twice weekly dose for Cohort 3 in Table 8-2 and 
Figure 8-1.  
Table 8-2. Algorithm to Set Twice-Weekly Dose for Cohort 2 Replacement/Expansion 
Subjects (Starting Dose 350 mg/m2) 
Brequinar PK* 
72h DHO** 
Action 
48h BRQ PK 
> 5 mcg/mL 
NA 
Decrease dose to 200 mg/m2 and continue weekly dosing, 
reassess BRQ PK 
BRQ PK  
Criteria Met* 
72h DHO Criteria  
NOT MET** 
Decrease dose to 200 mg/m2 and continue weekly dosing, 
reassess 72h DHO criteria 
BRQ PK  
Criteria Met* 
72h DHO Criteria  
MET** 
Begin twice-weekly dosing Week 2 or after 
*  Brequinar PK (BRQ PK) Criteria for Cohort replacements and Expansion Cohort: 48h BRQ ≤ 5 mcg/mL 
**72h DHO Criteria: 72h DHO < 48h DHO (on a downward slope) AND 72h DHO <5000 ng/mL 
 


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Figure 8-1. Algorithm to Set Twice-Weekly Dose 
 
8.5.2 Dose Adjustment Using 84h DHO  
After the twice-weekly dose has been determined using the above criteria and the subject has 
started to dose twice weekly, the twice-weekly dose may be further adjusted using the 84h DHO 
algorithm shown below. The 84h DHO level obtained prior to the first dose of a week will be used 
to adjust the next week’s dose as needed. This dose adjustment may be made on a continuing basis. 
If DHO levels are not available for dose adjustment decisions, confirm safety is acceptable but 
hold the dose until results are available. As soon as results are available, adjust dose as needed 
following criteria and resume dosing. Further adjustments are permitted using the 84h DHO results 
during twice weekly dosing. There is no maximum or minimum allowable dose during twice 
weekly dosing.  See Table 8-3 and Figure 8-2.  
 
 


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Table 8-3. Algorithm to Adjust Twice-Weekly Dose using 84h DHO for Cohort 2 
Replacements and Expansion Cohort 
84h DHO Criteria 
Action 
84h DHO < 1500 ng/mL 
Increase next week's dose by 75 mg/m2 
84h DHO ≥ 1500 ng/mL and < 5000 ng/mL 
Stable Dose. Check 84h DHO weekly x 12 weeks then 
every 2 weeks. Adjust dose PRN per 84h DHO criteria. 
84h DHO ≥ 5000 ng/mL 
HOLD. Notify subject not to take next dose. Hold dosing 
for one week. If next Day 1 84h DHO is < 5,000 ng/mL, 
decrease next dose by 75 mg/m2 and resume twice-weekly 
dosing. If next Day 1 84h DHO ≥ 5,000 ng/mL, no further 
dosing, discontinue the subject. 
 
 
Figure 8-2. Algorithm to Adjust Dose Using 84h DHO  
Each subject will continue twice-weekly dosing at the individually adjusted dose for up to 12 
months (total time from first dose) in the absence of unacceptable toxicity or disease progression. 
Additional intra-subject dose adjustment is permitted at any time throughout the study based on 
safety/tolerability and 84h DHO levels. Subjects who discontinue for any reason prior to the Week 
7 (Day 43) visit may be replaced.  


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8.6 MEDICATION/AE DIARY 
The participant will be provided with a study calendar of events and will be required to maintain 
a medication diary of each dose of medication. Subjects will be instructed to record the date and 
time each dose of brequinar is taken, indicating if any doses are missed. Subjects will be instructed 
to record adverse events and changes in concomitant medications in the subject calendars/diaries.  
Subjects will be instructed and reminded to bring the medication diary to each clinic visit for 
review. The diary will be returned to clinic staff at the end of each cycle and a new diary dispensed. 
8.7 BONE MARROW BIOPSY 
The participant will have a bone marrow sampling (aspiration and core biopsy) at baseline (prior 
to dosing), one for research purposes at the Week 4 visit (Day 22 ± 7 days), and one at the Week 
7 visit (Day 43 ± 7 days); thereafter, bone marrow sampling will be obtained every 12 weeks  ± 7 
days (or per institutional standard of care) and at the Final Visit. If a participant develops frank 
evidence of progression of disease during the course of treatment based on laboratory or clinical 
assessment, he/she will be discontinued from study treatment and can proceed with additional 
management off-study per discretion of the treating oncologist. If the results of the bone marrow 
sampling reveal disease progression at Visit 7 (Day 43) (defined as 43 days after initiating 
treatment or after 6 complete weeks after initiating study drug treatment regardless of number of 
doses), then the participant will be taken off treatment. Timing of the bone marrow biopsy 
procedure may be adjusted to ensure that results are available for any visit. Bone marrow sampling 
will include analysis of the aspirate on smear, core biopsy by microscopy, flow cytometry, and 
karyotype for cytogenetics. Molecular analysis will be performed on the screening bone marrow 
samples. 
8.8 EXPANSION COHORT 
Following completion of Cohort 2, an expansion cohort of up to 6 to 12 subjects may be added to 
further define the dosing, BRQ PK and DHO criteria and assess the safety, tolerability, and 
biological activity of the dosing scheme.  
The expansion cohort will follow the same visit procedures as Cohort 2.  
8.9 STUDY DRUG DISCONTINUATION 
If there is evidence of stable disease, partial response, or complete remission (CR, CRi, or CRh) 
at or prior to Visit 7 (43 days) or with the agreement of the principle investigator and sponsor, the 
participant may continue with brequinar treatment until there is evidence of disease progression, 
intolerable toxicity, or for a maximum of one year. Study drug will be discontinued for an 
individual subject if there is evidence of unacceptable safety/tolerability that does not resolve to ≤ 
Grade 2 within 2 weeks after stopping brequinar dosing.  


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PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 47 of 104 
PROTOCOL VERSION: FINAL v 7.0 
DATE:  21FEB2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
8.11.1 Gastric pH 
Whenever possible, participants should discontinue proton pump inhibitors, antacids, and H2-
receptor antagonists which increase the gastric pH and may reduce absorption of oral medications 
including brequinar resulting in decreased systemic exposure. Discontinuation of these 
medications is not required but is strongly recommended. 
8.12 TREATMENT COMPLIANCE 
Compliance will be assessed by reviewing the subject’s medication diary and accounting of 
returned clinical supplies.  
8.13 STORAGE, STABILITY, LABELING AND PACKAGING 
8.13.1 Storage and Stability 
The study drug is stored at room temperature. Stability testing is ongoing. 
8.13.2 Labeling and Packaging  
Each bottle for subject use will be labeled with at least the following information: 
For Clinical Trial Use Only 
Study Number: 
CCB-01 
Contents: 100 or 250 mg Brequinar capsules 
For oral use only. Take with approximately 8 ounces water every 3.5 days. 
Subject Number: XX-XXXX 
 
Treatment Duration: As directed 
IND: 138355             Clinical Batch Number: XXXXXXX  
Expiration Date: 
TBD 
Storage: Store at controlled room temperature  
Study Sponsor:  Clear Creek Bio, Inc., 585 Massachusetts Avenue, 4th 
Floor, Cambridge MA 02139 
Caution: New Drug – Limited by US Federal Law to Investigational Use
Only. To be used by Qualified Investigators only. 
8.13.3 Blinding and Randomization 
The trial will be conducted in an open-label manner. The brequinar capsules will be provided to 
each participating institution in bulk to be dispensed by the institution’s pharmacist per the 
designated mg/m2 dose for each subject. No randomization codes are necessary for this open-label 
study. 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 48 of 104 
PROTOCOL VERSION: FINAL v 7.0 
DATE:  21FEB2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
8.13.4 Unblinding/Expectedness 
It is not necessary to break the blind for this open label study as the treatment is known for each 
subject. 
Expectedness will be determined by establishing whether the adverse event is among those 
identified in the protocol and the Investigator’s Brochure or are commonly associated with AML 
and other hematologic malignancies.  The event will be considered expected if commonly 
associated with these diseases in the opinion of the investigator or Medical Monitor even if not 
specifically listed in these documents.  
8.13.5 Study Drug Accountability 
The study drug provided is for use only as directed in this protocol. 
The Investigator must keep a record of all study medication received, used and discarded.  It must 
be clear from the records which subject received which medication. Adequate drug is to be 
dispensed for each dosing period to allow for dosing every 3.5 days during the period until the 
next clinic visit, plus one additional dose to act as a spare in the event medication is unable to be 
used.  
The pharmacist/staff member responsible for drug accountability is to document the date and time 
of dispensing and for what subject the study drug was intended (i.e., record subject initials and 
birth date or other unique identifier). A pharmacy manual will be provided by the Sponsor detailing 
how to calculate the mg/m2 dose together with examples of combinations of the 100 and 250 mg 
capsules to provide the most efficient use of the clinical supplies. 
At the end of the study, any unused study drug will be returned to the Sponsor for destruction or 
destroyed locally; disposition of study drug will be documented.   
The Sponsor will be permitted access to the trial supplies at any time within usual business hours 
and with appropriate notice during or after completion of the study to perform drug accountability 
reconciliation. 
 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 49 of 104 
PROTOCOL VERSION: FINAL v 7.0 
DATE:  21FEB2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
9 
CONDUCT OF THE TRIAL 
9.1 ETHICAL AND REGULATORY CONSIDERATIONS 
The trial will be performed in accordance with the Declaration of Helsinki (1964) (Appendix F) 
as revised in Tokyo (1975), Venice (1983), Hong Kong (1989), South Africa (1996), Scotland 
(2000, Note of Clarification 2002 & 2004) and Seoul 2008 (Appendix A), and Fortaleza (Brazil) 
(2013), and with the ICH Tripartite Guideline on Good Clinical Practice (CPMP/ICH/135/95, 
Jan.97) and US FDA Regulations. 
9.2 INFORMED CONSENT 
The principles of informed consent in the current edition of the Declaration of Helsinki must be 
implemented in each clinical study before protocol-specified procedures are carried out.  Informed 
consent must be obtained in accordance with US Code of Federal Regulations (21 CFR Part 50) 
as well as local and national regulations. Information should be given in both oral and written form 
whenever possible and deemed appropriate by the Institutional Review Board (IRB). Subjects and 
their relatives, if necessary, must be given ample opportunity to inquire about details of the study. 
The Investigator or qualified designated person will verbally inform subjects as to the nature, 
expected duration and purpose of the trial, the administration of the Investigational Medicinal 
Product (IMP), and the hazards involved, as well as the potential benefits that may come from 
treatment with this IMP. The trial procedures will be explained in lay language and any questions 
will be answered. The subjects will be given an IRB-approved consent form. The subjects will be 
given appropriate time to consider their participation in the trial and have any questions answered 
prior to signing the consent form. If a subject agrees to participate, he/she will sign and date an 
informed consent form and be provided with a copy of the signed consent. All subjects who sign 
an informed consent form are to be recorded on the applicable screening log.   
The subject will be informed that his/her medical records will be subject to review by the Sponsor, 
Sponsor’s representatives, and possibly by a representative of the Food and Drug Administration 
and other relevant regulatory authorities. Subjects will be informed that they are free to refuse 
participation in this clinical investigation, and if they should participate, it will be made clear to 
them that they may withdraw from the trial at any time without prejudicing further medical care 
they may require. The subject will receive a copy of the consent form as well as an information 
sheet about the trial.  
Signed written informed consent must be obtained from every subject prior to any study-specific 
procedures.  Standard procedures carried out prior to signing the informed consent but within the 
time constraints of the protocol may be used for baseline evaluation; they need not be repeated. 
An original signed informed consent form will be filed in the Investigator Site File and will be 
subject to review by the Sponsor; a copy will be given to the subject and a copy will be filed with 
the subject’s medical notes. 


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PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 51 of 104 
PROTOCOL VERSION: FINAL v 7.0 
DATE:  21FEB2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
Schedule of Events. Standard chromosomal and mutational testing will be performed per 
institutional guidelines. 
See 15.1 Schedule of Events in Appendix A for the full list of study assessments and timings.  
Blood chemistry tests include blood urea nitrogen (BUN), creatinine, alkaline phosphatase (ALP), 
alanine amino transferase (ALT), aspartate amino transferase (AST), bilirubin, total protein, 
albumin, glucose, serum electrolytes (sodium, potassium, chloride, carbon dioxide/bicarbonate, 
and calcium), and lactate dehydrogenase (LDH).  
Hematology tests include hemoglobin, hematocrit, complete blood count with full differential and 
platelet count, and peripheral blast count.  
In addition to the already scheduled chemistry assessments, subjects taking potentially hepatotoxic 
drugs are permitted to have more frequent monitoring than indicated in the schedule of events, if 
ordered by the study team. 
9.5 STUDY CONDUCT 
9.5.1 Screening Visit (Study Days -14 to -1) 
These procedures must be completed within the 14 days prior to starting dosing. Obtain the 
subject’s written informed consent, then collect baseline information: 
- Demographics (height, weight, date of birth, gender, race, ethnicity); body surface area 
(BSA) determined at Screening will be utilized for all BSA-driven mg/m2 dosing 
calculations throughout the study. 
- Pertinent medical/surgical history (including AML/other hematologic malignancy 
diagnosis and laboratory and clinical evidence of progression, previous AML/other 
hematologic malignancy treatment, and any available chromosomal and mutational testing 
results per institutional guidelines) and concomitant medications. 
- Physical examination (including weight).  
- Vital signs (heart rate, respiratory rate, seated blood pressure, body temperature).  
- Pregnancy test for women of childbearing potential (WOCBP).  
- ECOG performance assessment.  
- Hematology/chemistry. 
- 12-lead ECG with QTcF.  
- Standard chromosomal and mutational testing per institutional guidelines. 
- Bone marrow sampling. 
- Confirm subject meets all inclusion and no exclusion criteria. 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 52 of 104 
PROTOCOL VERSION: FINAL v 7.0 
DATE:  21FEB2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
9.5.2 Treatment 
The treatment period begins with Cycle 1, Day 1 of the first 2-week dosing cycle. The laboratory 
manual provides procedures for processing, storage, and shipment of brequinar PK, DHO, and 
flow cytometry samples. If brequinar PK or DHO levels are not available for dose adjustment 
decisions, confirm safety is acceptable and continue to dose using the subject’s current dosing 
frequency and current dose until results are available. 
9.5.3 Dose Adjustment: Cycle 1 Week 1 (or Week 2 if dose reduced) 
Week 1(or Week 2) Day 1  
- Collect any adverse events or new concomitant medications since Screening.  
- Collect samples for baseline (pre-dose) brequinar/DHO, flow cytometry, and 
hematology/chemistry.  
- Conduct physical examination (including weight), vital signs, pregnancy test for WOCBP 
if >4 weeks since last test and 12-lead ECG if >4 weeks since last test.  
- Review results and confirm subject remains eligible for the study.  
- Dispense study medication.  
- Subject is to take the first dose at the clinic and remain for brequinar/DHO/flow cytometry 
sampling. Collect samples at 1, 2, 4, and 6 hours post dose during Week 1 only. 
- Dispense the subject’s calendar/diary. The diary will collect dates/times of study medication 
administration and AEs/new concomitant medications.  
- This week’s procedures may be repeated for Week 2 if necessary, with the exception that 
PK/DHO samples are to be obtained pre-dose only on Day 1 of Week 2 in addition to the 
daily samples on Days 2, 3, and 4. 
Week 1 or 2 Day 2:  
- Collect 24h post dose brequinar/DHO and flow cytometry samples.  
Week 1 or 2 Day 3:  
- Collect 48h post dose brequinar/DHO and flow cytometry samples.  
Week 1 or 2 Day 4:  
- Collect 72h post dose brequinar/DHO samples and flow cytometry samples.  
9.5.4 Maintenance Dose Cycle  
Once a subject reaches a twice-weekly dose (see Table 8-2 and Figure 8-2), the subject will be in 
the Maintenance Dose Cycle phase. Each Maintenance Dose Cycle is 2 weeks. The Maintenance 
Dose Cycle dose may be adjusted at any time using the 84h DHO criteria. 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 53 of 104 
PROTOCOL VERSION: FINAL v 7.0 
DATE:  21FEB2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
Maintenance Dose Cycle procedures will occur on Day 1 and Day 8 through Week 12 from study 
Day 1 as shown below.  After Week 12, the Maintenance Dose Cycle visit is once every 2 weeks 
(i.e., Day 1 only of each two-week cycle). 
Maintenance Dose Cycle Day 1: 
- Collect unused study medication and check the diary/elicit information about AEs/new 
concomitant medications since the last visit. 
- Collect pre-dose brequinar/DHO, hematology/chemistry samples, and flow cytometry 
sample.  
- Obtain vital signs; pregnancy test for WOCBP (every 4 weeks), 12-lead ECG (every 4 
weeks), and bone marrow sample (note that bone marrow is collected at the Week 4 visit 
(Day 22 ±7 days), at the Week 7 visit (Day 43 ±7 days), then every 12 weeks ±7 days or 
per institutional standard of care; the Day 43 sample will be assessed for hematological 
toxicity). 
- If subject is beginning or continuing twice-weekly dosing, review most recent 84h DHO 
level, review the laboratory results and safety information and determine whether the 
subject should maintain current dose (acceptable safety and 84h DHO meets criteria), 
increase dose (acceptable safety and 84h DHO < 1500 ng/mL) or hold study medication 
(unacceptable safety or 84h DHO ≥ 5000 ng/mL).  
- Dispense study medication. 
- Dispense calendar/diary.  
Maintenance Dose Cycle Day 8 (up to Week 12) 
- Collect pre-dose brequinar/DHO, and flow cytometry sample.  
- Review most recent 84h DHO level, review the laboratory results and safety information 
and determine whether the subject should maintain current dose (acceptable safety and 84h 
DHO meets criteria), increase dose (acceptable safety and DHO <1500 ng/mL) or hold 
study medication (unacceptable safety or 84h DHO ≥ 5000 ng/mL).  
9.5.5 Final Visit 
This visit is to take place when a subject is discontinuing from the study. 
- Collect and check the diary/elicit information about AEs/new concomitant medications 
since the last visit.  


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PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 56 of 104 
PROTOCOL VERSION: FINAL v 7.0 
DATE:  21FEB2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
10 ADVERSE EVENT REPORTING 
An adverse event is any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal relationship with 
this treatment.  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of the 
medicinal product, whether or not considered related to the medicinal product.  
Events that occur prior to dosing will be entered as medical history; AEs that occur after dosing 
will be entered on the AE form. 
Subjects will be questioned and observed for evidence of AEs, whether or not related to study 
drug. All AEs will be documented in the subject's medical record and CRF.  For any pre-existing 
condition or abnormal laboratory finding that changes in severity after dosing, this change should 
be recorded as an AE. New abnormal laboratory findings that are clinically significant are 
considered AEs. 
AEs will be collected beginning from the time of informed consent through at least 14 days after 
the final dose of study medication. AEs will be specified as pre-treatment or treatment-emergent. 
AE details are to be documented including start and stop date and times, whether continuous or 
intermittent, severity, any intervention utilized to correct the event (e.g., medication, surgery or 
other therapy), outcome and the relationship to the study drug.   
AEs identified in the protocol as critical to the evaluation of safety must be reported to the Sponsor 
by the Investigator according to the reporting requirements within the time periods specified in the 
protocol. 
AEs determined by the Investigator to be related to study drug must be followed until resolution 
or until they are considered stable or for at least 30 days after discontinuation of study drug, or 
until new treatment for AML/other hematologic malignancy is initiated, whichever occurs first.   
Any SAEs experienced after 30 days post the last dose of study drug should only be reported to 
the sponsor if the investigator suspects a causal relationship to the study drug.   
Abnormal laboratory values or test results occurring after study enrollment constitute AEs only if 
they induce clinical signs or symptoms, are considered clinically significant, require therapy (e.g., 
hematologic abnormality that requires transfusion or hematological stem cell support), or require 
changes in study drug (e.g., discontinuation of study drug). 
Death due to disease progression should not be reported as an SAE. Report death from disease 
progression on the End of Study and Death forms.  


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 57 of 104 
PROTOCOL VERSION: FINAL v 7.0 
DATE:  21FEB2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
If a death occurs during the SAE reporting period, the cause of death is considered as the AE and 
the death is considered its outcome. Death should be considered an outcome, not an event. The 
event or condition leading to death should be recorded and reported as a single medical concept 
on the Adverse Event eCRF. Generally, only one such event should be reported. “Fatal” will be 
recorded as the outcome of this respective event; death due to an outcome of an AE will not be 
recorded as separate event. If the primary cause of death is disease progression, the cause of death 
should be clearly identified as progression of cancer under study. 
In cases of surgical or diagnostic procedures, the condition leading to the procedure is considered 
as the AE instead of the procedure itself. Each AE will be coded by the Sponsor from the verbatim 
text to a preferred term using a thesaurus based on the Medical Dictionary for Regulatory Activities 
(MedDRA).  
The following guidelines will be followed for the recording and reporting of adverse and serious 
adverse events. 
1. Baseline events will be recorded in the medical history section of the case report form and 
will include the terminology event name, grade, and start date of the event.  The medical 
history section of the case report form will serve as the source document for baseline events 
once signed and dated by the principal investigator.   
a. Baseline events are any medical condition, symptom, or clinically significant lab 
abnormality present before the informed consent is signed. 
i. Hematologic laboratory abnormalities will not be recorded as baseline events 
for patients with acute leukemia, myelodysplastic syndrome, chronic 
lymphocytic leukemia, or chronic myeloid leukemia in blast phase. 
ii. If exact start date is unknown, month and year or year may be used as the start 
date of the baseline event. 
2. The maximum grade of the adverse event will be captured per course or protocol-defined 
visit date. 
3. These adverse events will be recorded in the case report form: 
a. Any grade adverse event that is possibly, probably, or definitely related to the study 
drug. 
b. All serious adverse events regardless of attribution to the study drug. 
c. Any grade adverse event regardless of attribution to the study drug that results in any 
dose modification. 
4. Hematologic adverse events will not be recorded or reported for studies in patients with acute 
leukemia, myelodysplastic syndrome, chronic lymphocytic leukemia, or chronic myeloid 
leukemia in blast phase except for: 
a. Prolonged myelosuppression as defined by the NCI-CTCAE criteria specific for 
leukemia, e.g. marrow hypocellularity on day 42 or later (6 weeks) from start of 
therapy without evidence of leukemia (< 5% blasts), or that results in dose 
modifications, interruptions or meets the protocol definition of DLT or SAE. 


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PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 61 of 104 
PROTOCOL VERSION: FINAL v 7.0 
DATE:  21FEB2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
10.4 SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTIONS (SUSARS) 
Suspected, unexpected, serious adverse reactions (SUSARs) are SAEs that are both related to the 
study drug (Relationship = Related) and unexpected (not previously described in the investigator’s 
brochure). All SUSARs will be reported in an expedited manner to the Sponsor or designee and 
IRB by the Investigators and to all relevant regulatory authorities by the Sponsor. Expectedness 
will be judged by the Medical Monitor and site PI. It is critical that all SAEs are reported within 
the 24-hour guideline so that the expectedness determination can be made. SUSARs require 
immediate attention and expedited reporting to relevant regulatory authorities. 
The Sponsor is to ensure that all relevant information about fatal or life-threatening SUSARs are 
appropriately recorded and reported to the concerned Regulatory Authority and to the concerned 
IRB(s) within seven (7) calendar days of the date of first report to the Medical Monitor/Sponsor. 
Follow-up information is to be subsequently communicated to the relevant Regulatory Authority 
within an additional eight calendar days. 
All other SUSARs are to be reported to the Regulatory Authority and to the IRB(s) concerned as 
soon as possible within a maximum of fifteen calendar days of first knowledge by the Medical 
Monitor/Sponsor. 
The Medical Monitor/Sponsor or designee must also inform all Investigators studying the 
investigational medicinal product about SUSARs and ensure that all IRBs have been notified. 
For reported deaths of a subject, the Investigator shall supply the Sponsor and the IRB(s) with 
additional information requested on an expedited basis.   
10.5 PREGNANCIES 
Pregnancy occurring in a female subject or a subject’s partner during the study period will be 
documented in the subject’s source documents and reported on a Pregnancy Form to the Sponsor 
Contact and to the IRB/IEC by the investigational staff within 1 working day of their knowledge 
of the event. The pregnancy information should be submitted using a Pregnancy Report Form. The 
collection period for a pregnancy occurring in a subject or a subject’s partner will begin at the first 
dose of study drug and will continue through 90 days after the last dose of study drug. Monitoring 
of the subject or partner should continue until the conclusion of the pregnancy, if the subject or 
subject’s partner has consented to this. Monitoring of the baby should continue for 3 months after 
birth, if the subject or subject’s partner has consented to this.  
 
Pregnancy itself is not an AE; it should be reported for tracking purposes. The Investigator or 
designee will discontinue the pregnant subject from the treatment aspects of the study, continue to 
follow her per protocol for safety outcomes only, and advise her to seek prenatal care and 
counseling from her primary care provider. Data on fetal outcome and breast-feeding will be 
collected for regulatory reporting and drug safety evaluation. 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 62 of 104 
PROTOCOL VERSION: FINAL v 7.0 
DATE:  21FEB2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
 If the pregnancy is due to a subject’s failure to comply with the contraceptive requirements of this 
protocol, this should also be documented as a protocol deviation.  
 
Complications of pregnancy or congenital abnormalities in the newborn child will be reported 
appropriately as AEs.  
The site clinical staff will request the pregnant subject to notify the site of the outcome of the 
pregnancy (i.e., birth, loss, or termination). To help ensure this, the site clinical staff will follow-
up with the subject until the end of pregnancy, with the subject’s consent. This request and the 
subject’s response will be documented in the subject’s source document. 
10.6 HEMATOLOGIC ADVERSE EVENTS 
It is recognized that laboratory value variability is a frequent and expected and may be present at 
Baseline when a subject enrolls in the study. In general, mild day to day fluctuation of laboratory 
values should not be classified as AEs. Fluctuations in laboratory values resulting from adverse 
changes in the patient’s medical condition should be reported as AEs. Laboratory abnormalities 
that constitute an AE in their own right as per CTCAE V4.03 criteria if applicable (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study drug), should be recorded on the AE eCRF. 
Whenever possible, a diagnosis, rather than a symptom should be provided (e.g., anemia instead 
of low hemoglobin). Laboratory abnormalities that meet the criteria for AEs should be followed 
until they have returned to normal or an adequate explanation of the abnormality is found. When 
an abnormal laboratory or test result corresponds to a sign/symptom of an already reported AE, it 
is not necessary to separately record the lab/test result as an additional event.  
Laboratory abnormalities that do not meet the definition of an AE should not be reported as AEs. 
A laboratory abnormality designated a Grade 3 or 4 event (severe) as per CTCAE does not 
automatically indicate a SAE unless it meets the definition of serious as defined below and/or as 
per Investigator’s discretion.  
For laboratory abnormalities and any AEs, it should be noted that the terms serious and severe are 
not symptoms. The term severe describes the intensity of the specific event (e.g., Grade 3 or 4). 
The term serious is based on patient and event outcomes or actions required as described in the 
protocol definition of SAEs and is usually associated with events posing a threat to the subject’s 
life or ability to function. A severe AE (Grade 3 or 4) does not necessarily need to be considered 
serious; laboratory abnormalities (such as WBC or platelet count) may be severe but not serious. 
After the subject has completed the first 42 days of treatment, hematologic dose-limiting toxicity 
(DLT) is defined as prolonged neutropenia with ANC < 500 from the start of therapy in the absence 
of disease, ≥ Grade 4 neutropenia, and/or ≥ Grade 4 thrombocytopenia, with a hypocellular bone 
marrow and no greater than 5% marrow blasts lasting for 2 weeks or more. Anemia will not be 
considered a hematologic AE for the definition of unacceptable safety. The timing of the bone 


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PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 65 of 104 
PROTOCOL VERSION: FINAL v 7.0 
DATE:  21FEB2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
 
Figure 10-1. Monitoring of Tumor Lysis Syndrome 
TLS Treatment 
TLS requires urgent inpatient management including intense nursing care, cardiac monitoring, 
nephrology consultation, and measurements of uric acid, creatinine, and electrolytes every four 
to six hours. Treat any electrolyte abnormalities and any acute renal injury.  


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 66 of 104 
PROTOCOL VERSION: FINAL v 7.0 
DATE:  21FEB2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
10.10 INFECTION PROPHYLAXIS 
Supportive care, including prophylactic antibiotics, antifungal and/or antiviral agents, are 
frequently used in neutropenic patients, and may be used per standard institutional practice and as 
deemed necessary by the investigator. 
10.11 GROWTH FACTOR SUPPORT 
The use of myeloid growth factors (granulocyte-colony stimulating factor [G-CSF] and 
granulocyte-macrophage colony-stimulating factor [GM-CSF]) may be given to support subjects 
who have developed Grade 4 neutropenia or Grade 3 neutropenia with fever and/or infection, per 
institutional guidelines. 
10.12 MANAGEMENT OF NAUSEA, VOMITING, AND DIARRHEA 
Recommended management of nausea and vomiting is to administer antiemetics. The 
recommended treatment for managing diarrhea is loperamide antidiarrheal therapy, 4 mg at first 
onset, followed by 2 mg with each loose movement until diarrhea-free for 12 hours (maximum 
dosage: 16 mg/24 hours). Adjunct anti-diarrheal therapy is permitted. 
 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 67 of 104 
PROTOCOL VERSION: FINAL v 7.0 
DATE:  21FEB2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
11 STATISTICAL CONSIDERATIONS 
A separate, detailed statistical analysis plan (SAP) will be finalized prior to locking the database. 
All analyses of safety and anti-leukemic activity for this open-label early Phase study will be 
descriptive in nature and presented by dose group and overall, as appropriate, for the dose-
adjustment phase and the expansion phase. Procedures for accounting for missing, unused and 
spurious data will be described in the SAP.   
Summaries for quantitative variables will include the mean, median, quartiles, standard deviation 
and error, minimum, and maximum. For qualitative variables, the summaries will include the 
number and percentage of subjects for each outcome, and the exact 95% CI, when appropriate. No 
hypothesis testing will be performed. Any statistical testing will be considered exploratory and 
descriptive. All computations will be performed using SAS® (Version 9.3 or higher). 
Subject disposition, subject demographics and baseline characteristics will be summarized. 
Subject data listings will also be provided. The following sections will briefly summarize of the 
planned statistical analyses and analysis sets for the primary and secondary endpoints. 
11.1 STUDY POPULATIONS FOR ANALYSIS 
The analysis sets are defined in Table 11-1. 
Table 11-1. Analysis Sets 
Analysis Set 
Description 
Enrolled Analysis Set 
All subjects who have been enrolled in the study. 
Safety Analysis Set 
All subjects who were administered brequinar. 
Efficacy Analysis Set 
All subjects with AML/other hematologic malignancy disease at baseline 
and who were administered brequinar. 
Pharmacokinetic Analysis Set 
All subjects who take at least 1 dose of brequinar and have at least 1 
quantifiable plasma concentration collected post-dose without important 
protocol deviations/violations or events thought to significantly affect the 
PK. 
The Efficacy Analysis Set will be used for efficacy analyses. The Safety Analysis Set will be used 
for safety analyses.   
11.2 SAFETY ANALYSES 
All safety analyses will be performed on the Safety Analysis Set.  Safety and tolerability will be 
assessed in terms of AEs, SAEs, safety laboratory data, physical examinations, vital signs, 12-lead 
ECGs and bone marrow sampling.  
Adverse event data will be descriptively evaluated. All AEs will be listed. The incidence and 
duration of TEAEs, defined as AEs occurring after the first dose of study treatment through 30 


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PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 72 of 104 
PROTOCOL VERSION: FINAL v 7.0 
DATE:  21FEB2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
11.8 INTERIM ANALYSIS 
No interim analysis is planned for this trial. 


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PROTOCOL NUMBER:  CCB-01  
 
 
 
 
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PROTOCOL VERSION: FINAL v 7.0 
DATE:  21FEB2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
correspondence. The original signed informed consent forms and the final report will be kept in 
the Investigator Site File. 
The Investigator will archive all essential documents. The medical files of trial subjects shall be 
retained in accordance with national legislation and in accordance with the maximum period of 
time permitted by the hospital, institution or private practice. The Investigator has a responsibility 
to retain essential documents for as long as is required by the Sponsor and applicable regulatory 
authorities.  It is the responsibility of the Sponsor to inform the Investigator as to when these 
documents no longer need to be retained. Investigators will be asked to contact the Sponsor prior 
to the destruction of any data or removal to another site if this occurs prior to the Sponsor 
notification that the documentation is no longer required. Any transfer of ownership of the data or 
of documents will be documented in writing.  The new owner will assume responsibility for data 
retention and archiving. 
Should the Investigator retire, relocate, or for other reasons withdraw from the responsibility of 
keeping the trial essential documents, custody must be transferred to a person who will accept that 
responsibility, and the Sponsor must be notified in writing of the name and address of said person. 
12.6 NON-PROTOCOL RESEARCH 
No investigational procedures other than those outlined in this protocol may be undertaken on the 
subjects in this trial without the prior written permission of the subject, the Sponsor, the IRB and, 
when appropriate, the regulatory authority. 
12.7 PUBLICATION 
The Sponsor acknowledges the benefit of making widely available the results of all clinical trials 
and intends to publish the results of this trial. All publications resulting from the clinical trial must 
be in a form that does not reveal technical information that the Sponsor considers confidential or 
proprietary.  A copy of any abstract, presentation or manuscript proposed for publication must be 
submitted to the Sponsor for review at least 30 days before its submission for any meeting or 
journal. In addition, if deemed necessary by the Sponsor for protection of proprietary information 
prior to patent filing, the Investigator agrees to a further delay of 60 days before any presentation 
or publication is submitted. The Sponsor reserves the right to include the report of this trial in any 
regulatory documentation or submission or in any informational materials prepared for the medical 
profession. 
Authorship determination will be at the discretion of the Sponsor and will include evaluation of 
the following criteria: Investigator must participate in the review of and content of the protocol; 
review and comment on the study results; participate in the writing, reviewing and commenting of 
the manuscript; and approve the final manuscript for submission. 
 


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PROTOCOL VERSION: FINAL v 7.0 
DATE:  21FEB2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
13 SPONSOR RESPONSIBILITIES 
13.1 GENERAL 
The Sponsor agrees to adhere to the ICH Note for Guidance on Good Clinical Practice 
(CPMP/ICH/135/95, Jan.97) and US FDA Regulations. It is the Sponsor's responsibility to obtain 
appropriate regulatory approval to perform the trial (if applicable). The Sponsor should notify 
promptly all concerned investigator(s), IRB(s) and the Regulatory Authority of findings that could 
adversely affect the health of the patients/ subjects, impact on the conduct of the trial or alter the 
Regulatory Authority’s authorization to continue the trial. If it is necessary to change or deviate 
from the protocol to eliminate an immediate hazard to the subjects the Sponsor will notify the 
relevant regulatory authority and relevant IRB of the new events, the measures taken and the plan 
for further action as soon as possible.  This will be by telephone in the first instance followed by a 
written report.   
On completion of the trial, the Sponsor will inform the regulatory authority that the trial has ended.  
If the study is terminated for any reason the Sponsor will provide a written statement to the relevant 
regulatory authority and the IRB with the reasons for termination of the trial. This will be 
conducted within 15 days of the decision to terminate the trial.  The Sponsor will report in an 
expeditious manner all suspected unexpected serious adverse reactions (SUSARs) to the relevant 
regulatory authority and IRBs.   
13.2  INDEMNITY 
The Sponsor will provide compensation insurance against any risk incurred by a subject as a result 
of participation in this trial. The Sponsor will indemnify the Investigators as detailed in a separate 
document. 
13.3  DATA MONITORING 
Suitably qualified and trained clinical research personnel of the Sponsor will visit the trial site at 
regular intervals during the trial for monitoring purposes and to assist the research staff with any 
queries. CRFs and source documentation will be available for review during monitoring visits to 
the trial site. The function of this monitoring is to ensure compliance with the protocol, adherence 
to regulatory and Good Clinical Practice obligations, proper maintenance of records including IMP 
accountability records, correct administration of IMP including storage conditions and accurate 
reporting of AEs.   
Once the data from the case report forms have been entered onto the database, they will be 
reviewed and the data verified against the subject’s source data. Any discrepancies will be tracked 
by paper or electronically with an electronic audit trail. 


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13.4  AUDIT 
The Sponsor has an obligation to audit a proportion of studies.  A department other than the clinical 
department will undertake this obligation. Therefore, the Sponsor, an independent auditor or a 
regulatory authority may audit the trial site and trial documentation. These audits may take place 
while the trial is being conducted or up to several years later.   
13.5  CONFIDENTIALITY 
The Sponsor will not keep any material on file bearing any subject’s name, and subjects’ 
confidentiality will be maintained at all times. 
13.6  FINANCE 
This will be the subject of a separate agreement between the Investigator/Institution and Sponsor. 


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14 REFERENCES 
1. Surveillance, Epidemiology, and End Results (SEER) Program, 1973-2015.
www.seer.cancer.gov.
2. Ng SB, Buckingham KJ, Lee C, et al. Exome sequencing identifies the cause of a 
mendelian disorder. Nature 2010; 42: 30-35.
3. Huang M, Wang Y, Collins M, et al. A77 1726 induces differentiation of human myeloid 
leukemia K562 cells by depletion of intracellular CTP pools. Mol Pharmacol 2002; 
62(3):463-472.
4. Sykes DB, Kfoury YS, Mercier FE, et al. Inhibition of dihydroorotate dehydrogenase 
overcomes differentiation blockade in acute myeloid leukemia. Cell 2016; 167(1): 
171-186.
5. Arteaga CL, Brown TD, Kuhn JG, et al. Phase I clinical and pharmacokinetic trial of 
Brequinar sodium (DuP 785: NSC 368390). Cancer Res 1989; 49(16): 4648-4653.
6. Burris HA 3rd, Raymond E, Awada A, et al. Pharmaocokinetic and phase I studies of 
brequinar (DUP 785; NSC 368390) in combination with cisplatin in patients with advanced 
malignancies. Invest New Drugs 1998; 16(1): 19-27.
7. Noe DA, Rowinsky EK, Shen HS, et al. Phase I and pharmacokinetic study of brequinar 
sodium (NSC 368390). Cancer Res 1990; 50(15): 4595 – 4599.
8. Schwartsmann G, Dodion P, Vermorken JB, et al. Phase I study of Brequinar sodium (NSC 
368390) in patients with solid malignancies. Cancer Chemother Pharmacol. 1990; 25(5):
345-351.
9. Brequinar Investigator’s Brochure
10. Döhner H, Estey E, Grimwade D, Amadori S, Applebaum FR, Büchner T, et al. Diagnosis 
and management of AML in adults: 2017 ELN recommendations from an expert 
international expert panel. Blood 2017; 129(4): 424-447.
11. Cairo MS, Coiffier B, Reiter A, et al. Recommendations for the evaluation of risk and 
prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant 
diseases: an expert TLS panel consensus. Br J Haematol 2010; 149:578.
12. Coiffer B, Altman A, Pui CH, et al. Guidelines for the management of pediatric and adult 
tumor lysis syndrome: an evidence-based review. J Clin Oncol 2008; 26:2767.
13. Howard SC, Jones, DF, Pui, C-H. The Tumor Lysis Syndrome. N Engl J Med 2011; 
364:1844-1854.
14. Kantarjian HM, Stein AS, Bargou RC, Grande Garcia C, Larson RA, Stelljes M, et al. 
Blinatumomab treatment of older adults with relapsed/refractory B-precursor acute 
lymphoblastic leukemia: Results from 2 phase 2 studies. Cancer 2016; 122(4): 2178-2185.
15. Cohen A, Barankiewicz J, Lederman HM, Gelfand EW. Purine and pyrimidine metabolism 
in human T lymphocytes. Regulation of deoxyribonucleotide metabolism. J Biol Chem. 
1983 Oct 25;258(20):12334–40.
16. Quéméneur L, Gerland L-M, Flacher M, French M, Revillard J-P, Genestier L. Differential 
control of cell cycle, proliferation, and survival of primary T lymphocytes by purine and 
pyrimidine nucleotides. J Immunol. 2003 May 15;170(10):4986-95.


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PROTOCOL VERSION: FINAL v 7.0 
DATE:  21FEB2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
15 APPENDICES 
15.1 APPENDIX A:  CCB-01 SCHEDULE OF EVENTS 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 80 of 104 
PROTOCOL VERSION: FINAL v 7.0 
DATE:  21FEB2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
CCB-01 Schedule of Events 
 
 
 
 
 
Proceduresa 
Screenb 
Cycle 1  
Week 1 or 2 
Maintenance 
Dose Cycle  
Final 
Visit  
F/U  
Phone 
Call 
Survival 
D1 
D2 -D4 
D1 & D8 
 
Final Visit  
+ 2 wks  
 
Informed Consentb 
X 
 
 
 
 
 
 
AE/Concomitant Medications  
X 
X 
X 
X 
X 
X 
 
Medical historyc  
X 
 
 
 
 
 
 
Demographicsd 
X 
 
 
 
 
 
 
Physical Examd 
X 
X 
 
 
X 
 
 
Vital Signsd 
X 
X 
 
X  
X 
 
 
Pregnancy Test (urine or serum) 
X 
 
 
X q 4 weeks 
X 
 
 
ECOG Performance Status 
X 
 
 
 
 
 
 
Hematology/Chemistrye 
X 
X 
 
X (D1 only) 
X 
 
 
Chromosomal/mutational testingf 
X 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
X q 4 weeks 
X 
 
 
Bone Marrow Samplingg, h 
X 
 
 
X q 12 weeks 
X 
 
 
Biobanking samplesg 
X 
 
 
X 
X 
 
 
Brequinar/DHO/Flow Cytometry Sampleh 
 
X 
X 
X 
X 
 
 
Ship DHO Plasma Samplesi 
 
 
X (D4) 
X 
X 
 
 
Dispense/Collect Study Medication  
 
X 
 
X 
X 
 
 
Dispense/Collect Subject Calendar/Diary 
 
X 
 
X 
X 
 
 
Survival Assessment 
 
 
 
 
 
 
X 
 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 81 of 104 
PROTOCOL VERSION: FINAL v 7.0 
DATE:  21FEB2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
a. Visit window of ± 1 day for Cycle 1 visits; window of ± 3 days for Maintenance Dose cycles. 
b. Obtain informed consent prior to performing any screening or study-specific procedures. Screening procedures must be performed 
within 14 days prior to initial study drug administration.  Procedures at C1D1 that are repeats of Screening may be omitted if <1 week 
since Screening assessment. ECG and pregnancy test frequency are every 4 weeks or per institutional guidelines. 
c. Medical history is to include AML/other hematologic malignancy diagnosis, previous AML/other hematologic malignancy 
treatment, and standard chromosomal and mutational results per institutional guidelines. 
d. Demographic information is to include date of birth, height, weight, race, and ethnic origin. Rectal examination may be deferred for 
Physical Examination. Vital signs include heart rate, respiratory rate, seated blood pressure, respiratory rate, oral/aural body 
temperature. Complete physical examination and vital signs once every 4 weeks or more often if needed to assess an AE. 
e. If additional complete blood count (CBC) with differential results are available (for example, daily reports when a subject is 
hospitalized), these results may be captured in the eCRF using an Unscheduled visit. 
f. Testing panel is per institutional standard of care; obtain sample at Screening. 
g. Bone marrow sampling local testing will include analysis of the aspirate on smear, core biopsy by microscopy, flow cytometry, and 
karyotype for cytogenetics. Local molecular analysis will be performed on the screening bone marrow samples only.  Bone marrow 
samples will be sent for biobanking for possible further analysis from Screening, Week 7 (Day 43), and Final Visit. Perform bone 
marrow sampling at screening, at Visit 4 (Day 22), Visit 7 (Day 43), then once every 12 weeks. Timing of this procedure may be 
adjusted to ensure results are available for the next clinic visit. Procedure window is ±7 days.  
h. Cycle 1 Day 1 sample window ±15 minutes through 6h draw; window for additional C1 draws ±2h; window for Dose Adjustment 
Week plasma brequinar/DHO draws ±2h; window for Maintenance Cycle samples is ±4h. Ensure 84h DHO trough samples (~84 
hours after most recent dose) are obtained prior to dosing.   
i. 
Process, store and ship these samples per the Laboratory Manual. 
j. 
Cycle 1 Week 1 procedures are to be repeated for Week 2 if starting dose was decreased to 200 mg/m2 or dose held until a twice-
weekly dose has been determined with the exception that PK/DHO/Flow samples will be obtained only once per day in Week 2. 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 82 of 104 
PROTOCOL VERSION: FINAL v 7.0 
DATE:  21FEB2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
15.2 APPENDIX B: ECOG PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal level.  Fully active, able to 
carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal level; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
level, but ambulatory and able to 
carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal level with effort; some signs 
or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal level or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance but is 
able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 83 of 104 
PROTOCOL VERSION: FINAL v 7.0 
DATE:  21FEB2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
15.3 APPENDIX C: BREQUINAR/DHO/FLOW CYTOMETRY SAMPLING 
Information is provided in a separate laboratory manual regarding collection, processing, storing, 
and shipment of samples.  
Cycle 1 Day 1 sample window ±15 minutes through 6h draw; window for additional C1 draws 
±2h; window for Dose Adjustment Week plasma brequinar/DHO draws ±2h; window for 
Maintenance Cycle samples is ±4h. Ensure 84h DHO trough samples (~84 hours after most recent 
dose) are obtained prior to dosing.   
Brequinar and DHO plasma samples and peripheral blood for flow cytometry are to be obtained 
at the following time points:  
 
Cycle 1 Week 1 (or 2) 
 
D1 
D2 
D 3 
D 4 
Time 
Point 
Pre-
dose 
1h* 
2h* 
4h* 
6h* 
24h 
48h 
72h 
*These time points to be obtained in Week 1 only. 
 
 
 
Maintenance Cycle 
(Day 8 through Week 12 only) 
 
D1 
D8 
Time 
Point 
Pre-dose ~84h after previous dose 
Pre-dose ~84h after previous dose 
 
 


PROTOCOL NUMBER:  CCB-01  
Page 84 of 104 
PROTOCOL VERSION: FINAL v 7.0 
DATE:  21FEB2020 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
15.4 APPENDIX D: COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS 
(CTCAE) 
https://evs.nci.nih.gov/ftp1/CTCAE/About.html 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 85 of 104 
PROTOCOL VERSION: FINAL v 7.0 
DATE:  21FEB2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
15.5  APPENDIX E: 
SAMPLE SUBJECT CONSENT FORM   
TITLE:  
A Phase 1b/IIa open-label, multi-center study to assess the safety, efficacy and 
pharmacokinetics of intrapatient dose-adjusted brequinar and inhibition of 
dihydroorotate dehydrogenase (DHODH) in adult subjects with acute myelogenous 
leukemia (AML) 
 
PROTOCOL NO.: 
CCB-01  
SPONSOR: 
 
Clear Creek Bio, Inc.  
 
 
585 Massachusetts Avenue, 4th Floor, 
 
 
Cambridge MA 02139 
 
INVESTIGATOR: 
 
<insert PI name> 
Site(s): 
 
<insert name> 
 
 
<insert address> 
STUDY-RELATED 
PHONE NUMBER(S): <insert name(s)> 
 
<insert number> 
 
<insert alternate number (24-hour contact number)> 
VERSION and DATE:  <e.g. CCB-01 Master ICF Version 4.0 21 February 2020> 
You are being asked to take part in a research study. Before you decide to participate, it is important 
for you to understand why the research is being done and what it will involve. Please take time to 
read the following information carefully and discuss it with others, if you wish, before deciding 
whether or not to take part. Ask us if there is anything that is not clear or if you would like more 
information. 
WHAT IS THE PURPOSE OF THE STUDY? 
The purpose of the study is to evaluate the safety, efficacy, pharmacokinetics (PK) (level of study 
medication in the blood) and the inhibition (decrease in level) of an enzyme called “dihydroorotate 
dehydrogenase” (DHODH). DHODH blocks the ability of blood cells formed in the bone marrow 
to differentiate (grow into mature white blood cells that can fight infection and platelets that help 
blood to clot). Brequinar is a drug that has been shown in animals in the laboratory to be able to 
decrease the level of DHODH and decrease leukemic cells in the bone marrow. Reducing DHODH 
level in patients with AML/other hematologic malignancy may help treat this type of leukemia by 
allowing cells in the bone marrow to grow into different types of mature cells.  


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PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 91 of 104 
PROTOCOL VERSION: FINAL v 7.0 
DATE:  21FEB2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
Risks from Study Procedures: 
Blood draws may cause pain, bleeding, and/or bruising. You may faint and/or develop an infection 
with redness and irritation of the vein at the site where blood is drawn. Frequent blood collection 
may cause anemia (low red blood cell count), which may create a need for blood transfusions. 
Having bone marrow sampling (biopsies and aspirations) performed may cause pain, bruising, 
bleeding, redness, low blood pressure, swelling, and/or infection at the site of the biopsies. An 
allergic reaction to the anesthetic may occur. A scar may form at the biopsy site. 
Bone marrow sampling will include analysis of the aspirate on smear, core biopsy by microscopy, 
flow cytometry, and karyotype for cytogenetics. You can talk with the study team about this 
testing. The type of genetic testing being performed for this study will not provide you or your 
doctor information about diseases that are passed down in families. It will not tell the study 
researchers anything that will prevent you from getting health insurance, and it will not tell the 
study researchers anything about any diseases or conditions you may get in the future. 
There may be risks or side effects that are unknown at this time. 
If a condition of which you were unaware is discovered during the study, a full report will be sent 
to your doctor if you request this.  You will be advised of the appropriate action to take for 
treatment. 
Pregnancy-Related Risks 
Taking part in this study can result in risks to an unborn or breastfeeding baby, so you should not 
become pregnant, breastfeed a baby, or father a child while participating in this study. If you are 
able to become pregnant or father a child, you must use birth control during the study and for at 
least 3 months after your last dose of study drug if you are sexually active. 
Birth control specifications: Female participants who are able to become pregnant must use 2 
methods of birth control while on this study. Male participants must use an effective barrier method 
(such as a condom) while on this study. 
Talk with the study team about acceptable methods of birth control to use while taking part in this 
study. 
Males: Tell the study team right away if your partner becomes pregnant or suspects pregnancy. 
Females: If you are pregnant, you will not be enrolled into this study. If you become pregnant or 
suspect that you are pregnant during the study, you must tell your doctor right away. 
Getting pregnant may result in your removal from this study.  


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 92 of 104 
PROTOCOL VERSION: FINAL v 7.0 
DATE:  21FEB2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
WHAT ARE THE POSSIBLE BENEFITS? 
The study drug may help to control the disease. Future patients may benefit from what is learned. 
There may be no benefits for you in this study.  
WILL IT COST ANYTHING TO BE IN THE STUDY? 
If you participate in this study, you will not have to pay for the cost of the study drug used in the 
study. 
You or your insurer will be responsible for the cost of your usual ongoing medical care, including 
procedures and non-study medications that the doctor or your regular doctor requires during this 
study as part of your usual medical care. If you have any questions, please ask the doctor and/or a 
member of the study staff about the costs that will or will not be covered by the sponsor. 
IS THERE PAYMENT FOR PARTICIPATION? 
You will not receive any payment for participation in this study. 
WHAT ARE THE ALTERNATIVES FOR TREATMENT? 
You do not have to participate in this research study to receive treatment. Instead, you may be 
eligible for recently approved therapies, and may be able to have a bone marrow transplant outside 
of this study. You may choose to receive other investigational therapies, if available. You may 
also choose not to have treatment for cancer at all. Regardless of your choices, you will receive 
appropriate medical care, including treatment for pain and other symptoms of cancer. Please note 
that you will be informed in a timely manner if new information becomes available that is relevant 
during your participation in this study. 
WHAT IF SOMETHING GOES WRONG? 
An important part of this study is to see if the investigational product causes side effects. You must 
inform the staff if you feel unwell or have any unusual symptoms at any time during the study, no 
matter how minor you think they are. If you experience such events, treatment will be made 
available by the doctor. 
You will be provided any reasonably necessary medical treatment for any injuries sustained as a 
result of participating in this study, except to the extent such costs are covered by your medical or 
hospital insurance or by governmental programs providing such coverage. You must follow the 
directions of the doctor to be eligible for this coverage. Neither the sponsor nor the doctor have 
plans to provide other compensation in the event of an injury. You are not giving up any of your 
legal rights by signing this consent form. 


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PROTOCOL NUMBER:  CCB-01  
 
 
 
 
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CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
<Insert email if applicable> 
The IRB will not be able to answer some study-specific questions however, you may contact the 
IRB if the research staff cannot be reached or if you wish to talk to someone other than the research 
staff.  
Do not sign this consent form unless you have had a chance to ask questions and have received 
satisfactory answers to all of your questions. 
You will be given a signed and dated copy of this consent form to keep. 
Thank you for taking the time to read this consent form. 
 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
Page 97 of 104 
PROTOCOL VERSION: FINAL v 7.0 
DATE:  21FEB2020 
 
 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
Consent Form Signature Page 
SUBJECT’S DATE OF BIRTH:  ______/______/______ 
  
mmm /    dd    /  yyyy 
Print Name of Investigator: 
 
 
Please initial 
box: 
1. I confirm that I have read this consent form for the above study and have 
had the opportunity to ask questions. 
 
2. I understand my participation is voluntary and I am free to withdraw at any 
time, without giving any reason, without my medical care or legal rights 
being affected. 
 
3. I understand that sections of any of my medical records may be looked at 
by responsible individuals from Clear Creek Bio, Inc. and/or its 
representatives or from regulatory authorities and the IRB where it is 
relevant to my taking part in research. I give permission for these individuals 
to have access to my records. 
 
4. I understand that my data may be transmitted outside the country to 
countries with less strict data protection laws. 
 
5. I agree to take part in the above study. 
 
 
By signing this consent form, I have not given up any of my legal rights. 
 
 
 
 
Printed Name of Subject                       Signature of Subject 
Date   
Time 
 
 
                                                                      
Printed Name of person conducting      Sign  
Date  
 
Time 
informed consent discussion 
 
 
Original with Investigator File 
1 copy for subject 
1 copy for Subject’s Medical Records 


PROTOCOL NUMBER:  CCB-01  
 
 
 
 
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CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
15.6 APPENDIX F:  WMA DECLARATION OF HELSINKI 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by 
the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000  
53th WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 added) 
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added) 
59th WMA General Assembly, Seoul, October 2008 
A. INTRODUCTION  
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including 
research on identifiable human material and data.  
The Declaration is intended to be read as a whole and each of its constituent paragraphs should 
not be applied without consideration of all other relevant paragraphs. 
2. Although the Declaration is addressed primarily to physicians, the WMA encourages other 
participants in medical research involving human subjects to adopt these principles. 
3. It is the duty of the physician to promote and safeguard the health of patients, including those 
who are involved in medical research. The physician's knowledge and conscience are dedicated 
to the fulfillment of this duty. 
4. The Declaration of Geneva of the WMA binds the physician with the words, "The health of 
my patient will be my first consideration," and the International Code of Medical Ethics 
declares that, "A physician shall act in the patient's best interest when providing medical care." 
5. Medical progress is based on research that ultimately must include studies involving human 
subjects. Populations that are underrepresented in medical research should be provided 
appropriate access to participation in research. 
6. In medical research involving human subjects, the well-being of the individual research subject 
must take precedence over all other interests. 


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7. The primary purpose of medical research involving human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic 
interventions (methods, procedures and treatments). Even the best current interventions must 
be evaluated continually through research for their safety, effectiveness, efficiency, 
accessibility and quality. 
8. In medical practice and in medical research, most interventions involve risks and burdens. 
9. Medical research is subject to ethical standards that promote respect for all human subjects and 
protect their health and rights. Some research populations are particularly vulnerable and need 
special protection. These include those who cannot give or refuse consent for themselves and 
those who may be vulnerable to coercion or undue influence. 
10. Physicians should consider the ethical, legal and regulatory norms and standards for research 
involving human subjects in their own countries as well as applicable international norms and 
standards. No national or international ethical, legal or regulatory requirement should reduce 
or eliminate any of the protections for research subjects set forth in this Declaration. 
B. BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH  
11. It is the duty of physicians who participate in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal 
information of research subjects. 
12. Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant sources 
of information, and adequate laboratory and, as appropriate, animal experimentation. The 
welfare of animals used for research must be respected.  
13. Appropriate caution must be exercised in the conduct of medical research that may harm the 
environment. 
14. The design and performance of each research study involving human subjects must be clearly 
described in a research protocol. The protocol should contain a statement of the ethical 
considerations involved and should indicate how the principles in this Declaration have been 
addressed. The protocol should include information regarding funding, sponsors, institutional 
affiliations, other potential conflicts of interest, incentives for subjects and provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation in 
the research study. The protocol should describe arrangements for post-study access by study 
subjects to interventions identified as beneficial in the study or access to other appropriate 
care or benefits. 


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15. The research protocol must be submitted for consideration, comment, guidance and approval 
to a research ethics committee before the study begins. This committee must be independent 
of the researcher, the sponsor and any other undue influence. It must take into consideration 
the laws and regulations of the country or countries in which the research is to be performed 
as well as applicable international norms and standards but these must not be allowed to reduce 
or eliminate any of the protections for research subjects set forth in this Declaration. The 
committee must have the right to monitor ongoing studies. The researcher must provide 
monitoring information to the committee, especially information about any serious adverse 
events. No change to the protocol may be made without consideration and approval by the 
committee. 
16. Medical research involving human subjects must be conducted only by individuals with the 
appropriate scientific training and qualifications. Research on patients or healthy volunteers 
requires the supervision of a competent and appropriately qualified physician or other health 
care professional. The responsibility for the protection of research subjects must always rest 
with the physician or other health care professional and never the research subjects, even 
though they have given consent. 
17. Medical research involving a disadvantaged or vulnerable population or community is only 
justified if the research is responsive to the health needs and priorities of this population or 
community and if there is a reasonable likelihood that this population or community stands to 
benefit from the results of the research. 
18. Every medical research study involving human subjects must be preceded by careful 
assessment of predictable risks and burdens to the individuals and communities involved in 
the research in comparison with foreseeable benefits to them and to other individuals or 
communities affected by the condition under investigation. 
19. Every clinical trial must be registered in a publicly accessible database before recruitment of 
the first subject. 
20. Physicians may not participate in a research study involving human subjects unless they are 
confident that the risks involved have been adequately assessed and can be satisfactorily 
managed. Physicians must immediately stop a study when the risks are found to outweigh the 
potential benefits or when there is conclusive proof of positive and beneficial results. 
21. Medical research involving human subjects may only be conducted if the importance of the 
objective outweighs the inherent risks and burdens to the research subjects. 
22. Participation by competent individuals as subjects in medical research must be voluntary. 
Although it may be appropriate to consult family members or community leaders, no 
competent individual may be enrolled in a research study unless he or she freely agrees. 


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CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
23. Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information and to minimize the impact of the study on their 
physical, mental and social integrity. 
24. In medical research involving competent human subjects, each potential subject must be 
adequately informed of the aims, methods, sources of funding, any possible conflicts of 
interest, institutional affiliations of the researcher, the anticipated benefits and potential risks 
of the study and the discomfort it may entail, and any other relevant aspects of the study. The 
potential subject must be informed of the right to refuse to participate in the study or to 
withdraw consent to participate at any time without reprisal. Special attention should be given 
to the specific information needs of individual potential subjects as well as to the methods 
used to deliver the information. After ensuring that the potential subject has understood the 
information, the physician or another appropriately qualified individual must then seek the 
potential subject's freely-given informed consent, preferably in writing. If the consent cannot 
be expressed in writing, the non-written consent must be formally documented and witnessed. 
25. For medical research using identifiable human material or data, physicians must normally seek 
consent for the collection, analysis, storage and/or reuse. There may be situations where 
consent would be impossible or impractical to obtain for such research or would pose a threat 
to the validity of the research. In such situations the research may be done only after 
consideration and approval of a research ethics committee. 
26. When seeking informed consent for participation in a research study the physician should be 
particularly cautious if the potential subject is in a dependent relationship with the physician 
or may consent under duress. In such situations the informed consent should be sought by an 
appropriately qualified individual who is completely independent of this relationship. 
27. For a potential research subject who is incompetent, the physician must seek informed consent 
from the legally authorized representative. These individuals must not be included in a 
research study that has no likelihood of benefit for them unless it is intended to promote the 
health of the population represented by the potential subject, the research cannot instead be 
performed with competent persons, and the research entails only minimal risk and minimal 
burden. 
28. When a potential research subject who is deemed incompetent is able to give assent to 
decisions about participation in research, the physician must seek that assent in addition to the 
consent of the legally authorized representative. The potential subject's dissent should be 
respected. 
29. Research involving subjects who are physically or mentally incapable of giving consent, for 
example, unconscious patients, may be done only if the physical or mental condition that 
prevents giving informed consent is a necessary characteristic of the research population. In 
such circumstances the physician should seek informed consent from the legally authorized 


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PROTOCOL NUMBER:  CCB-01  
 
 
 
 
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CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
35. In the treatment of a patient, where proven interventions do not exist or have been ineffective, 
the physician, after seeking expert advice, with informed consent from the patient or a legally 
authorized representative, may use an unproven intervention if in the physician's judgment it 
offers hope of saving life, re-establishing health or alleviating suffering. Where possible, this 
intervention should be made the object of research, designed to evaluate its safety and efficacy. 
In all cases, new information should be recorded and, where appropriate, made publicly 
available. 
22.10.2008 
 
 
 


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CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
15.7 APPENDIX G: INVESTIGATOR’S STATEMENT AND AGREEMENT 
STUDY NUMBER:   CCB-01 
STUDY TITLE:  A Phase 1b/2a open-label, multi-center study to assess the safety, efficacy and 
pharmacokinetics of intrapatient dose-adjusted brequinar and inhibition of dihydroorotate 
dehydrogenase (DHODH) in adult subjects with acute myelogenous leukemia (AML) 
INVESTIGATOR’S STATEMENT AND AGREEMENT 
I (the Investigator) have read this protocol and hereby agree to conduct the trial in accord with all 
of its provisions.  It is further agreed that the details of this trial and all information provided to 
me by Clear Creek Bio, Inc. (the Sponsor) will be held in the strictest confidence and will not be 
revealed for any reason without written authorization from Clear Creek Bio, Inc. except to those 
who are to participate in the conduct of the trial. 
I agree that all data, the case report forms and all materials provided for the conduct of the trial are 
the property of Clear Creek Bio, Inc. unless specified otherwise in writing. It is understood that 
Clear Creek Bio, Inc. will utilize the information derived from this trial in various ways, such as 
for submission to government regulatory agencies, required internal reports, and presentations 
without violating patient/ subject confidentiality in any way. 
I further agree that Clear Creek Bio, Inc. or its representatives will be permitted access, in 
accordance with current Good Clinical Practice Guidelines, to all data generated by this trial and 
the source documents from which case report form data were generated. 
PRINCIPAL INVESTIGATOR 
Printed Name: 
 
Signature:                                                                                           Date: 
 
Site Address:        
 
                                                         
 
                             


PROTOCOL NUMBER:  CCB-01  
Page 1 of 112 
PROTOCOL VERSION: FINAL v 8.0 
DATE: 09MAR2020 
CONFIDENTIAL:  Clear Creek Bio, Inc. 
STUDY PROTOCOL 
A Phase 1b/2a open-label, multi-center study to assess the safety, 
efficacy and pharmacokinetics of intrapatient dose-adjusted 
brequinar and inhibition of dihydroorotate dehydrogenase 
(DHODH) in adult subjects with acute myelogenous leukemia 
(AML)
Study No: CCB-01 
Version Date:  09 March 2020 
Sponsor: 
Clear Creek Bio, Inc. 
585 Massachusetts Avenue, 4th Floor, 
Cambridge MA 02139 
Sponsor Telephone: (617) 765-2252 
Sponsor Facsimile: (617) 863-2082 
IND Number: 138335 
This confidential document is the property of Clear Creek Bio, Inc.  No unpublished information contained herein 
may be disclosed without the prior written approval of Clear Creek Bio, Inc. This trial will be conducted in 
accordance with the ICH Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95, Jan.97), the Declaration 
of Helsinki (1964, 1975, 1983, 1989, 1996, 2000 (Note for Clarification 2002 & 2004) and 2008), FDA Regulations 
and locally applicable regulations. 


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TABLE OF CONTENTS 
2 SYNOPSIS .......................................................................................................................... 11 
3 INTRODUCTION .............................................................................................................. 27 
3.1 Background ................................................................................................................ 27 
Acute Myeloid Leukemia .................................................................................................. 27 
3.2 Dihydroorotate dehydrogenase (DHODH) ................................................................ 27 
3.3 Brequinar .................................................................................................................... 28 
3.4 Ribavirin ..................................................................................................................... 29 
3.5 Rationale for the Planned Trial .................................................................................. 31 
3.5.1 Brequinar Starting Dose Selection ............................................................................... 31 
3.5.2 Ribavirin Dosing .......................................................................................................... 32 
3.6 Risk/Benefit of Brequinar .......................................................................................... 32 
3.7 Risk/Benefit of Ribavirin ........................................................................................... 33 
3.8 Risks Associated with Participation in the Clinical Study ......................................... 33 
3.9 Possible Interactions with Concomitant Medical Treatments .................................... 33 
3.9.1 CYP Interactions .......................................................................................................... 34 
3.10 Steps to be Taken to Control or Mitigate Risks ......................................................... 34 
4 TRIAL OBJECTIVES ........................................................................................................ 35 
4.1 Primary Objective ...................................................................................................... 35 
4.2 Secondary Objectives ................................................................................................. 35 
4.3 Exploratory Objectives ............................................................................................... 35 
5 TRIAL DESIGN ................................................................................................................. 36 
6 TRIAL ENDPOINTS.......................................................................................................... 38 
6.1 Primary Endpoint ....................................................................................................... 38 
6.2 Secondary Endpoints .................................................................................................. 38 
6.3 Exploratory Endpoints................................................................................................ 38 
7 TRIAL POPULATION ....................................................................................................... 39 


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7.1 Number of Subjects .................................................................................................... 39 
7.2 Inclusion criteria ......................................................................................................... 39 
7.3 Exclusion Criteria ....................................................................................................... 40 
7.4 Inclusion of Women and Minorities........................................................................... 41 
8 STUDY TREATMENTS .................................................................................................... 42 
8.1 Description of Study Medications .............................................................................. 43 
8.1.1 Brequinar ...................................................................................................................... 43 
8.1.2 Ribavirin ....................................................................................................................... 43 
8.2 Treatment Administration .......................................................................................... 43 
8.3 Safety/Tolerability ...................................................................................................... 44 
8.3.1 Safety/Tolerability – Subject Level .............................................................................. 45 
8.3.2 Hematologic Toxicity ................................................................................................... 46 
8.4 Cohort Starting Doses ................................................................................................ 47 
8.5 Individual Dose Adjustment Guidelines .................................................................... 47 
8.5.1 Brequinar Exposure (BRQ PK) and 72h DHO Criteria to Set Twice-Weekly Dosing 48 
8.5.2 Ribavarin in Combination with Brequinar ................................................................... 49 
8.5.3 Ribavirin Dose Adjustment .......................................................................................... 49 
8.5.4 Dose Adjustment Using 84h DHO ............................................................................... 50 
8.6 Medication/AE Diary ................................................................................................. 52 
8.7 Bone Marrow Biopsy ................................................................................................. 52 
8.8 Expansion Cohort ....................................................................................................... 52 
8.9 Study Drug Discontinuation ....................................................................................... 52 
8.10 Brequinar Pharmacokinetics (PK)/Dihydroorotate (DHO) Plasma Levels/Flow 
Cytometry .......................................................................................................................... 53 
8.11 Concomitant Medication/Treatment .......................................................................... 53 
8.11.1 
Gastric pH ............................................................................................................... 54 
8.12 Treatment Compliance ............................................................................................... 54 


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8.13 Storage, Stability, Labeling and Packaging ............................................................... 54 
8.13.1 
Storage and Stability ............................................................................................... 54 
8.13.2 
Labeling and Packaging .......................................................................................... 54 
8.13.3 
Blinding and Randomization .................................................................................. 54 
8.13.4 
Unblinding/Expectedness ....................................................................................... 55 
8.13.5 
Study Drug Accountability ..................................................................................... 55 
8.13.6 
Prohibited Medications ........................................................................................... 55 
9 CONDUCT OF THE TRIAL.............................................................................................. 56 
9.1 Ethical and Regulatory Considerations ...................................................................... 56 
9.2 Informed Consent ....................................................................................................... 56 
9.3 Institutional Review Board / Ethics Committees ....................................................... 57 
9.4 Schedule of Events ..................................................................................................... 57 
9.5 Study Conduct ............................................................................................................ 58 
9.5.1 Screening Visit (Study Days -14 to -1) ........................................................................ 58 
9.5.2 Treatment...................................................................................................................... 59 
9.5.3 Dose Adjustment: Cycle 1 Week 1 (or Week 2 if dose reduced) ................................. 59 
9.5.4 Maintenance Dose Cycle .............................................................................................. 60 
9.5.5 Final Visit ..................................................................................................................... 61 
9.5.6 Telephone Follow Up Visit (2 weeks after Final Visit) ............................................... 61 
9.5.7 Unscheduled Visits ....................................................................................................... 61 
9.6 Compliance with Study Procedures ........................................................................... 61 
9.7 Early Withdrawal from the Study .............................................................................. 61 
9.8 Early Termination of the Study .................................................................................. 62 
10 ADVERSE EVENT REPORTING..................................................................................... 63 
10.1 Classification of Causality ......................................................................................... 64 
10.2 Classification of Severity ........................................................................................... 65 
10.3 Serious Adverse Event (SAE) Reporting ................................................................... 65 


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10.4 Suspected Unexpected Serious Adverse Reactions (SUSARs) ................................. 67 
10.5 Pregnancies................................................................................................................. 67 
10.6 Hematologic Adverse Events ..................................................................................... 68 
10.7 Management of Myelosuppression ............................................................................ 69 
10.8 Differentiation Syndrome ........................................................................................... 69 
10.9 Tumor Lysis Syndrome (TLS) ................................................................................... 70 
10.10 Infection Prophylaxis ............................................................................................... 72 
10.11 Growth Factor Support ............................................................................................. 72 
10.12 Management of Nausea, Vomiting, and Diarrhea .................................................... 72 
11 STATISTICAL CONSIDERATIONS................................................................................ 73 
11.1 Study Populations for Analysis .................................................................................. 73 
11.2 Safety Analyses .......................................................................................................... 73 
11.3 Efficacy Analyses ....................................................................................................... 74 
11.4 Other Endpoints.......................................................................................................... 77 
11.5 Sample Size Considerations ....................................................................................... 78 
11.6 Randomization ........................................................................................................... 78 
11.7 Pooling of Study Centers............................................................................................ 78 
11.8 Interim Analysis ......................................................................................................... 78 
12 INVESTIGATOR RESPONSIBILITIES ........................................................................... 79 
12.1 Investigator’s Performance ........................................................................................ 79 
12.2 Confidentiality ............................................................................................................ 79 
12.3 Source Documentation ............................................................................................... 79 
12.4 Data Collection ........................................................................................................... 80 
12.5 Case Report Forms, Investigator’s Site File and Record Retention ........................... 80 
12.6 Non-Protocol Research .............................................................................................. 81 
12.7 Publication .................................................................................................................. 81 
13 SPONSOR RESPONSIBILITIES ...................................................................................... 82 


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13.1 General ....................................................................................................................... 82 
13.2 Indemnity ................................................................................................................... 82 
13.3 Data Monitoring ......................................................................................................... 82 
13.4 Audit ........................................................................................................................... 83 
13.5 Confidentiality ............................................................................................................ 83 
13.6 Finance ....................................................................................................................... 83 
14 REFERENCES ................................................................................................................... 84 
15 APPENDICES .................................................................................................................... 86 
15.1 APPENDIX A:  CCB-01 Schedule of Events ............................................................ 86 
15.2 APPENDIX B: ECOG Performance Status Criteria .................................................. 89 
15.3 APPENDIX C: Brequinar/DHO/Flow Cytometry Sampling ..................................... 90 
15.4 APPENDIX D: Common Terminology Criteria for Adverse Events (CTCAE) ....... 91 
15.5 APPENDIX E:  Sample Subject Consent Form ......................................................... 92 
15.6 APPENDIX F:  WMA Declaration of Helsinki ....................................................... 105 
15.7 APPENDIX G: Investigator’s Statement and Agreement........................................ 111 
15.8 Appendix H: Ribavirin generic (ribavirin USP) capsules, for oral use Summary of 
Product Characteristics (SPC) ......................................................................................... 112 
 
 


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LIST OF TABLES 
 
Table 8-1. 
Exceptions to Grade 3 Nonhematologic AEs ......................................................... 46 
Table 8-2. 
Algorithm to Set Twice-Weekly Dose for Cohort 3/Expansion Subjects (Starting 
Dose 350 mg/m2) ..................................................................................................... 48 
Table 8-3. 
Algorithm to Adjust Twice-Weekly Dose using 84h DHO for Cohort 3 and 
Expansion Cohort ................................................................................................... 51 
Table 11-1. Analysis Sets........................................................................................................... 73 
Table 11-2. Efficacy Analyses ................................................................................................... 74 
 


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LIST OF FIGURES 
 
Figure 8-1. 
Algorithm to Set Twice-Weekly Dose ................................................................... 49 
Figure 8-2. Algorithm to Add and Adjust Ribavirin..................................................................... 50 
Figure 8-3. 
Algorithm to Adjust Dose Using 84h DHO ........................................................... 51 
Figure 10-1. 
Monitoring of Tumor Lysis Syndrome ............................................................... 71 
 


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ABBREVIATIONS 
Abbreviation 
Definition 
µg 
Microgram 
5-FU 
5-Fluorouracil  
AUC 
Area Under Curve 
BID 
Bis in die (two times a day) 
BLL 
Bi-lineal leukemia 
C6min 
Concentration at 6 minutes 
CHO/HGPRT 
Chinese hamster ovary cell/hypoxanthine-guanine phosphoribosyl-transferase 
CL 
Clearance 
ClR 
Low Renal Clearance 
ClT 
Low Plasma Total Clearance 
CRh 
Partial hematological response 
CRi 
Incomplete hematological response 
CT 
Computerized Tomography 
CYP 
Cytochrome P450 
DHO 
Dihydroorotate 
DHODH 
Dihydroorotate dehydrogenase 
DLT(s) 
Dose-Limiting Toxicity(ies) 
DNA 
Deoxyribonucleic Acid 
ECGs 
Electrocardiograms 
ECOG 
Eastern Cooperative Oncology Group 
ED50 
Median Effective Dose  
EORTC 
European Organisation for the Research and Treatment of Cancer 
ESR 
Erythrocyte Sedimentation Rate 
F 
Bioavailability  
FDA 
United States Food and Drug Administration 
g 
Grams 
GI 
Gastrointestinal 
G-R 
Good Risk Patients 
HPLC 
High-Performance Liquid Chromatography 
HIPAA 
Health Insurance Privacy and Portability Act 
Hr 
Hour 
IB 
Investigator Brochure 
IP 
Intraperitoneal 
IV 
Intravenous 
kg 
Kilograms 
l 
Liters 
LD(10, 50, 90) 
Lethal Dose(10%, 50%, 90%) 
LLN 
Lower limit of normal 
LPS 
Lipopolysaccharide 
M 
Molar 


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MPAL 
Mixed phenotypic acute leukemia 
Mg 
Milligram 
mL 
Milliliters 
MLED10 
Mouse Equivalent Lethal Dose for 10% of population 
mM 
Micromolar 
Mm 
Millimeters 
MRD 
Minimal Residual Disease 
MRT 
Long Median Residence Time 
MS 
Mucositis/stomatitis 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
NCI 
United States National Cancer Institute 
NMR 
Nuclear Magnetic Resonance Spectroscopy 
NSC 
National Service Center 
ORR 
Overall Response Rate 
PK 
Pharmacokinetic(s) 
PO 
Per Orem 
P-R 
Poor Risk Patients 
PR 
Partial Response 
PS 
Performance Status 
Pts. 
Patients 
QTcF 
Corrected QT interval by Fredericia 
RDP2 
Recommended Dose for Phase II 
RNA 
Ribonucleic Acid 
SC 
Subcutaneous  
SD 
Standard Deviation 
SE 
Standard Error 
SEM 
Standard error of the means 
SI 
Simulation Index 
SPC 
Summary of Product Characteristics 
t½  
Half-Life 
T-ALL 
T-cell lymphoblastic leukemia 
TEAE 
Treatment-emergent adverse event 
USP 
United States Pharmacopeia 
UV 
Ultraviolet 
V 
Volume 
Vd 
Volume of Distribution 
VdSS 
Steady-State Volume of Distribution 
WBC 
White Blood Cell 
WHO 
World Health Organization 
 
 


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2 
SYNOPSIS  
IND 
138,335 
Title 
A Phase 1b/2a open-label, multi-center study to assess the safety, efficacy 
and pharmacokinetics of intrapatient dose-adjusted brequinar and inhibition 
of dihydroorotate dehydrogenase (DHODH) in adult subjects with acute 
myelogenous leukemia (AML)  
Protocol 
CCB-01 
Investigational 
Medicinal 
Product and 
Dosage 
Brequinar is available as 100 and 250 mg oral capsules to be taken every 3.5 
days with approximately 240 mL of water. Each subject’s mg/m2 dose will 
be calculated based on body surface area at study entry; actual dose will be 
rounded down to the nearest mg based on available oral capsule doses. The 
brequinar dose will be adjusted based on PK and DHO levels. 
Ribavirin is available as 200 mg capsules to be taken BID. Ribavirin is to be 
taken with food. Ribavirin dosing will start at a fixed dose of 1000 mg BID 
after twice weekly brequinar dosing has started. The ribavirin dose will be 
adjusted per the guidelines below. 
Primary 
Objective 
● To determine the safety and tolerability of brequinar alone and in 
combination with ribavirin and the DHODH inhibitory level of brequinar 
in adult patients with AML and other hematological malignancies. 
Secondary 
Objectives 
 
 
● To determine the overall response rate (ORR) including complete 
remission (CR), CR with incomplete hematologic recovery (CRi), 
morphologic leukemia-free state (MLFS), and partial remission (PR) 
(criteria as defined in the ELN Guidelines, Döhner et al., 2017 and 
Cheson et al., 1990) and complete remission with partial hematological 
recovery (CRh). 
● To assess the rate of overall survival (OS) and event-free survival (EFS). 
● To evaluate duration of response.  
● To characterize the pharmacokinetic (PK) profile of brequinar 
● To characterize the dihydroorotate (DHO) plasma levels of brequinar 
after oral dosing. 
Exploratory 
Objectives 
● To assess the relationship between DHODH inhibition and the efficacy 
and safety of brequinar alone and in combination with ribavirin. 
● To evaluate molecular and cellular biomarkers that may be predictive of 
antitumor level and/or treatment resistance including cytogenetics, 
molecular profiling, and flow cytometry during and after treatment. 


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● To evaluate global gene expression profiles, DNA methylation profiles, 
and other potential prognostic markers to explore predictors of antitumor 
activity and/or resistance to treatment. 
Design 
This will be a Phase 1b/2a multi-center, open-label, non-randomized clinical 
trial to assess the safety, tolerability and efficacy of dose-adjusted brequinar 
alone and, beginning with Cohort 3, in combination with ribavirin in adult 
subjects with AML and other hematological malignancies. The study will 
also assess the inhibition of DHODH and the PK profile of brequinar in 
plasma. Subject dosing will be adjusted based on safety/tolerability, 
brequinar pharmacokinetics, and DHO levels. 
Up to 27 subjects are planned to be entered in this trial. Cohort 1 enrolled 5 
subjects. Cohort 2 enrolled 6 subjects with a starting dose of 500 mg/m2 once 
weekly. Three Cohort 2 subjects discontinued from the study prior to Day 43 
and may be replaced. 
Although the 500 mg/m2 starting dose of brequinar was well tolerated by most 
subjects, several subjects took as many as 4 to 5 weeks to achieve twice 
weekly dosing at doses lower than 500 mg/m2. In order to more quickly 
achieve the desired twice weekly dosing schedule, any newly enrolled Cohort 
2 subjects are to start with 350 mg/m2 once weekly. Approximately 3 
additional subjects may be enrolled into Cohort 2. If Cohort 3 regulatory 
approval is achieved prior to completing Cohort 2, it is not required to 
complete Cohort 2 before beginning enrollment into Cohort 3. Cohort 2 
subjects who are active in the study at the time of regulatory approval may roll 
over into Cohort 3.  
Cohort 3 will enroll approximately 6 to 9 subjects and may be followed by an 
expansion cohort of approximately 6 to 12 subjects. Cohort 3 and the 
Expansion Cohort will use the 350 mg/m2 starting dose. 
After both the brequinar 48h PK and 72h DHO level meet criteria described 
in the Individual Dose Adjustment Guidelines below, the subject is to move 
to twice weekly brequinar dosing on a continuing basis as tolerated. After 
moving to twice weekly brequinar dosing, the brequinar dose is to be reduced 
if needed per the algorithm below to achieve an 84h DHO of < 5000 ng/mL. 
After achieving a brequinar twice weekly dose that achieves 84h DHO < 5000 
ng/mL, ribavirin dosing will begin at 1000 mg BID in combination with twice 
weekly brequinar. After initiating ribavirin dosing, the brequinar dose will 
continue to be adjusted using the dosing adjustment algorithm below. After 
brequinar has reached a stable dose, ribavirin will be increased 400 mg BID 
every 4 weeks to a maximum of 1800 mg BID. 
Safety will be assessed utilizing physical examination, vital sign 
measurements, safety laboratory testing, 12-lead ECGs and bone marrow 


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sampling. Bone marrow sampling will also be utilized to measure response. 
Tolerability will be assessed by spontaneously reported and elicited adverse 
events. DHO level will be measured using a validated assay. Brequinar PK 
will be analyzed using standard PK parameters. Haptoglobin levels will be 
tested as needed to assess hemolytic anemia. 
Dosing will continue for up to 12 months in the absence of unacceptable 
toxicity or disease progression. Subjects who discontinue for any reason 
prior to at least 4 weeks of the brequinar/ribavirin combination may be 
replaced. 
Primary 
endpoints: 
● Safety/tolerability and DHO level relationship with safety and 
therapeutic brequinar levels   
Secondary 
endpoints: 
● Rates of treatment-emergent adverse events. 
● Overall Response Rate (ORR) including CR, CRi, CRh, MLFS, or PR. 
● Event free survival (EFS). 
● Duration of response. 
● PK profile of brequinar. 
● DHO plasma profile. 
Exploratory 
endpoints: 
● Relationship between DHODH inhibition and the efficacy and safety of 
brequinar. 
● Antitumor level based on molecular and cellular biomarkers including 
cytogenetics, molecular profiling, and flow cytometry during and after 
treatment. 
● Global gene expression profiles, DNA methylation profiles, and other 
potential prognostic markers to explore predictors of antitumor activity 
and/or resistance to treatment 
Sample Size: 
Up to 27 subjects  
Number of Sites: 
3 – 8 
Study Period: 
An enrollment period of 18 - 24 months is expected. 
Inclusion 
Criteria: 
 
1. Willing and able to provide written informed consent for the trial. 
2. Patients 18 years of age or older, with relapsed/refractory AML by 
World Health Organization classification, T-cell leukemia (T-ALL), 
bi-lineal leukemia (BLL), or mixed phenotypic acute leukemia 
(MPAL) and who have exhausted available therapy. 


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3. ECOG Performance Status 0 to 2. 
4. 12-lead ECG with no clinically unacceptable findings; adequate 
cardiac function/NYHA Class 0 to 2. 
5. Adequate hepatic function (unless deemed to be related to underlying 
leukemia). 
1. Direct bilirubin ≤ 2 x ULN 
2. ALT ≤ 3 x ULN 
3. AST ≤ 3 x ULN 
6. Adequate renal function as documented by creatinine clearance ≥ 50 
mL/min based on the Cockcroft-Gault equation. 
7. In the absence of rapidly proliferative disease, the interval from prior 
leukemia-directed therapy to first dose of study drug will be at least 7 
days for cytotoxic or non-cytotoxic (immunotherapy) agents. Use of 
supportive care measures per institution’s standard of care is 
permitted at any time. 
8. The effects of brequinar on the developing human fetus are unknown. 
For this reason, women of child-bearing potential and men must 
agree to use adequate contraception (hormonal or barrier method of 
birth control; abstinence) prior to study entry and for the duration of 
study participation. Should a woman become pregnant or suspect she 
is pregnant while she or her partner is participating in this study, she 
should inform her treating physician immediately. Men treated or 
enrolled on this protocol must also agree to use adequate 
contraception prior to the study, for the duration of study 
participation, and for 90 days after completion of brequinar 
administration. 
9. Male subjects must agree to refrain from sperm donation from initial 
study drug administration until 90 days after the last dose of study 
drug. 
Exclusion 
Criteria: 
1. Patients in need of immediate leukapheresis. 
2. Any concurrent uncontrolled clinically significant medical condition, 
laboratory abnormality, or psychiatric illness that could place the 
participant at unacceptable risk of study treatment. 
3. QTc interval using Fridericia’s formula (QTcF) ≥ 470 msec. 
Participants with a bundle branch block and prolonged QTc interval 
may be eligible after discussion with the medical monitor. 


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4. Pre-existing liver disease. 
5. The use of other chemotherapeutic agents or anti-leukemic agents is 
not permitted during study with the following exceptions: 
a. Intrathecal chemotherapy for prophylactic use or maintenance of 
controlled CNS leukemia. 
6. Presence of graft versus host disease (GVHD) which requires an 
equivalent dose of ≥ 0.5 mg/kg/day of prednisone or therapy beyond 
systemic corticosteroids (e.g. cyclosporine or other calcineurin 
inhibitors or other immunosuppressive agents used for GVHD). 
7. Active cerebrospinal involvement of AML, T-cell leukemia (T-
ALL), bi-lineal leukemia (BLL), or mixed phenotypic acute leukemia 
(MPAL). 
8. Diagnosis of acute promyelocytic leukemia (APL) 
9. Clinically active hepatitis B (HBV) or hepatitis C (HCV) infection. 
10. Severe gastrointestinal or metabolic condition that could interfere 
with the absorption of oral study medication. 
11. Prior malignancy, unless it has not been active or has remained stable 
for at least 2 years. Participants with treated non-melanoma skin 
cancer, in situ carcinoma or cervical intraepithelial neoplasia, 
regardless of the disease-free duration, are eligible if definitive 
treatment for the condition has been completed. Participants with 
organ-confined prostate cancer with no evidence of recurrent or 
progressive disease are eligible if at the active surveillance stage, 
hormonal therapy has been initiated, or the malignancy has been 
surgically removed or treated with definitive radiotherapy. 
12. Nursing women or women of childbearing potential (WOCBP) with 
a positive pregnancy test. 
13. Documented hemoglobinopathy. 
Treatment 
This is an open-label study of dose-adjusted brequinar for the treatment of 
AML and other hematologic malignancies. Brequinar is supplied as 100 mg 
or 250 mg oral capsules which will be used to dose subjects on a mg/m2 basis 
as described in the Cohort Starting Dose and Guidelines for Individual Dose 
Adjustment sections below. Ribavirin is supplied as 200 mg capsules and will 
be added in fixed doses as a combination therapy as described below.  
Procedures 
Screening Visit (Study Days -14 to -1) 


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These procedures must be completed within the 14 days prior to starting 
dosing. Obtain the subject’s written informed consent, then collect baseline 
information: 
• Demographics (height, weight, date of birth, gender, race, ethnicity); 
body surface area (BSA) determined at Screening will be utilized for 
all BSA-driven mg/m2 dosing calculations throughout the study. 
• Pertinent medical/surgical history (including AML/other hematologic 
malignancy diagnosis and laboratory and clinical evidence of 
progression, previous AML/other hematologic malignancy treatment, 
and any available chromosomal and mutational testing results per 
institutional guidelines) and concomitant medications. 
• Physical examination (including weight).  
• Vital signs (heart rate, respiratory rate, blood pressure, body 
temperature).  
• Pregnancy test for women of childbearing potential (WOCBP).  
• ECOG performance assessment.  
• Hematology/chemistry. 
• 12-lead ECG with QTcF. 
• Standard chromosomal and mutational testing per institutional 
guidelines. 
• Bone marrow sampling  
• Confirm subject meets all inclusion and no exclusion criteria. 
Treatment 
The treatment period begins with Cycle 1, Day 1 of the first dosing cycle. The 
laboratory manual provides procedures for processing, storage, and shipment 
of brequinar PK, DHO, and flow cytometry samples. If brequinar PK or DHO 
levels are not available for dose adjustment decisions, confirm safety is 
acceptable and continue to dose using the subject’s current dosing frequency 
and current dose until results are available.  
Dose Adjustment: Cycle 1 Week 1 (or Week 2) 
Week 1 (or Week 2) Day 1: 
• Collect any adverse events or new concomitant medications since 
Screening.  


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• Collect samples for baseline (pre-dose) brequinar/DHO, flow 
cytometry, and hematology/chemistry.  
• Conduct physical examination (including weight) if >4 weeks since 
last performed, vital signs, pregnancy test for WOCBP if >4 weeks 
since last test, and 12-lead ECG if >4 weeks since last test.  
• Review results and confirm subject remains eligible for the study.  
• Dispense study medication.  
• Subject is to take the first dose at the clinic and remain for 
brequinar/DHO/flow cytometry sampling. Collect samples at 1, 2, 4, 
and 6 hours post dose. 
• Dispense the subject’s calendar/diary. The diary will collect 
dates/times of study medication administration and AEs/new 
concomitant medications.  
• This week’s procedures may be repeated for Week 2 if necessary, with 
the exception that PK/DHO samples are to be obtained only pre-dose 
on Day 1 of Week 2. 
Week 1 (or Week 2) Day 2: Collect 24h post dose brequinar/DHO and flow 
cytometry samples.  
Week 1 (or Week 2) Day 3: Collect 48h post dose brequinar/DHO and flow 
cytometry samples.  
Week 1 (or Week 2) Day 4: Collect 72h post dose brequinar/DHO and flow 
cytometry samples.  
Maintenance Dose Cycle (visit every week up to Week 12 then every 2 
weeks) 
Once a subject reaches a twice-weekly dose, the subject will be in the 
Maintenance Dose Cycle phase. Each Maintenance Dose Cycle is 2 weeks. 
The Maintenance Dose Cycle dose may be adjusted at any time using the 84h 
DHO criteria. 
Maintenance Dose Cycle procedures will occur on Day 1 and Day 8 through 
Week 12 from study Day 1 as shown below. After Week 12, the Maintenance 
Dose Cycle visit is once every 2 weeks (i.e., Day 1 only of each two-week 
cycle). 
Maintenance Dose Cycle Day 1: 
• Collect unused study medication and check the diary/elicit information 
about AEs/new concomitant medications since the last visit. 


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• Collect pre-dose brequinar/DHO, hematology/chemistry, and flow 
cytometry sample.  
• Obtain vital signs; pregnancy test for WOCBP (every 4 weeks), 12-
lead ECG (every 4 weeks), and bone marrow sample (note that bone 
marrow is collected at the Week 4 visit (Day 22 ± 7 days), at the Week 
7 visit (Day 43 ± 7 days), then every 12 weeks ± 7 days or per 
institutional standard of care; the Day 43 sample will be assessed for 
hematological toxicity. 
• If subject is beginning or continuing twice-weekly dosing, review 
most recent 84h DHO level, review the laboratory results and safety 
information and determine whether the subject should maintain 
current dose (acceptable safety and 84h DHO meets criteria), increase 
dose (acceptable safety and 84h DHO < 1500 ng/mL) or hold study 
medication (unacceptable safety or 84h DHO ≥ 5000 ng/mL).  
• Dispense study medication. 
• Dispense calendar/diary.  
Maintenance Dose Cycle Day 8 (up to Week 12): 
• Collect pre-dose brequinar/DHO/flow cytometry sample.  
• Review most recent 84h DHO level, review the laboratory results and 
safety information and determine whether the subject should maintain 
current dose (acceptable safety and 84h DHO meets criteria), increase 
dose (acceptable safety and DHO < 1500 ng/mL) or hold study 
medication (unacceptable safety or 84h DHO ≥ 5000 ng/mL).  
Final Visit 
This visit is to take place when a subject is discontinuing from the study. 
• Collect and check the diary/elicit information about AEs/new 
concomitant medications since the last visit.  
• Collect brequinar/DHO/flow cytometry and hematology/chemistry 
samples.  
• Collect unused study medication. 
• Conduct physical examination if >4 weeks since last performed, 
collect vital signs; conduct pregnancy test for WOCBP if > 4 weeks 
since previously performed, 12-lead ECG if > 4 weeks since 
previously performed; collect bone marrow sampling if > 4 weeks 
since previously performed.  


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• Ensure all adverse events have been recorded. 
Telephone Follow Up Visit (2 weeks after Final Visit) 
Contact subject by telephone two weeks after Final Visit to determine 
subject’s survival status and to inquire if any new adverse events have 
occurred. Survival information will be collected while the subject is 
participating in the study (i.e., up to 2 weeks after last dose of study 
medication). 
Unscheduled Visits 
Unscheduled visits and tests to assess AEs are permitted as needed providing 
the AE onset occurs within two (2) weeks after the final dose. 
Safety/ 
Tolerability 
Safety/Tolerability – Subject Level 
Acceptable safety/tolerability for a subject through Day 42 is defined as no ≥ 
Grade 3, treatment-emergent, study-drug-related, non-hematologic adverse 
events. Due to the expected hematologic profile associated with AML, 
hematologic AEs of any grade will not be considered dose-limiting toxicity 
(DLT) during the first 42 days of dosing (i.e., assessed at the visit conducted 
on Day 43). Exceptions to the non-hematologic Grade 3 criterion are provided 
in the table below.  
If a dose is held due to safety/tolerability issues, the subject should continue 
to have scheduled assessments. 
If AEs have not resolved to ≤ Grade 2 after two weeks without dosing, dosing 
is to be discontinued for this subject. 
Exceptions to Grade 3 Nonhematologic AEs  
Condition 
Exception Description  
Nausea/ 
Emesis 
Grade 3 nausea and/or emesis resolving to less than or equal 
to Grade 2 or baseline within 1 week after the use of an 
optimal antiemetic regimen based on standard practice. 
Diarrhea 
Grade 3 diarrhea resolving to less than or equal to Grade 1 or 
baseline within 1 week after receiving the maximal 
supportive therapy based on standard practice. 
Laboratory 
abnormalities 
Asymptomatic Grade 3 laboratory abnormalities that are not 
considered to be clinically significant. 
Mucositis 
Grade 3 with duration < 1 week 
Fatigue 
Grade 3 with duration < 2 weeks 
 


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For the expansion cohort, the definition of unacceptable safety is expanded 
to include signs of hepatotoxicity (≥ Grade 2 toxicity for ALT and AST). 
Dosing is to be held for subjects who experience hepatotoxicity; dosing may 
resume only if the hepatotoxicity AE resolves to ≤ Grade 1 within two 
weeks. If the subject experiences a second episode of ≥ Grade 2 
hepatotoxicity after resuming dosing, dosing is to be discontinued for that 
subject. 
Hematologic Toxicity 
After the subject has completed the first 42 days of treatment, the definition 
of unacceptable safety expands to include hematologic AEs defined as 
prolonged neutropenia with ANC < 500 from the start of therapy in the 
absence of disease, ≥ Grade 4 neutropenia, and/or ≥ Grade 4 
thrombocytopenia, with a hypocellular bone marrow and no greater than 5% 
marrow blasts lasting for ≥ 2 weeks. Anemia will not be considered a 
hematologic AE for the definition of unacceptable safety. Febrile neutropenia 
is also excluded from the DLT definition for this population.  For clinic visits 
when bone marrow sampling is scheduled, the timing of the bone marrow 
sampling can be adjusted to ensure that the results are available at the time of 
the clinic visit. Hemolytic anemia has been reported in approximately 13% of 
subjects taking ribavirin in combination with interferon alfa-2a for hepatitis 
C. Decrease in haptoglobin levels to below the lower limit of normal in a 
subject with previously normal range haptoglobin prior to beginning ribavirin 
dosing will trigger an investigation of possible hemolysis in subjects taking 
the brequinar/ribavirin combination, and may lead to a discontinuation of 
ribavirin after discussion with the PI, Sponsor and Medical Monitor. 
Cohort Starting 
Doses 
Cohort 1 treated 5 subjects at 500 mg/m2 twice weekly. Cohort 2 treated 6 
subjects with this starting dose once weekly. Three Cohort 2 subjects 
discontinued prior to Day 43 and may be replaced using a starting dose of 350 
mg/m2. Cohort 3 and Expansion cohort subjects will have a starting dose of 
350 mg/m2. 
Expansion 
Cohort 
An expansion cohort of approximately 6 to 12 subjects may be added after 
completing Cohort 3 to obtain further information on safety, brequinar 
exposure, DHO levels, and the efficacy and safety of the ribavirin and 
brequinar combination. 
Guidelines for 
Brequinar 
Individual Dose 
Adjustment  
Brequinar PK and DHO samples will be obtained during Week 1. The results 
from Week 1 will be used to make decisions about the Week 2 dose and 
schedule. Subjects who meet the twice weekly brequinar PK and 72h DHO 
criteria in Week 1 (see algorithm below) may proceed to twice weekly dosing 
with 350 mg/m2 in Week 2. Subjects whose brequinar PK and DHO levels do 
not meet the twice weekly criteria at the 350 mg/m2 dose or have unacceptable 


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safety at this dose will have their dose decreased to 200 mg/m2 once weekly. 
For subjects requiring the dose decrease, brequinar PK and DHO samples will 
also be obtained daily on Days 1 – 4 during Week 2 (or when dosing resumes 
following an AE), and the Week 2 results will be used to make decisions about 
the Week 3 dose. If a subject still does not meet the twice weekly criteria or 
has unacceptable safety when dosed at 200 mg/m2 once weekly, discontinue 
the subject. 
 If brequinar PK or DHO levels are not available for dose adjustment 
decisions, hold dosing until results are available.  
Algorithm to Set Twice-Weekly Brequinar Dose for Cohort 3/Expansion 
Cohort (Starting Dose 350 mg/m2) 
Brequinar PK 
DHO 
Action 
48h BRQ PK 
> 5 mcg/mL 
NA 
Decrease dose to 200 mg/m2 and continu
weekly dosing, reassess BRQ PK 
BRQ PK  
Criteria Met* 
72h DHO Criteria  
NOT MET** 
Decrease dose to 200 mg/m2 and continu
weekly dosing, reassess 72h DHO criteria 
BRQ PK  
Criteria Met* 
72h DHO Criteria  
MET** 
Begin twice-weekly dosing Week 2 or afte
*  Brequinar PK (BRQ PK) Criteria for Cohort 3 and Expansion Cohort: 48h BRQ ≤ 5 mcg/m
**72h DHO Criteria: 72h DHO < 48h DHO (on a downward slope) AND 72h DHO <5000 n
After beginning twice weekly dosing, the brequinar dose is to be further 
reduced (if needed) to achieve an 84h DHO < 5000 ng/mL.  
Ribavirin dosing will begin when brequinar twice weekly dosing results in an 
84h DHO < 5000 ng/mL. See “Ribavirin Dosing” below for further 
instructions regarding ribavirin dosing.  
After starting ribavirin dosing, the twice weekly brequinar dose is to be further 
adjusted using the 84h DHO (trough) algorithm shown below. There is no 
upper or lower brequinar dose limit after achieving twice weekly dosing and 
ribavirin dosing has started. The 84h DHO level obtained 84 hours after a 
brequinar dose will be used to adjust the next dose as needed. This brequinar 
dose adjustment may be made every two weeks, if necessary. 
Algorithm to Adjust Twice-Weekly Dose using 84h DHO for Cohort 3 
and Expansion Cohort 
84h DHO (Trough)  
Action 
84h DHO < 1500 ng/mL 
Increase next week's dose by 75 mg/m2 
84h DHO ≥ 1500 ng/mL 
and < 5000 ng/mL 
Stable Dose. Check 84h DHO weekly through Week 12 
then every 2 weeks. Adjust dose prn per 84h DHO criteria. 


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84h DHO ≥ 5000 ng/mL 
HOLD. Notify subject not to take next dose. Hold dosing 
for one week. If next Day 1 84h DHO is < 5000 ng/mL, 
decrease dose by 75 mg/m2 and resume twice-weekly 
dosing. If next Day 1 84h DHO ≥ 5000 ng/mL, no further 
dosing, discontinue the subject. 
 
Each subject will continue twice weekly brequinar dosing at the individually 
adjusted dose for up to 12 months (total time from first dose) in the absence 
of unacceptable toxicity or disease progression. Additional intra-subject dose 
adjustment is permitted at any time throughout the study based on 
safety/tolerability and 84h DHO levels.  
The dose adjustment procedures may be revised after safety, brequinar PK, 
DHO plasma levels, and bone marrow results have been reviewed.  
Ribavirin Dosing 
Beginning with Cohort 3 and the expansion cohort (and for ongoing Cohort 2 
subjects who have rolled over into Cohort 3), ribavirin will be added 
beginning at 1000 mg BID following the initial brequinar only period 
described above. Ribavirin dosing will begin when brequinar dosing has 
moved to twice weekly and the twice weekly 84h DHO (DHO 84 hours after 
a twice weekly brequinar dose) is confirmed to be < 5000 ng/mL, expected to 
be a period of approximately 3 to 6 weeks. After reaching a stable brequinar 
dose as defined by the algorithm above, the ribavirin dose will be increased 
by 400 mg BID approximately every 4 weeks. The maximum ribavirin dose 
is 1800 mg BID. 
If a ribavirin-related adverse event occurs, ribavirin is to be held for 2 weeks 
and restarted if the AE resolves to < Grade 2. If ribavirin dosing can be 
restarted, the ribavirin dose will be reduced by 400 mg BID.  
Either brequinar or ribavirin may continue to be administered as a single agent 
if either study drug is discontinued due to unacceptable safety related to either 
agent. Cohort 2 subjects rolling over into Cohort 3 must meet the requirements 
for twice weekly dosing before beginning ribavirin dosing. 
Brequinar/DHO  
 Plasma samples for brequinar/DHO levels and peripheral blood for flow 
cytometry are to be obtained using the following schedule: 
• Cycle 1 Week 1 (and Week 2 if weekly dose decreased): Day 1 (prior 
to dosing, and 1, 2, 4, and 6 hours), Days 2, 3, and 4 (24h, 48h, and 
72h after dosing) 
• After starting twice-weekly dosing, obtain sample prior to dosing on 
Days 1 and 8 of each Maintenance Dose Cycle up to Week 12, then 
every 2 weeks (i.e., Day 1 of each two-week Maintenance Dose 
Cycle). 


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• Final Visit: obtain brequinar, DHO, and flow cytometry samples. 
Statistical 
Analysis 
A separate, detailed statistical analysis plan (SAP) will be finalized prior to 
locking the database. All analyses of safety and anti-leukemic activity for 
this open-label, early Phase study will be descriptive in nature and presented 
by dose group and overall, as appropriate, for the dose-adjustment phase and 
the expansion phase. Procedures for accounting for missing, unused and 
spurious data will be described in the SAP.   
Summaries for quantitative variables will include the mean, median, 
quartiles, standard deviation and error, minimum, and maximum. For 
qualitative variables, the summaries will include the number and percentage 
of subjects for each outcome, and the exact 95% CI, when appropriate. No 
hypothesis testing will be performed. Any statistical testing will be 
considered exploratory and descriptive. All computations will be performed 
using SAS® (Version 9.3 or higher). 
Subject disposition, subject demographics and baseline characteristics will 
be summarized. Subject data listings will also be provided.  
All safety analyses will be performed on the Safety Analysis Set.  Safety and 
tolerability will be assessed in terms of AEs, SAEs, safety laboratory data, 
physical examinations, vital signs, 12-lead ECGs and bone marrow 
sampling.  
Adverse event data will be descriptively evaluated. All AEs will be listed. 
The incidence and duration of treatment-emergent adverse events (TEAEs), 
defined as AEs occurring after the first dose of study treatment through 30 
days after the last dose of study treatment will be tabulated by Medical 
Dictionary for Regulatory Activities (MedDRA) preferred term and system 
organ class, and by severity and relationship to study treatment. All 
laboratory results, vital sign measurements, ECGs and bone marrow 
assessments will be summarized using appropriate descriptive statistics. 
Efficacy analysis is described below. 
Assess anti-leukemic activity by ELN Guidelines including CRh, as follows:  
• 
Overall Response rate (ORR) – the proportion of subjects in the 
Efficacy Analysis Set with a best overall response of CR, CRi, 
CRh, MLFS and PR  
• 
Complete Remission (CR) rate – the proportion of subjects in the 
Efficacy Analysis Set with a best overall response of CR 


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• 
Complete Remission with Incomplete Hematologic Recovery (CRi) 
rate – the proportion of subjects in the Efficacy Analysis Set with a 
best overall response of CRi 
• 
Complete remission with partial hematological recovery (CRh) – 
the proportion of subjects in the Efficacy Analysis Set with a best 
overall response of CRh 
• 
Morphologic Leukemia Free State (MLFS) rate – the proportion of 
subjects in the Efficacy Analysis Set with a best overall response of 
MLFS 
• 
Partial Remission (PR) rate – the proportion of subjects in the 
Efficacy Analysis Set with a best overall response of PR 
• 
Event-free survival (EFS) – the interval between first brequinar 
dose and relapse (≥5% bone marrow blasts, reappearance of blasts 
in blood, or development of extramedullary disease), disease 
progression, or death 
• 
Overall survival (OS) – the time from first dose of brequinar to date 
of death or last known alive date 
 
For ORR and other endpoints defined as proportions, estimated response 
rates and two-sided exact binomial 95% CIs will be provided. The 
distributions of EFS and other time-to-event endpoints will be summarized 
using the Kaplan-Meier method. Time to event analyses will be from first 
dose of brequinar. Censoring rules for time-to-event endpoints will be 
described in the SAP. 
In addition to the bone marrow and hematologic criteria above, the criteria 
used for treatment efficacy in T-ALL and other hematologic malignancies 
include that all previous extramedullary manifestations of disease must be 
absent (e.g., lymphadenopathy, splenomegaly, skin or gum infiltration, 
testicular masses, or CNS involvement).  
 
 
 


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CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
STUDY PERSONNEL 
SPONSOR CONTACT 
Name: 
Barbara Powers, MSN, Ph.D. 
Title: 
Clinical Operations 
Address: 
Clear Creek Bio, Inc. 
585 Massachusetts Avenue, 4th Floor, 
Cambridge, MA 02139 
Telephone No.: 
484-686-0545 
Fax No.: 
617-863-2082 
E-mail: 
bpowers@clearcreekbio.com  
 
SPONSOR MEDICAL CONTACT 
Name:  
Olga Prokopenko, MD (or other IQVIA Medical Monitor) 
Title: 
Senior Medical Director / Medical Monitor  
Address: 
IQVIA 
1700 Perimeter Park Drive 
Morrisville, NC 27560   
Telephone No.: 
O: +49 610 25790871 
M: +49 1522 8806304 
24-hour Safety No.: 
1-866-758-2798 or 919-313-7111 
E-mail: 
olga.prokopenko@iqvia.com  
YYA36071medmon.iqvia.com 
Medical Monitor Fax No.: 
206-826-0483 
 
SAE Reporting Fax:     
       919.313.1412 (US Toll-free:  1-866-761-1274) 
SAE Reporting email:  
       safety-inbox.biotech@iqvia.com 
 
LEAD INVESTIGATOR 
Name: 
Amir Fathi, MD 
Title: 
Assistant Professor of Medicine 
Affiliation: 
Massachusetts General Hospital 
Telephone No.: 
617-724-1124 
E-mail: 
afathi@mgh.harvard.edu 
 


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CONFIDENTIAL:  Clear Creek Bio, Inc. 
 
SUPPORT SERVICES 
 
CRO Project Manager 
Name: 
Mary Armstrong or current PM 
Company: 
IQVIA 
Address: 
1700 Perimeter Park Drive 
Morrisville, NC 27560 
E-mail: 
mary.armstrong@iqvia.com 
 
Data Management/eCRF PROVIDER 
Company: 
Address: 
 
Telephone No.: 
IQVIA 
1700 Perimeter Park Drive 
Morrisville, NC 27560  
919-972-2397 
Help Desk: 
1-866-342-0693 
Help Desk E-mail: 
sitesupport@iqvia.com 
 
STATISTICAL ANALYSIS 
Company: 
IQVIA 
Address: 
1700 Perimeter Park Drive 
Morrisville, NC 27560 
 
STUDY DRUG HOLDING COMPANY 
Name: 
Almac Clinical Services 
Address: 
25 Fretz Road 
Souderton, PA 18964 
Telephone No.: 
215-660-8500 
Email:  
clinicalservices@almacgroup.com 
 


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3 
INTRODUCTION 
3.1 BACKGROUND 
 
ACUTE MYELOID LEUKEMIA 
Acute myeloid leukemia (AML) is a malignant disorder of immature hematopoietic cells, 
characterized by differentiation arrest and rapid proliferation of abnormal myeloid precursors. 
These abnormal cells accumulate in the bone marrow and interfere with the production of normal 
blood cells. More than 20000 people are diagnosed with AML per year in the United States (US) 
(SEER, 2015 [1]). The median age at diagnosis is 67 years. 
Although there have been recent advances including midostaurin, enasidenib, CPX-351, 
gemtuzumab ozogomycin and venetoclax, outcomes for patients with AML and many other 
hematologic malignancies remain poor. With modern treatment regimens, expected complete 
remission (CR) rates are 60-70%, but long-term cure rates are 15-25%. Younger patients (i.e. those 
50 years of age or younger) with diploid karyotypes have a CR rate of 70-80% and cure rates of 
20-25%, while older patients and/or those with adverse cytogenetics have CR rates of 35-50% and 
cure rates of < 10% (SEER, 2015 [1]).  It is therefore critical to improve both the remission rate 
and the durability of remission in AML patients of all ages. 
3.2 DIHYDROOROTATE DEHYDROGENASE (DHODH) 
Dihydroorotate dehydrogenase (DHODH) catalyzes the fourth step in pyrimidine synthesis, the 
conversion of dihydroorotate (DHO) to orotate. The enzyme is located on the inner mitochondrial 
membrane and transfers electrons between DHO and complex III of the electron-transport chain 
via the reduction of its ubiquinone (coenzyme Q10) cofactor.  
DHODH is a ubiquitous, essential enzyme. The Miller syndrome, a rare autosomal recessive 
disorder in which patients have inherited hypomorphic mutations in both alleles of DHODH, 
results in multi-organ dysfunction (Ng et al., 2010 [2]). Two weak inhibitors of human DHODH 
are approved for clinical use. Leflunomide, a pro-drug, is used in the treatment of patients with 
rheumatoid arthritis. Its active form, teriflunomide, is marketed for multiple sclerosis. Leflunomide 
is known to affect erythroid differentiation of K562 cells in vitro, via the depletion of uridine 
triphosphate (UTP) and cytidine triphosphate (CTP) ribonucleotides (Huang et al., 2002 [3]). 
Despite the connection between bone marrow level, blood cell differentiation and DHODH, 
leukemia models of leflunomide have not been very promising. Leukemic mice treated with 
leflunomide demonstrated no reduction in leukemic burden and experienced significant weight 
loss and lethargy. 
Recent nonclinical studies have demonstrated that inhibition of DHODH can overcome myeloid 
differentiation arrest (Sykes et al., 2016 [4]). The mechanism through which a reduction in de novo 


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pyrimidine biosynthesis modulates myeloid differentiation is not clear. The differentiation effect 
of DHODH inhibitors appears to involve a combination of inhibition of nucleic acid synthesis, 
cell-cycle arrest, and changes in the post-translational glycosylation of important protein targets.  
Activated and proliferating T-cells have a particular dependence on nucleotide synthesis and 
nucleotide pools (Cohen et al., 1983 [15], Quéméneur et al., 2003 [16]), thus additional 
leukemias that may also benefit from brequinar’s mechanism of action include T-cell 
lymphoblastic leukemia (T-ALL), bi-lineal leukemia (BLL), and mixed phenotypic acute 
leukemia (MPAL).  
3.3 BREQUINAR 
It is well known that brequinar is a potent inhibitor of DHODH. Brequinar is one of more than 
300 quinoline-carboxylic acid derivatives prepared in an analog synthesis program in the 1980s, 
which was started after it was found that a compound of this class had antitumor activity. 
Brequinar was selected by DuPont for further development as a potential clinical drug 
because of its activity against experimental tumors and because its water solubility made it 
relatively straightforward to formulate. Ultimately, the rationale to use brequinar for the 
treatment of multiple solid tumors did not translate into efficacy after extensive clinical 
development and the project was terminated by DuPont in 1994. Clear Creek Bio exclusively 
licensed the historic data from Bristol Myers Squibb (that acquired DuPont in 2001). 
Sykes et al. (Sykes et al., 2016 [4]) showed that brequinar’s pro-myeloid differentiation activity 
might be useful for the treatment of AML. Utilizing a high throughput screening 
technique, brequinar was identified as a compound that overcame arrest of myeloid 
differentiation. Brequinar triggers myeloid differentiation in vitro and in vivo. Brequinar was 
highly active in vivo, as demonstrated in syngeneic murine AML models (HoxA9+Meis1 
and MLL/AF9) as well as xenotransplant AML models (THP1, HL60, MOLM13, OCI/
AML3). In an aggressive MLL/AF9 murine model of AML, treatment with brequinar 
promoted myeloid differentiation, reduced leukemic cell burden, and improved overall 
survival. Brequinar also led to a reduction in the number of leukemia stem cells, reduced 
colony-formation level, and depleted the number of leukemia-initiating cell level.  
In addition, Sykes and colleagues demonstrated that treatment with brequinar was better-
tolerated and more effective than treatment with cytotoxic chemotherapy in animal models. 
Brequinar was given for many weeks without cumulative toxicity. The effect of brequinar and 
DHODH inhibition on normal cells was also assessed through study of competitive bone 
marrow transplantation assays. Mice were treated with brequinar, 5-fluorouracil (5-FU), or 
induction chemotherapy, and their bone marrow was transplanted in competition (1:1) with 
normal (untreated) bone marrow to gauge the effect of therapy on hematopoietic stem cell (HSC) 
function. The fitness of HSCs from mice treated with brequinar were functionally equivalent 
to those of untreated mice when compared to that of HSCs exposed to 5-FU and 
induction chemotherapy, which promoted a marked decrease in fitness.  
CONFIDENTIAL:  Clear Creek Bio, Inc. 


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Sykes et al. administered brequinar at a dose and schedule (every 72 hours) that was non-toxic to 
the animals yet led to eradication of the leukemia cells. This schedule of administration was based 
on data demonstrating that the pro-differentiation effect of brequinar required a period of sustained 
DHODH-inhibition of approximately three days. This observation suggests that brequinar’s 
efficacy depends on producing approximately 72-hours “time-above-threshold” to maintain 
sustained DHODH inhibition. The hypothesis is that pyrimidine starvation via inhibition of 
DHODH for approximately 72 hours elicits pro-myeloid differentiation and leads to the anti-
leukemia efficacy of brequinar.  
Sykes et al. also showed that normal cells could tolerate longer periods of pyrimidine starvation 
than their leukemic counterparts. The proposed dosing regimen of brequinar in this clinical trial, 
CCB-01, is intended to take advantage of the different sensitivity of normal and leukemic cells 
and thus spare normal cells while eradicating leukemic cells.  
A pharmacodynamic marker of enzyme inhibition (i.e. target engagement) is required to 
accomplish this type of rational dosing approach. Sykes and colleagues demonstrated how 
DHODH inhibition could be monitored by the accumulation of the substrate DHO. Indeed, 
inhibition of the DHODH enzyme led to the rapid accumulation of intracellular DHO, which was 
reflected by accumulation of DHO in plasma hence the rationale for measuring plasma DHO as 
the pharmacodynamic marker in CCB-01.  
Given this new information, real-time monitoring of target engagement via plasma DHO of 
DHODH inhibition in each patient should permit identification of a brequinar dose that is both 
efficacious and well-tolerated. Maintaining intermittent DHODH inhibition for prolonged 
treatment cycles may be efficacious compared to previous studies using short periods and high 
doses followed by long periods of recovery.  
The prior data on the clinical evaluation of brequinar in patients with multiple solid tumors 
provides valuable safety data that supports the safety of the proposed dosage regimen. Brequinar 
has not been studied clinically in myeloid malignancies in the past. Given encouraging pre-clinical 
results, brequinar has been evaluated in phase 1 and phase 2 trials of more than 800 patients with 
advanced solid tumor malignancies (Arteaga 1989 [5], Burris 1998 [6], Noe 1990 [7], 
Schwartsmann 1990 [8]). These studies indicated a lack of efficacy for brequinar at the doses and 
schedules evaluated. However, many of these trials studied brequinar administered as a single, 
high dose infusion given weekly or daily x 5 days every 3-4 weeks or every day for 21 days. The 
lack of efficacy in the previous trials may have been due to the narrow therapeutic window with 
the high doses studied, and to the inability, or lack of knowledge, to use a pharmacodynamic 
marker such as plasma DHO to fine-tune a therapeutic window based on differential pyrimidine 
starvation of myeloid precursors versus normal cells.  
3.4 RIBAVIRIN 
Ribavirin is known to inhibit inosine-5’-monophosphate dehydrogenase (IMPDH), the enzyme 
that catalyzes the conversion of inosine 5’-phosphate (IMP) to xanthosine 5’-phosphate (XMP), 


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the first committed and rate-limiting step in the de novo synthesis of guanine nucleotides. Ribavirin 
plays an important role in the regulation of cell growth and is itself important in purine metabolism 
(Kentsis et al., 2005 [20]; Assouline et al., 2009 [17]; Tan et al., 2008 [23]). Ribavirin is marketed 
in combination with interferon alfa-2b for the treatment of chronic hepatitis C (ribavirin generic 
SPC, Appendix H, Section 15.8). Ribavirin’s ability to target the translation of oncogenes, 
particularly through inhibition of the eukaryotic translation initiation factor eIF4E, suggests that 
ribavirin may also be an effective cancer therapy (Kentsis et al., 2004 [21]; Kentsis et al., 2005 
[20]; Assouline et al., 2009 [17]; Borden, 2008 [19]). Elevated levels of eIF4E are found in M4/M5 
AML specimens (Assouline et al., 2009 [17]; Topisirovic et al., 2005 [22]; Topisirovic et al., 2003 
[24]), suggesting that AML specimens have developed an oncogene dependency on eIF4E. In 
contrast, monocytes from healthy individuals do not have higher eIF4E and ribavirin did not affect 
their growth. 
Ribavirin’s possible anti-cancer effect was explored in a Phase II clinical trial, where Assouline et 
al. demonstrated that ribavirin treatment in poor prognosis AML patients led to substantial clinical 
benefit (2009 [17]). A total of 13 patients were treated at ribavirin daily starting doses of 1000 
mg/day with escalation to 2800 mg/day. Several patients responded to ribavirin monotherapy with 
one complete remission, two partial remissions, two blast responses, and four stable diseases out 
of 11 evaluable patients. Although hemolytic anemia has been reported in connection with 
ribavirin treatment in hepatitis C patients, this reaction was not observed in the AML patients in 
this study. Additionally, no other ribavirin-related toxicities were observed for any patients in the 
trial, even after 9 months of treatment (Assouline et al., 2009 [17]). 
Although Borden and colleagues reported a benefit for ribavirin monotherapy as presented above, 
these researchers suggested that it would be important to increase the response rate as well as the  
duration of clinical responses (2010 [19]). After the monotherapy trial, Assouline and colleagues 
therefore opened a trial of ribavirin and low dose cytarabine (LDAC) in relapsed and refractory 
AML (2015 [18]). A total of 29 subjects were treated with twice-daily doses of 1000, 1400, 1800 
or 2200 mg ribavirin continuously and twice-daily 10 mg or 20 mg LDAC for ten days of every 
28-day cycle. The combination was tolerated with no unexpected adverse events. As reported in 
this study, hemolytic anemia that resolved on discontinuation of ribavirin was observed in 4 (14%) 
of subjects at ribavirin doses of 1000 (n = 1), 1800 (n = 1), and 2200 mg (n = 2). Ribavirin with 
low dose cytarabine (LDAC) combination treatment in this study resulted in two complete 
remissions, one partial remission and two blast responses. Their recommended phase II dose was 
twice-daily 1400 mg ribavirin and twice-daily 10 mg LDAC.  
The promising early results for ribavirin for treatment of AML in both monotherapy and 
combination settings led us to investigate the preclinical efficacy of a brequinar/ribavirin 
combination therapy (brequinar IB [9]), and this combination approach will be added to this 
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3.5 RATIONALE FOR THE PLANNED TRIAL 
This study is designed to obtain safety and efficacy data for brequinar in patients with AML and 
other hematologic malignancies including T-ALL, BLL, and MPAL as these diseases may benefit 
from brequinar and/or from a combination of brequinar and ribavirin treatment.  
Subject Population 
The population for this study is patients 18 years of age or older, with relapsed/refractory AML by 
World Health Organization classification and other hematologic malignancies including T-ALL, 
BLL, and MPAL that have failed prior standard therapy and for which no standard therapies are 
available that result in a durable remission.  
Study Treatments 
This is an open label study of oral brequinar using intra-subject dose adjustment. The possible 
benefit of brequinar in AML and other hematologic cancers has been previously discussed (Sykes 
et al., 2016).  
Ribavirin will be added in Cohort 3 as well as the expansion cohort, to be administered in 
combination with brequinar. As discussed above, ribavirin’s efficacy in AML as well as its 
apparent lack of toxicity as a single agent in the AML population (Assouline, et al; 2009 [17]) and 
its lack of additive toxicity in a preclinical model (Brequinar IB [9]) make it an attractive 
combination therapy. Furthermore, while brequinar inhibits a key step (DHODH) in pyrimidine 
synthesis, ribavirin inhibits a key step (IMPDH) in purine synthesis as well as acts to inhibit cap-
dependent translation. In this manner, both sides of nucleotide synthesis are targeted as well as 
those transcripts that rely on cap-dependent translation.  
Dosing of brequinar and ribavirin as well as the dose-adjustment schemes are presented in detail 
in Section 8.5. 
3.5.1 Brequinar Starting Dose Selection 
The rationale underlying the proposed dosage regimen for brequinar and the use of plasma DHO 
to guide dosing is the prior demonstration using nonclinical models by Sykes et al. (2016) [4] that 
malignant cells are more sensitive than normal cells to periods of DHODH inhibition. The 
objective is to identify a dose and regimen of brequinar that maintains suppression of DHODH 
adequate to induce differentiation and stop myeloid proliferation but avoid harming normal cells. 
These features have been realized in vivo in animal models. Specifically, intermittent dosing that 
preserved elevated levels of the metabolite DHO markedly reduced AML cells, preserved normal 
hematopoietic stem cells, and improved animal survival. These recent findings and historic 
pharmacokinetic (PK) and safety data from humans support the planned approach.  


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Rather than intermittent high doses as were given by DuPont, Clear Creek will use relatively low 
doses and prolonged exposure to brequinar. There will not be a lengthy conventional rest period 
as is generally required between infrequent high doses. There will instead be twice-weekly 
administration of lower doses with a dosing interval that allows enough time for normal cells to 
recover from or avoid pyrimidine starvation in between the periods of DHODH inhibition. Based 
on its average half-life of 10.5 hours and what has been observed in the clinical PK data (see the 
Brequinar IB [9]), brequinar plasma levels return to baseline at about 3.5 days or 84 hours after an 
oral dose. For this reason, the proposed clinical study includes a twice-weekly schedule of 
brequinar dosed approximately every 84 hours, while measuring brequinar PK and plasma DHO 
to fine-tune the dose that ensures sustained DHODH inhibition while avoiding adverse effects to 
normal cells. 
Safety data from previous oncology clinical studies of brequinar (see brequinar IB [9], Section 5) 
with maximum tolerated doses as high as 2250 mg/m2 repeated every 3 weeks suggested that a 
starting dose for Cohort 1 of 500 mg/m2 p.o. would be safe and well-tolerated in subjects with 
AML. This 500 mg/m2 starting dose was used in Cohorts 1 and 2 in this protocol, however Cohorts 
1 and 2 results indicate that a starting dose of 350 mg/m2 should allow subjects to more rapidly 
progress to the desired twice weekly dosing. The starting brequinar dose for the remainder of 
Cohort 2 was therefore reduced to 350 mg/m2. The starting brequinar dose for Cohort 3 and the 
expansion cohort will also be 350 mg/m2. This starting dose may be decreased, if necessary, to 
200 mg/m2 following the dose adjustment guidelines found in Section 8.5.1. After moving to twice 
weekly dosing, each subject’s subsequent brequinar dose is to be adjusted depending on the safety, 
tolerability, and DHO level obtained during treatment. See Section 8.5. 
3.5.2 Ribavirin Dosing 
For Cohort 3 and the expansion cohort, ribavirin 1000 mg BID will be added in combination with 
brequinar following a brequinar only period of approximately 3 to 6 weeks. Assuming acceptable 
safety, the ribavirin dose is to be escalated by 400 mg/BID approximately every 4 weeks to a 
maximum of 1800 mg/BID. Ongoing Cohort 2 subjects who have reached twice weekly dosing 
with 84h DHO < 5000 ng/mL may begin the ribavirin combination immediately. See Section 8. 
3.6 RISK/BENEFIT OF BREQUINAR 
As presented in the brequinar IB [9], more than 800 patients have been exposed to this compound 
for treatment of a variety of solid tumors at various treatment regimens, doses, and routes including 
a single dose, once weekly, twice weekly, single dose every 3 weeks, daily times 5 every 4 weeks, 
and daily times 21 days for multiple courses. The maximum intravenous dose given was 2,250 
mg/m2 every 3 weeks, and the maximum oral dose was 100 mg/m2 daily for 21 days. Study results 
have not shown evidence of efficacy in solid tumors at the doses and regimens studied. However, 
the preclinical work of Sykes et al (2016) [4] have demonstrated the efficacy of brequinar in a 
mouse model of leukemia, indicating that brequinar may be effective in patients with this type of 
leukemia. It is for this reason that study CCB-01 will study patients with AML.   


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A universal hallmark of leukemia is the arrest of leukemic myeloblasts at an immature and self-
renewing stage of development. Therapies that can overcome differentiation arrest caused by 
DHODH represent a powerful treatment strategy. A potential benefit of brequinar treatment is that 
brequinar has been identified as a compound that can inhibit DHODH.  
The major risk associated with brequinar is myelosuppression, particularly a decrease in platelet 
count. Patients with hematologic malignancies typically have a low platelet count due to their 
disease, and there is a risk that treatment with brequinar may worsen existing thrombocytopenia. 
3.7 RISK/BENEFIT OF RIBAVIRIN 
As presented above, ribavirin was associated with several complete, partial, and blast responses in 
two clinical trials of AML patients (Assouline et al., 2009 [17]; Assouline et al., 2015 [18]). 
Risks associated with ribavirin administration in 40% or greater of adult patients receiving 
ribavirin 
included 
fatigue/asthenia, 
headache, 
rigors, 
fevers, 
nausea, 
myalgia 
and 
anxiety/emotional lability/irritability. Hemolytic anemia occurred in approximately 13% of adult 
patients receiving ribavirin with interferon for hepatitis C; this effect was not observed in the 13 
AML patients treated with ribavirin (Assouline et al., 2009) with ribavirin monotherapy, but was 
reported in 14% of patients (4 of 29) in the Assouline et al., 2015 [18] study of ribavirin and low 
dose cytarabine. Additional safety information is provided in the ribavirin generic SPC (Appendix 
H Section 15.8). 
3.8 RISKS ASSOCIATED WITH PARTICIPATION IN THE CLINICAL STUDY 
In studies utilizing the weekly schedule of administration of brequinar in patients with refractory 
solid tumors, reversible myelosuppression, in particular thrombocytopenia, and mucositis have 
been the primary dose-limiting toxicities. In addition, skin rash, nausea/vomiting, fatigue, and 
leukopenia have been dose-limiting in trials utilizing other schedules of drug administration. The 
majority of these adverse effects have been less than grade IV in severity and resolve following 
discontinuation of dosing. Symptoms of tumor lysis syndrome have not previously been reported 
following exposure to brequinar, however clinicians will monitor for and treat this condition 
should it arise per the guidelines presented in Section 10.9. An increased risk of infection may 
occur due to the myelosuppressive effects of brequinar (particularly neutropenia); infection 
prophylaxis and treatment are described in Sections 10.10 and 10.11. Differentiation syndrome 
has been seen in other pro-differentiating agents and will be closely followed as described in 
Section 10.7.  
Risks associated with ribavirin administration in hepatitis C patients who also received interferon 
are presented in the ribavirin generic SPC found in Appendix H, Section 15.8. 
3.9 POSSIBLE INTERACTIONS WITH CONCOMITANT MEDICAL TREATMENTS 
Brequinar has been administered to subjects taking a variety of concomitant medications that are 
typical in cancer patients. No formal interaction studies have been conducted for these 


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medications, however, there have not been any reports of interactions with any medications during 
the clinical trials with more than 800 cancer patients.  
 
There is limited experience with ribavirin for treatment of AML and other hematologic 
malignancies and no formal interaction studies have been conducted for use of ribavirin with 
concomitant medications that are typical in cancer patients. However, experience with use of 
ribavirin and interferon in treatment of hepatitis C has concluded that ribavirin should not be given 
with nucleoside reverse transcriptase inhibitors such as didanosine or with azathioprine. Ribavirin 
should be taken with food. See ribavirin generic package insert, Appendix H Section 15.8. 
3.9.1 CYP Interactions 
No formal clinical drug-drug interaction studies have been performed for brequinar with 
medications commonly used in treating hematologic malignancies. The nonclinical studies 
performed to date have demonstrated there is no first-pass metabolism and there have been no 
apparent hepatotoxic effects in the clinical studies. Brequinar itself does not appear to be a 
substrate for metabolism by cytochrome P450 enzymes when tested under a variety of conditions. 
(See Brequinar Investigator’s Brochure [9]; nonclinical data on file with Clear Creek).  
Results of in vitro studies using both human and rat liver microsome preparations indicated little 
or no cytochrome P-450 enzyme-mediated metabolism of ribavirin, with minimal potential for P-
450 enzyme-based interactions (ribavirin generic SPC Appendix H Section 15.8). 
3.10 STEPS TO BE TAKEN TO CONTROL OR MITIGATE RISKS 
Guidelines for the prevention, monitoring and treatment of differentiation syndrome, tumor lysis 
syndrome, infection prophylaxis and growth factor support are provided in Section 10. 
Haptoglobin levels will be utilized to monitor possible hemolysis which was reported in some 
subjects taking ribavirin for hepatitis C (Vlierberghe et al., 2001 [26]) and some AML patients 
(Assouline et al., 2015 [18]). All subjects will be treated by highly experienced hematologic 
oncologists familiar with the treatment of pancytopenia and hemolytic anemia and their side 
effects. 


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4 
TRIAL OBJECTIVES 
4.1 PRIMARY OBJECTIVE 
The primary objective of this study is to determine the safety and tolerability of brequinar alone 
and in combination with ribavirin and the dihydroorotate dehydrogenase (DHODH) inhibitory 
activity of brequinar in adult patients with AML and other hematologic malignancies. 
4.2 SECONDARY OBJECTIVES 
The secondary objectives of this study are: 
•
To determine the overall response rate (ORR) including complete remission (CR), CR with 
incomplete hematologic recovery (CRi), morphologic leukemia-free state (MLFS), partial 
remission (PR) (criteria as defined in the ELN Guidelines, by Döhner et al., 2017 [10] and the 
Report of the National Cancer Institute-sponsored Workshop, Cheson et al., 1990 [25]) and 
complete remission with partial hematological recovery (CRh).
•
To assess the rate of overall survival (OS) and event-free survival (EFS)
•
To evaluate duration of response
•
To characterize the pharmacokinetic (PK) profile of brequinar.
•
To characterize the DHO plasma levels after oral dosing with brequinar.
4.3 EXPLORATORY OBJECTIVES 
The exploratory objectives of this study are: 
•
To assess the relationship between DHODH inhibition and the efficacy and safety of brequinar
alone and in combination with ribavirin.
•
To evaluate molecular and cellular biomarkers that may be predictive of antitumor level and/or
treatment resistance including cytogenetics, molecular profiling, and flow cytometry during
and after treatment.
•
To evaluate global gene expression profiles, DNA methylation profiles, and other potential
prognostic markers to explore predictors of antitumor activity and/or resistance to treatment.


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5 
TRIAL DESIGN 
This will be a Phase 1b/2a multi-center, open-label, non-randomized clinical trial to assess the 
safety, tolerability and efficacy of dose-adjusted brequinar alone and in combination with ribavirin 
in adult subjects with AML and other hematologic malignancies. The study will also assess the 
inhibition of DHODH and the PK profile of brequinar in plasma. Intra-subject dosing may be 
adjusted based on safety/tolerability, brequinar pharmacokinetics (PK), and DHO levels.  
Up to 27 subjects are planned to be entered in this trial. Cohort 1 enrolled 5 subjects. Cohort 2 
enrolled 6 subjects with a starting dose of 500 mg/m2 once weekly. Three Cohort 2 subjects 
discontinued from the study prior to Day 43 and may be replaced. 
Although the 500 mg/m2 starting dose of brequinar was well tolerated by many subjects, several 
subjects took as many as 4 to 5 weeks to achieve twice weekly dosing at doses lower than 500 
mg/m2. In order to more quickly achieve the desired twice weekly dosing schedule, any newly 
enrolled Cohort 2 subjects are to start with 350 mg/m2 once weekly. Approximately 3 additional 
subjects may be enrolled into Cohort 2. If Cohort 3 regulatory approval is achieved prior to 
completing Cohort 2, it is not required to complete Cohort 2 before beginning enrollment into 
Cohort 3. Cohort 2 subjects who are active in the study at the time of regulatory approval may roll 
over into Cohort 3.  
Cohort 3 will enroll approximately 6 to 9 subjects and may be followed by an expansion cohort of 
approximately 6 to 12 subjects. Cohort 3 and the Expansion Cohort will use the 350 mg/m2 starting 
dose. 
After both the brequinar 48h PK and 72h DHO level meet criteria described in the Individual Dose 
Adjustment Guidelines below, the subject is to move to twice weekly brequinar dosing on a 
continuing basis as tolerated. After moving to twice weekly brequinar dosing, the brequinar dose 
is to be reduced if needed per the algorithm below to achieve an 84h DHO of < 5000 ng/mL. After 
achieving a brequinar twice weekly dose that achieves 84h DHO < 5000 ng/mL, ribavirin dosing 
will begin at 1000 mg BID in combination with twice weekly brequinar. After initiating ribavirin 
dosing, the brequinar dose will continue to be adjusted using the dosing adjustment algorithm 
below. After brequinar has reached a stable dose, ribavirin will be increased 400 mg BID every 4 
weeks to a maximum of 1800 mg BID. 
Safety will be assessed utilizing physical examination, vital sign measurements, safety laboratory 
testing, 12-lead ECGs and bone marrow sampling. Bone marrow sampling will also be utilized to 
measure response. Tolerability will be assessed by spontaneously reported and elicited adverse 
events. DHO level will be measured using a validated assay. Brequinar PK will be analyzed using 
standard PK parameters. Haptoglobin levels may be utilized to assess hemolytic anemia. 
Dosing will continue for up to 12 months in the absence of unacceptable toxicity or disease 
progression. Subjects who discontinue for any reason prior to at least 4 weeks of the 
brequinar/ribavirin combination may be replaced. Safety will be assessed utilizing physical 
examination, vital sign measurements, safety laboratory testing, 12-lead ECGs and bone marrow 


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sampling. Bone marrow sampling will also be utilized to measure response. Tolerability will be 
assessed by spontaneously reported and elicited adverse events. DHO level will be measured using 
a validated assay. Brequinar PK will be analyzed using standard PK parameters.  
Study procedures are presented in detail in Section 8.  


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6 
TRIAL ENDPOINTS 
6.1 PRIMARY ENDPOINT 
• Safety/tolerability and DHO level relationship with safety and therapeutic brequinar levels   
6.2 SECONDARY ENDPOINTS 
• Rates of treatment-emergent adverse events. 
• Overall Response Rate (ORR) including CR, CRh, CRi, MLFS, or PR 
• Event-free survival (EFS). 
• Duration of response 
• PK profile of brequinar. 
• DHO plasma profile. 
6.3 EXPLORATORY ENDPOINTS 
• Relationship between DHODH inhibition and the efficacy and safety of brequinar.  
• Antitumor level based on molecular and cellular biomarkers including cytogenetics, molecular 
profiling, and flow cytometry during and after treatment. 
• Global gene expression profiles, DNA methylation profiles, and other potential prognostic 
markers to explore predictors of antitumor activity and/or resistance to treatment 


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7 
TRIAL POPULATION 
7.1 NUMBER OF SUBJECTS 
Subjects who meet all the inclusion and none of the exclusion criteria will be enrolled in the study 
until approximately 27 subjects have completed the study.     
7.2 INCLUSION CRITERIA 
1. Willing and able to provide written informed consent for the trial. 
2. Patients 18 years of age or older, with relapsed/refractory AML by World Health 
Organization (WHO) classification, T-cell leukemia (T-ALL), bi-lineal leukemia (BLL), 
or mixed phenotypic acute leukemia (MPAL) and who have exhausted available therapy.  
3. ECOG Performance Status 0 to 2. 
4. 12-lead ECG with no clinically unacceptable findings; adequate cardiac function/NYHA 
Class 0 to 2. 
5. Adequate hepatic function (unless deemed to be related to underlying leukemia). 
a. Direct bilirubin ≤ 2 x ULN 
b. ALT ≤ 3 x ULN 
c. AST ≤ 3 x ULN 
6. Adequate renal function as documented by creatinine clearance ≥ 50 mL/min based on the 
Cockcroft-Gault equation. 
7. In the absence of rapidly proliferative disease, the interval from prior leukemia-directed 
therapy to time of first dose of study drug will be at least 7 days for cytotoxic or non-
cytotoxic (immunotherapy) agents. Use of supportive care measures per institution’s 
standard of care is permitted at any time.  
8. The effects of brequinar on the developing human fetus are unknown.  For this reason, 
women of child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry and for the 
duration of study participation.  Should a woman become pregnant or suspect she is 
pregnant while she or her partner is participating in this study, she should inform her 
treating physician immediately.  Men treated or enrolled on this protocol must also agree 
to use adequate contraception prior to the study, for the duration of study participation, and 
for 90 days after completion of brequinar administration. 


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9. Male subjects must agree to refrain from sperm donation from initial study drug 
administration until 90 days after the last dose of study drug. 
7.3 EXCLUSION CRITERIA 
1. Patients in need of immediate leukapheresis. 
2. Any concurrent uncontrolled clinically significant medical condition, laboratory 
abnormality, or psychiatric illness that could place the participant at unacceptable risk of 
study treatment. 
3. QTc interval using Fridericia’s formula (QTcF) ≥ 470 msec. Participants with a bundle 
branch block and prolonged QTc interval may be eligible after discussion with the medical 
monitor. 
4. Pre-existing liver disease. 
5. The use of other chemotherapeutic agents or anti-leukemic agents is not permitted during 
study with the following exceptions: 
a. Intrathecal chemotherapy for prophylactic use or maintenance of controlled CNS 
leukemia. 
6. Presence of graft versus host disease (GVHD) which requires an equivalent dose of ≥ 
0.5mg/kg/day of prednisone or therapy beyond systemic corticosteroids (e.g. cyclosporine 
or other calcineurin inhibitors or other immunosuppressive agents used for GVHD). 
7. Active cerebrospinal involvement of AML, T-cell leukemia (T-ALL), bi-lineal leukemia 
(BLL), or mixed phenotypic acute leukemia (MPAL). 
8. Diagnosis of acute promyelocytic leukemia (APL). 
9. Clinically active hepatitis B (HBV) or hepatitis C (HCV) infection. 
10. Severe gastrointestinal or metabolic condition that could interfere with the absorption of 
oral study medication. 
11. Prior malignancy, unless it has not been active or has remained stable for at least 2 years. 
Participants with treated non-melanoma skin cancer, in situ carcinoma or cervical 
intraepithelial neoplasia, regardless of the disease-free duration, are eligible if definitive 
treatment for the condition has been completed. Participants with organ-confined prostate 
cancer with no evidence of recurrent or progressive disease are eligible if at the active 
surveillance stage, if hormonal therapy has been initiated or the malignancy has been 
surgically removed or treated with definitive radiotherapy. 


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12. Nursing women or women of childbearing potential (WOCBP) with a positive pregnancy 
test. 
13. Documented hemoglobinopathy. 
7.4 INCLUSION OF WOMEN AND MINORITIES 
Both men and women of all races and ethnic groups are eligible for this trial. 
 


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8 
STUDY TREATMENTS 
Up to 27 subjects are planned to be entered in this trial. Cohort 1 enrolled 5 subjects with a starting 
dose of 500 mg/m2 twice weekly. Cohort 2 enrolled 6 subjects with a starting dose of 500 mg/m2 
once weekly. Three Cohort 2 subjects discontinued from the study prior to Day 43 and may be 
replaced. 
Although the 500 mg/m2 starting dose of brequinar was well tolerated by most subjects, several 
subjects took as many as 4 to 5 weeks to achieve twice weekly dosing at doses lower than 500 
mg/m2. In order to more quickly achieve the desired twice weekly dosing schedule, any newly 
enrolled Cohort 2 subjects are to start with 350 mg/m2 once weekly. Approximately 3 additional 
subjects may be enrolled into Cohort 2. If Cohort 3 regulatory approval is achieved prior to 
completing Cohort 2, it is not required to complete Cohort 2 before beginning enrollment into 
Cohort 3. Cohort 2 subjects who are active in the study at the time of regulatory approval may roll 
over into Cohort 3.  
Cohort 3 will enroll approximately 6 to 9 subjects and may be followed by an expansion cohort of 
approximately 6 to 12 subjects. Cohort 3 and the Expansion Cohort will use the 350 mg/m2 starting 
dose. 
After both the brequinar 48h PK and 72h DHO level meet criteria described in the Individual Dose 
Adjustment Guidelines below, the subject is to move to twice weekly brequinar dosing on a 
continuing basis as tolerated. After moving to twice weekly brequinar dosing, the brequinar dose 
is to be reduced if needed per the algorithm below to achieve an 84h DHO of < 5000 ng/mL. After 
achieving a brequinar twice weekly dose that achieves 84h DHO < 5000 ng/mL, ribavirin dosing 
will begin at 1000 mg BID in combination with twice weekly brequinar. After initiating ribavirin 
dosing, the brequinar dose will continue to be adjusted using the dosing adjustment algorithm 
below. After brequinar has reached a stable dose, ribavirin will be increased 400 mg BID every 4 
weeks to a maximum of 1800 mg BID. 
Safety will be assessed utilizing physical examination, vital sign measurements, safety laboratory 
testing, 12-lead ECGs and bone marrow sampling. Bone marrow sampling will also be utilized to 
measure response. Tolerability will be assessed by spontaneously reported and elicited adverse 
events. DHO level will be measured using a validated assay. Brequinar PK will be analyzed using 
standard PK parameters. Haptoglobin levels may be tested to assess hemolytic anemia. 
Dosing will continue for up to 12 months in the absence of unacceptable toxicity or disease 
progression. Subjects who discontinue for any reason prior to at least 4 weeks of the 
brequinar/ribavirin combination may be replaced. 


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8.1 DESCRIPTION OF STUDY MEDICATIONS 
8.1.1 Brequinar 
Brequinar will be supplied as 100 and 250 mg capsules. Dosing will be determined on a mg/m2 
basis and will be adjusted based on tolerability, safety, brequinar PK, and DHO levels. Brequinar 
capsules should be taken whole; they should not be crushed or chewed. If the participant forgets 
to take the daily dose, he/she should make up the dose within 24 hours. Any medication remaining 
from extra supplies or missed doses should not be taken beyond the last scheduled day of brequinar 
administration but should be documented in the subject diary and returned by the participant for 
drug accountability purposes.  
8.1.2 Ribavirin 
Ribavirin will be supplied as 200 mg capsules. Dosing is a flat dose beginning at 1000 mg BID, 
escalating to 1400 mg and 1800 mg BID approximately every 4 weeks after a stable dose of 
brequinar has been achieved. Ribavirin should be taken with food (ribavirin generic SPC, 
Appendix H, Section 15.8). 
8.2 TREATMENT ADMINISTRATION 
Five subjects were enrolled in the now-completed Cohort 1. All subjects were dosed with twice 
weekly brequinar 500 mg/m2 for a range of 2 to 16 doses (one to 8 weeks). No additional subjects 
will be enrolled into Cohort 1. A total of 6 subjects were treated in Cohort 2 with a starting dose 
of 500 mg/m2 once weekly. These 6 Cohort 2 subjects took brequinar once weekly for at least two 
weeks (two total doses). Brequinar exposure and DHO levels were used to adjust the brequinar 
dose (if necessary) to meet brequinar PK and 72h DHO criteria described in Section 8.5.1. Subjects 
then moved to twice-weekly dosing (approximately every 3.5 days, e.g., Monday morning and 
Thursday evening) on a continuing basis. The brequinar dose was further adjusted if needed using 
the 84h DHO (trough) Criteria shown in Section 8.5.4.  
Three Cohort 2 subjects were not evaluable due to early discontinuation. Approximately 3 
additional subjects with a starting dose of 350 mg/m2 may be enrolled into Cohort 2 to replace 
these subjects. It is not necessary to complete enrollment in Cohort 2 if Cohort 3 regulatory 
approval is available before completing Cohort 2. 
For Cohort 3 and the expansion cohort, ribavirin will be added in combination with brequinar 
following a brequinar only period of approximately 3 to 6 weeks. Ribavirin dosing will begin as 
soon as brequinar dosing has moved to twice weekly and the twice weekly 84h DHO (DHO 84 
hours after a twice weekly brequinar dose) is confirmed to be < 5000 ng/mL. Cohort 3 may be 
followed by an expansion cohort of approximately 6 to 12 subjects. Brequinar PK and DHO 
samples will be obtained during Week 1. The results from Week 1 will be used to make decisions 
about the Week 2 dose and schedule. Subjects who meet the twice weekly brequinar PK and 72h 


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DHO criteria in Week 1 may proceed to twice weekly dosing with 350 mg/m2 in Week 2. For 
subjects whose brequinar PK and DHO levels do not meet the twice weekly criteria or who have 
unacceptable safety, decrease the dose to 200 mg/m2 once weekly. For these subjects, brequinar 
PK and DHO samples will also be obtained once daily on Days 1 – 4 during Week 2 (or when 
dosing resumes following an AE), and the Week 2 results will be used to make decisions about 
Week 3. If a subject still does not meet the twice weekly criteria when dosed at 200 mg/m2 once 
weekly, discontinue the subject. Subjects who discontinue for any reason prior to at least 4 weeks 
of the combination may be replaced with sponsor permission. The twice weekly brequinar dose 
may be adjusted as needed to establish the 84h DHO in the target range. 
Cohort 2 subjects who are ongoing at the time of Cohort 3 IRB approval (CCB-01 Amendment 
No. 08) and have begun twice weekly brequinar dosing may roll over into Cohort 3 and 
immediately begin ribavirin in combination with brequinar. 
Each dose of study drug is to be taken with approximately 240 mL of water. The ribavirin study 
medication should be taken with food. Each dose will generally consist of multiple capsules; the 
study medication does not need to be swallowed all at once but can be spread over up to 
approximately 15 minutes as needed. The chosen dosing schedule needs to accommodate clinic 
visits as well as shipping and receipt of the brequinar/DHO samples and results needed for dosing 
adjustments. Sample processing and shipping procedures will be addressed in a separate laboratory 
manual.  
8.3 SAFETY/TOLERABILITY 
Safety/tolerability is assessed for each subject at each study visit using the Common Terminology 
Criteria for Adverse Events v4.03 (CTCAE). Cohort 1 had a fixed starting dose of 500 mg/m2 with 
no dose escalation permitted. Cohort 2 started with 500 mg/m2 once weekly and had adjustments 
made to dose and dose frequency using safety/tolerability, brequinar exposure (PK), and DHO 
levels. As described above, any replacement Cohort 2 subjects will start at 350 mg/m2 once weekly 
with the goal of moving rapidly to twice weekly dosing. Cohort 3 and Expansion Cohort brequinar 
subjects will have a starting dose of 350 mg/m2. Ribavirin dosing will begin at 1000 mg BID. See 
Section 8.5 for brequinar dose adjustments and ribavirin dosing instructions. 
Safety at the subject level is defined in Section 8.3.1; hematologic toxicity is defined in Section 
8.3.2. The following adverse events are commonly observed in patients with hematologic 
malignancies and should be differentiated from possible adverse effects of brequinar: fatigue, 
fever, thrombocytopenia and other cytopenias, infection, pallor, shortness of breath, weight loss, 
night sweats, and anorexia. Any of these events can be serious in nature and may result in death. 
Disease progression is considered a lack of efficacy rather than an adverse event. Death from 
disease progression is to be reported as presented in Section 10. Hemolysis was reported in 
approximately 13% of subjects taking ribavirin with interferon for hepatitis C (see Appendix H, 
Section 15.8). A decrease in haptoglobin to below the lower limit of quantification for the local 
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treatment, which may lead to discontinuation of ribavirin dosing after discussion with the Sponsor 
and Medical Monitor. 
Adverse events commonly observed in patients treated with brequinar are provided in the 
Investigator’s Brochure and include thrombocytopenia, nausea, anemia, diarrhea, vomiting, 
leukopenia, stomatitis, rash, granulocytopenia, fatigue, and infection. In a study of 209 subjects 
treated once-weekly (DuP 785-012), the deaths of three patients were attributed to study drug 
toxicity (two to hemorrhage, one following acute renal failure). Severe toxicities grades (Grades 3 
to 4) which typically led to discontinuation in this study included hematologic toxicities (anemia, 
thrombocytopenia, leukopenia, granulocytopenia), digestive system toxicity (nausea, vomiting, 
stomatitis, others including gastric hemorrhage) and mucositis. 
In most instances, drug related toxicities were clinically manageable and reversible upon 
discontinuation of brequinar treatment. In a study where brequinar was dosed twice-weekly to 
solid tumor subjects, no drug-related deaths occurred. Stomatitis/mucositis was observed in 13 of 
the 19 (68%) patients across all doses. Mild to moderate (Grades 1 and 2) stomatitis was observed 
in 10 patients with a more severe (Grade 3) stomatitis seen in 3 patients at doses over 600 mg/m2. 
One patient at 600 mg/m2 had drug discontinuation due to drug-related stomatitis. 
Myelosuppression was the main dose-limiting toxicity (DLT) with thrombocytopenia (Grades 1-
4), observed after 2 to 9 doses above 600 mg/m2. Any of these events reported with brequinar use 
can be serious in nature and may result in death. 
Prescriptions can be provided in advance for supportive care for common brequinar-related AEs 
such as mucositis. 
Adverse Events associated with ribavirin administration in 40% or greater of adult patients 
receiving ribavirin and interferon in the hepatitis C studies included fatigue/asthenia, headache, 
rigors, fevers, nausea, myalgia and anxiety/emotional lability/irritability. Hemolytic anemia 
occurred in approximately 13% of adult hepatitis C patients receiving ribavirin with interferon. 
Hemolytic anemia was observed in 0 of 13 AML patients treated with ribavirin 
monotherapy (Assouline et al., 2009 [17]) and 4 of 29 (14%) of patients treated with 
ribavirin and LDAC (Assouline et al., 2015 [18]). Additional safety information is provided in 
the ribavirin generic SPC (Appendix H Section 15.8). 
8.3.1 Safety/Tolerability – Subject Level 
Safety/tolerability is assessed for each subject at each study visit using the Common Terminology 
Criteria for Adverse Events v4.03 (CTCAE). Acceptable safety/tolerability for a subject through 
Day 42 is defined as no ≥ Grade 3, treatment-emergent, study-drug-related, non-hematologic 
adverse events. Due to the expected hematologic profile associated with AML and other 
hematologic malignancies, hematologic AEs of any grade will not be considered a DLT during the 
first 42 days of dosing (i.e., assessed at the visit conducted on Day 43). Exceptions to the non-
hematologic Grade 3 criterion are provided in Table 8-1.  
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If a dose is held due to safety/tolerability issues, the subject should continue to have scheduled 
visits and assessments. 
If AEs have not resolved to ≤ Grade 2 after two weeks without dosing, dosing is to be discontinued 
for this subject. 
Table 8-1. Exceptions to Grade 3 Nonhematologic AEs  
Condition 
Exception Description  
Nausea/ 
Emesis 
Grade 3 nausea and/or emesis resolving to less than or equal to Grade 2 or baseline within 
1 week after the use of an optimal antiemetic regimen based on standard practice. 
Diarrhea 
Grade 3 diarrhea resolving to less than or equal to Grade 1 or baseline within 1 week after 
receiving the maximal supportive therapy based on standard practice. 
Laboratory 
abnormalities 
Asymptomatic Grade 3 laboratory abnormalities that are not considered to be clinically 
significant. 
Mucositis 
Grade 3 with duration < 1 week 
Fatigue 
Grade 3 with duration < 2 weeks 
After completion of the first 42 days of treatment, the definition of unacceptable safety is expanded 
to include signs of hepatotoxicity (≥ Grade 2 toxicity for ALT and AST). Dosing is to be held for 
at least one week (i.e., two doses if twice weekly) for subjects who experience hepatotoxicity; 
dosing may resume only if the hepatotoxicity AE resolves to ≤ Grade 1 within two weeks. If the 
subject experiences a second episode of ≥ Grade 2 hepatotoxicity after resuming dosing, dosing is 
to be discontinued for that subject. 
8.3.2 Hematologic Toxicity 
After the subject has completed the first 42 days of treatment, the definition of unacceptable safety 
expands to include hematologic AEs defined as prolonged neutropenia with ANC < 500 from the 
start of therapy in the absence of disease, ≥ Grade 4 neutropenia, and/or ≥ Grade 4 
thrombocytopenia, with a hypocellular bone marrow and no greater than 5% marrow blasts lasting 
for 2 weeks or more. Anemia will not be considered a hematologic AE for the definition of 
unacceptable safety. Febrile neutropenia is also excluded from the DLT definition for this 
population. For clinic visits when bone marrow sampling is scheduled, the timing of the bone 
marrow sampling can be adjusted to ensure that the results are available at the time of the clinic 
visit. Hemolytic anemia has been reported in approximately 13% of subjects taking ribavirin and 
interferon alfa-2a for hepatitis C. A decrease in haptoglobin level below the lower limit of normal 
(LLN) for the local laboratory will be used to trigger the investigation of possible hemolysis in 
subjects taking the brequinar/ribavirin combination or ribavirin alone and may lead to 
discontinuation of ribavirin after discussion with the Investigator, Sponsor and Medical Monitor. 
Haptoglobin testing should be conducted prior to administering any blood products transfusions 
when possible as transfusions may influence haptoglobin levels.  


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8.4 COHORT STARTING DOSES 
Cohort 1 treated 5 subjects at 500 mg/m2 twice weekly. Cohort 2 treated 6 subjects with this 
starting dose once weekly. Three Cohort 2 subjects discontinued prior to Day 43 and may be 
replaced using a starting dose of 350 mg/m2. Cohort 3 and Expansion cohort subjects will have a 
starting dose of 350 mg/m2. Each subject’s brequinar dosing frequency and dose may be adjusted 
as shown in the following sections. 
8.5 INDIVIDUAL DOSE ADJUSTMENT GUIDELINES 
Pre-clinical evidence (Sykes et al., 2016 [4]) suggests that a twice-weekly dose is most likely to 
lead to efficacy, therefore the goal is to adjust the brequinar dose to allow all subjects to dose on a 
twice-weekly basis. In order to move to twice-weekly dosing as quickly as possible, Cohort 3 
subjects will start with a once weekly dose of brequinar of 350 mg/m2. If the subject meets twice 
weekly dosing criteria with this dose, move the subject move to twice weekly dosing with 350 
mg/m2 in Week 2. If the twice weekly criteria are not met in Week 1 or there is unacceptable 
safety, decrease the dose for Week 2 to 200 mg/m2 (or when dosing resumes following an AE) and 
dose once. If the subject now meets dosing criteria with 200 mg/m2, begin twice weekly dosing 
with 200 mg/m2 in week 3 or as soon as safety is acceptable. If the twice weekly dosing criteria 
are not met with 200 mg/m2, discontinue this subject. Subjects who meet twice weekly dosing 
criteria will dose twice weekly (approximately every 3.5 days, e.g., Monday morning and 
Thursday evening) on a continuing basis.  
After beginning twice weekly dosing, the brequinar dose is to be further reduced (if needed) to 
achieve an 84h DHO < 5000 ng/mL.  
Ribavirin dosing will begin when brequinar twice weekly dosing results in an 84h DHO < 5000 
ng/mL. See “Ribavirin Dosing” below for further instructions regarding ribavirin dosing.  
After starting ribavirin dosing, the twice weekly brequinar dose is to be further adjusted using the 
84h DHO algorithm shown below. There is no upper or lower brequinar dose limit after achieving 
twice weekly dosing and ribavirin dosing has started. The 84h DHO level obtained 84 hours after 
a twice weekly brequinar dose will be used to adjust the next dose as needed. This brequinar dose 
adjustment may be made every two weeks, if necessary. 
Dose increases and continued dosing must first meet acceptable safety requirements as described 
in Section 8.3.1. If unacceptable safety occurs, hold dosing until AE resolves to ≤ grade 2, reduce 
dose by 150 mg/m2 and resume dosing. Discontinue the subject if a dose reduction leads to a dose 
of zero or the available capsule strengths cannot accommodate the designed mg/m2 dose. If 
brequinar PK or DHO levels are not available for dose adjustment decisions, hold dosing until 
results are available. 
The dose adjustment procedures and criteria may be revised after each preceding cohort’s safety, 
brequinar PK, DHO plasma levels, and bone marrow results have been reviewed. The dose 
adjustment process and criteria are described in the following sections. 


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8.5.1 Brequinar Exposure (BRQ PK) and 72h DHO Criteria to Set Twice-Weekly Dosing 
Both brequinar exposure (pharmacokinetics, PK) and dihydroorotate (DHO) levels are utilized to 
set the twice weekly dose. For Cohort 3, the initial goal is to identify a dose that results in brequinar 
PK approximately 48 hours after dosing of less than or equal to 5 mcg/mL (48h BRQ PK ≤ 5 
mcg/mL). Next check the DHO results obtained 48 and 72 hours after dosing. The twice weekly 
DHO criteria are that the DHO obtained 72 hours after dosing must be less than the DHO obtained 
48 hours after dosing (i.e., on a downward slope). In addition, the DHO level at 72 hours must be 
less than 5000 ng/mL. To summarize, 72h DHO < 48h DHO (on a downward slope) AND 72h 
DHO <5000 ng/mL. See the algorithm to set the twice weekly dose for Cohort 3 in Table 8-2 and 
Figure 8-1.  
Table 8-2. Algorithm to Set Twice-Weekly Dose for Cohort 3/Expansion Subjects (Starting 
Dose 350 mg/m2) 
Brequinar PK* 
72h DHO** 
Action 
48h BRQ PK 
> 5 mcg/mL 
NA 
Decrease dose to 200 mg/m2 and continue weekly dosing, 
reassess BRQ PK 
BRQ PK  
Criteria Met* 
72h DHO Criteria  
NOT MET** 
Decrease dose to 200 mg/m2 and continue weekly dosing, 
reassess 72h DHO criteria 
BRQ PK  
Criteria Met* 
72h DHO Criteria  
MET** 
Begin twice-weekly dosing Week 2 or after 
*  Brequinar PK (BRQ PK) Criteria for Cohort replacements and Expansion Cohort: 48h BRQ ≤ 5 mcg/mL 
**72h DHO Criteria: 72h DHO < 48h DHO (on a downward slope) AND 72h DHO <5000 ng/mL 
 


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Figure 8-1. Algorithm to Set Twice-Weekly Dose 
8.5.2 Ribavarin in Combination with Brequinar 
Beginning with Cohort 3 and the expansion cohort, ribavirin will be added beginning at 1000 mg 
BID following the initial brequinar only period. Ribavirin dosing will begin as soon as brequinar 
dosing has moved to twice weekly and the twice weekly 84h DHO (DHO 84 hours after a twice 
weekly brequinar dose) is confirmed to be < 5000 ng/mL, expected to be a period of approximately 
3 to 6 weeks. See Figure 8-2. 
8.5.3 Ribavirin Dose Adjustment 
Ribavirin dosing in combination with brequinar will be continued at 1000 mg BID for 
approximately 4 weeks or until brequinar has reached a stable twice weekly dose, whichever is 
longer. Approximately 4 weeks after reaching the twice weekly stable brequinar dose, increase the 
ribavirin dose 400 mg BID. Increase the ribavirin dose another 400 mg BID after another 4 weeks 
to a total of 1800 mg BID.  This dose will continue until the subject meets the criteria for study 
discontinuation (see Section 8.9). If suspected ribavirin-related toxicity occurs, hold ribavirin 
dosing for 2 weeks. If the ribavirin-related toxicity resolves to < Grade 2, decrease the ribavirin 
dose by 400 mg BID and resume dosing at the reduced dose. See Figure 8-2. Either brequinar or 
ribavirin may continue to be administered as a single agent if either study drug is discontinued due 


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to unacceptable safety related to either agent. Cohort 2 subjects rolling over into Cohort 3 must 
meet the requirements for twice weekly dosing before beginning ribavirin dosing. 
 
Figure 8-2. Algorithm to Add and Adjust Ribavirin 
 
8.5.4 Dose Adjustment Using 84h DHO  
After starting ribavirin dosing, the twice weekly brequinar dose is to be further adjusted using the 
84h DHO twice weekly adjustment algorithm shown below. There is no upper or lower brequinar 
dose limit after achieving twice weekly dosing and ribavirin dosing has started. The 84h DHO 
level obtained 84 hours after a brequinar dose will be used to adjust the next dose as needed. This 
brequinar dose adjustment may be made every two weeks, if necessary. 
This brequinar dose adjustment may be made on a continuing basis. If DHO levels are not available 
for dose adjustment decisions, confirm safety is acceptable but hold the dose until results are 
available. As soon as results are available, adjust dose as needed following criteria and resume 
dosing. Further adjustments are permitted using the 84h DHO results during twice weekly dosing. 
There is no maximum or minimum allowable dose during twice weekly dosing.  See Table 8-3 and 
Figure 8-3.  
 
 


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Table 8-3. Algorithm to Adjust Twice-Weekly Dose using 84h DHO for Cohort 3 and 
Expansion Cohort 
84h DHO Criteria 
Action 
84h DHO < 1500 ng/mL 
Increase next week's dose by 75 mg/m2 
84h DHO ≥ 1500 ng/mL and < 5000 ng/mL 
Stable Dose. Check 84h DHO weekly x 12 weeks then 
every 2 weeks. Adjust dose PRN per 84h DHO criteria. 
84h DHO ≥ 5000 ng/mL 
HOLD. Notify subject not to take next dose. Hold dosing 
for one week. If next Day 1 84h DHO is < 5000 ng/mL, 
decrease next dose by 75 mg/m2 and resume twice-weekly 
dosing. If next Day 1 84h DHO ≥ 5000 ng/mL, no further 
dosing, discontinue the subject. 
 
 
Figure 8-3. Algorithm to Adjust Dose Using 84h DHO  
Each subject will continue twice-weekly dosing at the individually adjusted dose for up to 12 
months (total time from first dose) in the absence of unacceptable toxicity or disease progression. 
Additional intra-subject brequinar dose adjustment is permitted at any time throughout the study 
based on safety/tolerability and 84h DHO levels. Subjects who discontinue for any reason prior to 
completing at least 4 weeks of combination therapy may be replaced.  


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8.6 MEDICATION/AE DIARY 
The participant will be provided with a study calendar of events and will be required to maintain 
a medication diary of each dose of medication. Subjects will be instructed to record the date and 
time each dose of brequinar is taken, indicating if any doses are missed. Subjects will be instructed 
to record adverse events and changes in concomitant medications in the subject calendars/diaries.  
Subjects will be instructed and reminded to bring the medication diary to each clinic visit for 
review. The diary will be returned to clinic staff at the end of each cycle and a new diary dispensed. 
8.7 BONE MARROW BIOPSY 
The participant will have a bone marrow sampling (aspiration and core biopsy) at baseline (prior 
to dosing), one for research purposes at the Week 4 visit (Day 22 ± 7 days), and one 4 weeks after 
initiating the combination with ribavirin (expected to be approximately Day 43 ± 7 days); 
thereafter, bone marrow sampling will be obtained every 12 weeks  ± 7 days (or per institutional 
standard of care) and at the Final Visit. If a participant develops frank evidence of progression of 
disease during the course of treatment based on laboratory or clinical assessment, he/she will be 
discontinued from study treatment and can proceed with additional management off-study per 
discretion of the treating oncologist. If the results of the bone marrow sampling reveal disease 
progression at approximately Visit 7 (Day 43) (defined as 43 days after initiating treatment or after 
6 complete weeks after initiating study drug treatment regardless of number of doses, but with at 
least 4 weeks of brequinar/ribavirin combination therapy), then the participant will be taken off 
treatment. Timing of the bone marrow biopsy procedure may be adjusted to ensure that results are 
available for any visit. Bone marrow sampling will include analysis of the aspirate on smear, core 
biopsy by microscopy, flow cytometry, and karyotype for cytogenetics. Molecular analysis will be 
performed on the screening bone marrow samples. 
8.8 EXPANSION COHORT 
Following completion of Cohort 3, an expansion cohort of up to 6 to 12 subjects may be added to 
further define the dosing, BRQ PK and DHO criteria and assess the safety, tolerability, and 
biological activity of the dosing scheme.  
The expansion cohort will follow the same visit procedures as Cohort 3.  
8.9 STUDY DRUG DISCONTINUATION 
If there is evidence of stable disease, partial response, or complete remission (CR, CRi, or CRh) 
at or prior to approximately Visit 7 (43 days, or at least 4 weeks after initiation of ribavirin) or 
with the agreement of the principle investigator and sponsor, the participant may continue with 
brequinar treatment until there is evidence of disease progression, intolerable toxicity, or for a 
maximum of one year. Study drug will be discontinued for an individual subject if there is evidence 
of unacceptable safety/tolerability that does not resolve to ≤ Grade 2 within 2 weeks after stopping 
brequinar or ribavirin dosing.  


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After treatment discontinuation, participants will be monitored for a minimum of 14 days after the 
last dose of brequinar or ribavirin or until they receive another treatment for their AML or other 
hematologic malignancy. Participants may discontinue treatment to receive a stem cell 
transplantation upon remission, if indicated. 
Suspected drug-related toxicities that lead to discontinuation should be considered separately for 
brequinar and ribavirin. It is not required to discontinue the subject from the study if either 
brequinar or ribavirin must be stopped; the subject may continue on single agent therapy with 
agreement of the PI, Sponsor, and Medical Monitor. 
The reason for study drug discontinuation will be recorded in the source document and the eCRF.  
8.10 BREQUINAR PHARMACOKINETICS (PK)/DIHYDROOROTATE (DHO) 
PLASMA LEVELS/FLOW CYTOMETRY 
Plasma samples for brequinar/DHO levels and peripheral blood for flow cytometry are to be 
obtained using the following schedule and as shown in Section 15.3: 
• Cycle 1 Week 1: Day 1 (prior to dosing, and 1, 2, 4, and 6 hours after dosing), Days 2, 3, 
and 4 (approximately 24h, 48h, and 72h after dosing) 
• Cycle 1 Week 2 (if needed due to dose reduction): Day 1 prior to dosing, Days 2, 3, and 4 
(approximately 24h, 48h, and 72h after dosing).  
• After starting twice-weekly dosing, obtain sample prior to dosing on Days 1 and 8 of each 
Maintenance Dose Cycle up to Week 12 from initial dose, then once every 2 weeks (i.e., 
Day 1 of each two-week Maintenance Dose Cycle). 
• Final Visit: obtain brequinar, DHO, and flow cytometry samples. 
The samples will be processed and shipped per the instructions in the laboratory manual. If the 
samples are drawn on a weekend, holiday, or after hours, obtain the samples on the specified study 
day and ship the samples as soon as possible. Directions regarding sample processing and shipping 
are presented in a separate laboratory manual. 
8.11 CONCOMITANT MEDICATION/TREATMENT 
Record the name, start date, indication for use, and whether ongoing or stopped for 
medications/treatments taken within two weeks prior to study entry as well as any medications 
taken during the study are to be recorded. The use of other chemotherapeutic agents or anti-
leukemic agents is not permitted during study with the following exceptions: 
• Intrathecal chemotherapy for prophylactic use or maintenance of controlled CNS leukemia; 
• Use of supportive care measures per institution’s standard of care are permitted at any 
time including hydroxyurea for the purpose of leukemic cytoreduction.  


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Transfusions are to be recorded beginning from up to 2 weeks prior to first dose of study drug 
and ongoing throughout the individual’s participation. 
8.11.1 Gastric pH 
Whenever possible, participants should discontinue proton pump inhibitors, antacids, and H2-
receptor antagonists which increase the gastric pH and may reduce absorption of oral medications 
including brequinar resulting in decreased systemic exposure. Discontinuation of these 
medications is not required but is strongly recommended. Ribavirin is to be taken with food 
(ribavirin generic SPC, Appendix H, Section 15.8). 
8.12 TREATMENT COMPLIANCE 
Compliance will be assessed by reviewing the subject’s medication diary and accounting of 
returned clinical supplies.  
8.13 STORAGE, STABILITY, LABELING AND PACKAGING 
8.13.1 Storage and Stability 
The study drug is stored at room temperature. Stability testing is ongoing. 
8.13.2 Labeling and Packaging  
Each bottle for subject use will be labeled with at least the following information: 
For Clinical Trial Use Only 
Study Number: 
CCB-01 
Contents: 100 or 250 mg Brequinar capsules 
For oral use only. Take with approximately 8 ounces water every 3.5 days. 
Subject Number: XX-XXXX 
 
Treatment Duration: As directed 
IND: 138355             Clinical Batch Number: XXXXXXX  
Expiration Date: 
TBD 
Storage: Store at controlled room temperature  
Study Sponsor:  Clear Creek Bio, Inc., 585 Massachusetts Avenue, 4th 
Floor, Cambridge MA 02139 
Caution: New Drug – Limited by US Federal Law to Investigational Use
Only. To be used by Qualified Investigators only. 
8.13.3 Blinding and Randomization 
The trial will be conducted in an open-label manner. The brequinar capsules will be provided to 
each participating institution in bulk to be dispensed by the institution’s pharmacist per the 


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designated mg/m2 dose for each subject. No randomization codes are necessary for this open-label 
study. 
8.13.4 Unblinding/Expectedness 
It is not necessary to break the blind for this open label study as the treatment is known for each 
subject. 
Expectedness will be determined by establishing whether the adverse event is among those 
identified in the protocol and the Investigator’s Brochure or are commonly associated with AML 
and other hematologic malignancies.  The event will be considered expected if commonly 
associated with these diseases in the opinion of the investigator or Medical Monitor even if not 
specifically listed in these documents.  
8.13.5 Study Drug Accountability 
The study drug provided is for use only as directed in this protocol. 
The Investigator must keep a record of all study medication received, used and discarded.  It must 
be clear from the records which subject received which medication. Adequate drug is to be 
dispensed for each dosing period to allow for dosing every 3.5 days during the period until the 
next clinic visit, plus one additional dose to act as a spare in the event medication is unable to be 
used.  
The pharmacist/staff member responsible for drug accountability is to document the date and time 
of dispensing and for what subject the study drug was intended (i.e., record subject initials and 
birth date or other unique identifier). A pharmacy manual will be provided by the Sponsor detailing 
how to calculate the mg/m2 dose together with examples of combinations of the 100 and 250 mg 
capsules to provide the most efficient use of the clinical supplies. 
At the end of the study, any unused study drug will be returned to the Sponsor for destruction or 
destroyed locally; disposition of study drug will be documented.   
The Sponsor will be permitted access to the trial supplies at any time within usual business hours 
and with appropriate notice during or after completion of the study to perform drug accountability 
reconciliation. 
8.13.6 Prohibited Medications 
Experience with use of ribavirin with interferon in treatment of hepatitis C has concluded that 
ribavirin should not be given with nucleoside reverse transcriptase inhibitors such as didanosine 
or with azathioprine. See ribavirin generic SPC, Appendix H Section 15.8. 
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9 
CONDUCT OF THE TRIAL 
9.1 ETHICAL AND REGULATORY CONSIDERATIONS 
The trial will be performed in accordance with the Declaration of Helsinki (1964) (Appendix F) 
as revised in Tokyo (1975), Venice (1983), Hong Kong (1989), South Africa (1996), Scotland 
(2000, Note of Clarification 2002 & 2004) and Seoul 2008 (Appendix A), and Fortaleza (Brazil) 
(2013), and with the ICH Tripartite Guideline on Good Clinical Practice (CPMP/ICH/135/95, 
Jan.97) and US FDA Regulations. 
9.2 INFORMED CONSENT 
The principles of informed consent in the current edition of the Declaration of Helsinki must be 
implemented in each clinical study before protocol-specified procedures are carried out.  Informed 
consent must be obtained in accordance with US Code of Federal Regulations (21 CFR Part 50) 
as well as local and national regulations. Information should be given in both oral and written form 
whenever possible and deemed appropriate by the Institutional Review Board (IRB). Subjects and 
their relatives, if necessary, must be given ample opportunity to inquire about details of the study. 
The Investigator or qualified designated person will verbally inform subjects as to the nature, 
expected duration and purpose of the trial, the administration of the Investigational Medicinal 
Product (IMP), and the hazards involved, as well as the potential benefits that may come from 
treatment with this IMP. The trial procedures will be explained in lay language and any questions 
will be answered. The subjects will be given an IRB-approved consent form. The subjects will be 
given appropriate time to consider their participation in the trial and have any questions answered 
prior to signing the consent form. If a subject agrees to participate, he/she will sign and date an 
informed consent form and be provided with a copy of the signed consent. All subjects who sign 
an informed consent form are to be recorded on the applicable screening log.   
The subject will be informed that his/her medical records will be subject to review by the Sponsor, 
Sponsor’s representatives, and possibly by a representative of the Food and Drug Administration 
and other relevant regulatory authorities. Subjects will be informed that they are free to refuse 
participation in this clinical investigation, and if they should participate, it will be made clear to 
them that they may withdraw from the trial at any time without prejudicing further medical care 
they may require. The subject will receive a copy of the consent form as well as an information 
sheet about the trial.  
Signed written informed consent must be obtained from every subject prior to any study-specific 
procedures.  Standard procedures carried out prior to signing the informed consent but within the 
time constraints of the protocol may be used for baseline evaluation; they need not be repeated. 
An original signed informed consent form will be filed in the Investigator Site File and will be 
subject to review by the Sponsor; a copy will be given to the subject and a copy will be filed with 
the subject’s medical notes. 


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The study should be discussed with the potential participant only after an initial review of his/her 
clinical status and appropriateness for participation have been evaluated to determine if he/she 
meets the subject selection criteria. 
A sample subject information sheet and consent form is attached to this protocol as Appendix E.  
The final version at each institution may differ depending on institutional requirements and 
standard formats. This protocol will not be amended for site specific changes to the sample. 
9.3 INSTITUTIONAL REVIEW BOARD / ETHICS COMMITTEES 
It is the responsibility of the Investigator to submit the protocol, consent form and information 
sheet to the IRB. An Investigator’s Brochure will be available for review by the IRB. The protocol 
and consent form must be approved by the IRB prior to the recruitment of the first subject. The 
template consent form may be revised in accordance with site-specific requirements with Sponsor 
review and approval. A copy of the IRB written approval must be provided to the Sponsor and 
investigator before the trial may start at that institution. Written approval from the IRB is also 
required for substantial protocol amendments prior to their implementation.    
A substantial amendment may arise from changes to the protocol or from new information relating 
to the scientific documents in support of the trial.  Amendments are “substantial” when they are 
likely to have an impact on: 
• the safety or physical or mental integrity of the subjects; 
• the scientific value of the trial; 
• the conduct or management of the trial; or 
• the quality or safety of any IMP used in the trial. 
If it is necessary to change or deviate from the protocol to eliminate an immediate hazard to the 
subjects, the Investigator will notify the Sponsor and the IRB of the new events and the measures 
taken as soon as possible.   
The Investigator will report promptly to the Sponsor and IRB any new information that may 
adversely affect the safety of the subjects or the conduct of the trial. On completion of the trial, the 
Investigator will inform the applicable IRB as per local IRB requirements that the trial has ended. 
If the study is terminated for any reason, the investigator will return all clinical supplies and study-
related equipment supplied by the Sponsor to the Sponsor unless otherwise specified.  
9.4 SCHEDULE OF EVENTS 
Physical examinations, vital signs, ECG, laboratory assessments, bone marrow sampling and other 
observations will be undertaken by experienced personnel throughout the study based on the 


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Schedule of Events. Standard chromosomal and mutational testing will be performed per 
institutional guidelines. 
See 15.1 Schedule of Events in Appendix A for the full list of study assessments and timings.  
Blood chemistry tests include blood urea nitrogen (BUN), creatinine, alkaline phosphatase (ALP), 
alanine amino transferase (ALT), aspartate amino transferase (AST), bilirubin, total protein, 
albumin, glucose, serum electrolytes (sodium, potassium, chloride, carbon dioxide/bicarbonate, 
and calcium), and lactate dehydrogenase (LDH).  
Hematology tests include hemoglobin, hematocrit, complete blood count with full differential, 
platelet count, peripheral blast count, and haptoglobin. Haptoglobin will be assessed pre-dose on 
the day ribavirin dosing is started, and also one week after starting ribavirin, 4 weeks after 
starting ribavirin, and one week after adjusting the dose of ribavirin. A haptoglobin result below 
the lower limit of normal (LLN) for the local laboratory will prompt a discussion with the 
Medical Monitor, Sponsor, and PI regarding whether the decrease is related to ribavirin use and 
whether the subject should stop dosing with ribavirin. Haptoglobin should be drawn prior to 
transfusion of blood products when possible. 
In addition to the already scheduled chemistry assessments, subjects taking potentially hepatotoxic 
drugs are permitted to have more frequent monitoring than indicated in the schedule of events, if 
ordered by the study team. 
9.5 STUDY CONDUCT 
9.5.1 Screening Visit (Study Days -14 to -1) 
These procedures must be completed within the 14 days prior to starting dosing. Obtain the 
subject’s written informed consent, then collect baseline information: 
- Demographics (height, weight, date of birth, gender, race, ethnicity); body surface area 
(BSA) determined at Screening will be utilized for all BSA-driven mg/m2 dosing 
calculations throughout the study. 
- Pertinent medical/surgical history (including AML/other hematologic malignancy 
diagnosis and laboratory and clinical evidence of progression, previous AML/other 
hematologic malignancy treatment, and any available chromosomal and mutational testing 
results per institutional guidelines) and concomitant medications. 
- Physical examination (including weight).  
- Vital signs (heart rate, respiratory rate, seated blood pressure, body temperature).  
- Pregnancy test for women of childbearing potential (WOCBP).  
- ECOG performance assessment.  
- Hematology/chemistry. 
- 12-lead ECG with QTcF.  


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- Standard chromosomal and mutational testing per institutional guidelines. 
- Bone marrow sampling. 
- Confirm subject meets all inclusion and no exclusion criteria. 
9.5.2 Treatment 
The treatment period begins with Cycle 1, Day 1 of the first 2-week dosing cycle. The laboratory 
manual provides procedures for processing, storage, and shipment of brequinar PK, DHO, and 
flow cytometry samples. If brequinar PK or DHO levels are not available for dose adjustment 
decisions, confirm safety is acceptable and continue to dose using the subject’s current dosing 
frequency and current dose until results are available. 
9.5.3 Dose Adjustment: Cycle 1 Week 1 (or Week 2 if dose reduced) 
Week 1 (or Week 2) Day 1  
- Collect any adverse events or new concomitant medications since Screening.  
- Collect samples for baseline (pre-dose) brequinar/DHO, flow cytometry, and 
hematology/chemistry.  
- Conduct physical examination (including weight), vital signs, pregnancy test for WOCBP 
if >4 weeks since last test and 12-lead ECG if >4 weeks since last test.  
- Review results and confirm subject remains eligible for the study.  
- Dispense study medication.  
- Subject is to take the first dose at the clinic and remain for brequinar/DHO/flow cytometry 
sampling. Collect samples at 1, 2, 4, and 6 hours post dose during Week 1 only. 
- Dispense the subject’s calendar/diary. The diary will collect dates/times of study medication 
administration and AEs/new concomitant medications.  
- This week’s procedures may be repeated for Week 2 if necessary, with the exception that 
PK/DHO samples are to be obtained pre-dose only on Day 1 of Week 2 in addition to the 
daily samples on Days 2, 3, and 4. 
Week 1 or 2 Day 2:  
- Collect 24h post dose brequinar/DHO and flow cytometry samples.  
Week 1 or 2 Day 3:  
- Collect 48h post dose brequinar/DHO and flow cytometry samples.  
Week 1 or 2 Day 4:  
- Collect 72h post dose brequinar/DHO samples and flow cytometry samples.  


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9.5.4 Maintenance Dose Cycle  
Once a subject reaches a twice-weekly dose (see Table 8-2 and Figure 8-3), the subject will be in 
the Maintenance Dose Cycle phase. Each Maintenance Dose Cycle is 2 weeks. The Maintenance 
Dose Cycle dose may be adjusted at any time using the 84h DHO criteria. 
Maintenance Dose Cycle procedures will occur on Day 1 and Day 8 through Week 12 from study 
Day 1 as shown below.  After Week 12, the Maintenance Dose Cycle visit is once every 2 weeks 
(i.e., Day 1 only of each two-week cycle). 
Maintenance Dose Cycle Day 1: 
- Collect unused study medication and check the diary/elicit information about AEs/new 
concomitant medications since the last visit. 
- Collect pre-dose brequinar/DHO, hematology/chemistry samples, and flow cytometry 
sample.  
- Obtain vital signs; pregnancy test for WOCBP (every 4 weeks), 12-lead ECG (every 4 
weeks), and bone marrow sample (note that bone marrow is collected at the Week 4 visit 
(Day 22 ±7 days), at the Week 7 visit (Day 43 ±7 days), then every 12 weeks ±7 days or 
per institutional standard of care; the Day 43 sample will be assessed for hematological 
toxicity). 
- If subject is beginning or continuing twice-weekly dosing, review most recent 84h DHO 
level, review the laboratory results and safety information and determine whether the 
subject should maintain current dose (acceptable safety and 84h DHO meets criteria), 
increase dose (acceptable safety and 84h DHO < 1500 ng/mL) or hold study medication 
(unacceptable safety or 84h DHO ≥ 5000 ng/mL).  
- Dispense study medication (either brequinar alone or brequinar and ribavirin). 
- Dispense calendar/diary.  
Maintenance Dose Cycle Day 8 (up to Week 12) 
- Collect pre-dose brequinar/DHO, and flow cytometry sample.  
- Review most recent 84h DHO level, review the laboratory results and safety information 
and determine whether the subject should maintain current dose (acceptable safety and 84h 
DHO meets criteria), increase dose (acceptable safety and DHO <1500 ng/mL) or hold 
study medication (unacceptable safety or 84h DHO ≥ 5000 ng/mL).  


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9.5.5 Final Visit 
This visit is to take place when a subject is discontinuing from the study. 
- Collect and check the diary/elicit information about AEs/new concomitant medications 
since the last visit.  
- Collect brequinar/DHO/flow cytometry and hematology/chemistry samples.  
- Collect unused study medication. 
- Conduct physical examination if >4 weeks since last performed, collect vital signs; 
conduct pregnancy test for WOCBP if > 4 weeks since previously performed, 12-lead 
ECG if > 4 weeks since previously performed; collect bone marrow sampling if > 4 
weeks since previously performed.  
- Ensure all adverse events have been recorded. 
9.5.6 Telephone Follow Up Visit (2 weeks after Final Visit) 
- Contact subject by telephone two weeks after Final Visit to determine subject’s survival 
status and to inquire if any new adverse events have occurred. Survival information will be 
collected while the subject is participating in the study (i.e., up to 2 weeks after last dose 
of study medication). 
9.5.7 Unscheduled Visits 
Unscheduled visits and tests to assess AEs are permitted as needed providing the AE onset occurs 
within two (2) weeks after the final dose. 
9.6 COMPLIANCE WITH STUDY PROCEDURES 
The time at which study procedures are conducted should follow the protocol timelines as closely 
as possible.  However, it is recognized in a clinical setting that protocol-specified timings may not 
occur exactly as specified in the protocol. Provided that activities are carried out within the 
identified windows, it will not be necessary to file a protocol deviation.   
9.7 EARLY WITHDRAWAL FROM THE STUDY  
A subject may withdraw from the study at any time for any reason or for one of the reasons listed 
below. The Sponsor or Investigator may also terminate a subject’s study participation after 
discussion with the other party if it is believed it would be unsafe for the subject to continue in the 
study.    


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Subjects must be withdrawn from the study if any of the following events occur: 
• Significant protocol violation or non-compliance, either on the part of the subject or the 
investigator or other site personnel; 
• Decision of the Investigator or Sponsor that removal is in the subject's best interest; 
• Severe unrelated medical illness or complication; 
• Safety reasons/ significant adverse event; 
• Subject request (withdrawal of consent); 
• Sponsor decision. 
Collect/conduct all evaluations for subjects who withdraw from the study prior to completing the 
treatment period, unless consent is withdrawn.     
9.8 EARLY TERMINATION OF THE STUDY 
If the Sponsor or an Investigator believes it would be unsafe to continue the study, or for any 
reason at the Sponsor’s request, the study may be terminated at that site or the entire study 
terminated after discussion with the other parties. 
The Sponsor will provide a written statement to the IRB and the relevant regulatory authority with 
the reasons for termination of the study. This will be conducted within 15 days of the decision to 
terminate the study.  
If the study is terminated, a close out monitoring visit will be performed and applicable procedures 
will be carried out to close the trial site(s). 
 


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10 ADVERSE EVENT REPORTING 
An adverse event is any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal relationship with 
this treatment.  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of the 
medicinal product, whether or not considered related to the medicinal product.  
Events that occur prior to dosing will be entered as medical history; AEs that occur after dosing 
will be entered on the AE form. 
Subjects will be questioned and observed for evidence of AEs, whether or not related to study 
drug. All AEs will be documented in the subject's medical record and CRF.  For any pre-existing 
condition or abnormal laboratory finding that changes in severity after dosing, this change should 
be recorded as an AE. New abnormal laboratory findings that are clinically significant are 
considered AEs. 
AEs will be collected beginning from the time of informed consent through at least 14 days after 
the final dose of study medication. AEs will be specified as pre-treatment or treatment-emergent. 
AE details are to be documented including start and stop date and times, whether continuous or 
intermittent, severity, any intervention utilized to correct the event (e.g., medication, surgery or 
other therapy), outcome and the relationship to the study drug.   
AEs identified in the protocol as critical to the evaluation of safety must be reported to the Sponsor 
by the Investigator according to the reporting requirements within the time periods specified in the 
protocol. 
AEs determined by the Investigator to be related to study drug must be followed until resolution 
or until they are considered stable or for at least 30 days after discontinuation of study drug.   
Any SAEs experienced after 30 days post the last dose of study drug should only be reported to 
the sponsor if the investigator suspects a causal relationship to the study drug.   
Abnormal laboratory values or test results occurring after study enrollment constitute AEs only if 
they induce clinical signs or symptoms, are considered clinically significant, require therapy, or 
require changes in study drug (e.g., discontinuation of study drug). 
Death due to disease progression should not be reported as an SAE. Report death from disease 
progression on the End of Study and Death forms.  
If a death occurs during the SAE reporting period, the cause of death is considered as the AE and 
the death is considered its outcome. Death should be considered an outcome, not an event. The 
event or condition leading to death should be recorded and reported as a single medical concept 


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on the Adverse Event eCRF. Generally, only one such event should be reported. “Fatal” will be 
recorded as the outcome of this respective event; death due to an outcome of an AE will not be 
recorded as separate event. If the primary cause of death is disease progression, the cause of death 
should be clearly identified as progression of cancer under study. 
In cases of surgical or diagnostic procedures, the condition leading to the procedure is considered 
as the AE instead of the procedure itself. Each AE will be coded by the Sponsor from the verbatim 
text to a preferred term using a thesaurus based on the Medical Dictionary for Regulatory Activities 
(MedDRA).  
The following guidelines will be followed for the recording and reporting of adverse and serious 
adverse events. 
1. Baseline events will be recorded in the medical history section of the case report form and 
will include the terminology event name, grade, and start date of the event.  The medical 
history section of the case report form will serve as the source document for baseline events 
once signed and dated by the principal investigator.   
a. Baseline events are any medical condition, symptom, or clinically significant lab 
abnormality present before the informed consent is signed. 
i. If exact start date is unknown, month and year or year may be used as the start 
date of the baseline event. 
2. The maximum grade of the adverse event will be captured per course or protocol-defined 
visit date. 
3. All adverse events will be recorded in the case report form. 
4. Serious adverse events will be reported to the IRB according to institutional policy. 
 The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html).   
10.1 CLASSIFICATION OF CAUSALITY 
Attribution is the relationship between an adverse event or serious adverse event 
and the study treatment. Attribution will be assigned as follows: 
• Definite – The AE is clearly related to the study treatment. 
• Probable – The AE is likely related to the study treatment 
• Possible – The AE may be related to the study treatment. 
• Unlikely - The AE is doubtfully related to the study treatment. 
• Unrelated - The AE is clearly NOT related to the study treatment 


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Guidance for assessing causality: 
The Investigator will need to determine whether an AE is considered related to (“caused by”’) the 
study drug rather than some underlying condition, for example, COVID-19.   
For the purposes of this study, ‘drug related’ shall mean ‘Definite’, ‘Probable’ and ‘Possible’ 
relationship to drug as determined by the PI. 
10.2 CLASSIFICATION OF SEVERITY 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03 will be utilized for AE reporting. All appropriate 
treatment areas should have access to a copy of the criteria. The CTCAE version 4.03. A copy of 
the CTCAE version 4.03 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm and in Appendix D. 
AEs that are expected are subject to expedited reporting only if the adverse event varies in nature, 
intensity or frequency from the expected toxicity information that is provided in the Investigator 
Brochure. 
10.3 SERIOUS ADVERSE EVENT (SAE) REPORTING 
The regulatory definition of a Serious Adverse Event (SAE) is any untoward medical occurrence 
or effect that at any dose: 
•
results in death;
•
is life threatening (at the time of the event);
•
requires in-patient hospitalization or prolongation of existing hospitalization;
•
results in persistent or significant disability / incapacity, or
•
is a congenital anomaly / birth defect;
•
all other events that are considered medically serious by the Investigator.
Disability is defined as a substantial disruption of a person’s ability to conduct normal life 
functions. 
A life-threatening adverse event is one that places the patient/subject, in the view of the 
Investigator, at immediate risk of death from the event as it occurred.  It does not include an event 
that, had it occurred in a more severe form, might have caused death.   
An unexpected adverse event is any adverse drug event, the nature or severity of which is not 
consistent with the applicable product information (e.g. Investigator’s brochure for an 
unauthorized investigational product or summary of product characteristics for an authorized 
product). 


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Enter only one event as the reason for the SAE on the SAE form.  Other non-serious events 
which did not directly result in the SAE should be detailed in the description section on the SAE 
form and listed separately as AEs if necessary. For fatal SAEs, report the cause of death as an 
SAE with a fatal outcome rather than reporting death as the SAE term. 
Note that hospitalizations for the following reasons should not be reported as SAEs: 
•
Routine treatment or monitoring of the studied indication, not associated with any
deterioration in condition;
•
Elective or pre-planned treatment for a pre-existing condition that is unrelated to the
indication under study and has not worsened since signing the informed consent;
•
Social reasons and respite care in the absence of any deterioration in the subject’s general
condition;
•
Note that treatment on an emergency outpatient basis that does not result in hospital
admission and involves an event not fulfilling any of the definitions of an SAE given
above is not an SAE.
Death due to disease progression is considered to be an Expected event in these patients with 
relapsed/refractory AML/other hematologic malignancy and does not require reporting on an 
expedited basis. 
ANY SERIOUS ADVERSE EVENT MUST BE REPORTED IMMEDIATELY (WITHIN 
24 HOURS) BY EMAIL OR FAX TO THE SPONSOR CONTACT USING THE FORM 
PROVIDED.  ENTER THE SUBJECT’S AVAILABLE INFORMATION INTO THE ECRF 
WITHIN 48 HOURS. 
The subjects are to be identified in the immediate and follow-up reports by unique code numbers 
supplied by the sponsor.  The email address and fax telephone number for reporting SAEs can be 
found below and at the front of this protocol.   
Reports relating to the subject’s subsequent medical course following an SAE must be submitted 
to the Sponsor contact until the event has subsided or, in case of permanent impairment, it 
stabilizes, and the overall clinical outcome has been ascertained. 
SAE REPORTING EMAIL: 
bpowers@clearcreekbio.com 
kumar@clearcreekbio.com 
MEDICAL MONITOR:  
Vikram Sheel Kumar, MD 
E-mail:
kumar@clearcreekbio.com 
Telephone:
(617) 899-8944
Sponsor Representative: 
Barbara Powers, MSN, Ph.D. 
E-mail:
bpowers@clearcreekbio.com  
Telephone:
484-686-0545


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All SAEs will be reported to the IRB periodically, at the end of the study or per local 
institutional guidelines.   
10.4 SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTIONS (SUSARS) 
Suspected, unexpected, serious adverse reactions (SUSARs) are SAEs that are both related to the 
study drug (Relationship = Related) and unexpected (not previously described in the investigator’s 
brochure). All SUSARs will be reported in an expedited manner to the Sponsor or designee and 
IRB by the Investigators and to all relevant regulatory authorities by the Sponsor. Expectedness 
will be judged by the Medical Monitor and site PI. It is critical that all SAEs are reported within 
the 24-hour guideline so that the expectedness determination can be made. SUSARs require 
immediate attention and expedited reporting to relevant regulatory authorities. 
The Sponsor is to ensure that all relevant information about fatal or life-threatening SUSARs are 
appropriately recorded and reported to the concerned Regulatory Authority and to the concerned 
IRB(s) within seven (7) calendar days of the date of first report to the Medical Monitor/Sponsor. 
Follow-up information is to be subsequently communicated to the relevant Regulatory Authority 
within an additional eight calendar days. 
All other SUSARs are to be reported to the Regulatory Authority and to the IRB(s) concerned as 
soon as possible within a maximum of fifteen calendar days of first knowledge by the Sponsor. 
The Sponsor or designee must also inform all Investigators studying the investigational medicinal 
product about SUSARs and ensure that all IRBs have been notified. 
For reported deaths of a subject, the Investigator shall supply the Sponsor and the IRB(s) with 
additional information requested on an expedited basis.   
10.5 PREGNANCIES 
Pregnancy occurring in a female subject or a subject’s partner during the study period will be 
documented in the subject’s source documents and reported to the Sponsor Contact and to the 
IRB/IEC by the investigational staff within 1 working day of their knowledge of the event. The 
collection period for a pregnancy occurring in a subject or a subject’s partner will begin at the first 
dose of study drug and will continue through 90 days after the last dose of study drug. Monitoring 
of the subject or partner should continue until the conclusion of the pregnancy, if the subject or 
subject’s partner has consented to this. Monitoring of the baby should continue for 3 months after 
birth, if the subject or subject’s partner has consented to this.  
 
Pregnancy itself is not an AE; it should be reported for tracking purposes. The Investigator or 
designee will discontinue the pregnant subject from the treatment aspects of the study, continue to 
follow her per protocol for safety outcomes only, and advise her to seek prenatal care and 
counseling from her primary care provider. Data on fetal outcome and breast-feeding will be 
collected for regulatory reporting and drug safety evaluation. 


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 If the pregnancy is due to a subject’s failure to comply with the contraceptive requirements of this 
protocol, this should also be documented as a protocol deviation.  
 
Complications of pregnancy or congenital abnormalities in the newborn child will be reported 
appropriately as AEs.  
The site clinical staff will request the pregnant subject to notify the site of the outcome of the 
pregnancy (i.e., birth, loss, or termination). To help ensure this, the site clinical staff will follow-
up with the subject until the end of pregnancy, with the subject’s consent. This request and the 
subject’s response will be documented in the subject’s source document. 
10.6 HEMATOLOGIC ADVERSE EVENTS 
It is recognized that laboratory value variability is a frequent and expected and may be present at 
Baseline when a subject enrolls in the study. In general, mild day to day fluctuation of laboratory 
values should not be classified as AEs. Fluctuations in laboratory values resulting from adverse 
changes in the patient’s medical condition should be reported as AEs. Laboratory abnormalities 
that constitute an AE in their own right as per CTCAE V4.03 criteria if applicable (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study drug), should be recorded on the AE eCRF. 
Whenever possible, a diagnosis, rather than a symptom should be provided (e.g., anemia instead 
of low hemoglobin). Laboratory abnormalities that meet the criteria for AEs should be followed 
until they have returned to normal or an adequate explanation of the abnormality is found. When 
an abnormal laboratory or test result corresponds to a sign/symptom of an already reported AE, it 
is not necessary to separately record the lab/test result as an additional event.  
Laboratory abnormalities that do not meet the definition of an AE should not be reported as AEs. 
A laboratory abnormality designated a Grade 3 or 4 event (severe) as per CTCAE does not 
automatically indicate a SAE unless it meets the definition of serious as defined below and/or as 
per Investigator’s discretion.  
For laboratory abnormalities and any AEs, it should be noted that the terms serious and severe are 
not symptoms. The term severe describes the intensity of the specific event (e.g., Grade 3 or 4). 
The term serious is based on patient and event outcomes or actions required as described in the 
protocol definition of SAEs and is usually associated with events posing a threat to the subject’s 
life or ability to function. A severe AE (Grade 3 or 4) does not necessarily need to be considered 
serious; laboratory abnormalities (such as WBC or platelet count) may be severe but not serious. 
After the subject has completed the first 42 days of treatment, hematologic dose-limiting toxicity 
(DLT) is defined as prolonged neutropenia with ANC < 500 from the start of therapy in the absence 
of disease, ≥ Grade 4 neutropenia, and/or ≥ Grade 4 thrombocytopenia, with a hypocellular bone 
marrow and no greater than 5% marrow blasts lasting for 2 weeks or more. Anemia will not be 
considered a hematologic AE for the definition of unacceptable safety. The timing of the bone 


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marrow sampling can be adjusted to ensure that the results are available for the visit on Day 43 
(Day 1 of Cycle 4). 
Participants with neutropenia or thrombocytopenia because of disease prior to the start of therapy 
do not require treatment interruption for myelosuppression. Dose reductions of brequinar in these 
participants should be considered on an individual case basis and discussed with the Sponsor. 
10.7 MANAGEMENT OF MYELOSUPPRESSION 
Myelosuppression and the related adverse events (thrombocytopenia, anemia, neutropenia, febrile 
neutropenia) are common in both treated and untreated patients with AML/other hematologic 
malignancy. Based on clinical observations with DHODH inhibition and with historical evidence 
from previous studies with brequinar, participants treated with brequinar may experience 
thrombocytopenia and neutropenia.   
If a participant achieves a clinical response including CR, CRi, CRh, or MLFS while on study and 
they have not recovered absolute neutrophil count (ANC) > 500/uL within 14 days of study drug 
interruption, brequinar dosing may be further interrupted until ANC recovers to > 500/uL, unless 
the low ANC is thought to be due to the underlying disease. Brequinar may be reinitiated at an 
adjusted dose per discussion with the Sponsor. Granulocyte colony-stimulating factor (GCSF) may 
be administered if in the best interest of the participant. 
10.8 DIFFERENTIATION SYNDROME 
Based on its proposed pro-differentiating mechanism of action, it is possible that participants 
receiving treatment with brequinar may develop signs and symptoms of differentiation syndrome 
(DS). Clinical features may include some or all of the following: unexplained fever, skin rash, 
hypoxia, respiratory compromise, interstitial pulmonary infiltrates, pleural and/or pericardial 
effusion, weight gain, and clinical deterioration. Laboratory features may include an increase in 
ANC and/or platelets. An increase in mature leukocytes may be observed in the bone marrow 
aspirate differential if a bone marrow biopsy is conducted during this time. However, no single 
sign or symptom may be considered per se as diagnostic of the syndrome, and other causes should 
be sought and excluded. 
It is recommended that the prophylactic and therapeutic measures indicated below be undertaken 
at the earliest manifestations of suspected differentiation syndrome: 
• Temporary hold of brequinar if clinical features cannot be medically managed with the 
following: 
- Control of leukocytosis with hydroxyurea;  
- Prompt administration of corticosteroids at a suggested dose of 10 mg of 
dexamethasone IV every 12 hours until disappearance of symptoms and signs, 


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continued for a minimum of 3 days; 
- Initiation of furosemide, if clinically required; 
- Prompt initiation of leukapheresis, if required. 
 
If brequinar dosing is held, brequinar may be reinitiated once the participant’s clinical condition 
improves, upon discussion with the Sponsor and Medical Monitor. 
10.9 TUMOR LYSIS SYNDROME (TLS) 
Tumor lysis syndrome (TLS) is characterized by nausea, vomiting, diarrhea, anorexia, lethargy, 
irregular heart rhythms, heart failure, hematuria, seizures, muscle cramps, syncope, tetany and 
possible sudden death due to the acute metabolic irregularities of hyperkalemia, 
hyperphosphatemia and hypocalemia associated with the breakdown of tumor cells secondary to 
cytotoxic therapy.  
While TLS was not observed in the previous extensive clinical experience with brequinar, the 
experience with brequinar in hematologic malignancies is limited. Signs and symptoms of TLS 
will therefore be carefully monitored particularly in the period that tumor lysis is most likely to 
occur (24-48 hours after first dose). The risk stratification in AML/other hematologic 
malignancy for TLS from the international guidelines by Cairo et al., 2010 [11] is as follows: 
• Low risk disease: WBC < 25 x 109 /L and LDH < 2 x upper limit of normal (ULN); 
• Intermediate risk disease (IRD): WBC 25 to 100 x 109 /L or WBC < 25 x 109 /L and LDH 
≥ 2 x ULN;  
• High risk disease (HRD): WBC ≥ 100 x 109 /L. 
The guidelines for the prevention, monitoring and treatment of TLS are described below:  
TLS Prevention [Recommended]:  
• IV hydration: aggressive hydration is recommended for patients at intermediate to high risk 
for TLS with a goal of initially 2 to 3 L/m2 per day of IV fluid per the international 
guidelines (Coiffer et al., 2008 [12]). 
• Hypouricemic agents: allopurinol for intermediate risk disease (IRD). 
TLS Monitoring: (Howard et al., 2011 [13]) 
• Figure 10-1 provides a flow chart for TLS monitoring. 


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Figure 10-1. Monitoring of Tumor Lysis Syndrome 
TLS Treatment 
TLS requires urgent inpatient management including intense nursing care, cardiac monitoring, 
nephrology consultation, and measurements of uric acid, creatinine, and electrolytes every four 
to six hours. Treat any electrolyte abnormalities and any acute renal injury.  


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10.10 INFECTION PROPHYLAXIS 
Supportive care, including prophylactic antibiotics, antifungal and/or antiviral agents, are 
frequently used in neutropenic patients, and may be used per standard institutional practice and as 
deemed necessary by the investigator. 
10.11 GROWTH FACTOR SUPPORT 
The use of myeloid growth factors (granulocyte-colony stimulating factor [G-CSF] and 
granulocyte-macrophage colony-stimulating factor [GM-CSF]) may be given to support subjects 
who have developed Grade 4 neutropenia or Grade 3 neutropenia with fever and/or infection, per 
institutional guidelines. 
10.12 MANAGEMENT OF NAUSEA, VOMITING, AND DIARRHEA 
Recommended management of nausea and vomiting is to administer antiemetics. The 
recommended treatment for managing diarrhea is loperamide antidiarrheal therapy, 4 mg at first 
onset, followed by 2 mg with each loose movement until diarrhea-free for 12 hours (maximum 
dosage: 16 mg/24 hours). Adjunct anti-diarrheal therapy is permitted. 
 


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11 STATISTICAL CONSIDERATIONS 
A separate, detailed statistical analysis plan (SAP) will be finalized prior to locking the database. 
All analyses of safety and anti-leukemic activity for this open-label early Phase study will be 
descriptive in nature and presented by dose group and overall, as appropriate, for the dose-
adjustment phase and the expansion phase. Procedures for accounting for missing, unused and 
spurious data will be described in the SAP.   
Summaries for quantitative variables will include the mean, median, quartiles, standard deviation 
and error, minimum, and maximum. For qualitative variables, the summaries will include the 
number and percentage of subjects for each outcome, and the exact 95% CI, when appropriate. No 
hypothesis testing will be performed. Any statistical testing will be considered exploratory and 
descriptive. All computations will be performed using SAS® (Version 9.3 or higher). 
Subject disposition, subject demographics and baseline characteristics will be summarized. 
Subject data listings will also be provided. The following sections will briefly summarize of the 
planned statistical analyses and analysis sets for the primary and secondary endpoints. 
11.1 STUDY POPULATIONS FOR ANALYSIS 
The analysis sets are defined in Table 11-1. 
Table 11-1. Analysis Sets 
Analysis Set 
Description 
Enrolled Analysis Set 
All subjects who have been enrolled in the study. 
Safety Analysis Set 
All subjects who were administered brequinar. 
Efficacy Analysis Set 
All subjects with AML/other hematologic malignancy disease at baseline 
and who were administered brequinar. 
Pharmacokinetic Analysis Set 
All subjects who take at least 1 dose of brequinar and have at least 1 
quantifiable plasma concentration collected post-dose without important 
protocol deviations/violations or events thought to significantly affect the 
PK. 
The Efficacy Analysis Set will be used for efficacy analyses. The Safety Analysis Set will be used 
for safety analyses.   
11.2 SAFETY ANALYSES 
All safety analyses will be performed on the Safety Analysis Set.  Safety and tolerability will be 
assessed in terms of AEs, SAEs, safety laboratory data, physical examinations, vital signs, 12-lead 
ECGs and bone marrow sampling.  
Adverse event data will be descriptively evaluated. All AEs will be listed. The incidence and 
duration of TEAEs, defined as AEs occurring after the first dose of study treatment through 30 


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days after the last dose of study treatment, will be tabulated by Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term and system organ class, and by severity and relationship to 
study treatment. All laboratory results, vital sign measurements, ECGs and bone marrow 
assessments will be summarized using appropriate descriptive statistics. 
11.3 EFFICACY ANALYSES 
Efficacy analyses will be performed using the Efficacy Analysis Set.  Table 11-2 summarizes the 
planned analysis of primary and secondary efficacy endpoints. 
Table 11-2. Efficacy Analyses 
Endpoint 
Statistical Analysis Methods 
Primary 
There is no primary efficacy endpoint for this study.  
Secondary 
• Assess anti-leukemic activity as follows:  
o Overall Response rate (ORR) – the proportion of subjects 
in the Efficacy Analysis Set with a best overall response of 
CR, CRi, CRh, MLFS and PR  
o Complete Remission (CR) rate – the proportion of subjects 
in the Efficacy Analysis Set with a best overall response of 
CR 
o Complete Remission with Incomplete Hematologic 
Recovery (CRi) rate – the proportion of subjects in the 
Efficacy Analysis Set with a best overall response of CRi 
o Complete remission with partial hematological recovery 
(CRh) – the proportion of subjects in the Efficacy Analysis 
Set with a best overall response of CRh 
o Morphologic Leukemia Free State (MLFS) rate – the 
proportion of subjects in the Efficacy Analysis Set with a 
best overall response of MLFS 
o Partial Remission (PR) rate – the proportion of subjects in 
the Efficacy Analysis Set with a best overall response of 
PR 
o Event-free survival (EFS) – the interval between first 
brequinar dose and relapse (≥5% bone marrow 
blasts, reappearance of blasts in blood, or development of 
extramedullary disease), disease progression, or death 
o Overall survival (OS) – the time from first dose of 
brequinar to date of death or last known alive date 
For ORR and other endpoints defined as proportions, estimated 
response rates and two-sided exact binomial 95% CIs will be provided.  
The distributions of EFS and other time-to-event endpoints will be 
summarized using the Kaplan-Meier method.  Time to event analyses 
may be performed for the above secondary endpoints from first dose 


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of brequinar. Censoring rules for time-to-event endpoints will be 
described in the SAP.  
Exploratory 
Will be described in the SAP finalized before database lock. 
Disease response for participants with AML/other hematologic malignancy will be assessed based 
on Döhner et al, 2017 [10]. 
Complete remission (CR):  
• Bone marrow showing less than 5% myeloblasts with normal maturation of all cell lines, 
• ANC of at least 1000/µL  
• Platelet count of 100,000/µL 
• Absence of blasts in peripheral blood 
• Absence of identifiable leukemic cells in the bone marrow 
• Absence of extramedullary disease.  
Complete Remission with Incomplete Blood Count Recovery (CRi):  
• Same as for CR but without achievement of ANC at least 1000/uL (CRi) and/or platelet 
count of 100,000/uL (CRp). 
Complete Remission with Partial Hematological Recovery (CRh) 
• Complete remission with partial hematological recovery defined as <5% of blasts in the 
bone marrow, no evidence of disease, and partial recovery of peripheral blood counts 
(platelets >50,000/microliter and ANC >500/microliter) (Kantarjian HM et al, 2016 [14]).  
Partial Remission:  
• All hematologic criteria of CR are fulfilled, and  
• A decrease of bone marrow blast percentage to 5% to 25%, and  
• Decrease of pretreatment bone marrow blast percentage by at least 50%. 


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Morphologic Leukemia Free State: 
• Bone marrow blasts <5%;  
• Absence of blasts with Auer rods;  
• Absence of extramedullary disease; 
• No hematologic recovery required 
Stable Disease: 
• Failure to achieve a response 
• Not meeting criteria for Progressive Disease 
Progressive Disease 
Evidence for an increase in bone marrow blast percentage and/or increase of absolute blast counts 
in the blood: 
• >50% increase in marrow blasts over baseline (a minimum 15% point increase is required 
in cases with <30% blasts at baseline; or persistent marrow blast percentage of >70% over 
at least 3 months; without at least a 100% improvement in absolute neutrophil count (ANC) 
to an absolute level [>0.5 x 109/L (500/μL), and/or platelet count to >50 x 109/L 
(50,000/μL) non-transfused]; or  
• >50% increase in peripheral blasts (WBC x % blasts) to >25 x 109/L (>25,000/μl) (in the 
absence of differentiation syndrome); or 
• New extramedullary disease 
Duration of Response  
• The duration of response is defined as the number of days from the time response criteria 
are initially met for CR, CRi, CRh, PR, or MLFS (whichever is first recorded) until the 
first date that recurrent or progressive disease is objectively documented, or death due to 
any cause. Participants without events reported are censored at the last disease evaluation. 
Clinical Benefit  
Requires one of the following in the absence of progression or CR/partial response and 
independent of marrow response to be considered a clinical benefit: 
• Erythroid response 


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o Transfusion Independence (TI) for ≥ 8 weeks for patients requiring at least 4 units 
of packed red blood cell transfusions in the previous 8 weeks. Only red blood cell 
transfusions given based on physician’s judgment for a pretreatment Hgb of ≤ 8.5 
g/dL will count in the red blood cell TI response evaluation. 
• Platelet response 
o Transfusion independence when previously requiring platelet transfusions of at 
least a rate of 4 platelet transfusions in the previous 8 weeks. 
Response Criteria in Other Hematologic Malignancies 
The criteria used for treatment efficacy in T-ALL and other hematologic malignancies are adapted 
from Cheson et al., 1990 [25].  In addition to the bone marrow and hematologic criteria above, all 
previous extramedullary manifestations of disease must be absent (e.g., lymphadenopathy, 
splenomegaly, skin or gum infiltration, testicular masses, or CNS involvement). Relapsed disease 
is defined as the reappearance of unequivocal leukemia blast cells in the blood or the bone marrow 
(> 5%), in the CNS (positive cytospin examination of cerebrospinal fluid) or in any other 
extramedullary site after a CR or progression to over 25% leukemia blasts cells in the marrow after 
a PR. 
11.4 OTHER ENDPOINTS 
Brequinar Pharmacokinetics (PK) and DHO Levels 
Blood samples for brequinar PK and DHO analyses will be obtained at pre-specified times. The 
following plasma parameters may be analyzed (including but not limited to): concentration 
maximum (Cmax), time of peak concentration (Tmax) elimination half-life (T1/2), and area under the 
concentration curve (AUC) estimated by compartmental and non-compartmental analysis 
(WinNonlin or similar). Additional parameters may be added as necessary. 
Concentration data, PK and DHO parameters will be tabulated and summarized using descriptive 
statistics.  Relationships between brequinar PK parameters and clinical outcomes (e.g., efficacy, 
toxicity) may be explored.  PK analyses will be performed on the PK Analysis Set. 
Relationships between DHO levels and PK and clinical outcomes (e.g., efficacy, toxicity) will be 
explored. 
Changes in myeloid markers per serial flow cytometry will be studied to look for evidence of 
myeloid differentiation. 


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11.5 SAMPLE SIZE CONSIDERATIONS 
Formal sample size calculations are not applicable for this phase 1b/2a, open label study. Up to 27 
subjects are planned to be entered in this trial: Cohort 1 had5 subjects; Cohort 2 will have 
approximately 6 evaluable subjects. Cohort 3 will have approximately 6 evaluable subjects. An 
expansion cohort of approximately 6 to 12 subjects will be enrolled to further refine brequinar PK 
and DHO criteria and to further assess the safety, tolerability, and biological activity of brequinar 
as monotherapy and in combination with ribavirin.   
11.6 RANDOMIZATION 
No randomization scheme is needed for this open label study. 
11.7 POOLING OF STUDY CENTERS 
Not applicable to this small, early phase study. 
11.8 INTERIM ANALYSIS 
No interim analysis is planned for this trial. 


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12 INVESTIGATOR RESPONSIBILITIES 
12.1 INVESTIGATOR’S PERFORMANCE 
The Investigator will ensure that all those concerned with conducting the trial are: 
• provided with copies of the protocol and all safety information prior to the start of the trial; 
• trained regarding the conduct of the study and the training has been documented. 
The Investigator will sign the Investigator’s Statement and Agreement (Appendix 15.7) to indicate 
commitment to comply with the contents. 
12.2 CONFIDENTIALITY 
The Investigator shall assure the subject that his/her identity will be protected and confidentiality 
will be maintained during all audits and inspections of the trial site and documentation. A unique 
number will be assigned to each subject at the start of the trial and this, with the subject’s initials, 
will be used to identify the subject. In some cases, a further step may be taken to assign “fake 
initials” to the subject, per individual site requirements. The subject’s number will be the site 
number followed by the number of this subject at this site and will be used as the unique identifier 
in the source records and on the CRF, on all trial correspondence and in the trial database. The 
Investigator will keep a list of identification codes or initials used for each subject along with the 
unique number assigned. 
All information provided to the Investigator relevant to the investigational medicinal product 
(IMP), as well as information obtained during the course of the trial will be regarded as 
confidential. The Investigator and members of his/her research team agree not to disclose or 
publish such information in any way to any third-party without prior written permission from the 
Sponsor which will not be unreasonably withheld, except as required by law, or as permitted by 
the Publications section of this protocol, Section 12.7. 
The Investigator will take all measures to ensure subject’s confidentiality will be maintained at all 
times. 
12.3 SOURCE DOCUMENTATION 
Investigators are to maintain adequate source documentation of the original study data, for 
example medication records, laboratory reports and pharmacy records as appropriate. The 
Investigator will allow inspections of the trial site and documentation by clinical research and audit 
personnel from the Sponsor, external auditors or representatives of regulatory authorities. The 
purpose of these inspections is to verify and corroborate the data collected on the CRFs. In order 
to do this, direct access to the subjects' medical or clinic records is necessary. The Investigator will 
ensure that certain information is contained in the medical or clinic records of the subject and that 
the entries are signed and dated, as follows: 


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• sufficient data to allow verification of the entry criteria in terms of past and present medical 
and medication histories; 
• a note on the day the subject entered the trial describing the trial number, the IMP being 
evaluated, the trial number assigned to that subject and a statement that consent was obtained; 
• a note of each subsequent trial visit including any concerns about AEs and their resolution; 
• notes of all concomitant medication taken by the subject, including start and stop dates; 
• a note of when the subject terminated from the trial, the reason for termination and the subject’s 
general condition at termination; 
• a copy of the signed informed consent form should be kept in the medical records of each 
subject during the clinical phase of the study. A signed copy should also be filed in the 
investigator file. 
12.4 DATA COLLECTION 
Suitably qualified and trained personnel at the trial site will ensure compliance with the protocol, 
adherence to ICH GCP obligations, proper maintenance of trial records including IMP 
accountability records, correct administration of IMP including storage conditions and accurate 
reporting of AEs. In addition, suitably qualified and trained clinical research personnel of the 
Sponsor will visit the trial site at regular intervals during the trial for monitoring purposes and to 
assist the research staff with any queries. All queries and discrepancies relating to the data 
collection are to be resolved at the completion of the trial. 
12.5 CASE REPORT FORMS, INVESTIGATOR’S SITE FILE AND RECORD 
RETENTION 
The Sponsor may provide the CRFs in paper, electronic (eCRF), or other media. The forms will 
be reviewed against source documentation at each monitoring visit. All CRFs and supporting 
source documentation must be completed and available to the Sponsor in a timely manner. 
Changes or corrections due to data clarification and resolutions will be tracked by paper or 
electronically with an audit trail. 
Prior to review of the case report forms by the Sponsor’s representative, they should be reviewed 
for completeness and accuracy by the Investigator or a member of the research team. 
The Investigator must maintain an Investigator Site File which includes, but is not limited to, the 
Investigator’s Brochure, the protocol plus any amendments, all correspondence with the IRB 
including the approval for the trial to proceed, Regulatory Authority approval/ notification (if 
applicable) including a sample of an approved informed consent, IMP accountability, Source 
Documents, investigator and staff curricula vitae (CVs,) trial documentation, and all trial 


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correspondence. The original signed informed consent forms and the final report will be kept in 
the Investigator Site File. 
The Investigator will archive all essential documents. The medical files of trial subjects shall be 
retained in accordance with national legislation and in accordance with the maximum period of 
time permitted by the hospital, institution or private practice. The Investigator has a responsibility 
to retain essential documents for as long as is required by the Sponsor and applicable regulatory 
authorities.  It is the responsibility of the Sponsor to inform the Investigator as to when these 
documents no longer need to be retained. Investigators will be asked to contact the Sponsor prior 
to the destruction of any data or removal to another site if this occurs prior to the Sponsor 
notification that the documentation is no longer required. Any transfer of ownership of the data or 
of documents will be documented in writing.  The new owner will assume responsibility for data 
retention and archiving. 
Should the Investigator retire, relocate, or for other reasons withdraw from the responsibility of 
keeping the trial essential documents, custody must be transferred to a person who will accept that 
responsibility, and the Sponsor must be notified in writing of the name and address of said person. 
12.6 NON-PROTOCOL RESEARCH 
No investigational procedures other than those outlined in this protocol may be undertaken on the 
subjects in this trial without the prior written permission of the subject, the Sponsor, the IRB and, 
when appropriate, the regulatory authority. 
12.7 PUBLICATION 
The Sponsor acknowledges the benefit of making widely available the results of all clinical trials 
and intends to publish the results of this trial. All publications resulting from the clinical trial must 
be in a form that does not reveal technical information that the Sponsor considers confidential or 
proprietary.  A copy of any abstract, presentation or manuscript proposed for publication must be 
submitted to the Sponsor for review at least 30 days before its submission for any meeting or 
journal. In addition, if deemed necessary by the Sponsor for protection of proprietary information 
prior to patent filing, the Investigator agrees to a further delay of 60 days before any presentation 
or publication is submitted. The Sponsor reserves the right to include the report of this trial in any 
regulatory documentation or submission or in any informational materials prepared for the medical 
profession. 
Authorship determination will be at the discretion of the Sponsor and will include evaluation of 
the following criteria: Investigator must participate in the review of and content of the protocol; 
review and comment on the study results; participate in the writing, reviewing and commenting of 
the manuscript; and approve the final manuscript for submission. 
 


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13 SPONSOR RESPONSIBILITIES 
13.1 GENERAL 
The Sponsor agrees to adhere to the ICH Note for Guidance on Good Clinical Practice 
(CPMP/ICH/135/95, Jan.97) and US FDA Regulations. It is the Sponsor's responsibility to obtain 
appropriate regulatory approval to perform the trial (if applicable). The Sponsor should notify 
promptly all concerned investigator(s), IRB(s) and the Regulatory Authority of findings that could 
adversely affect the health of the patients/ subjects, impact on the conduct of the trial or alter the 
Regulatory Authority’s authorization to continue the trial. If it is necessary to change or deviate 
from the protocol to eliminate an immediate hazard to the subjects the Sponsor will notify the 
relevant regulatory authority and relevant IRB of the new events, the measures taken and the plan 
for further action as soon as possible.  This will be by telephone in the first instance followed by a 
written report.   
On completion of the trial, the Sponsor will inform the regulatory authority that the trial has ended.  
If the study is terminated for any reason the Sponsor will provide a written statement to the relevant 
regulatory authority and the IRB with the reasons for termination of the trial. This will be 
conducted within 15 days of the decision to terminate the trial.  The Sponsor will report in an 
expeditious manner all suspected unexpected serious adverse reactions (SUSARs) to the relevant 
regulatory authority and IRBs.   
13.2  INDEMNITY 
The Sponsor will provide compensation insurance against any risk incurred by a subject as a result 
of participation in this trial. The Sponsor will indemnify the Investigators as detailed in a separate 
document. 
13.3  DATA MONITORING 
Suitably qualified and trained clinical research personnel of the Sponsor will visit the trial site at 
regular intervals during the trial for monitoring purposes and to assist the research staff with any 
queries. CRFs and source documentation will be available for review during monitoring visits to 
the trial site. The function of this monitoring is to ensure compliance with the protocol, adherence 
to regulatory and Good Clinical Practice obligations, proper maintenance of records including IMP 
accountability records, correct administration of IMP including storage conditions and accurate 
reporting of AEs.   
Once the data from the case report forms have been entered onto the database, they will be 
reviewed and the data verified against the subject’s source data. Any discrepancies will be tracked 
by paper or electronically with an electronic audit trail. 


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13.4  AUDIT 
The Sponsor has an obligation to audit a proportion of studies.  A department other than the clinical 
department will undertake this obligation. Therefore, the Sponsor, an independent auditor or a 
regulatory authority may audit the trial site and trial documentation. These audits may take place 
while the trial is being conducted or up to several years later.   
13.5  CONFIDENTIALITY 
The Sponsor will not keep any material on file bearing any subject’s name, and subjects’ 
confidentiality will be maintained at all times. 
13.6  FINANCE 
This will be the subject of a separate agreement between the Investigator/Institution and Sponsor. 


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elevated eIF4E. Haematologica. 2015; 100:e7. 
19. Borden K, Culjkovic-Kraljacic. Ribavirin as an anti-cancer therapy: acute myeloid 
leukemia and beyond? Leuk Lymphoma. 2010 October; 51(10):1805-1815. 
20. Kentsis A, Volpon L, Topisirovic I, et al. Further evidence that ribavirin interacts with 
eIF4E. RNA. 2005:11:1762-1766. 
21. Kentsis A, Topisirovic I, Culjkovic B, Shao L, Borden K. Ribavirin suppresses eIF4E-
mediated ongogenic transformation by physical mimicry of the 7-methyl guanosine mRNA 
cap. Proc Natl Acad Sci U S A. 2004; 101:18105-18110. 
22. Topisirovic I, Kentsis A, Perez J, Guzman M, Jordan, Borden K. Eukaryotic translation 
initiation factor 4E activity is modulated by HOXA9 at multiple levels. Mol Cell Biol. 
2005;25:1100-1112. 
23. Tan K, Culjkovic B, Amri A, Borden K. Ribavirin targets eIF4E dependent Akt survival 
signaling. Biochim Biophys Res Commu. 2008;375:341-345. 
24. Topisirovic I, Guzman M, McConnell M, Licht J, Culjkovic B, Neering S, Mordan, Borden 
K. Aberrant eukaryotic translation initiation factor 4E-dependent RNA transport impedes 
hematopoietic 
differentiation 
and 
contributes 
to 
leukemogenesis. 
Mol 
Cell 
Biol;2003:8992-9002. 
25. Cheson BD, Cassileth PA, Head DR, et al. Report of the National Cancer Institute-
sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia., 
J Clin Oncol, 1990, vol. 8 (pg. 813-819). 
26. Van Vlierberghe H, Delanghe J, De Vos M, Leroux-Roel G, BASL Steering Committee. 
Factors influencing ribavirin-induced hemolysis. Journal of Hepatology. 2001(34);911-
916. 


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15 APPENDICES 
15.1 APPENDIX A:  CCB-01 SCHEDULE OF EVENTS 


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CCB-01 Schedule of Events 
 
 
 
 
 
Proceduresa 
Screenb 
Cycle 1  
Week 1 or 2 
Maintenance 
Dose Cycle  
Final 
Visit  
F/U  
Phone 
Call 
Survival 
D1 
D2 -D4 
D1 & D8 
 
Final Visit  
+ 2 wks  
 
Informed Consentb 
X 
 
 
 
 
 
 
AE/Concomitant Medications  
X 
X 
X 
X 
X 
X 
 
Medical historyc  
X 
 
 
 
 
 
 
Demographicsd 
X 
 
 
 
 
 
 
Physical Examd 
X 
X 
 
 
X 
 
 
Vital Signsd 
X 
X 
 
X  
X 
 
 
Pregnancy Test (urine or serum) 
X 
 
 
X q 4 weeks 
X 
 
 
ECOG Performance Status 
X 
 
 
 
 
 
 
Hematology/Chemistrye 
X 
X 
 
X (D1 only) 
X 
 
 
Chromosomal/mutational testingf 
X 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
X q 4 weeks 
X 
 
 
Bone Marrow Samplingg, h 
X 
 
 
X q 12 weeks 
X 
 
 
Biobanking samplesg 
X 
 
 
X 
X 
 
 
Brequinar/DHO/Flow Cytometry Sampleh 
 
X 
X 
X 
X 
 
 
Ship DHO Plasma Samplesi 
 
 
X (D4) 
X 
X 
 
 
Dispense/Collect Study Medication  
 
X 
 
X 
X 
 
 
Dispense/Collect Subject Calendar/Diary 
 
X 
 
X 
X 
 
 
Survival Assessment 
 
 
 
 
 
 
X 
 


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a. Visit window of ± 1 day for Cycle 1 visits; window of ± 3 days for Maintenance Dose cycles. 
b. Obtain informed consent prior to performing any screening or study-specific procedures. Screening procedures must be performed 
within 14 days prior to initial study drug administration.  Procedures at C1D1 that are repeats of Screening may be omitted if <1 week 
since Screening assessment. ECG and pregnancy test frequency are every 4 weeks or per institutional guidelines. 
c. Medical history is to include AML/other hematologic malignancy diagnosis, previous AML/other hematologic malignancy 
treatment, and standard chromosomal and mutational results per institutional guidelines. 
d. Demographic information is to include date of birth, height, weight, race, and ethnic origin. Rectal examination may be deferred for 
Physical Examination. Vital signs include heart rate, respiratory rate, seated blood pressure, respiratory rate, oral/aural body 
temperature. Complete physical examination and vital signs once every 4 weeks or more often if needed to assess an AE. 
e. If additional complete blood count (CBC) with differential results are available (for example, daily reports when a subject is 
hospitalized), these results may be captured in the eCRF using an Unscheduled visit. 
f. Testing panel is per institutional standard of care; obtain sample at Screening. 
g. Bone marrow sampling local testing will include analysis of the aspirate on smear, core biopsy by microscopy, flow cytometry, and 
karyotype for cytogenetics. Local molecular analysis will be performed on the screening bone marrow samples only.  Bone marrow 
samples will be sent for biobanking for possible further analysis from Screening, Week 7 (Day 43), and Final Visit. Perform bone 
marrow sampling at screening, at Visit 4 (Day 22), Visit 7 (Day 43), then once every 12 weeks. Timing of this procedure may be 
adjusted to ensure results are available for the next clinic visit. Procedure window is ±7 days.  
h. Cycle 1 Day 1 sample window ±15 minutes through 6h draw; window for additional C1 draws ±2h; window for Dose Adjustment 
Week plasma brequinar/DHO draws ±2h; window for Maintenance Cycle samples is ±4h. Ensure 84h DHO trough samples (~84 
hours after most recent dose) are obtained prior to dosing.   
i. 
Process, store and ship these samples per the Laboratory Manual. 
j. 
Cycle 1 Week 1 procedures are to be repeated for Week 2 if starting dose was decreased to 200 mg/m2 or dose held until a twice-
weekly dose has been determined with the exception that PK/DHO/Flow samples will be obtained only once per day in Week 2. 


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15.2 APPENDIX B: ECOG PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal level.  Fully active, able to 
carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal level; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
level, but ambulatory and able to 
carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal level with effort; some signs 
or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal level or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance but is 
able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 


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15.3 APPENDIX C: BREQUINAR/DHO/FLOW CYTOMETRY SAMPLING 
Information is provided in a separate laboratory manual regarding collection, processing, storing, 
and shipment of samples.  
Cycle 1 Day 1 sample window ±15 minutes through 6h draw; window for additional C1 draws 
±2h; window for Dose Adjustment Week plasma brequinar/DHO draws ±2h; window for 
Maintenance Cycle samples is ±4h. Ensure 84h DHO trough samples (~84 hours after most recent 
dose) are obtained prior to dosing.   
Brequinar and DHO plasma samples and peripheral blood for flow cytometry are to be obtained 
at the following time points:  
 
Cycle 1 Week 1 (or 2) 
 
D1 
D2 
D 3 
D 4 
Time 
Point 
Pre-
dose 
1h* 
2h* 
4h* 
6h* 
24h 
48h 
72h 
*These time points to be obtained in Week 1 only. 
 
 
 
Maintenance Cycle 
(Day 8 through Week 12 only) 
 
D1 
D8 
Time 
Point 
Pre-dose ~84h after previous dose 
Pre-dose ~84h after previous dose 
 
 


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15.4 APPENDIX D: COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS 
(CTCAE) 
https://evs.nci.nih.gov/ftp1/CTCAE/About.html 


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15.5  APPENDIX E: 
SAMPLE SUBJECT CONSENT FORM   
TITLE:  
A Phase 1b/IIa open-label, multi-center study to assess the safety, efficacy and 
pharmacokinetics of intrapatient dose-adjusted brequinar and inhibition of 
dihydroorotate dehydrogenase (DHODH) in adult subjects with acute myelogenous 
leukemia (AML) 
 
PROTOCOL NO.: 
CCB-01  
SPONSOR: 
 
Clear Creek Bio, Inc.  
 
 
585 Massachusetts Avenue, 4th Floor, 
 
 
Cambridge MA 02139 
 
INVESTIGATOR: 
 
<insert PI name> 
Site(s): 
 
<insert name> 
 
 
<insert address> 
STUDY-RELATED 
PHONE NUMBER(S): <insert name(s)> 
 
<insert number> 
 
<insert alternate number (24-hour contact number)> 
VERSION and DATE:  <e.g. CCB-01 Master ICF Version 4.0 21 February 2020> 
You are being asked to take part in a research study. Before you decide to participate, it is important 
for you to understand why the research is being done and what it will involve. Please take time to 
read the following information carefully and discuss it with others, if you wish, before deciding 
whether or not to take part. Ask us if there is anything that is not clear or if you would like more 
information. 
WHAT IS THE PURPOSE OF THE STUDY? 
The purpose of the study is to evaluate the safety, efficacy, pharmacokinetics (PK) (level of study 
medication in the blood) and the inhibition (decrease in level) of an enzyme called “dihydroorotate 
dehydrogenase” (DHODH). DHODH blocks the ability of blood cells formed in the bone marrow 
to differentiate (grow into mature white blood cells that can fight infection and platelets that help 
blood to clot). Brequinar is a drug that has been shown in animals in the laboratory to be able to 
decrease the level of DHODH and decrease leukemic cells in the bone marrow. Reducing DHODH 
level in patients with AML/other hematologic malignancy may help treat this type of leukemia by 
allowing cells in the bone marrow to grow into different types of mature cells. After brequinar has 
been shown to be safe and well tolerated when given to you, another drug called ribavirin will be 
added as a combination treatment. 


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WHY HAVE I BEEN ASKED TO PARTICIPATE? 
You have been asked to consider participating in this study because you because you have 
AML/other hematologic malignancy that has not responded to treatment (refractory), or the 
leukemia has recurred (relapsed).  
HOW LONG WILL I BE IN THE STUDY? 
Your participation in this study will last approximately 7 - 12 months and approximately 27 
subjects will be participating in this study. If you respond (your leukemia improves) due to the 
effects of the study medication, you may be able to continue being treated for up to one year. You 
will begin the study by taking the study medication once a week for at least the first week. After 
the results of certain blood tests are known (level of study drug and the enzyme being tracked in 
this study), the dose may be adjusted and your schedule may be changed to twice-weekly or about 
every three-and-one-half (3.5) days, for example on Monday mornings and Thursday evenings for 
the remainder of the time you are participating in the study. You and your study team can decide 
on the exact schedule for you to take your medication. 
WHAT WILL HAPPEN TO ME IF I TAKE PART? 
If you decide to take part in the study, you will have the following procedures: 
Screening Assessment 
The Screening period is defined as the period prior to the administration of study drug. During this 
period, the investigator or designee will obtain/perform the following: 
• Written, informed consent; 
• Demographic details (height, weight, date of birth, race, ethnicity). 
• Pertinent medical/surgical history, medications you are currently taking or have taken 
recently. 
• Physical examination.  
• Vital signs (heart rate, respiratory rate, blood pressure, body temperature).  
• Pregnancy test for women of childbearing potential (WOCBP).  
• ECOG performance assessment (a measure of your ability to perform activities of daily 
living).  
• Blood samples for hematology/chemistry. 
• Standard chromosomal and mutational testing (blood samples) if not already done. 
• Bone marrow sampling (aspiration and biopsy). 
• 12-lead ECG with QTcF to assess cardiac function.  


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If you qualify for the study, the treatment period begins with Cycle 1, Day 1 of the first dosing 
cycle. 
Cycle 1 Week 1 (also Cycle 1 Week 2 if dose reduced after Week 1 dosing) 
• Week 1 (or Week 2) Day 1: 
At this visit you will: 
• Be asked about any new medical events or new or changed medications since your last 
visit.  
• Have blood samples taken for baseline brequinar/DHO, flow cytometry, and 
hematology/chemistry.  
• Have a physical examination (including weight) (unless within one week of Screening), 
vital signs, pregnancy test for women able to bear children, and 12-lead ECG.  
• If you qualify for the study and choose to participate, you will be given study 
medication to take while at this clinic visit.  
• You will take the first dose at the clinic and remain at the clinic for pharmacokinetic 
(PK) and dihydroorotate (DHO) blood sampling at 1, 2, 4, and 6 hours after this first 
dose. Each dose of study medication will be made up of several capsules, depending 
on what dose you will be taking. Take the medication with about 8 ounces of plain 
water. You can take more water than 8 ounces if needed. 
• Be given a calendar/diary you will use to write down the dates/times of study 
medication administration and any new medical events, new medications or a change 
in dose of any medications. Please bring your study medication and diary to every visit. 
● Week 1 (or 2) Day 2: You will come back to the clinic approximately 24 hours (the next day) 
after your first dose to have blood samples taken for brequinar/DHO and flow cytometry.  
● Week 1 (or 2) Day 3: You will come back to the clinic approximately 48 hours (2 days) after 
your first dose to have blood samples taken for brequinar/DHO and flow cytometry.  
● Week 1 (or 2) Day 4: You will come back to the clinic approximately 72 hours (3 days) after 
your first dose to have blood samples taken for brequinar/DHO and flow cytometry. 
  
Maintenance Dose Cycle (visit every week up to Week 12 then every 2 weeks) 
Once you reach a twice-weekly dose, you will be in the Maintenance Dose Cycle.  
In the first 12 weeks from starting study drug (after finding twice-weekly dosing), the Maintenance 
Dose Cycle procedures will occur every week on Day 1 and Day 8. After completing 12 weeks 
from starting study drug, you may come to the clinic for a Maintenance Dose Cycle visit once 
every 2 weeks (Day 1 only). 


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Maintenance Dose Cycle Day 1: 
At this visit you will:  
• Be asked about any new medical events or new or changed medications since your last 
visit.  
• Have blood samples taken for baseline brequinar/DHO, flow cytometry, and 
hematology/chemistry.  
• Have a physical examination every 4 weeks (including weight) (unless within one week 
of Screening), vital signs, pregnancy test for women able to bear children once every 4 
weeks, a 12-lead ECG once every 4 weeks, and a bone marrow sample every 12 weeks.  
• Take the first dose of the week at the clinic; if you have moved to twice-weekly dosing, 
you will be given adequate study medication for the second dose of the week to be 
taken 3.5 days after the first dose of the week; if beyond Week 12, adequate medication 
will be provided for the entire two-week cycle.  
• Be given a new calendar/diary you will use to write down the dates/times of study 
medication administration and any new medical events, new medications or a change 
in dose of any medications. Please bring your study medication and diary to every visit. 
 
Maintenance Dose Cycle Day 8: 
At this visit you will:  
• Be asked about any new medical events or new or changed medications since your last 
visit.  
• Have blood samples taken for baseline brequinar/DHO, and flow cytometry.  
• Take the first dose of the week at the clinic.  
• If you have moved to twice-weekly dosing, you will be given adequate study 
medication for the second dose of the week to be taken 3.5 days after the first dose of 
the week.  
• Be given a new calendar/diary you will use to write down the dates/times of study 
medication administration and any new medical events, new medications or a change 
in dose of any medications. Please bring your study medication and diary to every visit. 
• You will not need to have this visit after Week 12. 
Final Visit 
This visit is to take place when you are leaving the study. You will: 
• Be asked about any new medical events or new or changed medications since your last 
visit.  
• Have blood samples taken for baseline brequinar/DHO, flow cytometry, and 
hematology/chemistry.  


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• Have a physical examination (including weight), vital signs, pregnancy test for women 
able to bear children if more than 4 weeks since the last test, 12-lead ECG if more than 
4 weeks since the last test, and bone marrow sample if more than 4 weeks since the last 
test.  
• Any leftover study medication will be collected.  
• Your diary will be checked for any new medical events, new medications or a change 
in dose of any medications. 
Telephone Follow Up Visit (2 weeks after Final Visit) 
• You will be contacted by telephone approximately two weeks after Final Visit to 
inquire if any new adverse events have occurred. Survival information will be collected 
while you are participating in the study (i.e., up to 2 weeks after last dose of study 
medication). 
Unscheduled Visits 
You may ask to come to the clinic when needed to be seen for unscheduled visits and tests to assess 
any new medical events providing the onset occurs within two (2) weeks after you have taken the 
final dose of study medication. 
WHAT ARE THE POSSIBLE DISADVANTAGES AND RISKS OF TAKING PART IN 
THIS RESEARCH? 
Risks from brequinar:    
While participating in this study, you are at risk for side effects. These side effects will vary from 
person to person. The more commonly occurring side effects are listed in this form, as are rare but 
serious side effects. You should discuss these with the study doctor. You may also want to ask 
about uncommon side effects that have been observed in small numbers of patients but are not 
listed in this form.  
Brequinar has been given to more than 800 patients with various forms of cancer in more than 20 
clinical trials and has also been tested in patient with psoriasis (a skin condition) and those who 
have had a kidney or liver transplant. The most common side effects have been: 
• Thrombocytopenia/hemorrhage (low platelet count, platelets are a part of the blood that 
help your blood clot, they may need to be replaced) 
• Stomatitis/mucositis (the inside of your mouth and intestines may develop ulcers which 
make eating and drinking difficult) 
• Skin rash 
• Nausea 
• Vomiting 
• Diarrhea 


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• Neutropenia (low white blood cell count, which may reduce the body’s ability to fight 
infections) 
• Infections 
• Anemia (low red blood cell count, red cells carry oxygen) 
• Fatigue  
Some of these side effects were severe enough in patients treated with brequinar to require 
hospitalization or caused death. In most cases, these side effects went away within about 2 weeks 
after patients stopped taking brequinar, but that cannot be guaranteed as the drug may work 
differently for you. If you develop these side effects during the study, your study team may decide 
to have you temporarily stop taking brequinar to see if the side effects get better. You and your 
study team may also decide to either stop your study participation or reduce the dose of the study 
medication to see if you can tolerate a lower dose. 
Brequinar may cause a condition called differentiation syndrome. This is a condition that affects 
your blood cells which may be life-threatening or lead to death if not treated. Differentiation 
syndrome has not been previously seen with brequinar. Call your healthcare provider or go to the 
nearest hospital emergency room right away if you develop any of the following symptoms of 
differentiation syndrome: 
• Fever 
• Cough 
• Shortness of breath 
• Swelling of arms and legs, around the neck, groin, or underarm area 
• Fast weight gain (more than 10 pounds within a week) 
• Bone pain 
If you develop differentiation syndrome, your healthcare provider may start you on corticosteroids 
which you will either take by mouth or receive by vein. You may be monitored in the hospital. 
You may also develop Tumor Lysis Syndrome (TLS). TLS is characterized by nausea, vomiting, 
diarrhea, anorexia, lethargy, irregular heart rhythms, heart failure, hematuria, seizures, muscle 
cramps, syncope, tetany and possible sudden death due to the acute metabolic irregularities of 
low blood levels of potassium, phosphorous, and calcium associated with the breakdown of 
tumor cells secondary to cytotoxic therapy.  
While TLS was not observed in the previous subjects who took brequinar in a clinical trial, the 
experience with brequinar in AML/other hematologic malignancy is limited. Signs and symptoms 
of TLS will therefore be carefully monitored particularly in the period that tumor lysis is most 
likely to occur (24-48 hours after first dose). If you develop this condition, you will be carefully 
monitored and may need to be treated in the hospital. 


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Risks from Ribavirin 
Ribavirin is marketed for treatment of hepatitis C but will be used in this study as an anti-cancer 
medication. Risks commonly associated with ribavirin administration in adult patients receiving 
ribavirin included:  
• fatigue/asthenia  
• headache, rigors  
• fevers  
• nausea  
• myalgia  
• anxiety/emotional lability/irritability  
• hemolytic anemia  
Risks from Study Procedures: 
Blood draws may cause pain, bleeding, and/or bruising. You may faint and/or develop an infection 
with redness and irritation of the vein at the site where blood is drawn. Frequent blood collection 
may cause anemia (low red blood cell count), which may create a need for blood transfusions. 
Having bone marrow sampling (biopsies and aspirations) performed may cause pain, bruising, 
bleeding, redness, low blood pressure, swelling, and/or infection at the site of the biopsies. An 
allergic reaction to the anesthetic may occur. A scar may form at the biopsy site. 
Bone marrow sampling will include analysis of the aspirate on smear, core biopsy by microscopy, 
flow cytometry, and karyotype for cytogenetics. You can talk with the study team about this 
testing. The type of genetic testing being performed for this study will not provide you or your 
doctor information about diseases that are passed down in families. It will not tell the study 
researchers anything that will prevent you from getting health insurance, and it will not tell the 
study researchers anything about any diseases or conditions you may get in the future. 
There may be risks or side effects that are unknown at this time. 
If a condition of which you were unaware is discovered during the study, a full report will be sent 
to your doctor if you request this.  You will be advised of the appropriate action to take for 
treatment. 
Pregnancy-Related Risks 
Taking part in this study can result in risks to an unborn or breastfeeding baby, so you should not 
become pregnant, breastfeed a baby, or father a child while participating in this study. If you are 
able to become pregnant or father a child, you must use birth control during the study and for at 
least 3 months after your last dose of study drug if you are sexually active. 


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Birth control specifications: Female participants who are able to become pregnant must use 2 
methods of birth control while on this study. Male participants must use an effective barrier method 
(such as a condom) while on this study. 
Talk with the study team about acceptable methods of birth control to use while taking part in this 
study. 
Males: Tell the study team right away if your partner becomes pregnant or suspects pregnancy. 
Females: If you are pregnant, you will not be enrolled into this study. If you become pregnant or 
suspect that you are pregnant during the study, you must tell your doctor right away. 
Getting pregnant may result in your removal from this study.  
WHAT ARE THE POSSIBLE BENEFITS? 
Either or both or the combination of the study drugs may help to control the disease. Future patients 
may benefit from what is learned. There may be no benefits for you in this study.  
WILL IT COST ANYTHING TO BE IN THE STUDY? 
If you participate in this study, you will not have to pay for the cost of the study drug used in the 
study. 
You or your insurer will be responsible for the cost of your usual ongoing medical care, including 
procedures and non-study medications that the doctor or your regular doctor requires during this 
study as part of your usual medical care. If you have any questions, please ask the doctor and/or a 
member of the study staff about the costs that will or will not be covered by the sponsor. 
IS THERE PAYMENT FOR PARTICIPATION? 
You will not receive any payment for participation in this study. 
WHAT ARE THE ALTERNATIVES FOR TREATMENT? 
You do not have to participate in this research study to receive treatment. Instead, you may be 
eligible for recently approved therapies, and may be able to have a bone marrow transplant outside 
of this study. You may choose to receive other investigational therapies, if available. You may 
also choose not to have treatment for cancer at all. Regardless of your choices, you will receive 
appropriate medical care, including treatment for pain and other symptoms of cancer. Please note 
that you will be informed in a timely manner if new information becomes available that is relevant 
during your participation in this study. 
WHAT IF SOMETHING GOES WRONG? 


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An important part of this study is to see if the investigational product causes side effects. You must 
inform the staff if you feel unwell or have any unusual symptoms at any time during the study, no 
matter how minor you think they are. If you experience such events, treatment will be made 
available by the doctor. 
You will be provided any reasonably necessary medical treatment for any injuries sustained as a 
result of participating in this study, except to the extent such costs are covered by your medical or 
hospital insurance or by governmental programs providing such coverage. You must follow the 
directions of the doctor to be eligible for this coverage. Neither the sponsor nor the doctor have 
plans to provide other compensation in the event of an injury. You are not giving up any of your 
legal rights by signing this consent form. 
Certain tests, procedures, and/or drugs that you may receive as part of this study may be without 
cost to you because they are for research purposes only. However, your insurance provider and/or 
you may be financially responsible for the cost of care and treatment of any complications resulting 
from the research tests, procedures, and/or drugs. Standard medical care that you receive under 
this research study will be billed to your insurance provider and/or you in the ordinary manner. 
Before taking part in this study, you may ask about which parts of the research-related care may 
be provided without charge, which costs your insurance provider may pay for, and which costs 
may be your responsibility. You may ask that a financial counselor be made available to you to 
talk about the costs of this study. 
WILL ALL THE DOCUMENTS CONCERNING ME REMAIN CONFIDENTIAL? 
Yes. The company that is conducting this study will not keep any document on file that contains 
your name; you will only be identified by your initials and a subject number. It will be necessary 
for the sponsor, its representatives, the regulatory authorities, other institutions participating in the 
study, and possibly the Institutional Review Board (an IRB is a group of people who review the 
risks and benefits of a study) to review your medical records, but these will be treated in the 
strictest confidence permitted by law. If the results of the study are published, you will not be 
identified by name. Your personal health information (PHI) will be kept as confidentially as 
possible according to state and federal laws. However, in some situations, the Food and Drug 
Administration (FDA) could be required to reveal the names of participants. 
The permission to use your PHI will continue indefinitely unless you withdraw your authorization 
in writing.  
WILL INFORMATION ABOUT ME BEING IN THIS STUDY BE USED AND SHARED? 
This section explains how your medical and health records might be used and shared if you agree 
to participate in this study. If you do not sign this consent form, you cannot participate in the study. 


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During the study, the doctor and/or a member of the study staff will record health information 
about you (your “records”).  Your records include the data collected or reviewed during the study, 
including data about the physical examination, tests, and other procedures described above. Your 
records also will include identifying information, such as your name and address. 
By signing this consent form, you: 
• Allow the doctor and/or a member of the study staff to use your records to carry out this 
study. 
• Allow the doctor and/or a member of the study staff to share your records with the company 
paying for this study, Clear Creek Bio, Inc., their representatives, and other researchers 
involved in this study. These people will use these records to review the study and to check 
the safety of the study. 
• Allow the doctor or sponsor to publish results of the study in medical journals or to present 
results at meetings. If this happens, your name will not be used. The doctor also may share 
all of your records and this signed consent form with government agencies, including the 
U.S. Food and Drug Administration (FDA), and government agencies in other countries. 
They may also share your records with regulatory agencies. These agencies may use these 
records to check the information collected in this study, to check how the study is carried 
out, and to check subjects’ safety. 
There are national and state laws that state that the doctor must protect the privacy of your records.  
However, you do not have a guarantee of absolute privacy because of the need to share your 
information as described above. After the doctor shares your records with the sponsor and others, 
the laws may no longer protect the privacy of your records. These records might be shared with 
other people who do not have to protect the privacy of your records. 
If you get hurt or sick possibly because of being in the study, and you seek medical treatment: 
• The doctor and sponsor may obtain study-related records from your or other health care 
providers to learn more about the effects of the study and your condition. 
• Information about this study might be given to your insurance company or health care 
payer for the purpose of resolving your claim. 
• The sponsor might give information that identifies you to its insurance carrier for the 
purpose of resolving your insurance claim. 
You have the right to see and copy your records in the doctor’s possession. However, by signing 
this consent form, you agree that you might not be able to review some of these records related to 


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the study until after the study is complete. At that time, your right to see these records will be 
restored. 
This consent form has no expiration date.  If you do not cancel this consent form, then it will 
remain valid indefinitely. 
You will receive a signed and dated copy of this consent for your records. 
WHAT WILL HAPPEN TO THE RESULTS OF THE RESEARCH STUDY? 
The results of the study will be reported in a Clinical Study Report and may be published in 
scientific journals or presented in scientific meetings. The results of this study may also be used to 
support regulatory filings by the sponsor in support of the use of this medication for treating 
AML/other hematologic malignancy or other blood cancers or diseases. A description of this 
clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. law. This web 
site will not include information that can identify you. At most, the web site will include a summary 
of the results. You can search this web site at any time. 
WHO IS ORGANIZING AND FUNDING THE RESEARCH? 
The study has been organized and funded by Clear Creek Bio, Inc. The investigational medicinal 
product (study drug) is being provided by Clear Creek Bio, Inc. 
DO I HAVE TO TAKE PART? 
Your participation in this study is voluntary. You may decide not to participate, or you may leave 
the study at any time. Your decision will not result in any penalty or loss of benefits to which you 
are entitled. If you decide to take part, you will be asked to sign and date this consent form and 
given a copy to keep.   
Your participation in this study may be ended by the doctor, sponsor, the regulatory agencies or 
the Institutional Review Board (an IRB is a group of people who review the risks and benefits of 
a study).  They can end your participation for any of the following reasons without your consent: 
• if it is in your best interest; 
• you do not later consent to any future changes that may be made in the study plan; or 
• for any other reason. 
If this is the case, you will be given further instructions by the doctor for any final evaluations that 
may be needed. 
CONTACT FOR FURTHER INFORMATION 


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Any questions, concerns, or complaints about this study or if you feel you have had a 
research-related injury or reaction to the study drug should be directed to <insert PI name and 
contact information [24-hour contact]>. 
If you have questions about your rights as a research subject or for questions, concerns or 
complaints about the research, you may contact: 
<Insert IRB name > 
<Insert address> 
<Insert telephone number> 
<Insert email if applicable> 
The IRB will not be able to answer some study-specific questions however, you may contact the 
IRB if the research staff cannot be reached or if you wish to talk to someone other than the research 
staff.  
Do not sign this consent form unless you have had a chance to ask questions and have received 
satisfactory answers to all of your questions. 
You will be given a signed and dated copy of this consent form to keep. 
Thank you for taking the time to read this consent form. 
 


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Consent Form Signature Page 
SUBJECT’S DATE OF BIRTH:  ______/______/______ 
  
mmm /    dd    /  yyyy 
Print Name of Investigator: 
 
 
Please initial 
box: 
1. I confirm that I have read this consent form for the above study and have 
had the opportunity to ask questions. 
 
2. I understand my participation is voluntary and I am free to withdraw at any 
time, without giving any reason, without my medical care or legal rights 
being affected. 
 
3. I understand that sections of any of my medical records may be looked at 
by responsible individuals from Clear Creek Bio, Inc. and/or its 
representatives or from regulatory authorities and the IRB where it is 
relevant to my taking part in research. I give permission for these individuals 
to have access to my records. 
 
4. I understand that my data may be transmitted outside the country to 
countries with less strict data protection laws. 
 
5. I agree to take part in the above study. 
 
 
By signing this consent form, I have not given up any of my legal rights. 
 
 
 
 
Printed Name of Subject                       Signature of Subject 
Date   
Time 
 
 
                                                                      
Printed Name of person conducting      Sign  
Date  
 
Time 
informed consent discussion 
 
 
Original with Investigator File 
1 copy for subject 
1 copy for Subject’s Medical Records 


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15.6 APPENDIX F:  WMA DECLARATION OF HELSINKI 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by 
the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000  
53th WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 added) 
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added) 
59th WMA General Assembly, Seoul, October 2008 
A. INTRODUCTION  
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including 
research on identifiable human material and data.  
The Declaration is intended to be read as a whole and each of its constituent paragraphs should 
not be applied without consideration of all other relevant paragraphs. 
2. Although the Declaration is addressed primarily to physicians, the WMA encourages other 
participants in medical research involving human subjects to adopt these principles. 
3. It is the duty of the physician to promote and safeguard the health of patients, including those 
who are involved in medical research. The physician's knowledge and conscience are dedicated 
to the fulfillment of this duty. 
4. The Declaration of Geneva of the WMA binds the physician with the words, "The health of 
my patient will be my first consideration," and the International Code of Medical Ethics 
declares that, "A physician shall act in the patient's best interest when providing medical care." 
5. Medical progress is based on research that ultimately must include studies involving human 
subjects. Populations that are underrepresented in medical research should be provided 
appropriate access to participation in research. 
6. In medical research involving human subjects, the well-being of the individual research subject 
must take precedence over all other interests. 


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7. The primary purpose of medical research involving human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic 
interventions (methods, procedures and treatments). Even the best current interventions must 
be evaluated continually through research for their safety, effectiveness, efficiency, 
accessibility and quality. 
8. In medical practice and in medical research, most interventions involve risks and burdens. 
9. Medical research is subject to ethical standards that promote respect for all human subjects and 
protect their health and rights. Some research populations are particularly vulnerable and need 
special protection. These include those who cannot give or refuse consent for themselves and 
those who may be vulnerable to coercion or undue influence. 
10. Physicians should consider the ethical, legal and regulatory norms and standards for research 
involving human subjects in their own countries as well as applicable international norms and 
standards. No national or international ethical, legal or regulatory requirement should reduce 
or eliminate any of the protections for research subjects set forth in this Declaration. 
B. BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH  
11. It is the duty of physicians who participate in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal 
information of research subjects. 
12. Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant sources 
of information, and adequate laboratory and, as appropriate, animal experimentation. The 
welfare of animals used for research must be respected.  
13. Appropriate caution must be exercised in the conduct of medical research that may harm the 
environment. 
14. The design and performance of each research study involving human subjects must be clearly 
described in a research protocol. The protocol should contain a statement of the ethical 
considerations involved and should indicate how the principles in this Declaration have been 
addressed. The protocol should include information regarding funding, sponsors, institutional 
affiliations, other potential conflicts of interest, incentives for subjects and provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation in 
the research study. The protocol should describe arrangements for post-study access by study 
subjects to interventions identified as beneficial in the study or access to other appropriate 
care or benefits. 


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15. The research protocol must be submitted for consideration, comment, guidance and approval 
to a research ethics committee before the study begins. This committee must be independent 
of the researcher, the sponsor and any other undue influence. It must take into consideration 
the laws and regulations of the country or countries in which the research is to be performed 
as well as applicable international norms and standards but these must not be allowed to reduce 
or eliminate any of the protections for research subjects set forth in this Declaration. The 
committee must have the right to monitor ongoing studies. The researcher must provide 
monitoring information to the committee, especially information about any serious adverse 
events. No change to the protocol may be made without consideration and approval by the 
committee. 
16. Medical research involving human subjects must be conducted only by individuals with the 
appropriate scientific training and qualifications. Research on patients or healthy volunteers 
requires the supervision of a competent and appropriately qualified physician or other health 
care professional. The responsibility for the protection of research subjects must always rest 
with the physician or other health care professional and never the research subjects, even 
though they have given consent. 
17. Medical research involving a disadvantaged or vulnerable population or community is only 
justified if the research is responsive to the health needs and priorities of this population or 
community and if there is a reasonable likelihood that this population or community stands to 
benefit from the results of the research. 
18. Every medical research study involving human subjects must be preceded by careful 
assessment of predictable risks and burdens to the individuals and communities involved in 
the research in comparison with foreseeable benefits to them and to other individuals or 
communities affected by the condition under investigation. 
19. Every clinical trial must be registered in a publicly accessible database before recruitment of 
the first subject. 
20. Physicians may not participate in a research study involving human subjects unless they are 
confident that the risks involved have been adequately assessed and can be satisfactorily 
managed. Physicians must immediately stop a study when the risks are found to outweigh the 
potential benefits or when there is conclusive proof of positive and beneficial results. 
21. Medical research involving human subjects may only be conducted if the importance of the 
objective outweighs the inherent risks and burdens to the research subjects. 
22. Participation by competent individuals as subjects in medical research must be voluntary. 
Although it may be appropriate to consult family members or community leaders, no 
competent individual may be enrolled in a research study unless he or she freely agrees. 


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23. Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information and to minimize the impact of the study on their 
physical, mental and social integrity. 
24. In medical research involving competent human subjects, each potential subject must be 
adequately informed of the aims, methods, sources of funding, any possible conflicts of 
interest, institutional affiliations of the researcher, the anticipated benefits and potential risks 
of the study and the discomfort it may entail, and any other relevant aspects of the study. The 
potential subject must be informed of the right to refuse to participate in the study or to 
withdraw consent to participate at any time without reprisal. Special attention should be given 
to the specific information needs of individual potential subjects as well as to the methods 
used to deliver the information. After ensuring that the potential subject has understood the 
information, the physician or another appropriately qualified individual must then seek the 
potential subject's freely-given informed consent, preferably in writing. If the consent cannot 
be expressed in writing, the non-written consent must be formally documented and witnessed. 
25. For medical research using identifiable human material or data, physicians must normally seek 
consent for the collection, analysis, storage and/or reuse. There may be situations where 
consent would be impossible or impractical to obtain for such research or would pose a threat 
to the validity of the research. In such situations the research may be done only after 
consideration and approval of a research ethics committee. 
26. When seeking informed consent for participation in a research study the physician should be 
particularly cautious if the potential subject is in a dependent relationship with the physician 
or may consent under duress. In such situations the informed consent should be sought by an 
appropriately qualified individual who is completely independent of this relationship. 
27. For a potential research subject who is incompetent, the physician must seek informed consent 
from the legally authorized representative. These individuals must not be included in a 
research study that has no likelihood of benefit for them unless it is intended to promote the 
health of the population represented by the potential subject, the research cannot instead be 
performed with competent persons, and the research entails only minimal risk and minimal 
burden. 
28. When a potential research subject who is deemed incompetent is able to give assent to 
decisions about participation in research, the physician must seek that assent in addition to the 
consent of the legally authorized representative. The potential subject's dissent should be 
respected. 
29. Research involving subjects who are physically or mentally incapable of giving consent, for 
example, unconscious patients, may be done only if the physical or mental condition that 
prevents giving informed consent is a necessary characteristic of the research population. In 
such circumstances the physician should seek informed consent from the legally authorized 


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representative. If no such representative is available and if the research cannot be delayed, the 
study may proceed without informed consent provided that the specific reasons for involving 
subjects with a condition that renders them unable to give informed consent have been stated 
in the research protocol and the study has been approved by a research ethics committee. 
Consent to remain in the research should be obtained as soon as possible from the subject or 
a legally authorized representative. 
30. Authors, editors and publishers all have ethical obligations with regard to the publication of 
the results of research. Authors have a duty to make publicly available the results of their 
research on human subjects and are accountable for the completeness and accuracy of their 
reports. They should adhere to accepted guidelines for ethical reporting. Negative and 
inconclusive as well as positive results should be published or otherwise made publicly 
available. Sources of funding, institutional affiliations and conflicts of interest should be 
declared in the publication. Reports of research not in accordance with the principles of this 
Declaration should not be accepted for publication. 
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE 
31. The physician may combine medical research with medical care only to the extent that the 
research is justified by its potential preventive, diagnostic or therapeutic value and if the 
physician has good reason to believe that participation in the research study will not adversely 
affect the health of the patients who serve as research subjects. 
32. The benefits, risks, burdens and effectiveness of a new intervention must be tested against 
those of the best current proven intervention, except in the following circumstances: 
• The use of placebo, or no treatment, is acceptable in studies where no current proven 
intervention exists; or  
• Where for compelling and scientifically sound methodological reasons the use of placebo 
is necessary to determine the efficacy or safety of an intervention and the patients who 
receive placebo or no treatment will not be subject to any risk of serious or irreversible 
harm. Extreme care must be taken to avoid abuse of this option. 
33. At the conclusion of the study, patients entered into the study are entitled to be informed about 
the outcome of the study and to share any benefits that result from it, for example, access to 
interventions identified as beneficial in the study or to other appropriate care or benefits. 
34. The physician must fully inform the patient which aspects of the care are related to the 
research. The refusal of a patient to participate in a study or the patient's decision to withdraw 
from the study must never interfere with the patient-physician relationship. 


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35. In the treatment of a patient, where proven interventions do not exist or have been ineffective, 
the physician, after seeking expert advice, with informed consent from the patient or a legally 
authorized representative, may use an unproven intervention if in the physician's judgment it 
offers hope of saving life, re-establishing health or alleviating suffering. Where possible, this 
intervention should be made the object of research, designed to evaluate its safety and efficacy. 
In all cases, new information should be recorded and, where appropriate, made publicly 
available. 
22.10.2008 
 
 
 


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15.7 APPENDIX G: INVESTIGATOR’S STATEMENT AND AGREEMENT 
STUDY NUMBER:   CCB-01 
STUDY TITLE:  A Phase 1b/2a open-label, multi-center study to assess the safety, efficacy and 
pharmacokinetics of intrapatient dose-adjusted brequinar and inhibition of dihydroorotate 
dehydrogenase (DHODH) in adult subjects with acute myelogenous leukemia (AML) 
INVESTIGATOR’S STATEMENT AND AGREEMENT 
I (the Investigator) have read this protocol and hereby agree to conduct the trial in accord with all 
of its provisions.  It is further agreed that the details of this trial and all information provided to 
me by Clear Creek Bio, Inc. (the Sponsor) will be held in the strictest confidence and will not be 
revealed for any reason without written authorization from Clear Creek Bio, Inc. except to those 
who are to participate in the conduct of the trial. 
I agree that all data, the case report forms and all materials provided for the conduct of the trial are 
the property of Clear Creek Bio, Inc. unless specified otherwise in writing. It is understood that 
Clear Creek Bio, Inc. will utilize the information derived from this trial in various ways, such as 
for submission to government regulatory agencies, required internal reports, and presentations 
without violating patient/ subject confidentiality in any way. 
I further agree that Clear Creek Bio, Inc. or its representatives will be permitted access, in 
accordance with current Good Clinical Practice Guidelines, to all data generated by this trial and 
the source documents from which case report form data were generated. 
PRINCIPAL INVESTIGATOR 
Printed Name: 
 
Signature:                                                                                           Date: 
 
Site Address:        
 
                                                         
 
                             


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15.8 APPENDIX H: RIBAVIRIN GENERIC (RIBAVIRIN USP) CAPSULES, FOR 
ORAL USE SUMMARY OF PRODUCT CHARACTERISTICS (SPC) 
 


PACKAGE LEAFLET: INFORMATION FOR THE USER 
Ribavirin Aurobindo 200 mg capsules, hard 
Ribavirin 
 
Read all of this leaflet carefully before you start taking this medicine. 
 
Keep this leaflet. You may need to read it again. 
 
If you have any further questions, ask your doctor or pharmacist. 
 
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, 
even if their symptoms are the same as yours. 
 
If any of the side effects gets serious, or if you notice any side effects not listed in this 
leaflet, please tell your doctor or pharmacist. 
 
In this leaflet 
1.   What Ribavirin Aurobindo is and what it is used for 
2.   Before you take Ribavirin Aurobindo 
3.   How to take Ribavirin Aurobindo 
4.   Possible side effects 
5.   How to store Ribavirin Aurobindo 
6.   Further information 
 
1.  
WHAT RIBAVIRIN AUROBINDO IS AND WHAT IT IS USED FOR 
 
Ribavirin Aurobindo contain the active ingredient ribavirin. Ribavirin Aurobindo stops the 
multiplication of many types of viruses, including hepatitis C virus. Ribavirin Aurobindo must 
not be used without interferon alfa-2b, i.e. Ribavirin Aurobindo must not be used alone. 
 
Previously untreated patients: 
The combination of Ribavirin Aurobindo with interferon alfa-2b is used to treat patients 3 years 
of age and older who have chronic hepatitis C (HCV) infection. For children and adolescents 
weighing less than 47 kg a solution formulation is available. 
 
Previously treated adult patients: 
The combination of Ribavirin Aurobindo with interferon alfa-2b is used to treat adult patients 
with chronic hepatitis C, who have previously responded to treatment with an alfa interferon 
alone, but whose condition has recurred. 
 
There is no safety or efficacy information on the use of Ribavirin Aurobindo with pegylated or 
other forms of interferon (i.e., not alfa-2b). 
 
2.  
BEFORE YOU TAKE RIBAVIRIN AUROBINDO 
 
Ribavirin Aurobindo is not recommended for use in patients under the age of 3 years. 
 
DO NOT take Ribavirin Aurobindo 
If any of the following apply to you or your child you are caring for, do not take Ribavirin 
Aurobindo, and tell your doctor if you: 
 
 
are allergic (hypersensitive) to ribavirin or any of the other ingredients of Ribavirin 
Aurobindo capsules (see section 6, further information). 
 
are pregnant or planning to become pregnant. (see section “pregnancy and breast-
feeding).  
 
are breast-feeding. 
 
have had any previous severe heart problem, or have had any problems with the heart in the 
last 6 months  
 
have any severe medical conditions that leave you very weak, including severe kidney 
disease. 


 
have severe kidney disease and/or are on haemodialysis 
 
have had severe liver problems, which are not related to hepatitis C. 
 
have suffered from any blood disorder, for example anaemia (low blood count), 
thalassemia or sickle-cell anaemia. 
 
Have suffered from autoimmune disease in the past, or suffer from autoimmune hepatitis or 
are taking other medicine that suppress your immune system (that protects you against 
infection and some diseases). 
 
Children and adolescents must not take combination therapy with Ribavirin Aurobindo and 
alpha interferon when there is existence or history of serious nervous or mental problems, such 
as severe depression, suicidal thoughts or attempted suicide. 
 
You should tell your doctor if you have suffered from any other serious illness in the past. 
 
 
Reminder: Please read the “Do not use” section of the package leaflet for interferon alfa-2b 
before you begin combination treatment with Ribavirin Aurobindo. 
 
Take special care with Ribavirin Aurobindo 
 
Seek medical advice immediately if you develop symptoms of a severe allergic reaction 
(such as difficulty in breathing, wheezing or hives) while taking this treatment. 
 
      Children and adolescents weighing less than 47 kg: 
      The use of Ribavirin Aurobindo is not recommended.  
 
      You should tell your doctor if you or your child you are caring for: 
•     are an adult who has or had a severe nervous or mental disorder, confusion,    
      unconsciousness, or have had thoughts of suicide or have attempted suicide, or have a    
      history of substance abuse (e.g. alcohol or drugs) 
•     have ever had depression or develop symptoms associated with depression (e.g. feeling of   
sadness, dejection, etc.) while on treatment with Ribavirin . 
•     are a woman of childbearing age (see section “Pregnancy and breast-feeding”) 
•     are a male and your female partner is of childbearing age (see section “Pregnancy and 
breastfeeding”) 
•     had a previous serious heart condition or have cardiac disease 
•     are older than 65 years or if you have problems with your kidneys 
•     have or have had any serious illness 
•     have thyroid problems  
 
During treatment with Ribavirin Aurobindo in combination therapy with an alfa interferon, 
dental and gum disorders, which may lead to loss of teeth, have been reported. In addition, 
dry mouth that could have a damaging effect on teeth and membranes of the mouth has been 
reported during longterm treatment with ribavirin in combination therapy with an alpha 
interferon. You should brush your teeth thoroughly twice daily and have regular dental 
examinations. In addition some patients may experience vomiting. If you have this reaction, be 
sure to rinse your mouth thoroughly afterwards. 
 
During treatment with Ribavirin Aurobindo in combination therapy with an alpha interferon, 
patients may experience eye problems, or loss of vision in rare instances. If you receive 
ribavirin in combination with an alpha interferon, you should have a baseline eye examination. 
Any patient complaining of decrease or loss of vision must have a prompt and complete eye 
examination. Patients with preexisting eye disorders (e.g. diabetic or hypertensive retinopathy) 
should receive periodic eye exams during combination therapy with ribavirin and an alpha 
interferon. Combination therapy with ribavirin and an alpha interferon should be discontinued in 
patients who develop new or worsening eye disorders. 
 
 
Reminder: Please read the “Take special care” section of the Package Leaflet for interferon 
alfa-2b before you begin combination treatment. 


 
Taking other medicines 
 
Please tell your doctor or pharmacist if you or the child you are caring for: 
-         are taking or have recently taken any other medicines, including medicines obtained                             
without a prescription. 
- 
are receiving azathioprine in combination with ribavirin and pegylated alpha interferons 
and, therefore may be at an increased risk of developing severe blood disorders. 
-         are infected with both Human Immunodeficiency Virus (HIV-positive) and Hepatitis C 
Virus (HCV) and are being treated with an anti-HIV medicinal product(s) – [nucleoside 
reverse transcriptase inhibitor (NRTI), and/or highly active anti-retroviral therapy 
(HAART)]: 
-              Taking Ribavirin Aurobindo in combination with an alpha interferon and an 
anti-HIV medicinal product(s) may increase the risk of lactic acidosis, liver 
failure, and blood abnormalities development (reduction in number of red blood 
cells which carry oxygen, certain white blood cells that fight infection, and 
blood clotting cells called platelets). 
-  
With zidovudine or stavudine, it is not certain if ribavirin will change the way 
these medicines work. Therefore, your blood will be checked regularly to be 
sure that the HIV infection is not getting worse. If it gets worse, your doctor 
will decide whether or not your Ribavirin Aurobindo treatment needs to be 
changed. Additionally, patients receiving zidovudine with ribavirin in 
combination with alpha interferons could be at increased risk of developing 
anaemia (low number of red blood cells). Therefore the use of zidovudine and 
ribavirin in combination with alpha interferons is not recommended. 
-  
Due to the risk of lactic acidosis (a build-up of lactic acid in the body) and 
pancreatitis, the use of ribavirin and didanosine is not recommended and the 
use of ribavirin and stavudine should be avoided. 
-  
Co-infected patients with advanced liver disease receiving (HAART) may be at 
increased risk of worsening liver function. Adding treatment with alfa 
interferons alone or in combination with ribavirin may increase the risk in this 
patient subset. 
Reminder:  Please read the “Taking other medicines” section of the Package Leaflet for  
interferon alfa-2b before you begin combination treatment. 
 
Taking Ribavirin Aurobindo with food and drink 
Ribavirin Aurobindo must be taken with food. 
 
Pregnancy and breast-feeding 
If you are pregnant you must not take Ribavirin Aurobindo. Ribavirin Aurobindo can be very 
damaging to your unborn baby (embryo). 
 
Both female and male patients must take special precautions in their sexual activity if there is 
any possibility for pregnancy to occur: 
 
 
Girl or woman of childbearing age: 
You must have a negative pregnancy test before treatment, each month during treatment, and 
for the 4 months after treatment is stopped. You must use an effective contraceptive during the 
time you are taking ribavirin and for 4 months after stopping treatment. This should be 
discussed with your doctor.  
 
 
Men: 
Do not have sex with a pregnant woman unless you use a condom. This will lessen the 
possibility for ribavirin to be left in the woman’s body.  
If your female partner is not pregnant now but is of childbearing age, she must be tested for 
pregnancy each month during treatment and for 7 months after treatment has stopped. You or 
your female partner must use an effective contraceptive during the time you are taking Ribavirin 


Aurobindo and for 7 months after stopping the treatment. This should be discussed with your 
doctor (see section “Do not take Ribavirin Aurobindo”). 
 
If you are a woman who is breast-feeding, you must not take Ribavirin Aurobindo. Discontinue 
breastfeeding before starting to take Ribavirin Aurobindo. 
 
Driving and using machines 
Ribavirin Aurobindo has no effect on your ability to drive or use machines. However, interferon 
alfa-2b may cause sleepiness, tiredness or confusion.  
Do not drive or use any tools or machines if you feel tired or sleepy, or are confused. 
 
Important information about some of the ingredients of Ribavirin Aurobindo 
Each Ribavirin Aurobindo capsule contains a small amount of lactose. If you have been told by 
your doctor that you have an intolerance to some sugars, discuss with your doctor before 
taking this medicinal product. 
 
3.  
HOW TO TAKE RIBAVIRIN AUROBINDO 
 
General information about taking Ribavirin Aurobindo 
If the child you are caring for is under the age of 3 years, do not administer. 
 
Always take Ribavirin Aurobindo exactly as your doctor has told you. You should check with 
your doctor or pharmacist, if you are not sure.  
 
Do not take more than the recommended dosage and take the medicine for as long as prescribed. 
Your doctor has determined the correct dose of Ribavirin Aurobindo based on how much you or 
the child you are caring for weighs..  
 
Standard blood tests will be taken to check your blood, kidney and liver function. 
- 
Blood tests will be done regularly to help your doctor to know if this treatment is 
working.  
- 
Depending upon the results of these tests, your doctor may change/adjust the number of 
hard capsules you or the child you are caring for take, prescribe a different pack size of 
Ribavirin Aurobindo, and/or change the length of time to take this treatment. 
- 
If you have or develop severe kidney or liver problems, this treatment will be stopped. 
 
The usual dose, according to how much the patient weighs, is shown in the table below: 
1. Look for the line that shows how much the adult or child/adolescent weighs. 
Reminder:  If the child is under the age of 3 years, do not administer. 
2. Read across on the same line to see how many hard capsules to take. 
Reminder:  If your doctor’s instructions are different from the amounts in the below 
table, follow your doctor’s instructions. 
3. If you have any questions about the dose, ask your doctor. 
 
Ribavirin Aurobindo for oral use - dose based on body weight 
If the adult 
weighs 
(kg) 
 
Usual daily Ribavirin 
Aurobindo dose 
Number of 200 mg capsules 
 
< 65 
800 mg 
2 capsules in the morning and 2 capsules in the 
evening 
65 – 80 
1,000 mg 
2 capsules in the morning and 3 capsules in the 
evening 
81 - 105 
1,200 mg 
3 capsules in the morning and 3 capsules in the 
evening 
> 105 
1,400 mg 
3 capsules in the morning and 4 capsules in the 
evening 


 
If the 
child/adolescent 
weighs (kg) 
 
Usual daily Ribavirin 
Aurobindo dose 
Number of 200 mg capsules 
 
47 – 49 
600 mg 
1 capsule in the morning and 2 capsules in the 
evening 
50 – 65 
800 mg 
2 capsules in the morning and 2 capsules in the 
evening 
> 65 
see adult dose and corresponding number of hard capsules 
 
 
Take your prescribed dose by mouth with water and during your meal. Do not chew the hard 
capsules. For children or adolescents who cannot swallow a hard capsule, an oral solution of 
ribavirin is available. 
 
Reminder: Ribavirin Aurobindo is only to be used in combination with interferon alfa-2b or 
hepatitis C virus infection. For complete information be sure to read the “How to use” section of 
the Package Leaflet for  interferon alfa-2b. 
 
Interferon medicine that is used in combination with Ribavirin Aurobindo may cause unusual 
tiredness; if you are injecting this medicine yourself or giving it to a child, use it at bedtime. 
 
If you take more Ribavirin Aurobindo than you should 
Tell your doctor or pharmacist as soon as possible. 
 
If you forget to take Ribavirin Aurobindo 
If you are self-administering treatment, or if you are the caregiver of a child taking Ribavirin 
Aurobindo in combination with interferon alfa-2b, take/administer the missed dose as soon as 
possible during the same day. If an entire day has gone by, check with your doctor. Do not take 
a double dose to make up for a forgotten dose. 
 
4.  
POSSIBLE SIDE EFFECTS 
 
Please read the “Possible side effects” section of the Package Leaflet for interferon alfa-2b. 
 
Like all medicines, Ribavirin Aurobindo used in combination with  an alpha interferon product 
can cause side effects. although not everybody gets them.  
 
Psychiatric and Central Nervous System: 
Some people get depressed when taking ribavirin in combination treatment with an interferon, 
and in some cases people had thoughts about threatening the life of others, suicidal thoughts or 
aggressive behaviour (sometimes directed against others). Some patients have actually 
committed suicide. Be sure to seek emergency care if you notice that you are becoming 
depressed or have suicidal thoughts or change in your behaviour. You may want to consider 
asking a family member or close friend to help you stay alert to signs of depression or changes 
in your behaviour. 
 
Children and adolescents are particularly prone to develop depression when being treated with 
ribavirin and interferon alpha. Immediately contact the doctor or seek emergency treatment if 
they display any unusual behavioural symptoms, feel depressed, or feel they want to harm 
themselves or others. 
 
Growth and development (children and adolescents): 
During the one year of treatment with ribavirin, in combination with interferon alfa-2b, some 
children and adolescentsdid not grow or gain weight as much as expected. Some children did not 
reach their projected height within 1-5 years after completing treatment. 


 
 
Contact your doctor immediately if any of the following side effects occur during 
treatment with Ribavirin Aurobindo in combination with an alpha interferon product:  
 
chest pain or persistent cough 
 
changes in the way your heart beats 
 
fainting 
 
confusion, 
 
feeling depressed 
 
suicidal thoughts or aggressive 
behaviour,  
 
attempt suicide,  
 
thoughts about threatening the life 
of others, 
 
feelings of numbness or tingling 
 
trouble sleeping, thinking or 
concentrating 
 
severe stomach pain 
 
black or tar-like stools 
 
blood in stool or urine 
 
severe bleeding from your nose 
 
fever or chills beginning after a few 
weeks of treatment 
 
lower back or side pain 
 
 painful or difficult urination 
 
problems with your eyesight or 
hearing, 
 
severe skin rash or redness 
 
The frequency of possible side effects listed below is defined using the following convention: 
Very common (affects more than 1 user in 10) 
Common (affects 1 to 10 users in 100) 
Uncommon (affects 1 to 10 users in 1,000) 
Rare (affects 1 to 10 users in 10,000) 
Very rare (affects less than 1 user in 10,000) 
Not known (frequency cannot be estimated from the available data). 
The following side effects have been reported with the combination of ribavirin and an alpha 
interferon product in adults: 
 
Very commonly reported side effects: 
−    decreases in the number of red blood cells (that may cause fatigue, shortness of breath, 
dizziness), decrease in neutrophils (that make you more susceptible to different infections). 
−    difficulty concentrating, feeling anxious or nervous, mood swings, feeling depressed or 
irritable, tired feeling, trouble falling asleep or staying asleep, 
−    cough, dry mouth, pharyngitis (sore throat) 
−    diarrhoea, dizziness, fever, flu-like symptoms, headache, nausea, shaking chills, virus 
      infection, vomiting, weakness, 
−    loss of appetite, loss of weight, stomach pain, 
−    dry skin, irritation, pain or redness at the site of injection, hair loss, itching, muscle pain, 
      muscle aches, pain in joints and muscles, rash. 
 
Commonly reported side effects: 
−    decrease in blood clotting cells called platelets that may result in easy bruising and 
spontaneous bleeding, decrease in certain white blood cells called lymphocytes that help 
fight infection, decrease in thyroid gland activity (which may make you feel tired, 
depressed, increase your sensitivity to cold and other symptoms) excess of sugar or uric acid 
(as in gout) in the blood, low calcium level in the blood, severe anaemia 
−    fungal or bacterial infections, crying, agitation, amnesia, memory impaired, nervousness, 
abnormal behaviour, aggressive behaviour, anger, feeling confused, lack of interest, mental 
disorder, mood changes, unusual dreams, wanting to harm yourself, feeling sleepy, trouble 
sleeping, lack of interest in sex or inability to perform, vertigo (spinning feeling) 
−    blurred or abnormal vision, eye irritation or pain or infection, dry or teary eyes, changes in 
your hearing or voice, ringing in ears, ear infection, earache, cold sores (herpes simplex), 
change in taste, taste loss, bleeding gums or sores in mouth, burning sensation on tongue, 
sore tongue, inflamed gums, tooth problem, migraine, respiratory infections, sinusitis, nose 
bleed, nonproductive cough, rapid or difficult breathing, stuffy or runny nose, thirst, tooth 
disorder, 


−    cardiac murmur (abnormal heart beat sounds), chest pain or discomfort, feeling faint, feeling 
unwell, flushing, increased sweating, heat intolerance and excessive sweating, low or high 
blood pressure, palpitations (pounding heart beat), rapid heart rate. 
−    bloating, constipation, indigestion intestinal gas (flatus), increased appetite, irritated colon, 
irritation of prostate gland, jaundice (yellow skin), loose stools, pain on the right side 
around your ribs, enlarged liver, stomach upset, frequent need to urinate, passing more urine 
than usual, urinary tract infection, abnormal urine, 
−    difficult, irregular, or no menstrual period, abnormally heavy and prolonged menstrual 
periods, painful menstruation, disorder of ovary or vagina, breast pain, erectile problem, 
−    abnormal hair texture, acne, arthritis, bruising, eczema (inflamed, red, itchy and dryness of      
the skin with possible oozing lesions),hives, increased or decreased sensitivity to touch, nail 
disorder, muscle spasms, numbness or tingling feeling, limb pain, pain at the site of injection, 
pain in joints, shaky hands, psoriasis, puffy or swollen hands and ankles, sensitivity to sunlight, 
rash with raised spotted lesions, , redness of skin or skin disorder, swollen face, swollen glands 
(swollen lymph nodes), tense muscles, tumour (unspecified), unsteady when walking, water 
impairment. 
 
Uncommonly reported side effects: 
−    hearing or seeing images that are not present, 
−    heart attack, panic attack, 
−    hypersensitivity reaction to the medication, 
−    inflammation of pancreas, pain in bone, diabetes mellitus, 
−    muscle weakness. 
 
Rarely reported side effects: 
−    seizure (convulsions) 
−    pneumonia, 
−    diabetes, rheumatoid arthritis, kidney problems, 
−    dark or bloody stools, intense abdominal pain 
−    sarcoidosis (a disease characterised by persistent fever, weight loss, joint pain and swelling, 
      skin lesions and swollen glands), 
−    vasculitis. 
 
Very rarely reported side effects: 
−    suicide. 
 
stroke (cerebrovascular events)  
 
 
Not known side effects: 
−    thoughts about threatening the life of others, 
−    mania (excessive or unreasonable enthusiasm), 
−    pericarditis (inflammation of the lining of the heart), pericardial effusion [a fluid collection 
       that develops between the pericardium (the lining of the heart) and the heart itself. 
−    change in colour of the tongue. 
 
 
The following side effects have been reported with children and adolescents taking ribavirin 
and an interferon alfa-2b product: 
Very commonly reported side effects: 
−    decreases in the number of red blood cells (that may cause fatigue, shortness of breath, 
      dizziness) decrease in neutrophils (that make you more susceptible to different infections), 
−    decrease in thyroid gland activity (which may make you feel tired, depressed, increase your 
       sensitivity to cold and other symptoms), 
−    feeling depressed or irritable, feeling sick to stomach, feeling unwell, mood swings, tired 
       feeling, trouble falling asleep or staying asleep, virus infection, weakness, 
−    diarrhoea, dizziness, fever, flu-like symptoms, headache, loss of or increase in appetite, loss      
of weight, decrease in the rate of growth (height and weight), pain on right side of ribs, 


       pharyngitis (sore throat), shaking chills, stomach pain, vomiting,  
−    dry skin, hair loss, irritation, pain or redness at the site of injection, itching, muscle pain, 
       muscle aches, pain in joints and muscles, rash. 
 
Commonly reported side effects: 
−   decrease in blood clotting cells called platelets (that may result in easy bruising and 
     spontaneous bleeding), 
−   excess of triglycerides in the blood, excess of uric acid (as in gout) in the blood, increase in 
thyroid gland activity (which may cause nervousness, heat intolerance and excessive   
sweating, weight loss, palpitation, tremors), 
−   agitation, anger, aggressive behaviour, behaviour disorder, difficulty concentrating, 
emotional instability, fainting, feeling anxious or nervous, feeling cold, feeling confused, 
feeling of restlessness, feeling sleepy, lack of interest or attention, mood changes, pain, poor 
quality sleep, sleepwalking, suicide attempt, trouble sleeping, unusual dreams, wanting to 
harm yourself, 
−   bacterial infections, common cold, fungal infections, abnormal vision, dry or teary eyes, ear 
infection, eye irritation or pain or infection, change in taste, changes in your voice, cold  
sores, coughing, inflamed gums, nose bleed, nose irritation, oral pain, pharyngitis (sore 
throat), rapid breathing, respiratory infections, scaling lips and clefts in the corners of the 
mouth, shortness of breath, sinusitis, sneezing, sores in mouth, sore tongue, stuffy or runny 
nose, throat pain, toothache, tooth abscess, tooth disorder, vertigo (spinning feeling), 
weakness 
−  chest pain, flushing, palpitations (pounding heart beat), rapid heart rate, 
−  abnormal liver function, 
−  acid reflux, back pain, bedwetting, constipation, gastroesophageal or rectal disorder, 
incontinence, increased appetite, inflammation of the membrane of the stomach and  
intestine, stomach upset, loose stools, 
−  urination disorders, urinary tract infection, 
−  difficult, irregular or no menstrual period, abnormally heavy and prolonged menstrual 
periods, disorder of vagina, inflammation of the vagina, testis pain, development of male 
body traits, 
−  acne, bruising, eczema (inflamed, red, itchy and dryness of the skin with possible oozing 
     lesions), increased or decreased sensitivity to touch, increased sweating, increase in muscle 
    movement, tense muscle, irritation or itching at the site of injection, limb pain, nail disorder, 
    numbness or tingling feeling, pale skin, rash with raised spotted lesions, shaky hands, redness 
    of skin or skin disorder, skin discolouration, skin sensitive to sunlight, skin wound, swelling 
    due to a build-up of excess water, ,swollen glands (swollen lymph nodes), tremor, tumour 
    (unspecified). 
 
Uncommonly reported side effects 
−  abnormal behaviour, emotional disorder, fear, nightmare, 
−  bleeding of the mucous membrane that lines the inner surface of the eyelids, blurred vision, 
    drowsiness, intolerance to light, itchy eyes, facial pain, inflamed gums, 
−  chest discomfort, difficult breathing, lung infection, nasal discomfort, pneumonia, wheezing, 
−  low blood pressure, 
−  enlarged liver, 
−  painful menstruation, 
−  itchy anal area (pinworms or ascarids), blistering rash (shingles), decreased sensitivity to     
touch, muscle twitching, pain in skin, paleness, peeling of skin, redness, swelling. 
 
The attempt to harm yourself has also been reported in adults, children, and adolescents. 
Ribavirin Aurobindo in combination with an alpha interferon product may also cause: 
−  aplastic anaemia, pure red cell aplasia (a condition where the body stopped or reduced the 
    production of red blood cells); this causes severe anaemia, symptoms of which would include 
    unusual tiredness and a lack of energy, 
−  delusions 
−  upper and lower respiratory tract infection, 


−  inflammation of the pancreas, 
−  severe rashes which may be associated with blisters in the mouth, nose, eyes and other 
    mucosal membranes (erythema multiforme, Stevens Johnson syndrome), toxic epidermal 
    necrolysis (blistering and peeling of the top layer of skin), 
 
The following other side effects have also been reported with the combination of ribavirin and 
an alpha interferon product: 
−  abnormal thoughts, hearing or seeing images that are not present, altered mental status, 
    disorientation, 
−  angioedema (swelling of the hands, feet, ankles, face, lips, mouth, or throat which may cause 
    difficulty in swallowing or breathing), stroke (cerebrovascular events) 
−  Vogt-Koyanagi-Harada syndrome (an autoimmune inflammatory disorder affecting the eyes, 
     skin and the membranes of the ears, brain and spinal cord) 
−   bronchoconstriction and anaphylaxis (a severe, whole-body allergic reaction), constant   
cough,  
−  eye problems including damage to the retina, obstruction of the retinal artery, inflammation  
of the optic nerve, swelling of the eye and cotton wool spots (white deposits on the retina), 
−  enlarged abdominal area, heartburn, trouble having bowel movement or painful bowel 
    movement, 
−  acute hypersensitivity reactions including urticaria (hives), bruises, intense pain in a limb, leg 
    or thigh pain, loss of range of motion, stiffness, sarcoidosis, (a disease characterised by 
    persistent fever, weight loss, joint pain and swelling, skin lesions and swollen glands) 
 
Ribavirin Aurobindo in combination with peginterferon alfa-2b or interferon alfa-2b may also 
cause: 
− dark, cloudy or abnormally coloured urine. 
− difficulty breathing, changes in the way your heart beats, chest pain, pain down left arm, jaw 
 pain,  
− loss of consciousness, 
− loss of use, drooping or loss of power of facial muscles, loss of feeling sensation, 
− loss of vision, 
 
You or your caregiver should call your doctor immediately if you have any of these 
symptoms. 
If you are a HCV/HIV co-infected adult patients receiving anti-HIV treatment, the addition of 
Ribavirin Aurobindo in and peginterferon alfa- 2b may increase your risk of worsening liver 
function highly active anti-retroviral therapy (HAART) and increase your  risk of lactic 
acidosis, liver failure and blood abnormalities development (reduction in number of red blood 
cells which carry oxygen, certain white blood cells that fight infection, and blood clotting cells 
called platelets) (NRTI). 
 
In HCV/HIV co-infected patients receiving HAART, the following other side effects have 
occurred with the combination of ribavirin hard capsules and peginterferon alfa-2b (not listed 
above in adults side effects):  
- 
appetite decreased , 
- 
back pain, 
- 
CD4 lympocytes decreased, 
- 
Defective metabolism of fat, 
- 
Hepatitis, 
- 
Limb pain, 
- 
Oral candidiasis (oral thrush), 
- 
Various laboratory blood values abnormalities. 
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, 
please tell your doctor or pharmacist. 
 
 
 


5.  
HOW TO STORE RIBAVIRIN AUROBINDO 
 
Keep out of the reach and sight of children. 
Do not use Ribavirin Aurobindo after the expiry date, which is stated on the carton/blister after 
EXP. The expiry date refers to the last date of that month. 
 
This medicinal product does not require any special storage conditions. 
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist 
how to dispose of medicines no longer required. These measures will help to protect the 
environment. 
 
6.  
FURTHER INFORMATION 
 
What Ribavirin Aurobindo contains 
-  
The active substance is ribavirin.  
Each Ribavirin Aurobindo capsule contains 200 mg of ribavirin. 
 
-  
The other ingredients are cellulose, microcrystalline, lactose monohydrate, povidone, 
magnesium stearate. The capsule shell contains gelatine, titanium dioxide (E171) and 
sodium lauryl sulphate. The capsule shell imprint contains shellac, propylene glycol, 
potassium hydroxide, black iron oxide (E 172). 
 
What Ribavirin Aurobindo looks like and contents of the pack 
Capsule, hard 
White / White, size ‘1’ hard gelatin capsules filled with white to off-white granular powder and 
imprinted with ‘E’ on white cap and ‘81’ on white body with black ink.  
 
Ribavirin Aurobindo is available in PVC/PE/PVDC/Aluminium blisters and HDPE containers 
in the pack sizes of 
PVC/PE/PVDC/aluminium blister: 84, 112, 140 and 168 capsules 
HDPE bottle: 42 and 500 capsules 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder  
[To be completed nationally] 
 
Manufacturer 
[To be completed nationally] 
 
This medicinal product is authorised in the Member States of the EEA under the 
following names: 
Germany  
 Ribavirin Aurobindo 200 mg Hartkapseln 
Spain  
 Ribavirina Aurobindo 200 mg cápsulas duras EFG 
France  
Ribavirine Aurobindo 200 mg, gélule 
Italy  
 
 Ribavirina Aurobindo 
Portugal  
 Ribavirina Aurobindo 
Romania  
 Ribavirin Aurobindo 200 mg capsule 
United Kingdom Ribavirin 200 mg capsules 
 
This leaflet was last approved in {MM/YYYY}  
[To be completed nationally]