Conditions: AML CMML MDS
Keywords: Acute Myeloid Leukemia Chronic Myelomonocytic Leukemia Myelodysplastic Syndrome
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 55
Healthy volunteers: no

Brief summary:
A Phase 1/2a Dose Escalation Study of FF-10501-01 in Patients with Relapsed or Refractory Hematological Malignancies to determine the safety and tolerability. A total of 6 cohorts will be enrolled in Phase 1 to establish the MTD. A total of 20 subjects with MDS/CMML treated at the RP2D are planned, including MDS/CMML subjects treated at the RP2D in Phase 1.

Detailed description:
Subjects will receive FF-10501-01 orally on a twice daily schedule for 14, 21 or 28 days repeated every 28 days (=1 cycle). Disease assessments, including analysis of blood and bone marrow aspirates, will be performed at the end of Cycle 1 and every 2 cycles thereafter. Subjects who demonstrate objective response or stable disease will be allowed to continue therapy with FF-10501-01 until progression of disease, observation of unacceptable adverse events, intercurrent illness or changes in condition that prevent further study participation.

Arms:
arm 1: FF-10501-01 tablets BID every 14 days of a 28-day cycle. arm 2: FF-10501-01 tablets BID every 14 days of a 28-day cycle. arm 3: FF-10501-01 tablets BID every 14 days of a 28-day cycle. arm 4: FF-10501-01 tablets BID every 14 days of a 28-day cycle. arm 5: FF-10501-01 tablets BID every 14 days of a 28-day cycle. arm 6: FF-10501-01 tablets BID every 14 days of a 28-day cycle. arm 7: FF-10501-01 tablets BID every 21 days of a 28-day cycle. arm 8: FF-10501-01 tablets BID every 28 days of a 28 day cycle. arm 9: FF-10501-01 tablets BID every 21 days of a 28-day cycle.

Interventions: intervention 1: FF-10501-01
Intervention descriptions: intervention 1: FF-10501-01 will be administered orally on Days 1-14 of a 28-day cycle (Cohorts 1-6), Days 1-21 of a 28-say cycle (Cohort 7), Days 1-28 of a 28-day cycle (Cohort 8) or Days 1-21 of a 28-say cycle (Cohort 9). The dose-escalation will proceed until Maximum Tolerated Dose (MTD) is reached. The treatment will continue until disease progression, intolerable toxicity or investigation/subject decision.

Protocol document:
Prot_000.pdf: 
Protocol No. FF1050101US101 
 
FUJIFILM Pharmaceuticals U.S.A., Inc. 
 
CONFIDENTIAL 
Page 1 
PROTOCOL 
October 12, 2017 
 
Amendment 7 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
 
Protocol Number: 
FF1050101US101 
 
 
Protocol Title: 
A Phase 1/2a, dose-escalation study of FF-10501-01 for the 
treatment of advanced hematologic malignancies 
 
Study Chair: 
 
 
 
 
 
 
 
 
Guillermo Garcia-Manero, MD 
Professor of Medicine 
Chief, Section of Myelodysplastic Syndromes 
Deputy Chair, Translational Research 
Department of Leukemia  
The University of Texas MD Anderson Cancer Center 
1515 Holcombe Blvd. Unit 428 
Houston, TX 77030-4009 
Telephone: (713) 745-3428 
 
Clinical Operations 
Contact:  
 
 
 
 
 
 
 
Sponsor Medical 
Monitor: 
Susan Denton, RN 
Senior Project Manager 
Westat 
1600 Research Blvd. 
Rockville, MD 20850 
Telephone: (407) 699-0540 
Email: susandenton@westat.com 
 
Michael R. Kurman, MD 
FUJIFILM Pharmaceuticals U.S.A., Inc. 
One Broadway 
Cambridge, MA 02142 
Telephone: (201) 410-3205 
Email: mkurman@mkurmanconsulting.com 
 
Original Protocol 
Amendment 1 
February 24, 2014 
April 17, 2014 
Amendment 2 
Amendment 3 
Amendment 4 
Amendment 5 
Amendment 6 
September 22, 2014 (revised October 8, 2014) 
November 23, 2015 
July 26, 2016 
February 7, 2017 
July 14, 2017 
Amendment 7 
Oct 12, 2017 


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Amendment 7 
INVESTIGATOR SIGNATURE PAGE 
I have reviewed the above-titled protocol and agree that it contains all the information necessary to 
conduct the study as required. I will conduct the trial in accordance with the principles of ICH Good 
Clinical Practice, the Declaration of Helsinki and the applicable U.S. Food and Drug 
Administration (FDA) regulations. 
I will maintain as confidential all written and verbal information provided to me by the Sponsor, 
including but not limited to, the protocol, case report forms, investigator’s brochure, material 
supplied at investigator meetings, minutes of teleconferences, etc. Such material will only be 
provided as necessary to site personnel involved in the conduct of the trial, the Institutional Review 
Board (IRB) or local regulatory authorities. 
I will obtain written informed consent from each prospective trial subject or each prospective trial 
subject’s legal representative prior to conducting any protocol-specified procedures. The Informed 
Consent Document (ICD) used will have the approval of the IRB. 
I will maintain adequate source documents and record all observations, treatments and procedures 
pertinent to trial subjects in their medical records. I will accurately complete and submit the 
electronic case report forms supplied by the Sponsor in a timely manner. I will ensure that my 
facilities and records will be available for inspection by representatives of FUJIFILM 
Pharmaceuticals U.S.A., Inc. (FPHU), Westat, the IRB or local regulatory authorities. I will ensure 
that I and my staff are available to meet with representatives of FPHU and Westat during regularly 
scheduled monitoring visits. 
I will notify the Medical Monitor within 24 hours of any serious adverse events. Following this 
notification, a written report describing the serious adverse event will be provided to  FPHU/Westat 
as soon as possible, but no later than 5 days following the initial notification. 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
 
 
 
 
 
 
 
 
 
Principal Investigator’s Name (Print) 
 
 
 
 
 


Protocol No. FF1050101US101 
 
FUJIFILM Pharmaceuticals U.S.A., Inc. 
 
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Amendment 7 
SYNOPSIS 
Sponsor:   
FUJIFILM Pharmaceuticals U.S.A., 
Inc. 
Protocol Number:   
FF1050101US101 
Name of Study Drugs (reagents):   
FF-10501-01 
Protocol Title:   
A Phase 1/2a Dose-escalation Study of FF-10501-01 for 
the Treatment of Advanced Hematologic Malignancies 
Name of Active Ingredient:   
4-carbamoylimidazolium-5-olate  
Phase of Development:   
Phase 1/2a 
Primary Objective:   
• To determine the safety and tolerability in subjects who receive FF-10501-01 for the treatment 
of advanced hematologic malignancies 
Secondary Objectives: 
• To determine the overall response rates 
• To evaluate the proportion of subjects who achieve hematologic improvement in peripheral blood 
or bone marrow blast count 
• To evaluate progression-free survival (PFS) 
• To evaluate overall survival (OS) 
• To evaluate the pharmacokinetics of FF-10501 and M1 
• To evaluate xanthosine monophosphate (XMP) as a pharmacodynamic marker 
Methodology:   
This is a Phase 1/2a, dose-escalation study of FF-10501-01 for the treatment of advanced 
hematologic malignancies. 
A total of up to N= 68 subjects will be enrolled in the study. Subjects with acute myelogenous 
leukemia (AML) (Phase 1 only), myelodysplastic syndrome (MDS), and chronic myelomonocytic 
leukemia (CMML) will be included. 
Major selection criteria are: age ≥ 18 years, confirmed MDS/CMML or AML (Phase 1 only for 
AML) with documented disease progression following previous therapy, or subjects with AML ≥ 
60 years of age who are not candidates for other therapies (Phase 1 only). Subjects must be ≥ 3 
weeks beyond chemotherapy, radiotherapy, major surgery, or other experimental treatments, and 
recovered from all acute toxicities (≤ Grade 1), have adequate renal and hepatic function, and no 
known history of significant cardiac disease. 
Phase 1:  
14-day Schedule: Following Screening, a total of 6 cohorts of 3 subjects each received oral doses 
of 50, 100, 200, 300, 400 or 500 mg/m2 BID per day (100, 200, 400, 600, 800 or 1000 mg/m2/day) 
for 14 days, followed by 14 days off, repeated every 28 days (= 1 cycle). Three events of drug-
related atrial fibrillation (Grade 2) were reported in 2 subjects at a dose of 500 mg/m2 BID (Cohort 
6). Study drug was suspended in both subjects and all events resolved with oral metoprolol 
treatment. These events were medically important events and thus met the definition of dose-
limiting toxicity (DLT). No further enrollment was made at this dose level. The maximally tolerated 
dose (MTD) was declared at 1 dose level below the dose eliciting DLT, 400 mg/m2 BID, and this 


Protocol No. FF1050101US101 
 
FUJIFILM Pharmaceuticals U.S.A., Inc. 
 
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Amendment 7 
Sponsor:   
FUJIFILM Pharmaceuticals U.S.A., 
Inc. 
Protocol Number:   
FF1050101US101 
Methodology continued:  
cohort was expanded to 6 subjects. No DLTs have been observed in N=7 total subjects treated at 
400 mg/m2 BID x 14 days. 
21-day Schedule:  At the MTD of 400 mg/m2 BID, Cohort 7 was added to extend the BID dosing 
schedule to 21 days followed by 7 days off, repeated every 28 days (=1 cycle) (Amendment 3). 
28-day Schedule: At the MTD of 400 mg/m2 BID, Cohort 8 was added to extend the BID dosing 
schedule to 28 days continuous dosing each 28 days (=1 cycle) (Amendment 4). 
DLT is  defined as Grade 4 hematologic toxicity lasting 7 days or more; Grade 3 nonhematologic 
toxicity of any duration not amenable to supportive care; failure of platelets, absolute neutrophil 
count (ANC), or hemoglobin (Hb) to recover to Grade 1 within 12 weeks despite use of platelet 
and red blood cell (RBC) transfusions and/or growth factors; febrile neutropenia (defined as 
ANC<1000/mm3 with a single temperature of > 38.3°C or sustained temperature of ≥ 38°C for over 
one hour); Grade 3 thrombocytopenia associated with bleeding; or other important medical event. 
For all subject cohorts, if 1 of 3 subjects per cohort experiences DLT, the cohort will be expanded 
to 6. If 2 of 6 subjects per cohort experience DLT, all further dose escalation will stop. If 0 of 3 or 
≤ 1 of 6 subjects per cohort experience DLT by Day 28 following dosing of FF-10501-01, dose 
escalation will proceed to the next cohort. At the MTD of 400 mg/m2 BID, the longest schedule of 
administration below the schedule of administration eliciting DLT will be declared the 
recommended Phase 2 dose (RP2D) and schedule. A total of 6 subjects will be treated at the RP2D 
and schedule. No intra-subject dose escalation will be allowed from previous dose levels/schedules 
of administration until at least one subject has completed Cycle 1 at the longer schedule of 
administration (e.g., 21 or 28 days) with no Grade 2 or greater toxicities observed. Additionally, 
patients currently on study will have the option to extend their current dosing schedule to 21 days, 
followed by 7 days off, repeated every 28 days (=1 cycle), or 28 days of continuous dosing, 
whichever is chosen as the best schedule, if seen in the patient’s best interest by the principal 
investigator. Dose level adjustments for DLT will be made. Subjects who experience DLT at the 
first dose level, 50 mg/m2 BID, will not be dose-reduced. Up to 48 subjects are planned for Phase 
1. 
Phase 2a: Once 6 subjects are treated at the RP2D and schedule in Phase 1, 1 additional cohort will 
enroll 20 subjects with MDS/CMML who have relapsed from, or are refractory to, prior 
hypomethylating agent (HMA) therapy. Subjects enrolled in Phase 1 at the RP2D and schedule and 
who meet the Phase 2a selection criteria will count towards the Phase 2a accrual. Dose level 
adjustments for adverse events will be made. 
During the study, a Safety Review Committee, consisting of the actively recruiting investigators, 
the Medical Monitor, and FPHU, will review data from each cohort on an ongoing basis. 
 


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Amendment 7 
Sponsor:   
FUJIFILM Pharmaceuticals U.S.A., 
Inc. 
Protocol Number:   
FF1050101US101 
Methodology continued:  
Subjects on the 21-day schedule will receive FF-10501-01 on a BID schedule. For all subjects on 
the 21-day dosing schedules, blood samples for pharmacokinetic assessment of FF-10501 and M1 
in plasma will be collected on Cycle 1 Day 1 pre-dose (any time), between 0.5-1 hr post-dose, and 
between 2-4 hr post-dose, and Day 15 pre-dose (within 15 minutes prior to dosing), between 0.5-1 
hr post-dose, and between 2-4 hr post-dose.  
Blood concentration of xanthosine monophosphate (XMP) will be assessed as a pharmacodynamic 
endpoint.  
For subjects on the 21-day dosing schedules, blood samples for XMP assessment will be collected 
on Cycle 1 Day 1 pre-dose (any time), between 0.5-1 hr post-dose, and between 2-4 hr post-dose, 
and Day 15 pre-dose (within 15 minutes prior to dosing), between 0.5-1 hr post-dose, and between 
2-4 hr post-dose.  
Disease assessments, including analysis of blood and bone marrow aspirates, will be performed at 
the end of Cycle 1 and Cycle 3 and every 2 cycles thereafter. Disease assessments may be 
performed at other time points at the discretion of the investigator. 
Subjects who demonstrate objective response (OR) or stable disease (SD) will be allowed to 
continue therapy with FF-10501-01 until progression of disease, observation of unacceptable 
adverse events, intercurrent illness or changes in the subject’s condition that prevents further study 
participation. 
Blood for hematology, platelet and serum chemistry determinations will be collected within 28 
days of Cycle 1 Day 1, on Days 1, 8, 15 and 22 of Cycle 1, on Day 1 of each subsequent cycle and 
at the End of Study Visit. Urine will be collected for urinalysis within 28 days of Cycle 1 Day 1, 
on Day 1 of each subsequent cycle and at the End of Study Visit. 
Number of Subjects and Centers:  Phase 1: Up to 48 subjects are planned for the dose-escalation 
phase. Phase 2a: A total of 20 subjects with MDS/CMML treated at the RP2D are planned, 
including MDS/CMML subjects treated at the RP2D in Phase 1. Therefore, up to 68 total subjects 
are planned. 
The study will be conducted at up to seven sites. 
Duration of Study: The accrual phase for the Phase 1 dose escalation phase is expected to be 12 
– 18 months. The expected accrual for the Phase 2a expansion phase is expected to be 6 – 12 
months, with the last subject followed up to 6 months, for a total study duration of 30 – 36 months. 
The anticipated accrual rate for the Phase 2a portion is 4 – 5 subjects per month. 


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Sponsor:   
FUJIFILM Pharmaceuticals U.S.A., 
Inc. 
Protocol Number:   
FF1050101US101 
Inclusion Criteria: 
• Males and females ≥ 18 years of age 
• Subjects with confirmed advanced hematologic malignancies:  
• 
Phase 1: 
• 
High-risk MDS/CMML (defined as ≥ 10% peripheral blood or marrow blasts and/or 
International Prognostic Scoring System [IPSS] score ≥ 1.5) and relapsed or refractory 
to prior therapy 
• 
AML relapsed or refractory to prior therapy, or ≥ 60 years of age and not a candidate 
for other therapies 
• 
Phase 2a: 
• 
MDS/CMML, relapsed from, or refractory to, prior HMA therapy; the latter defined as 
failure to achieve clinical remission (CR), partial remission (PR) or hematologic 
improvement (HI) after previous HMA therapy (≥ 4 cycles of azacitidine or decitabine), 
or progression during, or toxicity to, previous HMA therapy precluding further HMA 
treatment, and 
• 
Bone marrow blast count ≥ 10% or peripheral blast count ≥ 5%, or IPSS-R score ≥ 3.5 
• At least 3 weeks beyond the last chemotherapy, targeted anticancer agent, major surgery or 
experimental treatment and recovered from all acute toxicities (≤ Grade 1). Hydroxyurea used 
to control peripheral blast counts is permitted up to Day 7 of treatment on study. 
• Adequate performance status: Eastern Cooperative Oncology Group (ECOG) ≤ 2 
• Adequate renal and hepatic function: 
• 
Creatinine ≤ 2.0 mg/dL, or calculated creatinine clearance ≥ 45 mL/minute per the 
Cockcroft-Gault formula 
• 
Total bilirubin ≤ 2 times the upper limit of normal (ULN) 
• 
ALT and AST ≤ 2 times ULN 
• Negative serum pregnancy test within 14 days prior to the first dose of study therapy for women 
of child-bearing potential (WCBP), defined as a sexually mature woman who has not undergone 
a hysterectomy or who has not been naturally post-menopausal for at least 24 consecutive 
months (i.e., who has had menses any time in the preceding 24 consecutive months). Sexually 
active WCBP and male subjects must agree to use adequate methods to avoid pregnancy (oral, 
injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier 
contraceptive with spermicide; or vasectomized partner) throughout the study and for 28 days 
after the completion of study treatment. 
• 
Ability to provide written informed consent 


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Amendment 7 
Sponsor:   
FUJIFILM Pharmaceuticals U.S.A., 
Inc. 
Protocol Number:   
FF1050101US101 
Exclusion Criteria: 
• 
Known history of active coronary artery disease, angina, myocardial infarction, congestive 
heart failure, cardiac arrhythmia or any other type of heart disease present within the last 6 
months 
• 
Known family history of hereditary heart disease 
• 
QT interval corrected for rate (QTc) > 450 msec on the electrocardiogram (ECG) obtained at 
Screening 
• 
Concomitant medication(s) that may cause QTc prolongation or induce Torsades de Pointes, 
with the exception of anti-microbials that are used as standard of care to prevent or treat 
infections and other such drugs that are considered by the Investigator to be essential for the 
care of the patient 
• 
Presence of active central nervous system (CNS) leukemia. Subjects adequately treated for 
CNS leukemia documented by 2 consecutive cerebrospinal fluid samples negative for leukemia 
cells are eligible. Subjects with no history of CNS leukemia will not be required to undergo 
cerebrospinal fluid sampling for eligibility. 
• 
Known positive for human immunodeficiency virus (HIV), hepatitis B virus surface antigen 
(HBsAg), or hepatitis C virus (HCV) 
• 
Active infection requiring intravenous (IV) anti-infective usage within the last 7 days prior to 
study treatment 
• 
Any other medical intervention or other condition which, in the opinion of the Principal 
Investigator, could compromise adherence to study requirements or confound the interpretation 
of study results 
• 
Pregnant or breast-feeding 
• 
Treatment with any investigational product within 28 days prior to Screening 
Criteria for Evaluation:   
Safety: Safety will be assessed through the monitoring of adverse events (AEs), clinical laboratory 
parameters (hematology, serum chemistry, urinalysis), vital sign measurements, ECGs and physical 
examinations. Adverse events will be classified according to the Medical Dictionary for Regulatory 
Affairs (MedDRA) and graded according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE) version 4.03. 
Efficacy: Efficacy assessment for AML will be performed using a modification of the 
recommendations of the International Working Group for Diagnosis, Standardization of Response 
Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid 
Leukemia. Efficacy assessments for subjects with MDS or CMML will be performed using a 
modification of the International Working Group Response Criteria in Myelodysplasia. Efficacy 
assessments for any subject may be performed at other time points at the discretion of the 
investigator. 
Pharmacokinetics: Pharmacokinetic determinations will be performed. 
Pharmacodynamics: XMP will be determined in peripheral blood. 


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Amendment 7 
Sponsor:   
FUJIFILM Pharmaceuticals U.S.A., 
Inc. 
Protocol Number:   
FF1050101US101 
Investigational Product:   
FF-10501-01 is an oral antimetabolite anticancer drug. It is a competitive inhibitor of inosine 5’- 
monophosphate dehydrogenase (IMPDH). FF-10501-01 is supplied in 50 and 200 mg tablets for 
oral administration. FF-10501-01 should be stored at room temperature (20 – 25 °C). 
FF-10501-01 is manufactured for FPHU by Patheon (Missisauga, Ontario, Canada) and will be 
provided by the sponsor (FPHU). 
Reference Therapy:  None 
Statistical Methods:   
Safety Endpoint Analyses: 
Safety endpoints for AEs include the following: incidences of all treatment-emergent adverse 
events (TEAEs) and all serious adverse events (SAEs); incidences of TEAEs and SAEs by severity; 
incidences of TEAEs and SAEs by relationship to study medications; incidences of all Grade 3 and 
4 TEAEs and by severity and relationship to study medications; and discontinuation of subjects 
from the study due to AEs or death. Safety endpoints for AEs, clinical laboratory tests, vital signs, 
ECGs and physical examinations will be specified in the statistical analysis plan. All safety 
endpoints will be summarized using descriptive statistics. 
Efficacy Endpoint Analyses: 
The primary endpoint will be the proportion of subjects who achieve an objective response (OR) 
as best response (CR, CRi or PR). Each dose cohort will be analyzed independently. For the primary 
efficacy endpoint, OR by disease type (AML, MDS, CMML) will be summarized using the number 
and percentage of subjects with an OR. The proportion of subjects with hematologic improvement 
in peripheral blood or bone marrow blast count and 90% confidence intervals will be estimated. 
For secondary endpoints, PFS and OS, curves will be estimated for each dose cohort and disease 
type using Kaplan-Meier product-limit estimates. 
Pharmacokinetic and Pharmacodynamic Endpoint Analyses: Analysis plans will be described in 
the written plans provided by the laboratories performing the analyses. 


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TABLE OF CONTENTS 
INVESTIGATOR SIGNATURE PAGE......................................................................... 2 
SYNOPSIS ......................................................................................................................... 3 
LIST OF FIGURES ........................................................................................................ 12 
LIST OF APPENDICES ................................................................................................ 12 
LIST OF ABBREVIATIONS ........................................................................................ 13 
1. 
INTRODUCTION......................................................................................... 15 
1.1. FF-10501-01 Background ..................................................................................... 15 
1.2. SM-108 Preclinical Summary ............................................................................... 15 
1.3. SM-108 Previous Human Experience ................................................................... 16 
1.3.1. Phase 1 Study in Advanced Solid Tumors or Hematologic Malignancies ..... 16 
1.3.2. Phase 2 Study in Advanced Lung Cancer ....................................................... 16 
1.3.3. Phase 2 Study in Advanced Hematologic Malignancies ................................ 17 
1.4. FF-10501-01 Preclinical Pharmacology ............................................................... 18 
1.4.1. Induction of differentiation in myeloid leukemia cell lines ............................ 18 
1.4.2. In Vitro Growth Inhibition in Myeloid Leukemia Cell Lines......................... 19 
1.4.3. Inhibition of Growth in an Azacitidine-resistant Cell Line ............................ 20 
1.4.4. FF10501-01 Mechanism of Action ................................................................. 20 
1.4.5. Anti-tumor Activity in a Human Myeloid Leukemia SKM-1 Xenograft Model 
in Mice ............................................................................................................ 21 
1.5. FF-10501-01 Preclinical Pharmacokinetic, Metabolism, Excretion ..................... 22 
1.5.1. Single Oral Dose Pharmacokinetics ................................................................ 22 
1.5.2. Multiple Dose Oral Pharmacokinetics ............................................................ 22 
1.5.3. Distribution ..................................................................................................... 23 
1.5.4. Metabolism ..................................................................................................... 23 
1.5.5. Excretion ......................................................................................................... 23 
1.6. Toxicology ............................................................................................................ 24 
1.6.1. Repeat-dose Toxicity Studies in Rats ............................................................. 24 
1.6.2. Repeat-dose Toxicity Studies in Dogs ............................................................ 24 
1.6.3. Genotoxicity .................................................................................................... 25 
1.6.4. Phototoxicity ................................................................................................... 25 
1.7. FF-10501-01 Experience in Humans .................................................................... 25 
1.7.1. Japan Phase 1 Study ........................................................................................ 25 
1.7.2. U.S. Phase 1/2a Study ..................................................................................... 26 
1.8. Dose Rationale ...................................................................................................... 27 
2. 
STUDY OBJECTIVES ................................................................................. 27 
2.1. Primary Objective: ................................................................................................ 27 
2.2. Secondary Objective: ............................................................................................ 27 
3. 
INVESTIGATIONAL PLAN ...................................................................... 28 
3.1. Overall Study Design ............................................................................................ 28 
3.2. Number of Subjects and Centers ........................................................................... 30 
3.3. Duration of Study .................................................................................................. 30 
3.4. Criteria for Termination of the Study ................................................................... 30 
4. 
STUDY POPULATION ............................................................................... 31 
4.1. Inclusion Criteria .................................................................................................. 31 
4.2. Exclusion Criteria ................................................................................................. 32 


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4.3. Discontinuation of Subjects .................................................................................. 32 
4.3.1. Procedures for Withdrawal ............................................................................. 32 
4.3.2. Replacement of Study Subjects ...................................................................... 33 
5. 
Study TREATMENT .................................................................................... 33 
5.1. FF-10501-01 Investigational Product Description................................................ 33 
5.2. Study Drug Administration ................................................................................... 33 
5.3. Treatment Duration ............................................................................................... 34 
5.4. Dosing Delays and Dose Modifications Due to Toxicity ..................................... 34 
5.4.1. Toxicity Grading Criteria ................................................................................ 34 
5.4.2. Instructions Regarding Dose Delays and Dose Modifications ....................... 34 
5.5. Supportive Care Guidelines .................................................................................. 35 
5.6. Prior and Concomitant Medications and Therapies .............................................. 35 
5.6.1. Permitted Medications .................................................................................... 35 
5.6.2. Prohibited Therapy.......................................................................................... 35 
5.7. Packaging and Labeling ........................................................................................ 36 
5.8. Shipping and Storage ............................................................................................ 36 
5.9. Drug Accountability.............................................................................................. 36 
6. 
STUDY PROCEDURES .............................................................................. 36 
6.1. Screening Procedures ............................................................................................ 36 
6.2. Requirements During Treatment Cycle 1 ............................................................. 37 
6.2.1. Cycle 1, Day 1................................................................................................. 37 
6.2.2. Cycle 1, Day 8 (+/- 1 day) .............................................................................. 37 
6.2.3. Cycle 1, Day 15 (+/- 1 day) ............................................................................ 37 
6.2.4. Cycle 1, Day 22 (+/- 1 day) ............................................................................ 38 
6.2.5. End of Cycle 1 (Day 28 +/- 3 days) ................................................................ 38 
6.3. Requirements During Treatment Cycles After Cycle 1 (Cycles 2, 3, 4, etc.) ....... 38 
6.3.1. Day 1 (+/- 3 days, except for pre-dose procedures; ECG) .............................. 38 
6.3.2. End of Cycle 3 and Every 2 Cycles Thereafter............................................... 39 
6.4. At Relapse or Progression of Disease ................................................................... 39 
6.5. End of Study (Safety Visit, 28 days ± 5 days after the last dose of study drug) .. 39 
6.6. Long-term Follow-up ............................................................................................ 40 
7. 
Description of Assessments .......................................................................... 40 
7.1. Safety Assessments ............................................................................................... 40 
7.1.1. Adverse Event Definition ............................................................................... 40 
7.1.2. Serious Adverse Event .................................................................................... 41 
7.1.3. Unexpected Adverse Event ............................................................................. 41 
7.1.4. Adverse Event Reporting Period .................................................................... 41 
7.1.5. Recording of Adverse Events ......................................................................... 41 
7.1.5.1. Maximum Intensity ............................................................................... 42 
7.1.5.2. Relationship to Study Drug ................................................................... 42 
7.1.6. Most Commonly Expected Adverse Events ................................................... 43 
7.1.7. Adverse Event Reporting ................................................................................ 43 
7.1.8. Adverse Event and Serious Adverse Event Follow-Up .................................. 44 
7.1.9. Ongoing Safety Evaluation ............................................................................. 44 
7.1.10. 
Clinical Laboratory Tests .......................................................................... 45 
7.1.11. 
Vital Sign Measurements .......................................................................... 45 


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7.1.12. 
Physical Examinations .............................................................................. 45 
7.1.13. 
Electrocardiograms ................................................................................... 45 
7.2. Efficacy Assessments............................................................................................ 46 
7.2.1. Criteria for Evaluation of Response and Progression ..................................... 46 
7.2.2. Disease Response Criteria ............................................................................... 46 
7.2.2.1. Subjects with AML ............................................................................... 46 
7.2.2.2. Subjects with MDS or CMML .............................................................. 46 
7.2.3. Efficacy Endpoints .......................................................................................... 48 
7.2.3.1. Primary Efficacy Endpoint ................................................................... 48 
7.2.3.2. Secondary Efficacy Endpoints .............................................................. 48 
7.2.4. Timing of Assessments to Determine Response ............................................. 49 
7.2.5. Pharmacokinetic Endpoints ............................................................................ 49 
7.2.6. Pharmacodynamic (PD) Endpoint .................................................................. 49 
8. 
STATISTICAL METHODOLOGY............................................................ 49 
8.1. Determination of Sample Size .............................................................................. 49 
8.2. Analysis Populations ............................................................................................. 49 
8.3. Statistical Analysis Methods ................................................................................. 50 
8.3.1. Safety Analyses ............................................................................................... 50 
8.3.1.1. Adverse Events ..................................................................................... 50 
8.3.1.2. 
Laboratory Data .................................................................................... 50 
8.3.1.3. Vital Signs ............................................................................................. 51 
8.3.1.4. Other Safety Data .................................................................................. 51 
8.3.2. Efficacy Analyses ........................................................................................... 51 
8.3.2.1. Primary Efficacy Endpoint ................................................................... 51 
8.3.2.2. Secondary Efficacy Endpoints .............................................................. 51 
8.3.3. Pharmacokinetic Endpoint Analysis ............................................................... 51 
8.3.4. Pharmacodynamic Endpoint Analysis ............................................................ 51 
8.3.5. Other Summaries ............................................................................................ 52 
9. 
STUDY MANAGEMENT ............................................................................ 52 
9.1. Data Management ................................................................................................. 52 
9.2. Monitoring ............................................................................................................ 52 
9.3. Audits and Inspections .......................................................................................... 52 
9.4. Amendments ......................................................................................................... 53 
9.5. Record Keeping .................................................................................................... 53 
9.5.1. Health Insurance Portability Accountability Act of 1996............................... 53 
9.5.2. Financial Disclosure........................................................................................ 53 
9.5.3. Access to Original Records ............................................................................. 53 
9.5.4. Retention of Study Documents ....................................................................... 53 
10. 
ADMINISTRATIVE STRUCTURE OF THE STUDY ............................ 54 
11. 
REFERENCES .............................................................................................. 55 


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 LIST OF TABLES 
Table 1. Phase 2 Study in Hematologic Malignancies: Clinical Response by Dose ........ 17 
Table 2. Phase 2 Study Hematologic Malignancies: Adverse Events in ≥ 2% Patients ... 18 
Table 3. Cell Growth Inhibition by FF-10501-01 and Azacitidine on Human Myeloid 
Leukemia Cell Lines ......................................................................................................... 19 
Table 4. Cell Growth Inhibition by FF-10501-01, Azacitidine and Decitabine in 
Azacitidine-resistant Cell Line (SKM-1/AR) ................................................................... 20 
Table 5. Inhibition of Human IMPDH1 and IMPDH2 by FF-10501RMP-Na, FF-10501-
01 and Mycophenolic Acid ............................................................................................... 20 
Table 6. Reporting Guidelines for Adverse Events .......................................................... 43 
Table 7. Clinical Laboratory Parameters .......................................................................... 45 
 
LIST OF FIGURES 
Figure 1. FF-10501 Structure and Mechanism of Action ................................................. 15 
Figure 2. Induction and Expression of HbF in K562 Human Myeloid Leukemia Cell Line 
Treated with FF-10501-01, Sodium Butyrate or Azacitidine ........................................... 18 
Figure 3. Induction and Expression of Cell Surface Antigens in the K562 (A) and 
MOLM-13 (B) Human Myeloid Leukemia Cell Lines Treated with FF-10501-01, Sodium 
Butyrate or Azacitidine ..................................................................................................... 19 
Figure 4. Effect on Intracellular GTP Levels in SKM-1 Human Myeloid Leukemia Cell 
Line Treated with FF-10501-01 or Mycophenolic Acid ................................................... 21 
Figure 5. Anti-tumor and Body Weight Data in a Human Myeloid Leukemia SKM-1 
Xenograft Model in Mice Treated with FF-10501-01 or Azacitidine .............................. 21 
Figure 6. FF-10501 Plasma Concentrations in Fasted or Non-fasted Rats Following a 
Single Oral or Intravenous Dose ....................................................................................... 22 
 
LIST OF APPENDICES 
Appendix A. Number of Tablets to be Administered Per Dose Level ............................. 58 
Appendix B. FF-10501-01 Dosing Delays and Dose Modifications ................................ 60 
Appendix C. Drugs Known to Prolong QT Interval or Induce Torsades de Pointes ........ 61 
Appendix D. Schedule of Study Procedures ..................................................................... 65 
Appendix E. Ethical Standards ......................................................................................... 67 
Appendix F. Investigator Obligations ............................................................................... 69 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
6-MP 
6-mercaptopurine 
6-TG 
6-thioguanine 
AE 
Adverse event 
ALL 
Acute lymphocytic leukemia 
ALT (SGPT) 
Alanine transaminase 
AML 
Acute myelogenous leukemia 
ANC 
Absolute neutrophil count 
Ara-C 
Cytosine arabinoside 
AST (SGOT) 
Aspartate transaminase 
BID 
Twice a day 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations 
C max 
Peak concentration 
CML 
Chronic myelocytic leukemia 
CMML 
Chronic myelomoncytic leukemia 
CNS 
Central nervous system 
CR 
Complete remission/complete response 
CRi 
Complete remission with incomplete blood count recovery 
CRF 
Case report form 
CTCAE 
Common terminology criteria for adverse events 
dL 
Decaliter 
DLT 
Dose limiting toxicity 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic data capture 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FPHU 
FUJIFILM Pharmaceuticals, U.S.A., Inc. 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte colony-stimulating factor 
GM-CSF 
Granulocyte-macrophage colony-stimulating factor 
GTP 
Glutamyl transpeptidase 
Hb 
Hemoglobin 
HBsAg 
Hepatitis B surface antigen 
HCG 
Human chorionic gonadotropin 
HCV 
Hepatitis C virus 
HDPE 
High density polyethylene 
HI 
Hematologic improvement 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
HMA 
Human immunodeficiency virus 
Hypomethylating agent 
ICD 
Informed consent document 
ICH 
International Conference on Harmonisation 


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Abbreviation 
Definition 
IMPDH 
Inosine 5’- monophosphate dehydrogenase 
IND 
Investigational New Drug 
IPSS 
IPSS-R 
International Prognostic Scoring System 
International Prognostic Scoring System Revised 
IRB 
Institutional Review Board 
IV 
Intravenous 
kg 
Kilogram 
L 
Liter 
LD10 
Lethal dose 10% 
m2 
Meters squared 
MDS 
Myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
Maximum tolerated dose 
mg 
Milligram 
mL 
Milliliter 
NCI 
National Cancer Institute 
OR 
Objective response 
ORR 
Overall response rate 
OS 
Overall survival 
PD 
Pharmacodynamic 
PFS 
Progression-free survival 
PK 
Pharmacokinetic 
PPS 
Per protocol set 
PR 
Partial remission/partial response 
Q 
Every 
QTc 
RBC 
QT interval corrected for rate 
Red blood cell 
RP2D 
Recommended Phase 2 dose 
SAE 
Serious adverse event 
T1/2  
Half-life 
TEAE 
Treatment-emergent adverse event 
TID 
Three times a day 
Tmax 
Time to peak concentration 
U 
Units 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WCBP 
Woman of child-bearing potential 
WHO 
World Health Organization 
XMP 
Xanthosine monophosphate 
 


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1. INTRODUCTION 
1.1. 
FF-10501-01 Background 
FF-10501-01 (5-hydroxy-1H-imidazole-4-carboxamide 3/4 hydrate), is the ¾ hydrate of 
FF-10501, an oral antimetabolite anticancer agent. It is a potent competitive inhibitor of 
inosine 5’- monophosphate dehydrogenase (IMPDH), a key enzyme involved in de novo 
purine synthesis, and inhibits deoxyribonucleic acid (DNA) synthesis of guanine 
monophosphate from xanthosine monophosphate. The chemical structure and mechanism 
of action of FF-10501 is depicted in Figure 1. 
 
 
Figure 1. FF-10501 Structure and Mechanism of Action 
FF-10501-01 contains the same active pharmaceutical ingredient as SM-108, a compound 
discovered in the 1980s and developed through Phase 1 and 2 clinical studies by Sumitomo 
Chemical Co. FF-10501-01 drug substance is manufactured identically to SM-108, but the 
synthetic process was improved to increase the purity of FF-10501-01, which ensures better 
drug substance stability and a more stable FF-10501-01 drug product. SM-108 is the 
compound designation for studies previously conducted by Sumitomo. FF-10501-01 was 
used as the test article in all studies conducted under the direction of FUJIFILM. 
1.2. 
SM-108 Preclinical Summary 
SM-108 was found to have a different spectrum of activity from conventional 
antipurinergic agents, 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG). Most notably, 
SM-108 demonstrated collateral sensitivity with greater therapeutic effect on a 6-MP-
resistant murine leukemia cell line, P388, than on 6-MP-sensitive strains. Among murine 
experimental tumors, Ehrlich carcinoma, sarcoma 180, Lewis lung carcinoma, colon 26, 
colon 38, L1210 and P388 were highly responsive to SM-108, especially following 
intermittent administrations per day, rather than daily administration and inhibited the 
growth of selected human tumor cell lines derived from hematologic malignancies and 
some solid tumors (lung, prostate cancers and choriocarcinoma).1,2,3,4 
The lethal dose 10% (LD10) following oral administration to mice for 5 days was 4800 


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mg/m2/day with QD dosing, 2610 mg/m2/day with TID dosing (Q 4 hours only in daytime), 
and 135 mg/m2/day with TID dosing (Q 8 hours).5 
Teratology studies previously conducted by Sumitomo in the mouse, rat and rabbit were 
positive.6 This is not an unexpected finding for cytotoxic agents used as anticancer 
treatment, and precautions will be taken to avoid pregnancy in the proposed clinical study. 
1.3. 
SM-108 Previous Human Experience 
A total of three SM-108 clinical studies in patients with hematologic malignancies or lung 
cancer were previously conducted by Sumitomo in the 1980s at doses ranging from 20 to 
2500 mg/m2. The majority of the Phase 2 study dose regimens were 100-300 mg/m2 BID 
(200 to 600 mg/m2/day). A total of 265 patients were treated in these studies and efficacy 
was seen in patients with hematologic malignancies. 
1.3.1. Phase 1 Study in Advanced Solid Tumors or Hematologic Malignancies 
In a Phase 1 study of oral SM-108 in patients with advanced solid tumors or hematologic 
malignancies, 73 patients were treated on a 5-day consecutive schedule at doses ranging 
from 20 to 2500 mg/m2.5 Adverse events were reported in 23 of 73 patients (31.5%), 
however a correlation between adverse events and dose was unclear. The maximum 
tolerated dose (MTD) and doses eliciting dose-limiting toxicity (DLT) were not 
determined. The most common adverse events reported were gastrointestinal; nausea (11 
patients, 15%), anorexia (7 patients, 10%), emesis (5 patients, 7%). Elevated AST (to > 45 
U), ALT (to > 50U) and uric acid (to ≥ 8 mg/dL) also were noted in some patients. In 31 
patients with hematologic malignancies enrolled in the study, 2 of 3 patients with atypical 
leukemia achieved a complete response, and 2 of 12 patients with acute myeloid leukemia 
(AML) and 1 of 1 patient with acute lymphocytic leukemia (ALL) achieved a partial 
response (PR). Mean days to response ranged from 12 to 18 days. No responses were noted 
in the 42 patients with solid tumors. 
A dose-dependent increase in serum levels of SM-108 were observed up to 2000 
mg/m2/day, with time to peak serum concentration (Tmax) of 2 hours at ≤ 100 mg/m2 and 
Tmax of 4 hours at doses ≥ 240 mg/m2. A total of 40 – 60% of the administered drug was 
excreted in active form in the urine over 24 hours post-dose, suggesting primary renal 
elimination. 
1.3.2. Phase 2 Study in Advanced Lung Cancer 
In an early Phase 2 study, 27 patients with advanced lung cancer (primarily 
adenocarcinoma) received SM-108 at oral doses of 200 mg/m2 BID or TID (400 or 600 
mg/m2/day) for ≥ 2 weeks (400 mg/m2/day) or for ≥ 4 weeks (600 mg/m2/day).5 One patient 
achieved a minor response at a dose of 600 mg/m2/day). No true objective responses (ORs) 
were observed. The most commonly reported adverse events were gastrointestinal 
(anorexia, malaise, nausea/emesis), in 4 of 12 (33%) and 6 of 15 (40%) of patients receiving 
400 and 600 mg/m2/day, respectively. The incidence of hematological adverse events 
(neutropenia, thrombocytopenia and decreased hemoglobin [Hb]) was 2 of 12 (17%) and 
4 of 15 (27%) of patients receiving 400 and 600 mg/m2/day, respectively. Nadirs occurred 


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at approximately 4 -6 weeks of treatment in both groups, and return to baseline parameters 
was noted within 2 weeks. 
1.3.3. Phase 2 Study in Advanced Hematologic Malignancies 
A larger Phase 2 study was conducted in patients with advanced hematologic 
malignancies.7 A total of 165 patients were enrolled; 85 had received prior therapy with 
antimetabolites, including 6-MP or cytosine arabinoside (ara-C). Patients were treated with 
SM-108 orally, at doses of 70, 200 or 300 mg/m2 BID (140, 400 or 600 mg/m2/day). In 39 
patients with chronic myelogenous leukemia (CML), 21 had complete responses (CRs) and 
6 had PRs for an OR rate of 69%.  Among 30 patients with AML, 7 had PRs (23%). Among 
36 patients with MDS, 1 had a CR, 12 had PRs for an ORR of 36%. For 13 patients with 
polycythemia rubra, 4 had CRs and 7 had PRs for an ORR of 84.6%). The RR rate was 
highest in patients with CML and MDS at doses of ≥ 600 mg/m2/day. Clinical responses 
by dose are described in Table 1. 
Table 1. Phase 2 Study in Hematologic Malignancies: Clinical Response by Dose  
Diagnosis 
 
Dose 
(mg/day) 
CML 
MDS 
Polycythaemia 
vera 
AML 
Total 
(%) 
CMMoL 
RAEB RAEB in
T 
Total 
< 200 
 
 
1/2 
 
½ 
 
0/2 
1/4 
(25) 
200 to < 400 
1/1 
1/1 
0/1 
0/3 
1/5 
2/2 
1/3 
5/11 
(45.5) 
400 to < 600 
2/4 
0/1 
2/7 
0/3 
2/11 
3/3 
2/11 
9/29 
(31) 
600 to < 800 20/22 
4/7 
2/3 
2/4 
8/14 
6/8 
2/10 
36/54 
(66.7) 
800 to < 1000 
4/11 
0/2 
0/1 
1/1 
¼ 
 
2/4 
7/19 
(36.8) 
1000 ≤  
0/1 
 
 
 
 
 
 
0/1 
Total (%) 
27/39 
(69.2) 
5/11 
(45.5) 
5/14 
(35.7) 
3/11 
(27.3) 
13/36 
(36.1) 
11/13 (84.6) 
7/30  
(23.3) 
58/118 
(49.1) 
The most commonly reported adverse events were gastrointestinal (nausea, anorexia, 
vomiting, abdominal discomfort; 66%), followed by allergic symptoms (rash, pruritis; 1%). 
Changes in laboratory values occurred in 30 of 165 (18%) of patients, all were 
transient/reversible and most were ≤ Grade 2. A total of 14 patients (8%) experienced bone 
marrow suppression (neutropenia, thrombocytopenia, reduced Hb). The nadir was reached 
in 2 -3 weeks for white blood cell (WBC) count and platelets, 5 weeks for Hb, and recovery 
from nadir to pre-dose values was approximately 2 weeks (Table 2). 
 
 
 
 
 
 


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Table 2. Phase 2 Study Hematologic Malignancies: Adverse Events in ≥ 2% Patients 
Total Number of Patients 
 
165 
Number of Patients 
Reporting (%) 
Increased ALT 
16 (9.7) 
Nausea 
15 (9.1) 
Increased AST 
14 (8.5)  
Loss of appetite 
11 (6.7)  
Decreased platelet count 
8 (4.8) 
Rash 
7 (4.2) 
Vomiting 
6 (3.6) 
Decreased hemoglobin 
4 (2.4) 
Abdominal discomfort 
3 (1.8) 
General malaise 
3 (1.8) 
Decreased WBC 
3 (1.8) 
Increased total bilirubin 
3 (1.8) 
Increased GTP 
3 (1.8) 
1.4. 
FF-10501-01 Preclinical Pharmacology  
1.4.1. Induction of differentiation in myeloid leukemia cell lines 
In the K562 human myeloid leukemia cell line, FF-10501-01induced the expression of fetal 
hemoglobin (HbF) over a concentration range of 1 to 1000 μmol/L in a dose-dependent 
manner.8 Increased HbF production in K562 cells is a measure of reactivation of fetal Hb 
production in K562 cells, hence a measure of induction of cell differentiation (Figure 2). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 2. Induction and Expression of HbF in K562 Human Myeloid Leukemia Cell 
Line Treated with FF-10501-01, Sodium Butyrate or Azacitidine 
FF-10501-01 also induced the expression of the CD235a and CD11b cell surface antigens 
in a dose-dependent manner in the K562 and MOLM-13 human myeloid leukemia cell 
lines, respectively.9 Increased CD235a (glycophorin A) and CD11b (CR3) are used as 
measures of induction of cell differentiation (Figure 3). 
 
 
 


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Figure 3. Induction and Expression of Cell Surface Antigens in the K562 (A) and 
MOLM-13 (B) Human Myeloid Leukemia Cell Lines Treated with FF-10501-01, 
Sodium Butyrate or Azacitidine  
1.4.2. In Vitro Growth Inhibition in Myeloid Leukemia Cell Lines  
FF-10501-01 inhibited the growth of the five human myeloid leukemia cell lines MOLM-
13, SKM-1, HNT-34, OCI-M2, and K562 at mean IC 50 levels of 7.8, 21.5, 51.9, 204.2, and 
10.7 μmol/L, respectively (Table 3).10 
Table 3. Cell Growth Inhibition by FF-10501-01 and Azacitidine on Human Myeloid 
Leukemia Cell Lines 
Cell line 
IC 50 (μmol/L) 
FF-10501-01 
Azacitidine 
MOLM-13 
7.8 ± 0.6 
0.7 ± 0.1 
SKM-1 
21.5 ± 2.6 
1.7 ± 0.1 
HNT-34 
51.9 ± 3.8 
2.0 ± 0.2 
OCI-M2 
204.2 ± 20.6 
2.0 ± 0.1 
K562 
10.7 ± 1.0 
2.4 ± 0.1 


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1.4.3. Inhibition of Growth in an Azacitidine-resistant Cell Line 
An azacitidine-resistant cell line was produced with the SKM-1 human myeloid leukemia 
cell line (SKM-1/AR).11 The ability of FF-10501-01 to inhibit the growth of the parent and 
resistant lines was investigated. The IC 50 of FF-10501-01 in the resistant cell line was 9.49 
μmol/L versus 36.27 and > 700 μmol/L for azacitidine and 5-aza-2’-deoxycytidine 
(decitabine), respectively (Table 4). 
Table 4. Cell Growth Inhibition by FF-10501-01, Azacitidine and Decitabine in 
Azacitidine-resistant Cell Line (SKM-1/AR) 
Cell line 
IC 50 (μmol/L) 
FF-10501-01 
Azacitidine 
Decitabine 
SKM-1 
23.47 ± 2.32 
1.85 ± 0.09 
0.13 ± 0.01 
SKM-1/AR 
9.49 ± 0.42 
36.27 ± 0.17 
> 700 
 
1.4.4. FF10501-01 Mechanism of Action 
At concentrations of 1 to 1000 nmol/L, the active form of FF-10501 (monosodium salt, 
FF-10501 ribosyl monophosphate [FF-10501RMP-Na]) inhibited the enzymatic activity of 
human inosine 5′-monophosphate dehydrogenase (IMPDH) 1 and IMPDH2.12 IC 50 values 
were 29.0 and 31.8 nmol/L, respectively, versus 26.4 and 27.8 nmol/L for mycophenolic 
acid. FF-10501-01 inhibited IMPDH1 and IMPDH2 by 5.6% and −11.1%, respectively, at 
a concentration of 10000 nmol/L (Table 5). 
Table 5. Inhibition of Human IMPDH1 and IMPDH2 by FF-10501RMP-Na, FF-
10501-01 and Mycophenolic Acid 
Enzyme 
IC 50 (nmol/L) 
Enzyme activity 
inhibition at 10000 
nmol/L (%) 
FF-10501RMP·Na 
Mycophenolic acid 
FF-10501-01 
Human IMPDH1 
29.0 ± 10.3 
26.4 ± 1.5 
5.6 ± 16.6 
Human IMPDH2 
31.8 ± 5.6 
27.8 ± 8.3 
-11.1 ± 9.8 
 
In the SKM-1 human myeloid leukemia cell line, FF-10501-01 lowered intracellular GTP 
levels in a dose-dependent manner at concentrations of 1 to 100 μmol/L (Figure 4).13 


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Figure 4. Effect on Intracellular GTP Levels in SKM-1 Human Myeloid Leukemia 
Cell Line Treated with FF-10501-01 or Mycophenolic Acid 
1.4.5. Anti-tumor Activity in a Human Myeloid Leukemia SKM-1 Xenograft 
Model in Mice 
In mice subcutaneously injected with the SKM-1 human myeloid leukemia cell line, FF-
10501-01 significantly inhibited the growth of tumors when orally administered at 480 
mg/kg/day (5 cycles consisting of 3 daily doses x 2 days followed by 4 days rest x 5 cycles) 
as did azacitidine at 5 mg/kg/day (p<0.05).14 Transient post-administration weight loss was 
observed in all groups dosed with FF-10501-01 and azacitidine (Figure 5). The arrows 
indicate daily dosing relative to body weight determination. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 5. Anti-tumor and Body Weight Data in a Human Myeloid Leukemia SKM-1 
Xenograft Model in Mice Treated with FF-10501-01 or Azacitidine 
 


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1.5. 
FF-10501-01 Preclinical Pharmacokinetic, Metabolism, Excretion 
1.5.1. Single Oral Dose Pharmacokinetics 
FF-10501-01 was administered once orally at FF-10501 (free form) doses of 10, 40, 80, or 
160 mg/kg to non-fasted female mice demonstrated that C max and the area under the 
concentration-time curve (AUC 0-24 and AUC) increased with increasing doses over the 
dose range of 10 to 160 mg/kg.15 The increase was nearly dose proportional from 10 to 80 
mg/kg and less than dose proportional from 80 to 160 mg/kg. The Tmax was 0.5 hours for 
all dose groups. The terminal half-time (t ½) ranged from 1.3 to 2.5 hours and was not dose 
proportional.  
Changes in plasma concentrations in fasted or non-fasted male rats after an oral or 
intravenous dose of 15 mg/kg of FF-10501-01 are shown in Figure 6. The bioavailability 
of FF-10501-01 in fasted and non-fasted rats was 51.7% and 39.5%, respectively, 
indicating that food effects are minimal.16 Half-life was slightly longer in the non-fasted 
animals (2.2 hours) versus the fasted animals (1.5 hours). 
 
Figure 6. FF-10501 Plasma Concentrations in Fasted or Non-fasted Rats Following a 
Single Oral or Intravenous Dose 
1.5.2. Multiple Dose Oral Pharmacokinetics 
Once-daily doses of 0.6, 3, and 15 mg/kg of FF-10501-01 (doses in FF-10501 free form) 
were repeatedly orally administered to male and female rats for 1 month.17 The C max and 
AUC 0-24 of FF-10501 on the first and last days of dosing increased in proportion to dose 
in the male and female animals. Systemic exposure to FF-10501 at the final dose was 
generally higher than at the first dose in both the male and female animals (0.8- to 2.6-fold 
higher). C max and AUC 0-24 at the first and last doses were generally higher in the females 
than in the males (1.0- to 2.2-fold higher). 
1
10
100
1000
10000
100000
0
2
4
6
8
10
12
Time (hr)
p.o. (fasting) 
p.o. (non fasting)
i.v. (non fasting)
Plasma  concentration of  FF-10501 (ng/mL)


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As in the rats, the C max and AUC 0-24 of FF-10501 in male and female dogs upon repeated 
oral doses of 10, 30, or 100 mg/kg FF-10501-01 (doses in FF-10501 free form) once daily 
for 1 month increased in a dose-dependent manner.18 T½ was generally 3 – 4 hours in most 
groups, with females in the 100 mg/kg dose group exhibiting a t ½ of 7.5 hours after 28 
days of repeat dosing. C max and AUC remained relatively stable over the 28-day dosing 
period in all groups, demonstrating little evidence of accumulation. 
1.5.3. Distribution 
Radioactivity was widely distributed to the tissues of non-fasted male rats given a single 
oral dose of 15 mg/kg of 14C-FF-10501-01.19,20 Concentrations reached a maximum at 2 
hours post-dose in most of the tissues. Disregarding the gastrointestinal tract, in which 
concentrated drug was expected due to the route of administration, the maximum 
concentrations in the kidneys and bladder were higher than plasma concentrations, but 
distribution to the cerebellum, cerebrum, and other central nervous system tissues was low. 
Concentrations in the other tissues were comparable to those in the plasma. The compound 
did not exhibit affinity for melanin-containing tissues. At 96 hours post-dose, only trace 
amounts of radioactivity were noted in the colon contents, but radioactivity was at or below 
the limit of detection in all tissues at this time. 
Tissue distribution in the elimination phase was investigated in male dogs orally dosed 
with a single dose of 15 mg/kg of 14C-FF-10501-01.21 Levels were high in the liver at 48 
and 72 hours postdose. The tissue-to-plasma ratio of radioactivity at these times was 15.14 
and 11.91, respectively. At 72 hours postdose levels of radioactivity were, in comparison 
to the plasma, higher in all tissues other than the cerebellum, fat, pancreas, and testes, but 
radioactivity was eliminated over time in parallel with or more rapidly than the elimination 
from the plasma. 
The serum protein binding of 14C-FF-10501 was uniformly low in all species, ranging from 
1.4% to 3.2% in mice, 0.8% to 3.4% in rats, 1.6% to 2.8% in dogs, and 0.7% to 1.6% in 
humans.22 
1.5.4. Metabolism 
Metabolites of FF-10501-01 in the plasma, urine, bile (rats only), and feces of rats and dogs 
were investigated.21,23,24 The parent drug, FF-10501, the ribose form (M1), the glucuronic 
acid conjugate, the pyranoside form, and two sulfate conjugates were identified in the 
plasma and urine. Unknown metabolites were also identified in the plasma, urine, bile and 
feces. 
In an investigation of inhibitory effects on human liver cytochrome P-450 isozyme activity 
(CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4), FF-10501-01 mildly inhibited the 
metabolic activity of each isozyme studied as evidenced by IC 50s of not less than 1240 
μmol/L in each case.25 Therefore, no drug-drug interactions are expected. 
1.5.5. Excretion 
In non-fasted male rats receiving a single oral dose of 14C-FF-10501-01, 80.3%, 27.1%, 
and 2.5% of the radioactivity dosed was excreted in the urine, feces, and expiratory air, 


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respectively, by 72 hours post-dose.26 Total cumulative excretion was 110.2%. The 
radioactivity excreted in the bile by 24 hours post-dose was only 1.0% of the amount dosed. 
In non-fasted male dogs receiving a single oral dose of 14C-FF-10501-01, 76.63% and 
10.45% of the radioactivity dosed was excreted in the urine and feces, respectively, by 24 
hours post-dose.20 Moreover, 79.42% and 12.07% of the radioactivity dosed was excreted 
in the urine and feces by 72 hours post-dose. Total cumulative excretion was 97.33%. 
Therefore, the kidney appears to be the major route of elimination (~80%) with a lesser 
amount of drug found in the feces (~10 – 20%). 
1.6. 
Toxicology 
1.6.1. Repeat-dose Toxicity Studies in Rats 
A 2-week repeated oral dose toxicity study of FF-10501-01 (FF-10501 equivalent doses of 
1, 5, 25 mg/kg/day) was conducted in rats.27 At the dose of 25 mg/kg, suppressed body 
weight gain or weight loss, low food consumption, and gastrointestinal injury were 
observed, and two of the five males died. No abnormalities were noted with 1 mg/kg. 
Changes in hematological test values attributable to myelosuppression were observed at 
doses of 5 mg/kg and greater. The MTD was determined to be 5 mg/kg/day (30 mg/m2/day). 
No deaths were observed in a 2-week intermittent oral dose toxicity study in rats (3 cycles 
of FF-10501-01, as FF-10501 equivalent doses of 15, 45, 90, or 180 mg/kg oral doses once 
daily for 2 consecutive days followed by withdrawal for 4 days).28 Suppressed body weight 
gain and myelosuppression were noted at the doses of 15 mg/kg and greater. Low food 
consumption and gastrointestinal injury were observed at doses of ≥ 90 mg/kg. 
No deaths were observed in a 1-month repeated oral dose toxicity study of FF-10501-01 in 
rats (FF-10501 equivalent doses of 0.6, 3, 15 mg/kg/day).17 No abnormalities were 
observed at 0.6 mg/kg. At doses of 3 mg/kg and greater, suppressed body weight gain and 
a low bone marrow nucleated cell count were noted. Low food consumption, changes in 
hematological test values attributable to myelosuppression, and gastrointestinal injury were 
observed at 15 mg/kg. Suppressed body weight gain and low food consumption were 
observed continuously until the end of the recovery period in the males dosed with 15 
mg/kg, but the other changes recovered or showed tendencies toward recovery during a 1-
month recovery period. The no observed adverse effect level in the 1-month repeated oral 
dose toxicity study in rats was 0.6 mg/kg/day. The MTD was determined to be 15 
mg/kg/day (90 mg/m2/day). 
1.6.2. Repeat-dose Toxicity Studies in Dogs 
In a 2-week repeat oral dose toxicity study of FF-10501-01 in dogs (FF-10501 equivalent 
doses of 10, 30, 100 mg/kg/day), no deaths were observed, and no abnormalities were 
observed at 10 mg/kg.29 Gastrointestinal injury was observed at doses of 30 mg/kg and 
greater. In the 30 mg/kg group, histopathological examinations revealed slight cell debris 
in the crypt lumen of the duodenum and minimum single cell necrosis in the crypt 
epithelium of the colon and rectum. No abnormalities were noted in the other tests. In the 
100 mg/kg group, soft stool, body weight loss, and low food consumption and weight loss 
were noted in one of the two animals, and the affected animal showed dark red area in the 


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mucosa of the ileum and cecum during necropsy. No toxicologically significant changes 
were noted in electrocardiography or other testing. In conclusion, gastrointestinal effects 
were observed at doses of 30 mg/kg and greater, and soft stool, body weight loss, and low 
food consumption were observed at 100 mg/kg in the study. The MTD was determined to 
be 100 mg/kg/day (2000 mg/m2/day). 
In a 1-month repeat oral dose toxicity study of FF-10501-01 in dogs (FF-10501 equivalent 
of 10, 30, 100 mg/kg/day), two of the five females dosed with 100 mg/kg were necropsied 
on Day 14 of dosing because of moribund condition.18 No abnormalities were observed at 
10 mg/kg. Gastrointestinal injury was observed at doses of 30 mg/kg and greater. Low food 
consumption and weight loss were noted at 100 mg/kg. In the recovery study, soft stool, 
which was noted during the treatment period, resolved on Day 5 of recovery (Day 1 of 
recovery is the day after the final dose). Body weight and food consumption rapidly 
recovered. The histopathological changes in the gastrointestinal tract and other changes 
observed during the dosing period had recovered or showed tendencies toward recovery in 
the tests performed at the end of the recovery period. In conclusion, gastrointestinal injury 
was observed in the males and females of the groups receiving 30 mg/kg or greater. The 
MTD was determined to be 30 mg/kg/day (600 mg/m2/day). 
The dog proved to be the more relevant of the species regarding the tolerability of FF-
10501-01, as demonstrated in previous human clinical studies of SM-108. 
1.6.3. Genotoxicity 
Negative results were obtained in bacterial reverse mutation assays.30 
In vitro chromosomal aberration tests performed in a cell line derived from Chinese 
hamster lung (CHL/IU cells) showed that FF-10501-01 induced chromosomal aberrations 
both with and without metabolic activation.31 
1.6.4. Phototoxicity 
The findings of visible-ultraviolet absorption spectrometry of FF-10501-01 indicate a low 
potential for phototoxicity.32 
Additional information can be found in the FF-10501-01 Investigator’s Brochure. 
1.7. 
FF-10501-01 Experience in Humans 
1.7.1. Japan Phase 1 Study 
A Phase 1 study of FF-10501-01 conducted by FUJIFILM (Toyama Chemical) in Japan in 
patients with MDS, was completed. In this study, patients received FF-10501-01 at doses 
of 200, 300 and 400 mg BID (400, 600 and 800 mg/day) for 14 days continuously followed 
by 14 days off therapy (28-day cycle).33 A total of 9 patients were treated. No DLTs were 
observed. One study drug-related serious adverse event (SAE) (Grade 4 neutropenia) 
occurred in Cycle 1 in one subject treated with FF-10501 800 mg/day. Two study drug-
related SAEs (Grade 3 anemia and Grade 3 pneumonia) occurred in Cycle 5 in two subjects 
treated with FF-10501 400 mg/day. The most common adverse events (AEs) in all patients, 
regardless of causality, were anemia, rash, and platelet count decreased (33.3%, 3 of 9 


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subjects each). The treatments after cycle 1 were extended in 8 patients out of 9 in each 
treatment cohort; 3 at 400 mg/day, 3 at 600 mg/day and 2 at 800 mg/day. 
The median number of treatment cycles were 4 (range 2-5) at 400 mg/day, 13 (range 2-18) 
at 600 mg/day, and 2 (range 1-7) at 800 mg/day. One patient at 600 mg/day has received a 
total of 18 cycles to date and remains on study. C max and AUC increased with increasing 
FF-10501-01 dose. Tmax was 2 to 4 hours and the drug was nearly eliminated within 24 
hours after administration. The cumulative urinary excretion rate of FF-10501 up to 24 
hours after administration was 25 to 45%. No accumulation of FF-10501 was observed. 
1.7.2. U.S. Phase 1/2a Study 
Study FF1050101US101 is ongoing in the United States in patients with AML, MDS or 
CMML. In Phase 1, dose levels of 50, 100, 200, 300, 400 and 500 mg/m2 BID for 14 days, 
followed by 14 days off therapy, or 400 mg/m2 BID for 21 days, followed by 7 days off 
therapy, repeated every 28 days have been studied to date. A total of 33 patients have been 
treated to date on study (25 AML, 8 MDS). 
Three events of drug-related atrial fibrillation (Grade 2) were reported in 2 subjects at a 
dose of 500 mg/m2 BID (Cohort 6). Study drug was suspended in both subjects and all 
events resolved with oral metoprolol treatment. These events were medically important 
events and thus met the definition of dose-limiting toxicity (DLT). No further enrollment 
was made at this dose level. The maximally tolerated dose (MTD) was declared at 1 dose 
level below the dose eliciting DLT, 400 mg/m2 BID, and this cohort was expanded to 6 
subjects. No DLTs have been observed in N=7 total subjects treated at 400 mg/m2 BID x 
14 days. 
At the MTD of 400 mg/m2 BID, Cohort 7 was added to extend the BID dosing schedule to 
21 days followed by 7 days off, repeated every 28 days (=1 cycle) (Amendment 3). No 
DLTs occurred have occurred to date. 
At the MTD of 400 mg/m2 BID, Cohort 8 was added to extend the BID dosing schedule to 
28 days continuous dosing (=1 cycle) (Amendment 4). No DLTs have occurred to date. 
The median number of prior treatments is 2 (range 1 - 7), all relapsed or refractory to prior 
hypomethylating agents (azacitidine, decitabine). The median number of treatment cycles 
is 2 (range 1 – 28). 
The most common AEs include Grade 1 or 2 fatigue, diarrhea, and nausea, with drug-
related Grade 3 or 4 AEs reported for 1 patient in the 200 mg/m2 BID dose group 
(thrombocytopenia, neutropenia and bone marrow aplasia) and 1 patient in the 300 mg/m2 
BID dose group (mucositis); the events resolved without sequelae. 
Partial remissions have occurred in 3 AML patients (50, 100 and 400 mg/m2 BID) after 1 
– 3 cycles, lasting for at least 28, 5 and 6 cycles, respectively. A total of 8/25 (32%) AML 
patients, including the 3 PRs, have attained stable disease control with no disease 
progression over 4 – 28 cycles. A marrow complete response was achieved in 1 MDS 
patient treated at 400 mg/m2 BID x 14 days after 1 cycle and was sustained for 14 cycles. 
A major platelet response was observed in 1 patient treated at 400 mg/m2 BID x 21 days, 
sustained for 1 cycle. Four of 8 MDS patients (50%), including the marrow CR, attained 
stable disease control with no disease progression over 3, 5, 14 and 17 cycles, respectively. 


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FF-10501-01 was rapidly absorbed with mean Tmax of 2.74 hours and mean t ½ of 4.05 
hours. Drug exposure (AUC 0–24 and AUC course) increased with dose in a near linear 
manner. 
Potent suppression of circulating xanthosine monophosphate (XMP), a marker of IMPDH 
activity, has been observed following FF-10501-01 administration on Day 1 of Cycles 1 
and 2 at doses ≥ 50 mg/m2 BID. 
1.8. 
Dose Rationale  
In the SM-108 Phase 2 study described above, patients with hematologic malignancies 
showed responses at oral doses of 200 – 300 mg/m2 BID (400 – 600 mg/m2/day) 
administered for 14-day cycles. The toxicology findings in repeat dose studies in the rat 
and dog indicate a dose of 15 mg/kg (equivalent to 90 mg/m2) in the rat for up to 1 month 
was well-tolerated with few effects, and a dose of 10 mg/kg (equivalent to 200 mg/m2) in 
the dog up to 1 month exhibited no adverse effects. The dog appears to be the more relevant 
toxicology species based on prior human safety experience. Therefore, the starting dose in 
this study will be 50 mg/m2 BID, which represents a 4-fold margin of safety over the MTD 
in the dog, escalating to 500 mg/m2 BID, administered orally in 14-day cycles. 
Since the study started, FF-10501-01 has been found to be well-tolerated up to a dose of 
400 mg/m2 BID orally x 28 days continuous dosing. Long-term stable disease has been 
observed in some MDS and AML patients (up to 28 cycles), as noted above. 
The regimen for phase 2 is 400 mg/m2 BID x 21 days out of a 28-day cycle. 
2. STUDY OBJECTIVES 
2.1. 
Primary Objective:   
• To determine the safety and tolerability in subjects who receive FF-10501-01 
for the treatment of advanced hematologic malignancies 
2.2. 
Secondary Objective: 
• To determine the overall response rates 
• To evaluate the proportion of subjects who achieve hematologic improvement 
in peripheral blood or bone marrow blast count 
• To evaluate progression-free survival (PFS) 
• To evaluate overall survival (OS) 
• To evaluate the pharmacokinetics of FF-10501 and M1 
• To evaluate the xanthosine monophosphate (XMP) as a pharmacodynamic 
marker 


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3. INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design 
This is a Phase 1/2a, dose-escalation study of FF-10501-01 for the treatment of advanced 
hematologic malignancies. 
A total of up to N=68 subjects will be enrolled in the study. Subjects with acute 
myelogenous leukemia (AML) (Phase 1 only), myelodysplastic syndrome (MDS), and 
chronic myelomonocytic leukemia (CMML) will be included. 
Major selection criteria are: age ≥ 18 years, confirmed MDS/CMML or AML (Phase 1 
only for AML) with documented disease progression following previous therapy, or 
subjects with AML ≥ 60 years of age who are not candidates for other therapies (Phase 1 
only). Subjects must be ≥ 3 weeks beyond chemotherapy, radiotherapy, major surgery, or 
other experimental treatments, and recovered from all acute toxicities (≤ Grade 1), have 
adequate renal and hepatic function, and no known history of significant cardiac disease. 
Phase 1:  
14-day Schedule: Following Screening, a total of 6 cohorts of 3 subjects each received oral 
doses of 50, 100, 200, 300, 400 or 500 mg/m2 BID per day (100, 200, 400, 600, 800 or 
1000 mg/m2/day) for 14 days, followed by 14 days off, repeated every 28 days (= 1 cycle). 
Three events of drug-related atrial fibrillation (Grade 2) were reported in 2 subjects at a 
dose of 500 mg/m2 BID (Cohort 6). Study drug was suspended in both subjects and all 
events resolved with oral metoprolol treatment. These events were medically important 
events and thus met the definition of dose-limiting toxicity (DLT). No further enrollment 
was made at this dose level. The maximally tolerated dose (MTD) was declared at 1 dose 
level below the dose eliciting DLT, 400 mg/m2 BID, and this cohort was expanded to 6 
subjects. No DLTs have been observed in N=7 total subjects treated at 400 mg/m2 BID x 
14 days. 
21-day Schedule: At the MTD of 400 mg/m2 BID, Cohort 7 was added to extend the BID 
dosing schedule to 21 days followed by 7 days off, repeated every 28 days (=1 cycle) 
(Amendment 3). 
28-day Schedule: At the MTD of 400 mg/m2 BID, Cohort 8 was added to extend the BID 
dosing schedule to 28 days continuous dosing each 28 days (= 1 cycle) (Amendment 4). 
DLT is defined as Grade 4 hematologic toxicity lasting 7 days or more; Grade 3 
nonhematologic toxicity of any duration not amenable to supportive care; failure of 
platelets, absolute neutrophil count (ANC), or hemoglobin (Hb) to recover to Grade 1 
within 12 weeks despite use of platelet and red blood cell (RBC) transfusions and/or growth 
factors; febrile neutropenia (defined as ANC<1000/mm3 with a single temperature of > 
38.3°C or sustained temperature of ≥ 38°C for over one hour); Grade 3 thrombocytopenia 
associated with bleeding; or other important medical event. 
For all subject cohorts, if 1 of 3 subjects per cohort experiences DLT, the cohort will be 
expanded to 6. If 2 of 6 subjects per cohort experience DLT, all further dose escalation will 
stop. If 0 of 3 or ≤ 1 of 6 subjects per cohort experience DLT by Day 28 following dosing 
of FF-10501-01, dose escalation will proceed to the next cohort. At the MTD of 400 mg/m2 
BID, the longest schedule of administration below the schedule of administration eliciting 


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DLT will be declared the recommended Phase 2 dose (RP2D) and schedule. A total of 6 
subjects will be treated at the RP2D and schedule. No intra-subject dose escalation will be 
allowed from previous dose levels/schedules of administration until at least one subject has 
completed Cycle 1 at the longer schedule of administration (e.g., 21 or 28 days) with no 
Grade 2 or greater toxicities observed. 
Additionally, patients currently on study will have the option to extend their current dosing 
schedule to 21 days, followed by 7 days off, repeated every 28 days (=1 cycle) or 28 days 
of continuous dosing, whichever is chosen as the best schedule, if seen in the patient’s best 
interest by the principal investigator. Dose level adjustments for DLT will be made. 
Subjects who experience DLT at the first dose level, 50 mg/m2 BID, will not be dose-
reduced. Up to 48 subjects are planned for Phase 1. 
Phase 2a: Once 6 subjects are treated at the RP2D and schedule in Phase 1, 1 additional 
cohort will enroll 20 subjects with MDS/CMML who have relapsed from, or are refractory 
to, prior hypomethylating agent (HMA) therapy. Subjects enrolled in Phase 1 at the RP2D 
and schedule and who meet the Phase 2a selection criteria will count towards the Phase 2a 
accrual. Dose level adjustments for adverse events will be made. 
During the study, a Safety Review Committee, consisting of the actively recruiting 
investigators, the Medical Monitor, and FPHU, will review data from each cohort on an 
ongoing basis. 
Subjects on the 21-day schedule will receive FF-10501-01 on a BID schedule. For all 
subjects on the 21-day dosing schedules, blood samples for pharmacokinetic assessment of 
FF-10501 and M1 in plasma will be collected on Cycle 1 Day 1 pre-dose (any time), 
between 0.5-1 hr post-dose, and between 2-4 hr post-dose, and Day 15 pre-dose (within 15 
minutes prior to dosing), between 0.5-1 hr post-dose, and between 2-4 hr post-dose. 
Blood concentration of xanthosine monophosphate (XMP) will be assessed as a 
pharmacodynamic endpoint.  
For subjects on the 21-day dosing schedules, blood samples for XMP assessment will be 
collected on Cycle 1 Day 1 pre-dose (any time), between 0.5-1 hr post-dose, and between 
2-4 hr post-dose, and Day 15 pre-dose (within 15 minutes prior to dosing), between 0.5-1 
hr post-dose, and between 2-4 hr post-dose. 
Disease assessments, including analysis of blood and bone marrow aspirates, will be 
performed at the end of Cycle 1 and Cycle 3 and every 2 cycles thereafter. Disease 
assessments may be performed at other time points at the discretion of the investigator. 
Subjects who demonstrate objective response (OR) or stable disease (SD) will be allowed 
to continue therapy with FF-10501-01 until progression of disease, observation of 
unacceptable adverse events, intercurrent illness or changes in the subject’s condition that 
prevents further study participation. 
Blood for hematology, platelet and serum chemistry determinations will be collected 
within 28 days of Cycle 1 Day 1, on Days 1, 8, 15, and 22 of Cycle 1, on Day 1 of each 
subsequent cycle, and at the End of Study Visit. Urine will be collected for urinalysis within 
28 days of Cycle 1, on Day 1 of each subsequent cycle and at the End of Study Visit. 


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Safety will be assessed through the monitoring of adverse events (AEs), clinical laboratory 
parameters (hematology, serum chemistry), vital sign measurements, electrocardiograms 
(ECGs) and physical examinations. Adverse events will be classified according to the 
Medical Dictionary for Regulatory Affairs (MedDRA) and graded according to the 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI 
CTCAE) version 4.03. 
Efficacy assessment for AML will be performed using a modification of the 
recommendations of the International Working Group for Diagnosis, Standardization of 
Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials 
in Acute Myeloid Leukemia. Efficacy assessments for subjects with MDS or CMML will 
be performed using a modification of the International Working Group Response Criteria 
in Myelodysplasia. Efficacy assessments for any subject may be performed at other time 
points at the discretion of the investigator.  
Pharmacokinetic determinations will be performed. 
XMP will be determined in peripheral blood as a pharmacodynamics endpoint. 
3.2. 
Number of Subjects and Centers 
Phase 1: Up to 48 subjects are planned for the dose-escalation phase. Phase 2a: A total of 
20 subjects with MDS/CMML treated at the RP2D are planned, including MDS/CMML 
subjects treated at the RP2D in Phase 1. Therefore, up to 68 subjects are planned.  
The study will be conducted at up to seven sites.  
3.3. 
Duration of Study 
The accrual phase for the Phase 1 dose-escalation phase is expected to be 12 – 18 months. 
The expected accrual phase for the Phase 2a expansion phase is expected to be 6 – 12 
months, with the last subject followed for up to 6 months, for a total study duration of 30 
– 36 months. The anticipated accrual rate for the Phase 2a portion is 4 – 5 subjects per 
month. 
3.4. 
Criteria for Termination of the Study 
If the sponsor, investigator, study monitor, or officials from the Food and Drug 
Administration (FDA) discover conditions arising during the study that indicate that the 
study should be halted or that the study site should be terminated, this action may be taken 
after appropriate consultation between the sponsor and investigator.   
Conditions that may warrant termination include, but are not limited to, the following: 
• The discovery of an unexpected, serious, or unacceptable risk to subjects enrolled 
in the study 
• A decision on the part of the sponsor to suspend or discontinue testing, evaluation, 
or development of the product 
• Failure of an investigator to enroll subjects into the study at an acceptable rate 


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• Failure of an investigator to comply with pertinent FDA regulations 
• Submission of knowingly false information from the study site to the sponsor, study 
monitor, or the FDA 
• Insufficient adherence to protocol requirements  
Study termination and follow-up would be performed in compliance with the conditions 
set forth in 21 CFR 312.50 and 21 CFR 312.56. 
4. STUDY POPULATION 
4.1. 
Inclusion Criteria 
Subjects must meet all of the following criteria to participate in the study: 
• Males and females ≥ 18 years of age 
• Subjects with confirmed hematologic malignancies:  
• Phase 1: 
• High-risk MDS/CMML (defined as ≥ 10% peripheral blood or marrow 
blasts and/or International Prognostic Scoring System [IPSS]34 score ≥ 1.5) 
and relapsed or refractory to prior therapy 
• AML relapsed or refractory to prior therapy, or ≥ 60 years of age and not a 
candidate for other therapies 
• Phase 2a: 
• MDS/CMML, relapsed from, or refractory to prior HMA therapy; the latter 
defined as failure to achieve clinical remission (CR), partial remission (PR) 
or hematologic improvement (HI) after previous HMA therapy (≥ 4 cycles 
of azacitidine or decitabine), or progression during, or toxicity to, previous 
HMA therapy precluding further HMA treatment, and 
• Bone marrow blast count ≥ 10% or peripheral blast count ≥ 5%, or IPSS-
R35 score ≥ 3.5 
• At least 3 weeks beyond the last chemotherapy, targeted anticancer agent, major 
surgery or experiment treatment and recovered from all acute toxicities (≤ Grade 
1). Hydroxyurea used to control peripheral blast counts is permitted up to Day 7 of 
treatment on study.  
• Adequate performance status: Eastern Cooperative Oncology Group (ECOG) ≤ 2 
• Adequate renal and hepatic function: 
• Creatinine < 2.0 mg/dL, or calculated creatinine clearance ≥ 45 mL/minute per 
the Cockcroft-Gault formula  
• Total bilirubin ≤ 2 times the upper limit of normal (ULN) 
• ALT and AST < 2 times ULN 


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• Negative serum pregnancy test within 14 days prior to first dose of study therapy 
for women of child-bearing potential (WCBP), defined as a sexually mature woman 
who has not undergone a hysterectomy or who has not been naturally post-
menopausal for at least 24 consecutive months (i.e., who has had menses any time 
in the preceding 24 consecutive months). Sexually active WCBP and male subjects 
must agree to use adequate methods to avoid pregnancy (oral, injectable, or 
implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier 
contraceptive with spermicide; or vasectomized partner) throughout the study and 
for 28 days after the completion of the study treatment. 
• Ability to provide written informed consent 
4.2. 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study:   
• Known history of active coronary artery disease, angina, myocardial infarction, 
congestive heart failure, cardiac arrhythmia or any other type of heart disease 
present within the last 6 months 
• Known family history of hereditary heart disease 
• QT interval corrected for rate (QTc) > 450 msec on the electrocardiogram (ECG) 
obtained at Screening 
• Concomitant medication(s) that may cause QTc prolongation or induce Torsades 
de Pointes with the exception of anti-microbials that are used as standard of care to 
prevent or treat infections and other such drugs that are considered by the 
Investigator to be essential for the care of the patient 
• Presence of active central nervous system (CNS) leukemia. Subjects adequately 
treated for CNS leukemia documented by 2 consecutive cerebrospinal fluid samples 
negative for leukemia cells are eligible. Subjects with no history of CNS leukemia 
will not be required to undergo cerebrospinal fluid sampling for eligibility. 
• Any other medical intervention or other condition which, in the opinion of the 
Principal Investigator, could compromise adherence with study requirements 
• Known positive for human immunodeficiency virus (HIV), hepatitis B virus 
surface antigen (HBsAg), or hepatitis C virus (HCV) 
• Active infection requiring intravenous (IV) anti-infective usage within the last 7 
days prior to study treatment 
• Pregnant or breast-feeding 
• Treatment with any investigational product within 28 days prior to Screening 
4.3. 
Discontinuation of Subjects  
4.3.1. Procedures for Withdrawal  
Any subject may be removed from study for the following reasons: 


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• Subject withdrawal of the informed consent 
• Subject noncompliance 
• An increasing or unexpected pattern of unacceptable toxicity 
• Disease progression 
• Investigator judgment when the well-being and best interest of the subject is 
compromised 
Subjects experiencing unacceptable toxicity should be removed from the study once 
complete resolution of toxicity has been documented. Individual subjects may be 
discontinued from the study by the investigator or sponsor at any time if either determines 
that it is not in the best interest of the subject to continue.   
Any subject who becomes pregnant during the study must be discontinued from the study 
immediately, but should be followed through delivery or termination of the pregnancy.  
Subjects should also notify the investigator if they become pregnant within 28 days 
following the last dose of study drug. FPHU/Westat also must be notified if a subject 
becomes pregnant on study. 
If a subject is discontinued from the study before completing the specified duration of 
treatment, they should be encouraged to complete the end-of-study assessments and to 
agree to report any serious adverse events for 28 days following the last dose of study drug. 
The date the subject is withdrawn and the primary reason for discontinuation will be 
recorded on the case report form (CRF).   
4.3.2. Replacement of Study Subjects 
Subjects who are screened, but do not receive FF-10501-01 will be replaced. 
5. STUDY TREATMENT 
5.1. 
FF-10501-01 Investigational Product Description 
FF-10501-01 is an oral antimetabolite anticancer drug. It is a competitive inhibitor of 
IMPDH.  
FF-10501-01 is a white powder provided in the form of film-coated immediate release 
tablets. In addition to FF-10501-01, formulation components include lactose monohydrate, 
light anhydrous silicic acid, carmellose calcium, hydroxypropyl cellulose, magnesium 
stearate, hypromellose, titanium dioxide, talc, and carnauba wax. FF-10501-01 is 
manufactured for FPHU by Patheon (Missisauga, Ontario, Canada) and will be provided 
by the sponsor (FPHU). 
5.2. 
Study Drug Administration 
FF-10501-01 will be provided directly from the drug distribution center designated by 
FPHU.  
Subjects should be scheduled to begin study therapy following completion of Screening. 
FF-10501-01 will be administered orally at the dose level prescribed per cohort twice each 


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day (approximately every 12 hours). For subjects on the 21-day dosing schedule, 
treatment will be continuous for 21 days for each 28-day cycle (=1 cycle). See Appendix 
A for drug dispensing guidelines. 
A sufficient supply of FF-10501-01 will be dispensed to the subject by the investigator or 
trained designee for the subject to take on an outpatient basis between visits. 
The following instructions should be reviewed with the subject and a written copy of the 
instructions provided to the subject: 
• Take the prescribed dose of FF-10501-01 tablets (either 50 mg or 200 mg or both) 
by mouth twice each day with the second dose about 12 hours after the first dose.  
• Take the tablets with a full glass of water (approximately 8 ounces). Swallow the 
tablets whole. Tablets should be taken in the fasting state, approximately 2 hours 
before or 2 hours after a meal.  
• Your dose may be reduced if you have side effects. If a dose reduction is required, 
follow the instructions given by your doctor. Do not reduce the dose unless your 
doctor tells you to do so.  
• If a scheduled dose of study drug is missed and less than 6 hours have passed since 
the scheduled dosing time, immediately take the missed dose. If more than 6 hours 
have passed since the scheduled dosing time, do not take the missed dose. Wait and 
take the next regularly scheduled dose. 
• Each day record the number and dosage of tablets taken on the diary card. If a dose 
is missed, include the reason the dose was not taken. 
• Return the diary card to your study doctor at each visit.  
• Return opened and unopened bottles in which the tablets were dispensed.  
• Adherence with the study treatment regimen must be assessed at each visit by 
checking the returned drug supply and reviewing the diary card. Study drug therapy 
must be reported in the appropriate case report form (CRF) module. 
5.3. 
Treatment Duration 
Treatment will continue until confirmation of disease progression, unacceptable toxicity, 
or subject decision to discontinue therapy 
5.4. 
Dosing Delays and Dose Modifications Due to Toxicity 
5.4.1. Toxicity Grading Criteria 
Toxicity grading is based on NCI Common Terminology Criteria for Adverse Event v 4.03 
(http://evs.nci.nih.gov/ftp1/CTCAE/About.html). 
5.4.2. Instructions Regarding Dose Delays and Dose Modifications  
Adverse events considered for treatment interruption and dose reduction will exclude the 
events assessed by the investigator as exclusively related to underlying disease or medical 


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condition/concomitant treatment. If treatment must be delayed for reasons other than 
toxicity, contact the Medical Monitor to discuss the reasons for delay and plans for 
resuming study therapy. 
• Treatment may be delayed up to 14 days. If the subject has completed two cycles 
and, in the investigator’s opinion, is receiving benefit, treatment may be delayed 
for longer than 14 days and then resumed following a discussion with the Medical 
Monitor.  
• Subjects who experience a toxicity requiring reduction in dose level may continue 
treatment at the lower dose level until disease progression or unacceptable toxicity. 
Once the dose has been reduced it may not be escalated to the starting dose. 
• See Appendix B for FF-10501-01 dose modification requirements. 
5.5. 
Supportive Care Guidelines 
• Medications may be administered for the management of symptoms associated with 
the administration of FF-10501-01, as required. 
• Prophylactic pre-medication will not be used routinely. Adequate treatment for 
nausea and/or vomiting and diarrhea is permitted during Cycle 1. After Cycle 1, 
prophylaxis of nausea and/or vomiting and diarrhea is permitted. 
• Granulocyte stimulating growth factors (e.g., G-CSF or GM-CSF) are not allowed 
during Cycle 1 except for the following situations (defined as DLTs): Grade 4 
neutropenia lasting 7 days or more, or failure of the absolute neutrophil count 
(ANC) to recover to Grade 1 within 12 weeks. After Cycle 1, use of granulocyte 
growth factors are allowed for prophylaxis or management of neutropenia. 
• Erythropoiesis-stimulating agents, transfusions, etc. are permitted for management 
of hematologic toxicities. 
5.6. 
Prior and Concomitant Medications and Therapies 
5.6.1. Permitted Medications 
All medications and other treatments taken by subjects 4 weeks before and throughout the 
study period will be recorded in the CRF module. Any changes in documented, permitted 
concomitant medications being taken at the beginning of the clinical trial or added during 
the time the subject is participating in this study must be recorded in the CRF module.  
5.6.2. Prohibited Therapy  
Concurrent anti-tumor therapy of any kind or any other investigational agent is prohibited.  
Concomitant medication(s) that may cause QTc prolongation or induce Torsades de 
Pointes are prohibited, with the exception of anti-microbials that are used as standard of 
care to prevent or treat infections and other such drugs that are considered by the 
Investigator to be essential for the care of the patient. See Appendix C for a list of drugs 
that may cause QTc prolongation or induce Torsades de Pointes.  


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5.7. 
Packaging and Labeling  
FF-10501-01 will be supplied in 50 and 200 mg tablets for oral dosing. The study drug will 
be packaged in bottles labeled with pill strength and other information as per local 
regulatory requirements.  
5.8. 
Shipping and Storage 
The drug product has been demonstrated to be stable when stored in the defined container 
closure, high density polyethylene (HDPE) bottles. FF-10501-01 should be stored at room 
temperature (20 – 25 °C).  
5.9. 
Drug Accountability  
The investigator must maintain accurate records of receipt of study drug, dispensing 
information, and the prompt return or destruction of unused supplies. A drug accountability 
log will be supplied to each clinical site for purposes of recording study drug dispensation 
for the study and will be monitored by sponsor personnel. If the site has an electronic study 
drug accountability form that is in keeping with institutional practice and the form collects 
the same information as the form supplied by the Sponsor, this form may be substituted for 
the Sponsor’s drug accountability form. 
Unused or expired FF-10501-01 tablets will be destroyed per institutional policy.  
6. STUDY PROCEDURES 
See Schedule of Study Procedures in Appendix D. 
6.1. 
Screening Procedures 
The following evaluation includes standard tests are to be performed within 28 days of 
study treatment to determine subject eligibility.  
• Administration of informed consent 
• Medical history, physical examination and vital signs 
• ECOG Performance Status 
• Height and weight 
• The following lab tests: 
o Hematology 
o Serum chemistry 
o Urinalysis 
• Beta HCG for WCBP 
• 12-lead ECG 
• Review of concomitant medications 
• Disease-specific assessment (BM aspirate) 


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6.2. 
Requirements During Treatment Cycle 1 
6.2.1. Cycle 1, Day 1 
• Abbreviated physical examination 
• Vital signs 
• ECOG Performance Status 
• Weight 
• The following lab tests: 
o Hematology, if not performed within the previous 24 hours 
o Serum chemistry, if not performed within the previous 24 hours 
o Urinalysis, if not performed within the previous 24 hours 
• 12-lead ECG, pre-dose and approximately 3 hours post-dose (following morning 
dose only) 
• Review of concomitant medications 
• Assessment of adverse events 
• For subjects on 21-day dosing schedules: Peripheral blood collection in heparin for 
PK and XMP assessments, pre-dose (any time), between 0.5-1 hr post-dose, and 
between 2-4 hr post-dose 
• For subjects on 21-day dosing schedule: Dispense 21-day supply of FF-10501-01 
study drug for Cycle 1 
• Assessment for survival 
6.2.2. Cycle 1, Day 8 (+/- 1 day) 
• Vital signs 
• The following lab tests: 
o Hematology 
o Serum chemistry 
• Review of concomitant medications 
• Assessment of adverse events 
• Review subject medication diary for FF-10501-01 study drug 
• Assessment for survival 
6.2.3. Cycle 1, Day 15 (+/- 1 day) 
• Vital signs 
• The following lab tests: 


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o Hematology 
o Serum chemistry 
• 12-lead ECG, pre-dose and approximately 3 hours post-dose (following morning 
dose only) 
• Review of concomitant medications 
• Assessment of adverse events 
• For subjects on 21-day dosing schedules: Peripheral blood collection in heparin for 
PK and XMP assessments, pre-dose (within 15 minutes prior to dosing), between 
0.5-1 hr post-dose, and between 2-4 hr post-dose 
• Assessment for survival 
6.2.4. Cycle 1, Day 22 (+/- 1 day) 
• Vital signs 
• The following lab tests: 
o Hematology 
o Serum chemistry 
• Review of concomitant medications 
• Assessment of adverse events 
• Assessment for survival 
6.2.5. End of Cycle 1 (Day 28 +/- 3 days) 
• Bone marrow aspirate (unless peripheral blood absolute blast count is ≥ 5.0 x 109 
cells/L) 
• Disease Response Assessment 
• Review of concomitant medications 
• Assessment of adverse events 
• Assessment for survival 
6.3. 
Requirements During Treatment Cycles After Cycle 1 (Cycles 2, 3, 4, etc.) 
6.3.1. Day 1 (+/- 3 days, except for pre-dose procedures; ECG) 
• Abbreviated physical examination 
• Vital signs 
• ECOG Performance Status 
• Weight 


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• The following lab tests (within 3 days of each cycle): 
o Hematology 
o Serum chemistry 
o Urinalysis 
• 12-lead ECG, pre-dose and approximately 3 hours post-dose (following morning 
dose only) 
• Review of concomitant medications 
• Assessment of adverse events 
• Assessment for survival 
• For subjects on 21-day dosing schedule: Dispense 21-day supply of FF-10501-01 
study drug for cycle 
6.3.2. End of Cycle 3 and Every 2 Cycles Thereafter 
• Bone marrow aspirate (unless peripheral blood absolute blast count is ≥ 5.0 x 109 
cells/L) 
• Review of concomitant medications 
• Assessment of adverse events 
• Disease Response Assessment 
• Assessment for survival 
6.4. 
At Relapse or Progression of Disease 
• Bone marrow aspirate (unless peripheral blood absolute blast count is ≥ 5.0 x 109 
cells/L) 
• Review of concomitant medications 
• Assessment of adverse events 
• Disease Response Assessment 
• Assessment for survival 
6.5. 
End of Study (Safety Visit, 28 days ± 5 days after the last dose of study drug) 
• Physical examination 
• Vital signs 
• ECOG Performance Status 
• Weight 
• The following lab tests: 
o Hematology 


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o Serum chemistry 
o Urinalysis 
• 12-lead ECG 
• Review of concomitant medications 
• Assessment of adverse events 
• Assessment for survival 
6.6. 
Long-term Follow-up 
Long-term follow-up will consist of a clinic visit or telephone call to assess survival every 
3 months for up to 6 months. 
7. DESCRIPTION OF ASSESSMENTS 
7.1. 
Safety Assessments 
7.1.1. Adverse Event Definition 
An adverse event (AE) includes any noxious, pathological, or unintended change in 
anatomical, physiological, or metabolic functions as indicated by physical signs, 
symptoms, and/or laboratory changes occurring whether or not temporally associated with 
study drug administration and whether or not considered related to study drug. This 
definition includes an exacerbation of pre-existing medical conditions or events, 
intercurrent illnesses, hypersensitivity reactions, drug interactions, or clinically significant 
laboratory findings.   
An AE does not include the following: 
• Medical or surgical procedures, e.g., tooth extraction, transfusion, surgery (The 
medical condition that leads to the procedure is to be recorded as an AE.) 
• Pre-existing conditions or procedures present or detected at the start of the study 
that do not worsen 
• Hospitalization for elective surgeries or for other situations in which an untoward 
medical event has not occurred 
• Abnormal laboratory value, unless it is clinically significant 
• Overdose of study drug or concomitant medication unaccompanied by 
signs/symptoms (If sign/symptoms occur, the final diagnosis should be recorded as 
an AE.)  
• Pregnancy by itself, unless a complication occurs during pregnancy leading to 
hospitalization; in this case (The medical condition that leads to the hospitalization 
is to be recorded as the AE.) 
• A significant worsening of the disease under investigation which is captured as an 
efficacy parameter in this study and, thus, is not to be recorded as an AE.  


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7.1.2. Serious Adverse Event 
A serious adverse event (SAE) is defined as an adverse event that results in any of the 
following outcomes: 
• Death 
• Life-threatening, i.e., immediate risk of death from the event as it occurred; (This 
does not include an adverse event that, had it occurred in a more serious form, might 
have caused death.) 
• Persistent or substantial disability/incapacitation 
• Results in or prolongs an existing inpatient hospitalization 
• Congenital anomaly/birth defect 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based on medical judgment, they may 
jeopardize the subject or may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 
7.1.3. Unexpected Adverse Event 
An AE or suspected adverse reaction is considered "unexpected" if it is not listed in the 
Investigator’s Brochure or is not listed at the specificity or severity that has been observed; 
or, is not consistent with the risk information described in the protocol or elsewhere. For 
example, under this definition, hepatic necrosis would be unexpected (by virtue of greater 
severity) if the Investigator’s Brochure referred only to elevated hepatic enzymes or 
hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be 
unexpected (by virtue of greater specificity) if the Investigator’s Brochure listed only 
cerebral vascular accidents.  
"Unexpected," as used in this definition, also refers to AEs or suspected adverse reactions 
that are mentioned in the Investigator’s Brochure as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the investigational therapy, but are not 
specifically mentioned as occurring with the investigational therapy. 
7.1.4. Adverse Event Reporting Period 
The adverse event reporting period begins from the date of the first dose of study drug to 
28 days following the last dose of study drug. 
7.1.5. Recording of Adverse Events 
Each AE should be recorded in standard medical terminology on the AE CRF module. 
Whenever possible, the AE should be evaluated and reported as a diagnosis rather than as 
individual signs or symptoms. For example, cough, runny nose, sneezing, sore throat, and 
head congestion should be reported as ‘upper respiratory infection’. If a definitive 
diagnosis is not possible, the individual signs and symptoms should be recorded.  Dates of 


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start (onset) and stop (recovery), action taken, and outcome will be recorded in the AE CRF 
module. 
All clinically significant abnormal changes in laboratory parameters will be recorded as an 
AE on the AE module, with the following exceptions: clinically significant abnormal 
laboratory changes determined to be related to the study condition and concomitant 
conditions, e.g., diabetes, of which the investigator was previously aware and that have not 
worsened. 
The investigator will evaluate all AEs with regard to maximum intensity and relationship 
to study drug, as follows. 
7.1.5.1. Maximum Intensity 
Maximum intensity should be assigned using one of the severity grades as outlined in the 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE 
v4.0); if the AE is not specifically listed in CTCAE v4.03, use the following grades: 
• Grade 1: mild 
• Grade 2: moderate 
• Grade 3: severe 
• Grade 4: life-threatening or disabling 
• Grade 5: death 
7.1.5.2. Relationship to Study Drug 
The degree of certainty with which an AE is attributed to study drug (or alternative causes, 
e.g., natural history of the underlying diseases, concomitant therapy, etc.) will be 
determined by how well the event can be understood in terms of known pharmacology of 
the study drug and/or reactions of similar nature previously observed with study drug.  Each 
AE will be assigned one of the following five categories: 
• Not related: There is not a temporal relationship to the study drug (e.g., too early, 
too late), or there is a reasonable causal relationship to another drug, concurrent 
illness, or circumstance. 
• Unlikely related: There is a temporal relationship to study drug, but there is not a 
reasonable causal relationship between the time of study drug administration and 
the AE (i.e., it is doubtful the AE is related to the study drug); could be reasonably 
explained by other factors, including underlying disease, complications, 
concomitant drugs, or concurrent treatment. 
• Possibly related: There is a reasonable temporal sequence from time of study drug 
administration (e.g., occurred in a time frame relevant to study drug dose); or for 
which the possibility of the study drug being the causative factor (e.g., existence of 
similar reports attributed to the study drug; reactions attributable to the 
pharmacological effect) could not be excluded, although other factors such as 


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underlying disease, complications, concomitant drugs, or concurrent treatment are 
presumable. 
• Probably related: There is a reasonable temporal sequence from time of study drug 
administration; and for which the possibility of factors other than the study drug 
administration, such as underlying disease, complications, concomitant drugs, or 
concurrent treatment, could not be excluded as the cause. 
• Definitely related: Follows a clear temporal sequence from time of study drug 
administration; could not be possibly explained by the known characteristics of the 
subject’s clinical state, environmental or toxic factors, or other modes of therapy 
administered to the subject; follows a response pattern known to be associated with 
study drug administration. 
7.1.6. Most Commonly Expected Adverse Events 
The most commonly reported adverse events in a Phase 2 study of 165 subjects with 
hematologic malignancies at doses of 14 – 600 mg/m2 BID were nausea (9%), anorexia 
(7%), rash (4%), vomiting (4%), abdominal discomfort (2%) and pruritis (1%). Changes 
in laboratory values were elevated ALT (10%), AST (9%), thrombocytopenia (5%), 
decreased hemoglobin (2%), neutropenia (2%) and decreased bilirubin (2%).  All other 
adverse events were reported at incidences of 1% or less. Laboratory changes were reported 
as temporary, ≤ Grade 2, and reversible. For bone marrow changes, nadir was reached in 2 
-3 weeks for neutropenia, 3 weeks for platelets and 5 weeks for hemoglobin. Recovery 
from nadir values was approximately 2 weeks for all parameters.7 
7.1.7. Adverse Event Reporting 
Each AE is to be reported by the investigator as serious or non-serious according to the 
definitions in Section 7.1.2 above. This classification determines the regulatory reporting 
procedures to be followed as described in Table 6. 
Table 6. Reporting Guidelines for Adverse Events 
Any SAE, regardless of relationship to investigational therapy that occurs within 28 days 
following the last dose of study drug must be reported to the Medical Monitor within 24 
hours after the site becomes aware of the event. The investigator is encouraged to discuss 
with the Medical Monitor any adverse experiences for which the issue of reportability is 
unclear or questioned. The initial report should be followed by submission of a more 
detailed SAE Report when follow-up information is available.  
Gravity of AE 
Reporting Time to  
FPHU/Westat 
Type of Report 
Serious 
Within 24 hours after the site 
becomes aware of the event 
Initial SAE Report  
Non-Serious 
Per AE CRF module 
Completed AE CRF Module 


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If the SAE occurs more than 28 days after the last dose of study drug, SAEs should be 
reported only if considered related to FF-10501-01. In the event of subject death, the 
reason for death should be recorded as the SAE, with ‘death’ recorded as the outcome on 
the SAE CRF module. 
The SAE also will be recorded as an AE on the AE CRF module. Note: the SAE Report is 
different from the AE CRF. In areas of both forms where the same data are reported, the 
forms will be completed in a consistent manner. For example, the same term should be 
used for the AE on both forms, with the same start and stop dates, action taken, outcome, 
etc. A checkbox on the AE CRF module for whether the AE resulted in an SAE, will link 
the two types of report for a given event. 
An SAE Report should be prepared with as much available information concerning the 
event as possible so that a written report can be filed with the appropriate regulatory 
authorities. If causality cannot be determined definitively at the time of the SAE 
occurrence, it is important to notify FPHU/Westat within the timeline stated above, and to 
attribute the relationship as ‘Not Assessable’ (only applicable for the initial SAE Report). 
When new significant information is obtained and the outcome and attribution of the event 
is known, the investigator will communicate this in a follow-up SAE Report. This relevant 
information will be provided in a timely manner to allow reporting to regulatory authorities 
within the required reporting period. Any SAE follow-up information requested by 
FPHU/Westat should be provided in a timely manner. 
As necessary, the SAE Report should be accompanied by relevant pages from the CRFs, 
e.g., medical history, AEs, concomitant medications. Additional information may be 
requested by FPHU/Westat in an expedited manner to ensure that the initial reporting of 
the SAE made to the regulatory authorities complies with the required time frame. 
FPHU/Westat may be required to collect and report additional information to the regulatory 
authorities in a follow-up report, containing a final evaluation of the event, including copies 
of hospital reports, autopsy reports, or other relevant information.  
7.1.8. Adverse Event and Serious Adverse Event Follow-Up 
All AEs and SAEs should be followed until resolution, return to baseline, or until the point 
it is deemed that further recovery is unlikely. All measures required for AE management 
and the ultimate outcome of the AE will be recorded in the source document and AE CRF 
module. 
7.1.9. Ongoing Safety Evaluation 
A study safety evaluation will be conducted on a regular (monthly) basis by teleconference. 
Dose exposure, dose-limiting toxicity, AE/SAE profiles and clinical laboratory 
abnormalities, and other safety measures will be reviewed during each convened meeting. 
Subject accrual will not be interrupted during the regular scheduled safety evaluations. 
These discussions will be led by the FPHU Medical Monitor and clinical site investigators. 


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7.1.10. Clinical Laboratory Tests 
Clinical laboratory tests include hematology, serum chemistry, urinalysis and bone marrow 
aspirate (Table 7). 
Table 7. Clinical Laboratory Parameters 
Hematology 
Serum Chemistry 
Urinalysis 
Bone Marrow Aspirate 
Red blood cell 
count 
Serum creatinine 
pH 
Marrow blast percent 
Hemoglobin 
BUN 
Blood 
Marrow cellularity percent 
Hematocrit 
Glucose (non-
fasting) 
Nitrites 
Cell line maturation 
White blood cell 
count 
Albumin 
Glucose 
Auer rods 
Differential: 
AST 
Ketones 
Dysplasia 
   Neutrophils 
ALT 
Leucocytes 
Cytogenetic abnormalities 
   ANC 
LDH 
Protein 
 
   Lymphocytes 
Total bilirubin 
Microscopic 
examination 
 
   Monocytes 
Total protein 
 
 
   Eosinophils 
Alkaline 
phosphatase 
 
 
   Basophils 
Calcium 
 
 
Platelets 
Phosphorus 
 
 
Blasts percent 
Magnesium 
 
 
 
Sodium 
 
 
 
Potassium 
 
 
 
Chloride 
 
 
 
Bicarbonate 
 
 
7.1.11. Vital Sign Measurements 
Vital sign measurements include blood pressure and pulse rate.  Additional measurements 
may be obtained if clinically indicated.  Any value considered clinically significant by the 
investigator will be recorded as an AE on the CRF. Clinically significant changes compared 
to baseline values should be followed until clinical resolution.   
7.1.12. Physical Examinations 
Complete physical examinations include the following body system evaluations:  General 
Appearance, Skin, Musculo-skeletal, Eyes, Ears, Nose, Throat, Cardiovascular, Chest, 
Abdomen, Lymph Nodes, and Neurological. 
Symptom-oriented evaluations will be performed when clinically indicated.  Weight will 
be measured at Screening, Day 1 of each treatment cycle and the End of Study Visit.    
7.1.13. Electrocardiograms 
12-Lead ECGs will be performed at Screening, Cycle 1, Days 1 and 15, Day 1 of each 
subsequent cycle, and at End of Study.  


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7.2. 
Efficacy Assessments 
7.2.1. Criteria for Evaluation of Response and Progression 
Evaluation of response to treatment and determination of disease progression in subjects 
with AML will be evaluated using criteria defined in Revised Recommendations of the 
International Working Group for Diagnosis, Standardization of Response Criteria, 
Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid 
Leukemia.
36 Efficacy assessments for subjects with MDS or CMML will be assessed using 
the modified International Working Group Response Criteria in Myelodysplasia.37 
7.2.2. Disease Response Criteria 
7.2.2.1. Subjects with AML 
• 
Complete Remission (CR) 
The subject must be free of all symptoms related to leukemia and have an 
absolute neutrophil count > 1.0 x 109/L, platelet count ≥ 100 x 109/L, and 
normal bone marrow with < 5% blasts and no Auer rods 
• 
Complete Remission with Incomplete Blood Count Recovery (CRi) 
As per CR but with residual thrombocytopenia (platelet count < 100 x 109/L) 
or residual neutropenia (absolute neutrophil count < 1.0 x 109/L) 
• 
Partial Remission (PR) 
A ≥ 50% decrease in bone marrow blasts to 5 to 25% abnormal cells in the 
marrow; or CR with ≤ 5% blasts if Auer rods are present 
• 
Treatment Failure 
Treatment has failed to achieve CR, CRi, or PR.    
 
• 
Recurrence 
Relapse after confirmed CR:  reappearance of leukemic blasts in peripheral 
blood or ≥ 5% blasts in the bone marrow not attributable in the Investigator’s 
opinion to any other cause (e.g., bone marrow regeneration after consolidation 
therapy) or appearance of new dysplastic changes 
7.2.2.2. Subjects with MDS or CMML 
• 
Complete Remission (CR) 
The subject must be free of all symptoms related to leukemia and have an 
absolute neutrophil count ≥ 1.0 x 109/L, platelet count ≥ 100 x 109/L, bone 
marrow ≤ 5% myeloblasts, with normal maturation of all cell lines, hemoglobin 
≥ 11g/dL, and no blasts in the peripheral blood 
 
• 
Partial Remission (PR) 


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All CR criteria with ≥50% decrease in bone marrow blasts over pre-treatment 
(but still > 5%)   
 
• 
Marrow CR 
In bone marrow, ≤ 5% myeloblasts and decrease by ≥ 50% over pre-treatment  
• 
Hematologic Improvement (HI) (subjects with MDS only)  
− Erythroid Response (HI-E) 
o Major Response 
◊ For subjects with pretreatment hemoglobin < 11 g/dL, > 2 g/dL 
increase in hemoglobin 
◊ For 
RBC 
transfusion-dependent 
subjects, 
transfusion 
independence 
o Minor Response 
◊ For subjects with pretreatment hemoglobin < 11 g/dL, 1 to 2 
g/dL increase in hemoglobin 
◊ For RBC transfusion-dependent subjects, ≥ 50% decrease in 
transfusion requirements  
− Platelet Response (HI-P) 
o Major Response 
◊ For subjects with a pretreatment platelet count < 100 x 109/L, an 
absolute increase of ≥ 30 x 109/L 
◊ For platelet transfusion-dependent subjects, stabilization of 
platelet transfusion independence 
 
 
 
o Minor Response 
◊ For subjects with a pretreatment platelet count < 100 x 109/L, a 
≥ 50% increase in platelet count with a net increase > 10 x 109/L 
but < 30 x 109/L 
− Neutrophil Response (HI-N) 
o Major Response 
◊ For absolute neutrophil count (ANC) < 1.5 x 109/L before 
therapy, ≥ 100% increase or an absolute increase of ≥ 0.5 x 
109/L, whichever is greater 
o Minor Response 


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◊ For ANC < 1.5 x 109/L before therapy, ANC ≥ 100%, but 
absolute increase < 0.5 x 109/L 
• 
Progressive Disease 
Subject did not achieve PR, CR or marrow CR or is otherwise a non-responder. 
• 
Relapse after CR or PR 
One or more of the following:  
− Return to pretreatment bone marrow blast percentage 
− Decrement of ≥ 50% from maximum remission/response levels in 
granulocytes or platelets 
− Reduction in hemoglobin concentration by ≥ 2 g/dL or transfusion 
dependence. 
 
• 
Progression or Relapse after Hematologic Improvement 
One or more of the following: 
− A ≥ 50% decrement from maximum response levels in granulocytes or 
platelets 
− A reduction in hemoglobin concentration by ≥ 2 g/dL 
− Transfusion 
7.2.3. Efficacy Endpoints 
7.2.3.1. Primary Efficacy Endpoint 
To evaluate the proportion of subjects with objective response achieved within 3 cycles of 
treatment with FF-10501-01 (i.e., within 3 months) in subjects with relapsed/refractory 
AML or relapsed/refractory high-risk MDS or CMML.   
• Subjects with AML 
Objective responses for subjects with AML include complete remission (CR), 
complete remission with incomplete blood count recovery (CRi) and partial 
remission (PR) as defined above. 
 
• Subjects with MDS  
Objective responses for subjects with high-risk MDS include complete 
remission (CR), partial remission (PR), and marrow CR as defined above. 
 
• Subjects with CMML 
Objective responses for subjects with CMML include complete remission (CR), 
partial remission (PR) and marrow CR as defined above. 
7.2.3.2. Secondary Efficacy Endpoints 
The proportion of subjects with MDS who have hematologic improvement in peripheral 
blood or bone marrow blast count at any time after initiation of treatment with FF-10501-


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01. Hematologic improvement in blast count is defined as ≥ 50% reduction in peripheral 
blood or bone marrow blast count when compared with the baseline value. 
Progression-Free Survival: length of time from the date of first administration of study 
drug to the first objective evidence of disease progression or death, whichever is earlier. 
Overall Survival: length of time from the date of first administration of study drug to the 
date of death from any cause   
7.2.4. Timing of Assessments to Determine Response 
Disease assessments will be made at the end of Cycle 1 and Cycle 3 and every two cycles 
thereafter. Disease assessments may be made at other time points at the discretion of the 
Investigator.     
7.2.5. Pharmacokinetic Endpoints 
Mean plasma concentrations of FF-10501 will be determined at each time point. Because 
plasma concentrations will be determined at a limited number of time points during the 
study, a complete pharmacokinetic profile of FF-10501-01 at each dose level will not be 
possible. Limited pharmacokinetic analyses will be performed. 
7.2.6. Pharmacodynamic (PD) Endpoint 
XMP is an intermediate in purine metabolism. It is formed from inosine 
monophosphate via the action of IMPDH, and is converted to guanosine monophosphate 
(GMP) via the action of GMP synthase (see Figure 1). The mechanism of action of FF-
10501-01, namely, inhibition of IMPDH, should be associated with a decrease in XMP. 
Therefore, as a measure of pharmacologic activity of FF-10501-01 and preliminary 
measure of efficacy, levels of XMP in peripheral blood cells will be assessed in this study.  
8. STATISTICAL METHODOLOGY 
8.1. 
Determination of Sample Size 
Phase 1: The sample size reflects requirements associated with a 3+3 design. A total of 3 
to 36 subjects are planned (3 to 6 subjects in each of 6 dose cohorts).  
Phase 2: The sample size reflects an additional 20 MDS/CMML patients to be treated at 
the MTD. 
8.2. 
Analysis Populations 
The full analysis set (FAS) includes all subjects who are administered any fraction of a 
dose of study medication.  For a particular measure, the per-protocol set (PPS) includes 
those subjects in the FAS who have a valid baseline and one or more post-treatment 
assessments for that measure of interest.  
The FF-10501-01 PK population consists of all subjects in the FAS who complete all PK 
assessments.   


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The FF-10501-01 PD population consists of all subjects in the FAS who complete all PD 
assessments. 
8.3. 
Statistical Analysis Methods 
All data will be analyzed using Statistical Analysis System (SAS Version 9.3 or higher for 
Windows, SAS Institute, Cary, NC). Continuous variables will be summarized using 
number, mean, standard deviation, median, minimum, and maximum. Categorical 
variables will be summarized using number and frequencies. 
8.3.1. Safety Analyses 
8.3.1.1. Adverse Events 
All safety endpoints will be summarized using descriptive statistics and will be based on 
the FAS dataset. 
All AEs will be coded based on the Medical Dictionary for Regulatory Affairs (MedDRA; 
Version 15.0 or higher). An AE will be considered a treatment emergent adverse event 
(TEAE) if the onset is after the first dose of study drug or if the condition was present at 
baseline but worsened after the first dose.  
All AEs for each subject will be listed, including intensity grading, relationship to study 
drug, action taken and outcome. Subject listings of deaths, SAEs, and AEs leading to 
treatment discontinuation will be provided. Subject narratives will be provided for deaths, 
SAEs and other significant AEs. Summary tables will be prepared to examine TEAE 
severity and relationship to study treatment. 
AE summaries will be produced separately for each dose cohort and overall, and each 
disease cohort by dose and overall. All summaries will show, by subject group, dose cohort 
and overall, the number and percentage of subjects experiencing at least 1 TEAE of each 
preferred term, arranged by system organ class, and the number of occurrences of the event. 
Separate summaries will be produced by relationship to study medication, by severity, and 
for those events with an incidence rate of at least 2% in any group or overall. 
SAEs will be summarized in a similar manner; overall, by relationship to study medication, 
and by severity. 
In addition to the above, summaries of the number and percentage of subjects discontinuing 
the study due to AEs and, due to death, will be presented.  
8.3.1.2. Laboratory Data 
Laboratory data will be listed by subject. Values above and below normal ranges will be 
indicated, and whether statistically significant. All laboratory values will be graded 
according to the NCI-CTCAE version 4.03 criteria. Laboratory data will be summarized 
by actual value and change from baseline using number of non-missing observations, mean 
standard deviation, median, minimum and maximum. In addition, shift tables and the 
incidence of Grade 3 or 4 laboratory values will be presented.  


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8.3.1.3. Vital Signs 
Vital signs will be listed by subject. Values above and below normal ranges will be 
indicated as will clinical significance. Vital sign data will be summarized by actual value 
and change from baseline using number of non-missing observations, mean, standard 
deviation, median, minimum and maximum. 
8.3.1.4. Other Safety Data 
Data collected for physical examinations, ECGs and related measures will be listed. 
8.3.2. Efficacy Analyses 
8.3.2.1. Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of subjects treated at the MTD in each 
disease cohort (AML, MDS or CMML) with objective response (OR) within 3 cycles of 
study drug (i.e., within 3 months). For subjects with AML, OR is CR, CRi, or PR, as 
defined above. For subjects with MDS or CMML, OR is CR, PR or marrow CR, as defined 
above. The proportion of subjects in each disease cohort treated at the MTD will be 
summarized, and 90% confidence intervals will be estimated.    
8.3.2.2. Secondary Efficacy Endpoints 
The proportion of MDS subjects with hematologic improvement in the peripheral blood or 
bone marrow as defined as ≥ 50% reduction in blast count when compared with the baseline 
value. The 90% confidence interval will be estimated and provided.  
Progression-free survival and overall survival curves will be estimated at the MTD by 
disease cohort using Kaplan-Meier product limit estimates. Median and 90% confidence 
interval of time-to-event will be estimated. Progression-free survival will be calculated 
from the date of first dose of study drug to the date of first objective evidence of disease 
progression or death, whichever is earlier. Overall survival will be calculated from the date 
of first dose of study drug to the date of death due to any cause. Subjects who did not 
experience progression or death will be censored at the last follow-up time point. 
8.3.3. Pharmacokinetic Endpoint Analysis 
Mean plasma concentrations of FF-10501 and plasma M1 will be determined at each time 
point for evaluation of dose-linearity. Because a limited number of plasma concentrations 
will be determined, full determination of routine pharmacokinetic parameters may not be 
possible. In addition to mean plasma concentrations, as the data allow, additional 
pharmacokinetic analyses will be provided (trough levels, t 1/2, Tmax, C max, AUC, etc.) 
8.3.4. Pharmacodynamic Endpoint Analysis 
Change from baseline in XMP levels will be measured in blood samples collected from 
each subject during the study. Correlations between XMP and PK levels of FF-10501 will 
be made. Pharmacodynamic parameters will be summarized using descriptive statistics 


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including the number of subjects, mean, standard deviation, minimum, median, maximum, 
range, and coefficient of variation.     
8.3.5. Other Summaries 
Demographics and concomitant medications, including antibiotic usage, will be 
summarized using descriptive statistics.  Medical history findings and protocol deviations 
will be listed but not summarized. 
9. STUDY MANAGEMENT 
9.1. 
Data Management 
The investigator is responsible for completing and maintaining adequate and accurate 
source documentation.  Source documentation constitutes original records, which may 
include: progress notes, medication administration records, laboratory reports, ECG 
tracings, discharge summaries, CRF worksheets, etc. Data for this study will be submitted 
electronically. Access to the database will be provided following a brief on-line training 
session. Each user will receive a unique username and password, which should not be 
shared. The investigator must sign the investigator’s statement for each subject indicating 
that the data reported are accurate. See Appendix E for Ethical Standards to be followed 
during the study.  
9.2. 
Monitoring 
The Sponsor and Westat are responsible for ensuring the proper conduct of the study with 
regard to ethics, protocol adherence, site procedures, integrity of the data, and applicable 
laws and/or regulations. At regular intervals during the study and following completion of 
the study, the sponsor’s study monitors will contact the study site via visits to the site, 
telephone calls, and letters in order to review study progress, CRF completion, and address 
any concerns or questions regarding the study conduct.  During monitoring visits, the 
following aspects of study conduct will be carefully reviewed:  informed consent of 
subjects, subject recruitment, subject compliance with the study procedures, source data 
verification, drug accountability, use of concomitant therapy by subjects, AE and SAE 
documentation and reporting, and quality of data.  Records pertaining to these aspects are 
expected to be kept current. 
9.3. 
Audits and Inspections 
The Sponsor, Westat, a regulatory authority, or an IRB may visit the study site at any time 
during the study or after completion of the study to perform audits or inspections. The 
purpose of a sponsor audit or regulatory inspection is to systematically and independently 
examine all study-related activities and documents to determine whether these activities 
were conducted according to the protocol, GCP, ICH guidelines, and any other applicable 
regulatory requirements. Investigators should contact FPHU/Westat immediately if 
contacted by a regulatory agency about an inspection at their site. 


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9.4. 
Amendments 
Any amendments to the protocol will be written and approved by the Sponsor. All 
amendments must be submitted to the IRB for approval prior to implementing the changes. 
In some instances, an amendment requires changes to the informed consent form, which 
also must be submitted for IRB approval prior to administration to subjects. If any changes 
to the CRF are required, Westat will issue supplemental or revised CRF pages on behalf of 
the sponsor. 
9.5. 
Record Keeping 
9.5.1. Health Insurance Portability Accountability Act of 1996 
The investigator agrees to comply with all applicable federal, state, and local laws and 
regulations relating to the privacy of subject health information, including, but not limited 
to, the Standards for Individually Identifiable Health Information, 45 CFR. Parts 160 and 
164 (the Health Insurance Portability Accountability Act of 1996 [HIPAA] Privacy 
Regulation). The investigator shall ensure that study subjects authorize the use and 
disclosure of protected health information in accordance with HIPAA Privacy Regulation 
and in a form satisfactory to the sponsor. See Appendix F for Investigator Obligations. 
9.5.2. Financial Disclosure 
The investigator shall provide to the sponsor sufficient accurate financial information to 
allow the sponsor and Westat to submit complete and accurate financial certification or 
disclosure statements to the FDA. The investigator shall promptly update this information 
if any relevant changes occur in the course of the study or for one year following 
completion of the study. 
9.5.3. Access to Original Records 
It is an expectation of regulatory authorities that monitors, auditors, and representatives of 
national and international government regulatory agency bodies have access to original 
source documentation to ensure data integrity. “Original” in this context is defined as the 
first documentation of an observation and does not differentiate between hard copy and 
electronic records.   
9.5.4. Retention of Study Documents 
Study-related records must be retained for at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region, or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.  These documents 
should be retained for a longer period, however, if required by applicable regulatory 
requirements or by an agreement with the sponsor. 
The investigator must not destroy any study-related records without receiving approval 
from the sponsor. The investigator must notify the sponsor in the event of accidental loss 


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or destruction of any study records. If the investigator leaves the institution where the study 
was conducted, the sponsor must be contacted to arrange alternative record storage options. 
10. ADMINISTRATIVE STRUCTURE OF THE STUDY 
Westat will be responsible for data management, statistical analyses, and clinical study 
report writing. Clinical monitors under the direction of Westat will be used to monitor the 
study. Clinical laboratory parameters will be assessed by local laboratories and results 
recorded in the CRF module.  


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11. REFERENCES
1. Fukui M, Inaba M, Tsukagoshi S, et al. New antitumor imidazole derivative, 5-
carbamoyl-l-H-imidazol-4-yl piperonylate, as an inhibitor of purine synthesis and its 
activation by adenine phosphoribosyltransferase. Cancer Res 1982; 42:1098-1102. 
2. Nakamura M, Furui M, Morisada S, et al. Antitumor activity of oral administered 4-
carbamoylimidazolium-5-olate (SM-108).4; Jap J Cancer and Chemo 1985; 
12(10):2030-2036. 
3. Nakamura M, Takada H, Fukui M, et al. Antiproliferative effect of 4-
carbamoylimidazolium-5-olate (SM-108) against human tumor cell lines. Proceedings 
44th General Meeting of Japanese Cancer Association 1984. 
4. Yoshida N, Nakamura M, Fukui M, et al. Optimal treatment schedule and antitumor 
spectrum of 4-carbamoylimidazolium-5-olate (SM-108) in murine tumors. Cancer Res 
1983; 43:5851-5856. 
5. Kimura K, Suzuoki Y, Ogawa M, Miyazaki T, Uzuka Y, Sakai Y, Ohno R, Yamada K, 
Ota K, Yoshida T, Masaoka T, Kimura I, Konno K, Niitani H, Yoshida S. Phase I study 
and early Phase II study for lung cancer of SM-108 (4-carbamoylimidazolium-5-olate). 
Jap J Cancer and Chemo 1989; 16(1):113-121.  
6. Teratological studies of SM-108 (FF-10501), summary of data on file, FUJIFILM, 
Japan. 
7. Kimura K, Yamada K, Uzuka Y, Masaoka T, Hirano M, Ohno R, Ogawa M. Phase II 
study of SM-108 (4-carbamoylimidazolium-5-olate) on hematologic malignancies. Jap 
J Cancer and Chemo 1989; 6(1):123-130. 
8. Kuwayama S. Induction of differentiation of myeloid leukemia cell lines by FF-10501-
01 – Evaluation of hemoglobin expression –. Fujifilm Corporation Pharmaceutical and 
Healthcare Research Laboratories final report (study no. FF-10501-A02), 2012. 
9. Kuwayama S. Induction of differentiation of myeloid leukemia cell lines by FF-10501-
01 – Evaluation of the expression of surface antigens CD235a and CD11b –. Fujifilm 
Corporation Pharmaceutical and Healthcare Research Laboratories final report (study 
no. FF-10501-A04), 2012. 
10. Kuwayama S. Growth inhibitory effect of FF-10501-01 on myeloid leukemia cell lines 
in vitro. Fujifilm Corporation Pharmaceutical and Healthcare Research Laboratories 
final report (study no. FF-10501-A03), 2011. 
11. Kuwayama S. Growth inhibitory effect of FF-10501-01 on a 5-azacytidine-resistant 
myeloid leukemia cell line in vitro. Fujifilm Corporation Pharmaceutical and 
Healthcare Research Laboratories final report (study no. FF-10501-A07), 2012. 
12. Murase M. Analysis of the action mechanism of FF-10501-01 (2) – Evaluation of 
IMPDH enzyme-inhibitory activity –. Fujifilm Corporation Pharmaceutical and 
Healthcare Research Laboratories final report (study no. FF-10501-A06), 2012. 
13. Murase M. Analysis of the action mechanism of FF-10501-01 (1) – Effect of FF-10501-
01 on intracellular GTP in human myeloid leukemia cell line, SKM-1 –. Fujifilm 


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Corporation Pharmaceutical and Healthcare Research Laboratories final report (study 
no. FF-10501-A05), 2012. 
14. Yamamoto M. Antitumor effects of FF-10501-01 in an SKM-1 cell-transplanted mouse 
model. Ina Research Inc. (study no. JL11170), 2012. 
15. Oishi K. PK study of FF-10501-01 in mice. Ina Research Inc. (study no. JL12064), 
2012. 
16. Fujisawa E. Pharmacokinetics after single administration of FF-10501-01 to rats —The 
effect of food intake and oral bioavailability – . Toyama Chemical Research 
Laboratories internal report (study no. 54_243), 2011. 
17. Uchida H. One-month repeated oral dose toxicity study of FF-10501-01 in rats 
followed by a 1-month recovery period. Mitsubishi Chemical Medience Corporation 
(study no. P110305), 2012. 
18. Uchida H. One-month repeated oral dose toxicity study of FF-10501-01 in dogs 
followed by a 1-month recovery period. Mitsubishi Chemical Medience Corporation 
(study no. P110306), 2012. 
19. Handa K. Tissue distribution of radioactivity in rat following a single oral 
administration of 14C-FF-10501-01. Toyama Chemical Research Laboratories internal 
report (study no. 54_233), 2012. 
20. Suzuki M. Whole-body autoradiography in rats after single oral administration of 14C-
FF-10501-01. Sekisui Medical Co., Ltd. ADME & Toxicology Research Institute 
(study no. AE-6691-G), 2011. 
21. Sakai N. Blood and plasma concentrations, tissue distribution, metabolism, and 
excretion of 14C-FF-10501-01 in male dogs after a single oral administration. 
Mitsubishi Chemical Medience Corporation Nonclinical Research Center (study no. 
B110574), 2011. 
22. Yoshida T. In vitro serum protein binding of 14C-FF-10501. Toyama Chemical 
Research Laboratories internal report (study no. 54_242), 2011. 
23. Nakagawa Y. The in vivo metabolic profiles of 14C-FF-10501 in rats –The metabolites 
in the plasma, urine, bile, and feces after a single oral administration of 14C- FF-10501-
01–. Toyama Chemical Research Laboratories internal report (study no. 54_234), 2011. 
24. Nozawa K. Structure elucidation of metabolites in rats and dogs after a single oral 
administration of 14C-FF-10501-01 by LC/MS/MS system. Sekisui Medical Co., Ltd. 
ADME & Toxicology Research Institute (study no. AE-6869-G), 2012. 
25. Sakai M. Inhibitory effects of FF-10501-01 and its metabolite FF-10501M1 on 
catalytic activities of human cytochrome P-450 isozymes. Toyama Chemical Research 
Laboratories internal report (study no. 54_263), 2012. 
26. Takahashi T. Excretion of radioactivity in the urine, feces, bile, and expired air 
following a single oral administration of 14C-FF-10501-01 to rats. Toyama Chemical 
Research Laboratories internal report (study no. 54_232), 2011. 


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27. Nojima N. Two-week repeated oral dose toxicity study of MBR-108 in rats (dose-
finding study). In-house Report in Research Laboratories, Toyama Chemical Co., Ltd., 
(study no. 57_121), 2011. 
28. Ogata H. Two-week intermittent oral dose toxicity study of FF-10501-01 in rats. 
Mitsubishi Chemical Medience Corporation (study no. P110682), 2012. 
29. Furubo S. Two-week repeated oral dose toxicity study of MBR-108 in beagle dogs 
(dose-finding study). In-house Report in Research Laboratories, Toyama Chemical Co., 
Ltd., (study no. 57_131), 2011. 
30. Mochizuki S. Bacterial reverse mutation test of FF-10501-01. In-house Report in 
Research Laboratories, Toyama Chemical Co., Ltd., (study no.: Z7), 2011. 
31. Kito N. Chromosomal aberration test of FF-10501-01 in cultured mammalian cells. In-
house Report in Research Laboratories, Toyama Chemical Co., Ltd., (study no.: Z8), 
2011. 
32. Yamamoto Y. Quality test of FF-10501-01 (lot no. 55T-2-100401, at the time of 
manufacture). In-house Report in Research Laboratories, Toyama Chemical Co., Ltd., 
(study no. Z1), 2010. 
33. Miyazaki Y, Iwamura H. Interim Japanese Phase I Study Report, Toyama Chemical 
Co., Ltd., FUJIFILM Group, (study no. FF1050101JP101), data on file as of October 
28, 2015. 
34. Greenberg P, Cox C, LeBeau M, Fenaux P, et al. International scoring system for 
evaluating prognosis in myelodysplastic syndromes. Blood 1997; 89(6): 2079-2088. 
35. Greenberg P, Tuechler H, Schanz J, et al. Revised International Prognostic Scoring 
System (IPSS-R) for myelodysplastic syndromes. Blood 2012; 120(12): 2454-2465.  
36. Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, et al. 
Revised recommendations of the International Working Group for Diagnosis, 
Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards 
for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol 2003; 21(24):4642-
4649. 
37. Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal for 
modification of the International Working Group (IWG) response criteria in 
myelodysplasia. Blood 2006; 108(2): 419-425. 
 


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Appendix A. Number of Tablets to be Administered Per Dose Level 
Dose Level 50 mg/m2 BID 
Body Surface 
Area (m2) 
Total mg each Dose  
Number Tablets Each 
Dose (50 mg) 
Number Tablets Each 
Dose (200 mg)  
≤ 2.00 
100  
2 
0 
2.01 – 3.49 
150 
3 
0 
≥ 3.5 
200 
0 
1 
 
Dose Level 100 mg/m2 BID 
Body Surface 
Area (m2) 
Total mg each Dose  
Number Tablets Each 
Dose (50 mg) 
Number Tablets Each 
Dose (200 mg)  
≤ 1.50 
150  
3 
0 
1.51 – 2.00 
200 
0 
1 
≥ 2.01 
250 
1 
1 
 
Dose Level 200 mg/m2 BID 
Body Surface 
Area (m2) 
Total mg each Dose  
Number Tablets Each 
Dose (50 mg) 
Number Tablets Each 
Dose (200 mg)  
≤ 1.25 
250  
1 
1 
1.26 – 1.62 
300  
2 
1 
1.63 – 1.87 
350 
3 
1 
1.88 – 2.12 
400 
0 
2 
≥ 2.13 
450 
1 
2 
 
Dose Level 300 mg/m2 BID 
Body 
Surface Area 
(m2) 
Total mg each Dose  
Number Tablets Each 
Dose (50 mg) 
Number Tablets Each 
Dose (200 mg) 
≤ 1.37 
400 
0 
2 
1.38 – 1.51 
450 
1 
2 
1.52 – 1.65 
500 
2 
2 
1.66 – 1.77 
550 
3 
2 
1.78 – 2.05 
600 
0 
3 
2.06 – 2.17 
650 
1 
3 
≥ 2.18 
700 
2 
3 
 
 
 
 
 
 
 
 


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Dose Level 400 mg/m2 BID 
Body 
Surface Area 
(m2) 
Total mg each Dose  
Number Tablets Each 
Dose (50 mg) 
Number Tablets Each 
Dose (200 mg) 
≤ 1.25 
500  
2 
2 
1.26 – 1.37 
550 
3 
2 
1.38 – 1.51 
600 
0 
3 
1.52 – 1.65 
650 
1 
3 
1.66 – 1.77 
700 
2 
3 
1.78 – 1.91 
750 
3 
3 
1.92 – 2.05 
800 
0 
4 
2.06 – 2.17 
850 
1 
4 
≥ 2.18 
900 
2 
4 
 
 


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Appendix B. FF-10501-01 Dosing Delays and Dose Modifications 
Toxicity  
CTCAE Grade 
During a Course of Therapy 
Dose Adjustment for Next Treatment, (mg/m2) BID* (%) 
 
 
50 
100 
200 
300 
400 
Grade 1 
Maintain dose level 
 
Grade 2 
-1st occurrence 
 
-2nd occurrence 
 
-3rd occurrence 
 
-4th occurrence 
 
Interrupt until resolved to Grade 0-1 
 
Interrupt until resolved to Grade 0-1 
 
Interrupt until resolved to Grade 0-1 
 
Discontinue treatment permanently 
OR dose reduce (200 – 400 mg/m2 
BID dose groups only) 
 
50 (100%) 
 
- 
 
- 
 
- 
 
 
100 (100%) 
  
50 (50%) 
 
- 
 
- 
 
200 (100%) 
 
150 (75%) 
 
100 (50%) 
 
50 (25%) 
 
300 (100%) 
 
225 (75%) 
 
150 (50%) 
 
  75 (25%) 
 
400 (100%) 
 
300 (75%) 
 
200 (50%) 
 
100 (25%) 
Grade 3 
-1st occurrence 
 
-2nd occurrence 
 
-3rd occurrence 
 
Interrupt until resolved to Grade 0-1 
 
Interrupt until resolved to Grade 0-1 
 
Discontinue treatment permanently 
OR dose reduce (200 – 400 mg/m2 
BID dose groups only) 
 
- 
 
- 
 
- 
 
50 (50%) 
 
- 
 
- 
 
150 (75%) 
100 (50%) 
  50 (25%) 
 
225 (75%) 
150 (50%) 
 75 (25%) 
 
300 (75%) 
200 (50%) 
100 (25%) 
Grade 4 
-1st occurrence 
 
Discontinue permanently, OR, if 
physician deems it to be in the 
subject’s best interest to continue, 
interrupt and/or dose reduce until 
resolved to Grade 0-1  
(200 – 400 mg/m2 dose groups only) 
 
- 
 
- 
 
100 (50%) 
  
50 (25%) 
 
150 (50%) 
 
75 (25%) 
 
200 (50%) 
 
100 (25%) 
*Round up calculated unit dose to next unit dose based on tablet dose strength 


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Appendix C. Drugs Known to Prolong QT Interval or Induce Torsades de Pointes 
 
The last revision date: November 2, 2016 
 
Generic Name 
Brand Names (Partial 
List) 
Drug Class 
Therapeutic Use 
Amiodarone 
Cordarone, 
Pacerone, 
Nexterone 
Antiarrhythmic 
Abnormal heart 
rhythm 
Anagrelide 
Agrylin, Xagrid 
Phosphodiesterase 3 
inhibitor 
Thrombocythemia 
Arsenic trioxide 
Trisenox 
Anticancer 
Cancer (leukemia) 
Astemizole (Removed from 
Market) 
Hismanal 
Antihistamine 
Allergic rhinitis 
Azithromycin 
Zithromax, Zmax 
Antibiotic 
Bacterial infection 
Bepridil (Removed from Market) 
Vascor 
Antianginal 
Angina Pectoris 
(heart pain) 
Chloroquine 
Aralen 
Antimalarial 
Malaria 
Chlorpromazine 
Thorazine, 
Largactil, 
Megaphen 
Antipsychotic / 
Antiemetic 
Schizophrenia, 
nausea, many others 
Cilostazol 
Pletal 
Phosphodiesterase 3 
inhibitor 
Intermittent 
claudication 
Ciprofloxacin 
Cipro, Cipro-XR, Neofloxin 
Antibiotic 
Bacterial infection 
Cisapride (Removed from 
Market) 
Propulsid 
GI stimulant 
Increase GI motility 
Citalopram 
Celexa, Cipramil 
Antidepressant, SSRI 
Depression 
Clarithromycin 
Biaxin, Prevpac 
Antibiotic 
Bacterial infection 
Cocaine 
Cocaine 
Local anesthetic 
Anesthesia (topical) 
Disopyramide 
Norpace 
Antiarrhythmic 
Abnormal heart 
rhythm 
Dofetilide 
Tikosyn 
Antiarrhythmic 
Abnormal heart 
rhythm 
Domperidone (Only on Non US 
Market) 
Motilium, Motillium, 
Motinorm Costi, Nomit 
Antinausea 
Nausea, vomiting 
CredibleMeds Known QTDrug List 


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Generic Name 
Brand Names (Partial 
List) 
Drug Class 
Therapeutic Use 
Donepezil 
Aricept 
Cholinesterase 
inhibitor 
Dementia 
(Alzheimer's 
Dronedarone 
Multaq 
Antiarrhythmic 
Abnormal heart 
rhythm 
Droperidol 
Inapsine, Droleptan, 
Dridol, Xomolix 
Antipsychotic / 
Antiemetic 
Anesthesia (adjunct), 
nausea 
Erythromycin 
E.E.S., Robimycin, EMycin, 
Erymax, Ery-Tab, Eryc 
Ranbaxy, Erypar, Eryped, 
Erythrocin Stearate 
Filmtab, Erythrocot, E-
Base, Erythroped, Ilosone, 
MY-E, Pediamycin, Zineryt, 
Abboticin, Abboticin-ES, 
Erycin, PCE Dispertab, 
Stiemycine, Acnasol, 
Tiloryth 
Antibiotic 
Bacterial infection, 
increase GI motility 
Escitalopram 
Cipralex, Lexapro, Nexito, 
Anxiset-E (India), Exodus 
(Brazil), Esto (Israel), 
Seroplex, Elicea, Lexamil, 
Lexam, Entact (Greece), 
Losita (Bangladesh), 
Reposil (Chile), Animaxen 
(Colombia), Esitalo 
(Australia), Lexamil (South 
Africa) 
Antidepressant, SSRI 
Depression (major), 
anxiety disorders 
Flecainide 
Tambocor, Almarytm, 
Apocard, Ecrinal, Flécaine 
Antiarrhythmic 
Abnormal heart 
rhythm 
Fluconazole 
Diflucan, Trican 
Antifungal 
Fungal infection 
Gatifloxacin (Removed from 
Market) 
Tequin 
Antibiotic 
Bacterial infection 
Grepafloxacin (Removed from 
Market) 
Raxar 
Antibiotic 
Bacterial infection 
Halofantrine 
Halfan 
Antimalarial 
Malaria 


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Generic Name 
Brand Names (Partial 
List) 
Drug Class 
Therapeutic Use 
Haloperidol 
Haldol (US & UK), 
Aloperidin, Bioperidolo, 
Brotopon, Dozic, 
Duraperidol (Germany), 
Einalon S, Eukystol, 
Halosten, Keselan, Linton, 
Peluces, Serenace, 
Serenase, Sigaperidol 
Antipsychotic 
Schizophrenia, 
agitation 
Ibogaine (Only on Non US Market) 
None 
Psychedelic 
Narcotic, 
addiction, 
unproven 
Ibutilide 
Corvert 
Antiarrhythmic 
Abnormal heart 
rhythm 
Levofloxacin 
Levaquin, Tavanic 
Antibiotic 
Bacterial infection 
Levomepromazine (Only on Non 
US Market) 
Nosinan, Nozinan, 
Levoprome 
Antipsychotic 
Schizophrenia 
Levomethadyl acetate (Removed 
from Market) 
Orlaam 
Opioid agonist 
Narcotic dependence 
Levosulpiride (Only on Non US 
Market) 
Lesuride, Levazeo, Enliva 
(with rabeprazole) 
Antipsychotic 
Schizophrenia 
Mesoridazine (Removed from 
Market) 
Serentil 
Antipsychotic 
Schizophrenia 
Methadone 
Dolophine, Symoron, 
Amidone, Methadose, 
Physeptone, Heptadon 
Opioid agonist 
Narcotic dependence, 
pain 
Moxifloxacin 
Avelox, Avalox, Avelon 
Antibiotic 
Bacterial infection 
Ondansetron 
Zofran, Anset, Ondemet, 
Zuplenz, Emetron, 
Ondavell, Emeset, 
Ondisolv, Setronax 
Antiemetic 
Nausea, vomiting 
Oxaliplatin 
Eloxatin 
Antineoplastic Agent 
Cancer 
Papaverine HCl (Intra-
coronary) 
none 
Vasodilator, Coronary 
Diagnostic adjunct 
Pentamidine 
Pentam 
Antifungal 
Fungal infection 
(Pneumocystis 
pneumonia) 


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Generic Name 
Brand Names (Partial 
List) 
Drug Class 
Therapeutic Use 
Pimozide 
Orap 
Antipsychotic 
Tourette's Disorder 
Probucol (Removed from 
Market) 
Lorelco 
Antilipemic 
Hypercholesterolemia 
Procainamide 
Pronestyl, Procan 
Antiarrhythmic 
Abnormal heart 
rhythm 
Propofol 
Diprivan,  Propoven 
Anesthetic, general 
Anesthesia 
Quinidine 
Quinaglute, Duraquin, 
Quinact, Quinidex, Cin-
Quin, Quinora 
Antiarrhythmic 
Abnormal heart 
rhythm 
Roxithromycin (Only on Non US 
Market) 
Rulide, Xthrocin, Roxl-
150, Roxo, Surlid, Rulide, 
Biaxsig, Roxar, 
Roximycinv, Roxomycin, 
Rulid, Tirabicin, Coroxin 
Antibiotic 
Bacterial infection 
Sevoflurane 
Ulane, Sojourn 
Anesthetic, general 
Anesthesia 
Sotalol 
Betapace, Sotalex, Sotacor Antiarrhythmic 
Abnormal heart 
rhythm 
Sparfloxacin (Removed from 
Market) 
Zagam 
Antibiotic 
Bacterial infection 
Sulpiride (Only on Non US 
Market) 
Dogmatil, Dolmatil, 
Eglonyl, Espiride, 
Antipsychotic, atypical 
Schizophrenia 
Sultopride (Only on Non US 
Market) 
Barnetil,  Barnotil,  Topral 
Antipsychotic, atypical 
Schizophrenia 
Terfenadine (Removed from 
Market) 
Seldane 
Antihistamine 
Allergic rhinitis 
Terlipressin  (Only on Non US 
Market) 
Teripress, Glypressin, 
Terlipin, Remestyp, Tresil, 
Teriss and others 
Vasoconstrictor 
Septic shock 
Thioridazine 
Mellaril, Novoridazine, 
Thioril 
Antipsychotic 
Schizophrenia 
Vandetanib 
Caprelsa 
Anticancer 
Cancer (thyroid) 
 


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Appendix D. Schedule of Study Procedures 
 
 
Study Activity 
Screeninga 
Treatment Cycle 1 
Treatment Cycles after Cycle 1 
Progression 
or Relapse 
End of 
Studyo 
Long-Term 
Follow-Upp 
Day 
1 
Day 
8k 
Day 
15k 
Day 
22k 
End of 
Cycle 1l 
 
Day 1m 
End of 
Cycle 3n 
 
 
 
Signed ICD 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Physical 
examination 
X 
Xj 
 
 
 
 
Xj 
 
 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
ECOG Performance 
Status 
X 
X 
 
 
 
 
X 
 
 
X 
 
Height  
X 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
X 
 
 
X 
 
Hematologyb 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
Serum chemistryc 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
Urinalysisd 
X 
X 
 
 
 
 
X 
 
 
X 
 
Beta-hCG for WCBP 
X 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
Xe 
 
Xe 
 
 
Xe 
 
 
X 
 
Concomitant 
medications 
X 
Continuous 
 
Adverse Event 
assessment 
 
Continuous 
 
Bone Marrow 
Aspiratef 
X 
 
 
 
 
X 
 
X 
X 
 
 
Disease Response 
Assessmentg 
X 
 
 
 
 
X 
 
X 
X 
 
 
Peripheral blood for 
PK assessmenth 
 
X 
 
X 
 
 
 
 
 
 
 
Peripheral blood for 
PD (XMP) 
assessmenth 
 
X 
 
X 
 
 
 
 
 
 
 
Administration of  
FF-10501-01i 
 
BID x 21 days 
 
 
 
BID x 21 days 
 
 
 
Assessment of 
survival  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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a Screening to be performed within 28 days of Cycle 1, Day 1 
b Hematology collected at Screening, Days 1, 8, 15 and 22 of Cycle 1, Day 1 of each subsequent cycle (within 3 days of Day 1 of each subsequent cycle) and End of Study. See Table 
7 for tests to be conducted at each time point. 
c Serum chemistry collected at Screening, Days 1, 8, 15 and 22 of Cycle 1, Day 1 of each subsequent cycle (within 3 days of Day 1 of each subsequent cycle) and End of Study. See 
Table 7 for tests to be conducted at each time point. 
d Urinalysis collected at Screening, Day 1 of Cycle 1, Day 1 of each subsequent cycle (within 3 days of Day 1 of each subsequent cycle) and End of Study. See Table 7 for tests to be 
conducted at each time point. 
e ECGs performed pre-dose and approximately 3 hours post-dose (following morning dose only)  
f Bone marrow aspirate required at Screening; at end of Cycles 1 and 3, every 2 cycles thereafter, and at relapse/progression, unless peripheral blood absolute count is ≥ 5.0 x 109 
cells/L. See Table 7 for tests to be conducted at each time point. 
g Disease Response Assessment may include bone marrow assessment, hematology for blood counts, physical exam, etc.  
h Subjects on the 21-day dosing schedules: Peripheral blood collected in heparin for PK and PD assessment at Cycle 1, Day 1 pre-dose (any time), between 0.5-1 hr post-dose, and 
between 2-4 hr post-dose, and Cycle 1 Day 15 pre-dose (within 15 min prior to dosing), 0.5-1 hr post-dose, and 2-4 hr post-dose.  
i Subjects on 21-day schedule, dose BID daily x 21 days each 28-day cycle 
j Abbreviated physical exam 
k Day 8, 15, or 22 +/- 1 day, except for pre-dose procedures for the cycle (e.g., ECG)  
l Day 28 +/- 3 days  
m Day 1 +/- 3 days except, for pre-dose procedures for the cycle (e.g., ECG)  
n And every 2 cycles thereafter  
o End of Study (Safety) visit should be 28 days from last dose of study medication (+/- 5 days) 
p Long-term follow-up for 6 months consists of clinic visits or telephone calls every 3 months to assess survival status 
 
 
 


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Appendix E. Ethical Standards 
 
Ethics and Regulatory Considerations 
This study will be conducted according to Good Clinical Practice (GCP), US 21 Code of 
Federal Regulations (CFR) Part 50, (Protection of Human Subjects), US 21 CFR Part 56 
(Institutional Review Boards), International Conference on Harmonisation Guidance for 
Industry, E6 Good Clinical Practice:  Consolidated Guidance, the Nuremberg Code, and 
the Declaration of Helsinki. 
 
General Instructions 
The U.S. Food and Drug Administration (FDA) regulates studies of drugs, biologics, and 
medical devices.  Consequently, these studies are subject to GCP and FDA regulations and 
guidance issued by the FDA and are included in, but not limited to, the following parts of 
the CFR and guideline document: 
 
• 21 CFR Part 11 – Electronic Records; electronic signatures  
• 21 CFR Part 50 – Protection of Human Subjects 
• 21 CFR Part 54 – Financial Disclosure 
• 21 CFR Part 56 – Institutional Review Boards 
• 21 CFR Part 312 – Investigational New Drug Application 
• FDA Guidance for Industry: Oversight of Clinical Investigations —A Risk-Based 
Approach to Monitoring, August 2013 
• FDA Guidance for IRBs, Clinical Investigators, and Sponsors, June 2010  
• FDA Guidance for Industry: Investigator Responsibilities – Protecting the Rights, 
Safety, and Welfare of Study Subjects, October 2009 
• FDA Guidance for Industry and Investigators: Safety Reporting Requirements for 
INDs and BA/BE studies, December 2012 
• Guidance for Industry E6 Good Clinical Practice: Consolidated Guidance, 1996 
 
Copies of these materials are available from the sponsor upon request.  The purpose of 
these regulations and legal obligations is to define the standards and principles for the 
proper conduct of clinical trials that have been developed by the medical, scientific, and 
regulatory communities.  They are not intended to impede or restrict clinical research. 
 
The ethical standards defined within GCP are intended to ensure that: 
 
• Human subjects are provided with an adequate understanding of the possible risks 
of their participation in the study, and that they have a free choice to participate or 
not; 
• The study is conducted with diligence and in conformance with the protocol in such 
a way as to insure the integrity of the findings; 
• The potential benefits of the research justify the risks. 
 


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FPHU is the sponsor of the Investigational New Drug Application (IND).  The sponsor, or 
designee, if regulatory obligations have been transferred, is responsible for the following: 
• Selecting qualified investigators, 
• Providing investigators with the information they need to properly conduct an 
investigation, 
• Ensuring proper monitoring of the investigation, 
• Ensuring that the study is conducted according to the general investigational plan 
and protocols contained in the IND, 
• Maintaining the IND, and  
• Ensuring that FDA and all participating investigators are properly informed of 
significant new information regarding adverse effects or risks associated with the 
drug being studied. 


Protocol No. FF1050101US101  
 
 
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Appendix F. Investigator Obligations 
Per Title 21 of the US Government Code of Federal Regulations (21 CFR) Parts 50 and 56, 
the study protocol and the final version of the subject informed consent form will be 
approved by the institutional review board (IRB) before enrollment of any subjects.  The 
opinion of the IRB will be dated and given in writing. A copy of the letter of approval from 
the IRB and a copy of the approved informed consent form will be received by the sponsor 
prior to shipment of study medication supplies to the investigator. 
The investigator will ensure that the IRB will be promptly informed of all changes in the 
research activity and of all unanticipated problems including risk to subjects. The 
investigator will also ensure that no changes will be made to the protocol without IRB 
approval. 
As a part of the IRB requirement for continuing review of approved research, the 
investigator will be responsible for submitting periodic progress reports to the IRB at 
intervals appropriate to the degree of subject risk involved, but no less than once per year. 
Written informed consent must be given freely and obtained from every subject prior to 
clinical trial participation. The rights, safety, and well-being of the trial subjects are the 
most important considerations and should prevail over interests of science and society. 
As described in GCP guidelines and FDA regulations, study personnel involved in 
conducting this trial will be qualified by education, training, and experience to perform 
their respective task(s). A FDA Form 1572 will be collected, listing the principal 
investigator and sub-investigators involved in the study. Study personnel will not include 
individuals against whom sanctions have been invoked after scientific misconduct or fraud 
(e.g., loss of medical licensure, debarment). Quality assurance systems and procedures will 
be implemented to assure the quality of every aspect of the study. 
Protection of Human Subjects (21 CFR Part 50)   
Informed consent must be obtained from every subject before entry into a clinical study.  
It must be given freely and not under duress. Consent must be documented by use of an 
IRB-approved consent form and signed by the subject or the subject’s legally authorized 
representative. The Department of Health and Human Services suggests that when minors 
are involved, a parent or guardian should sign the consent form. If the minor is an 
adolescent, his signature should also be included. Non-English-speaking subjects must be 
presented with a consent form written in a language that they understand.  A copy of the 
signed consent form must be given to the subject signing it. Another copy must be kept in 
the investigator’s files and made available to and FDA representatives upon request. If, for 
any reason, subject risk is increased as the study progresses, a revised, IRB-approved 
consent form must be signed by the subject. Before the study begins, a sample of the 
consent form must be provided to the sponsor for review. The FDA may reject otherwise 
scientifically valid studies if proper informed consent has not been obtained from all 
subjects. 
Only in the case of a life-threatening incident may an investigational product be used 
without prior signed consent. In such an emergency situation, separate certifications must 
be written both by a physician not participating in the study and by the investigator. The 
certifications, along with the protocol and informed consent, must be sent to the IRB within 


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5 working days. In this situation, the investigator may not administer any subsequent 
product to that subject until informed consent and IRB approval are obtained. 
Informed Consent 
Written informed consent must be obtained from each subject prior to entry in the study.  
One copy of the signed informed consent document will be given to the subject, and another 
will be retained by the investigator. Additionally, the participant must be allowed adequate 
time to consider the potential risks and benefits associated with his/her participation in the 
study. The signed and dated consent must be retained with the study records and a copy 
provided to each participant. 
In situations where the participant is not legally competent to provide consent 
(i.e., mentally incapacitated), written consent must be obtained from a parent, legal 
guardian, or legal representative. In these situations, the consent must be signed and dated 
by a witness. 
The informed consent document must have been reviewed and approved by the sponsor 
and by the investigator’s IRB prior to the initiation of the study. The document must 
contain the eight basic elements of informed consent and may contain the six additional 
elements described in 21 CFR Part 50. The attached Declaration of Helsinki-provides 
further details regarding the specific requirements for informed consent. Every consent 
form must include the following eight elements: 
• A statement that the study involves research, an explanation of the purpose of the 
research and the expected duration of the subject’s participation, a description of 
the procedures to be followed, and identification of any procedures that are 
experimental 
• A description of any reasonably foreseeable risks or discomforts to the subject 
• A description of any benefits to the subject or to others that may reasonably be 
expected from the research 
• A disclosure of appropriate alternative procedures or course of treatment, if any, 
that might be advantageous to the subject 
• A statement describing the extent, if any, to which confidentiality of records 
identifying the subject will be maintained and noting the possibility that the FDA 
and representatives may inspect the records 
• An explanation as to whether any compensation or medical treatments are available 
if injury occurs for research involving more than minimal risk.  The explanation 
should involve a description of the compensation or treatment available, or a 
statement describing where further information may be obtained 
• An explanation of whom to contact for answers to pertinent questions about the 
research and the subject’s rights and whom to contact in the event of a 
research-related injury 
• A statement that participation is voluntary, that refusal to participate will involve 
no penalty or loss of benefits to which the subject is otherwise entitled, and that the 


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subject may discontinue participation at any time without penalty or loss of benefits 
to which the subject is otherwise entitled. 
 
Additional Elements of Informed Consent 
When appropriate, one or more of the following elements of information shall also be 
included in the consent form: 
• A statement that the particular treatment or procedure may involve risks to the 
subject (or to the embryo or fetus, if the subject is or may become pregnant) which 
are currently unforeseeable 
• Anticipated circumstances under which the subject’s participation may be 
terminated by the investigator without regard to the subject’s consent 
• Any additional costs the subject may incur from participation in the research 
• The consequences of a subject’s decision to withdraw from the research and 
procedures for orderly termination of participation by the subject 
• A statement that significant new findings developed during the course of the 
research that may relate to the subject’s willingness to continue participation will 
be provided to the subject 
• The approximate number of subjects involved in the study 
Nothing in these regulations is intended to limit the authority of a physician to provide 
emergency medical care to the extent the physician is permitted to do so under applicable 
federal, state, or local laws. 
The informed consent requirements in these regulations are not intended to preempt any 
applicable federal, state, or local laws that require additional information to be disclosed in 
order that informed consent be legally effective.  Some states, such as California and 
Oregon, require further action on the investigator’s part concerning subject consent. 
Institutional Review Board (IRB) Ethic Review Committee (ERC) Review/Approval 
The protocol and informed consent for this study, including advertisements used to recruit 
participants, must be reviewed and approved by an appropriate IRB/ERC prior to 
enrollment of participants in the study. It is the responsibility of the investigator to assure 
that all aspects of the ethical review are conducted in accordance with the current 
Declaration of Helsinki, International Conference on Harmonization (ICH) Good Clinical 
Practices, and/or local laws, whichever provide the greatest level of protection. A letter 
documenting the IRB/ERC approval which specifically identifies the study/protocol and a 
list of the committee members must be received by the sponsor prior to initiation of the 
study.  Amendments to the protocol will be subject to the same requirements as the original 
protocol. 
A progress report with a request for re-evaluation and re-approval will be submitted by the 
investigator to the IRB/ERC at intervals required by the IRB/ERC, and not less than 
annually. A copy of the report will be sent to the sponsor.   


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When the sponsor provides the investigator with a Safety Report, the investigator must 
promptly forward a copy to the IRB/ERC. 
After completion or termination of the study, the investigator will submit a final report to 
the IRB/ERC and to the sponsor, if required. This report should include: deviations from 
the protocol, the number and types of participants evaluated, the number of participants 
who discontinued (with reasons), results of the study, if known, and significant AEs, 
including deaths 
Study Files  
The investigator is required to maintain complete and accurate study documentation in 
compliance with current Good Clinical Practice standards and all applicable federal, state, 
and local laws, rules, and regulations related to the conduct of a clinical study.  
Patient Confidentiality 
The anonymity of participating subjects must be maintained. Subjects will be identified by 
their initials and an assigned subject number on CRFs and other documents submitted to 
the clinical monitor. Documents that will be submitted to the clinical monitor and that 
identify the subject (e.g., the signed informed consent document) must be maintained in 
strict confidence by the principal investigator, except to the extent necessary to allow 
auditing by the FDA, the clinical monitor, or sponsor personnel. 
Investigational Product Accountability 
The investigator or designee is responsible for accountability of the investigational product 
at the site. The investigator or designee must maintain records of the product’s delivery to 
the site, inventory at the site, use by each subject, and return to the sponsor or alternative 
disposition of any unused product. These records must include dates, quantities, 
batch/serial/lot numbers, and expiration dates (if applicable). 
The investigator should ensure that the investigational product is used only in accordance 
with the protocol.   
 
 
 

SAP_001.pdf: 
FUJIFILM Pharmaceuticals U.S.A., Inc. 
   
FF1050101US101 
 
 
A Phase 1/2a, Dose-escalation Study of FF-10501-01 for the 
Treatment of Advanced Hematologic Malignancies 
    
 
 
Statistical Analysis Plan 
 
 
September 4, 2018 
 
Version 3.2 
 
 
 
 
 
Prepared By: 
Ken Gerald & Judy Chen 
Biostatisticians 
 
 
Westat 
5615 Kirby Drive, Suite 710 
Houston, TX 77005 
 
 
 
CONFIDENTIAL 
 
 
CONFIDENTIAL
3486


Table of Contents 
 
1. 
Project Overview ........................................................................................................... 5 
1.1. Project Design ........................................................................................................... 5 
1.2. Objectives .................................................................................................................. 5 
1.2.1. Primary Objective .............................................................................................. 5 
1.2.2. Secondary Objective .......................................................................................... 5 
1.3. Treatment(s) .............................................................................................................. 6 
1.3.1. Treatment Assignments ...................................................................................... 6 
1.3.2. Selection and Timing of Doses .......................................................................... 6 
1.4. Procedures ................................................................................................................. 7 
1.4.1. Subject Identification ......................................................................................... 7 
1.4.2. Randomization ................................................................................................... 7 
1.4.3. Blinding/Unblinding ........................................................................................... 7 
1.4.4. Replacement ....................................................................................................... 7 
1.4.5. Data Monitoring ................................................................................................. 8 
2. 
Statistical Analysis Considerations ............................................................................... 8 
2.1. Sample Size and Power ............................................................................................. 8 
2.2. Analysis Populations ................................................................................................. 8 
2.2.1. Full Analysis Set (FAS) Population ................................................................... 8 
2.2.2. Randomized Population ..................................................................................... 8 
2.2.3. Per Protocol Set (PPS) Population ..................................................................... 8 
2.2.4. Safety Population ............................................................................................... 9 
2.2.5. PK/PD Population .............................................................................................. 9 
2.3. Data Handling ........................................................................................................... 9 
2.3.1. Measurement Times ........................................................................................... 9 
2.3.1.1. Visit Windows ............................................................................................. 9 
2.3.1.2. Baseline Values ........................................................................................... 9 
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2.3.2. Missing Data Conventions ................................................................................. 9 
2.3.3. Imputation of Incomplete Dates ......................................................................... 9 
2.4. Statistical Methods .................................................................................................. 10 
2.4.1. General Overview and Plan of Analysis .......................................................... 10 
2.4.2. Hypothesis Testing ........................................................................................... 10 
2.4.3. Modeling .......................................................................................................... 10 
2.4.4. Multiplicity Issues/Multiple Comparisons ....................................................... 10 
2.4.5. Project Center Effects ....................................................................................... 10 
2.4.6. Interim Analysis ............................................................................................... 10 
2.4.7. Pharmacokinetic and Pharmacodynamic Analyses .......................................... 10 
3. 
Statistical Analysis ...................................................................................................... 10 
3.1. Enrollment and Disposition of Subjects .................................................................. 10 
3.2. Baseline Characteristics .......................................................................................... 11 
3.2.1. Demographic .................................................................................................... 11 
3.2.2. Physical Characteristics .................................................................................... 11 
3.2.3. Disease Characteristics ..................................................................................... 11 
3.3. Analysis of Efficacy ................................................................................................ 12 
3.3.1. Primary Endpoints ............................................................................................ 12 
3.3.2. Secondary Endpoints ........................................................................................ 12 
3.3.3. Exploratory/Other Analyses ............................................................................. 12 
3.4. Analysis of Safety and Tolerability ......................................................................... 12 
3.4.1. Study Drug Administration .............................................................................. 12 
3.4.2. Adverse Events ................................................................................................. 13 
3.4.3. Clinical Laboratory Results .............................................................................. 13 
3.4.4. Vital Signs ........................................................................................................ 13 
3.4.5. Physical/Other Examinations ........................................................................... 13 
3.4.6. Treatment Discontinuation, Project Termination, and Death ........................... 14 
4. 
Proposed Summary Tables, Graphs and Listings........................................................ 14 
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4.1. Mock Tables ............................................................................................................ 14 
4.1.1. Subject Disposition .......................................................................................... 14 
4.1.2. Demographics and Baseline Characteristics .................................................... 14 
4.1.3. Prior and Concomitant Medication .................................................................. 14 
4.1.4. Primary Efficacy Summaries............................................................................ 14 
4.1.5. Secondary Efficacy Summaries ........................................................................ 14 
4.1.6. Safety Summaries ............................................................................................. 14 
4.1.6.1. Study Drug Administration ....................................................................... 14 
4.1.6.2. Adverse Events Summaries ....................................................................... 14 
4.1.6.3. Laboratory Assessments ............................................................................ 15 
4.1.6.4. Other Safety Summaries ............................................................................ 15 
4.2. Mock Graphs ........................................................................................................... 15 
4.3. Mock Listings .......................................................................................................... 15 
 
 
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1.  Project Overview 
1.1. Project Design  
 
(Protocol Amendment #7). This is a Phase 1/2a, dose-escalation study of FF-10501-01 for the 
treatment of advanced hematologic malignancies. A total of up to N=68 subjects will be enrolled 
in the study. Subjects with acute myelogenous leukemia (AML), myelodysplastic syndrome 
(MDS), and chronic myelomonocytic leukemia (CMML) will be included. The accrual phase for 
the Phase 1 dose escalation phase is expected to be 12-18 months. The expected accrual for the 
Phase 2a expansion phase is expected to be 6-12 months, with the last subject followed up to 6 
months, for a total study duration of 30-36 months. The anticipated accrual rate is 4 – 5 subjects 
per month. 
 
During the study, a Safety Review Committee, consisting of the actively recruiting investigators, 
the Medical Monitor, and FUJIFILM Pharmaceuticals U.S.A., Inc. (FPHU), will review data from 
each cohort on an ongoing basis. 
 
Subjects who demonstrate objective response (OR) or stable disease (SD) will be allowed to 
continue therapy with FF-10501-01 until progression of disease, observation of unacceptable 
adverse events, intercurrent illness or changes in the subject’s condition that prevents further study 
participation. 
 
Safety will be assessed through the monitoring of adverse events (AEs), clinical laboratory 
parameters (hematology, serum chemistry), vital sign measurements, electrocardiograms (ECGs) 
and physical examinations.  
 
Efficacy assessment for AML will be performed using a modification of the recommendations of 
the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment 
Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. Efficacy 
assessments for subjects with MDS or CMML will be performed using a modification of the 
International Working Group Response Criteria in Myelodysplasia. Efficacy assessments for any 
subject may be performed at other time points at the discretion of the investigator. 
 
Pharmacokinetic determinations will be performed. XMP will be determined in peripheral blood 
as a pharmacodynamics endpoint. Details of the PK analysis will be outlined in a separate 
Pharmacokinetic Report Analysis Plan.  
1.2. Objectives 
1.2.1. Primary Objective 
To determine the safety and tolerability in subjects who receive FF-10501-01 for the 
treatment of advanced hematologic malignancies. 
1.2.2. Secondary Objective 
 
 
To determine the overall response rates 
 
To evaluate the proportion of subjects who achieve hematologic improvement in 
peripheral blood or bone marrow blast count 
 
To evaluate progression-free survival (PFS) 
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 
To evaluate overall survival (OS) 
 
To evaluate the pharmacokinetics of FF-10501 and M1 
 
To evaluate xanthosine monophosphate (XMP) as a pharmacodynamic marker 
1.3. Treatment(s) 
1.3.1. Treatment Assignments 
 
Phase 1:  
 
14-day Schedule: Following Screening, a total of 6 cohorts of 3 subjects each received oral 
doses of 50, 100, 200, 300, 400 or 500 mg/m2 BID per day (100, 200, 400, 600, 800 or 1000 
mg/m2/day) for 14 days, followed by 14 days off, repeated every 28 days (= 1 cycle). Three 
events of drug-related atrial fibrillation (Grade 2) were reported in 2 subjects at a dose of 500 
mg/m2 BID (Cohort 6). Study drug was suspended in both subjects and all events resolved 
with oral metoprolol treatment. These events were medically important events and thus met 
the definition of dose-limiting toxicity (DLT). No further enrollment was made at this dose 
level. The maximally tolerated dose (MTD) was declared at 1 dose level below the dose 
eliciting DLT, 400 mg/m2 BID, and this cohort was expanded to 6 subjects. No DLTs were 
observed in N=7 total subjects treated at 400 mg/m2 BID x 14 days. 
 
21-day Schedule: At the MTD of 400 mg/m2 BID, Cohort 7 was added to extend the BID 
dosing schedule to 21 days followed by 7 days off, repeated every 28 days (=1 cycle). 
 
28-day Schedule: At the MTD of 400 mg/m2 BID, Cohort 8 is added to extend the BID dosing 
schedule to 28 days continuous dosing each 28 days (=1 cycle). 
 
DLT is defined as Grade 4 hematologic toxicity lasting 7 days or more; Grade 3 
nonhematologic toxicity of any duration not amenable to supportive care; failure of platelets, 
absolute neutrophil count (ANC), or hemoglobin (Hb) to recover to Grade 1 within 12 weeks 
despite use of platelet and red blood cell (RBC) transfusions and/or growth factors; febrile 
neutropenia (defined as ANC<1000/mm3 with a single temperature of > 38.3°C or sustained 
temperature of ≥ 38°C for over one hour); Grade 3 thrombocytopenia associated with 
bleeding; or other important medical event.  
 
At the MTD of 400 mg/m2 BID, the 28-day continuous schedule of administration resulted in 
a higher rate of adverse events with no additional efficacy versus the 21-day schedule. 
Therefore, the recommended Phase 2 dose (RP2D) and schedule was determined to be 400 
mg/m2 BID on a 21-day schedule of administration, repeated every 28 days. 
 
Phase 2a: Once 6 subjects are treated at the RP2D and schedule in Phase 1, 1 additional cohort 
will enroll 20 subjects with MDS/CMML who have relapsed from, or are refractory to, prior 
hypomethylating agent (HMA) therapy. Subjects enrolled in Phase 1 at the RP2D and 
schedule and who meet the Phase 2a selection criteria will count towards the Phase 2a accrual. 
Dose level adjustments for adverse events will be made. 
1.3.2. Selection and Timing of Doses 
 
For all subject cohorts, if 1 of 3 subjects per cohort experiences DLT, the cohort will be 
expanded to 6. If 2 of 6 subjects per cohort experience DLT, all further dose escalation will 
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stop. If 0 of 3 or ≤ 1 of 6 subjects per cohort experience DLT by Day 28 following dosing of 
FF-10501-01, dose escalation will proceed to the next cohort. At the MTD of 400 mg/m2 
BID, the longest schedule of administration below the schedule of administration eliciting 
DLT will be declared the recommended Phase 2 dose (RP2D) and schedule. A total of 6 
subjects will be treated at the RP2D and schedule. No intra-subject dose escalation will be 
allowed from previous dose levels/schedules of administration until at least one subject has 
completed Cycle 1 at the longer schedule of administration (e.g., 21 or 28 days) with no Grade 
2 or greater toxicities observed. Additionally, patients currently on study will have the option 
to extend their current dosing schedule to 21 days, followed by 7 days off, repeated every 28 
days (=1 cycle), or 28 days of continuous dosing, whichever is chosen as the best schedule, 
if seen in the patient’s best interest by the principal investigator. Dose level adjustments for 
DLT will be made. Subjects who experience DLT at the first dose level, 50 mg/m2 BID, will 
not be dose-reduced. Up to 48 subjects are planned for Phase 1. 
 
Subjects on the 21-day schedule will receive FF-10501-01 on a BID schedule. For all subjects 
on the 21-day dosing schedules, blood samples for pharmacokinetic assessment of FF-10501 
and M1 in plasma will be collected on Cycle 1 Day 1 pre-dose (any time), between 0.5-1 hr 
post-dose, and between 2-4 hr post-dose, and Day 15 pre-dose (within 15 minutes prior to 
dosing), between 0.5-1 hr post-dose, and between 2-4 hr post-dose.  
 
Subjects who demonstrate objective response (OR) or stable disease (SD) will be allowed to 
continue therapy with FF-10501-01 until progression of disease, observation of unacceptable 
adverse events, intercurrent illness or changes in the subject’s condition that prevents further 
study participation. 
1.4. Procedures 
1.4.1. Subject Identification  
 
Once study eligibility has been determined, a subject will be enrolled into the study and will 
be assigned a sequential Subject Identification number within each participating site. The 
identification number will consist of a 2-digit site number, 1-digit cohort number, and a 2 
digit subject number. The subject identification number will be assigned sequentially within 
the cohort. The cohort number will remain the same if a subject’s dose is increased or 
decreased. If a subject is replaced, the identification number will not be reassigned. 
1.4.2. Randomization 
 
Not Applicable 
1.4.3. Blinding/Unblinding 
 
This is an unblinded study. 
1.4.4. Replacement 
 
Subjects who are enrolled and are assigned a Subject Identification number but do not 
receive FF-10501-01 will be replaced. 
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1.4.5. Data Monitoring 
 
During the study, a Safety Review Committee, consisting of the actively recruiting 
investigators, the Medical Monitor, and FUJIFILM Pharmaceuticals (FPHU), will review 
data from each cohort on an ongoing basis. 
 
The Sponsor is responsible for ensuring the proper conduct of the study with regard to ethics, 
protocol adherence, site procedures, integrity of the data, and applicable laws and/or 
regulations. At regular intervals during the study and following completion of the study, the 
sponsor’s study monitors will contact the study site via visits to the site, telephone calls, and 
letters in order to review study progress, CRF completion, and address any concerns or 
questions regarding the study conduct. During monitoring visits, the following aspects of 
study conduct will be carefully reviewed: informed consent of subjects, subject recruitment, 
subject compliance with the study procedures, source data verification, drug accountability, 
use of concomitant therapy by subjects, AE and SAE documentation and reporting, and 
quality of data. Records pertaining to these aspects are expected to be kept current. 
 
2. Statistical Analysis Considerations 
2.1. Sample Size and Power 
 
Up to 68 total subjects are planned in this study. 
 
Phase 1: Up to 48 subjects are planned for Phase 1. The sample size reflects requirements 
associated with a 3+3 design. A total of 3 to 48 subjects are planned (3 to 6 subjects in up to 
8 dose cohorts). 
 
Phase 2a: The sample size reflects an additional 20 patients to be treated at the RP2D and 
schedule with CMML/MDS.  
2.2. Analysis Populations  
 
 
2.2.1. Full Analysis Set (FAS) Population 
The full analysis set (FAS) includes all subjects who are administered any fraction of a dose 
of study medication 
2.2.2. Randomized Population  
Since this is not a randomized study, there is no randomized population. 
2.2.3. Per Protocol Set (PPS) Population 
For a particular measure, the per protocol set (PPS) includes those subjects in the FAS who 
have a valid baseline and one or more post-treatment assessments for that measure of interest.  
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2.2.4. Safety Population 
 
All safety endpoints will be based on the FAS dataset. 
2.2.5. PK/PD Population  
The FF-10501-1 PK population consists of all subjects in the FAS who complete at least one 
post-dose PK assessment. The PD population consists of all subjects in the FAS who 
complete at least one post-dose PD assessment.  
2.3. Data Handling 
2.3.1. Measurement Times 
2.3.1.1. Visit Windows  
 
Visit windows will not be used. The visit time point entered on the case report forms 
will be used. Unscheduled assessments, if any, will be listed, but will not be included 
in tabulations by visit. 
2.3.1.2. Baseline Values  
 
The screening assessments are performed within 28 days of Cycle 1, Day 1, before the 
first dose of study medication. Unless otherwise mentioned, baseline will be the last 
observation before patients receive initially assigned dose.  Generally, this will be 
Cycle 1 Day 1 pre-dose measurements. If a pre-dose assessment is not performed on 
Cycle 1 Day 1, the immediate previous non-missing value, including screening, will 
be treated as baseline. If there are multiple baseline assessments, the most recent one 
will be flagged as the baseline value and will be used for statistical analysis 
(evaluations may occur on the same day as Study Day 1, prior to dosing).  
 
2.3.2. Missing Data Conventions 
 
Unless otherwise specified, missing data will be considered missing and will not be imputed.  
2.3.3. Imputation of Incomplete Dates 
 
Imputation of partial dates may be performed during the data analysis and will be documented. 
For start date of Adverse Event (AE) or Concomitant Medication (CM) with a missing day, 
the imputed date is the first day of the month. For stop date of AE or CM with a missing day, 
the imputed date is the last day of the month. For start date with both missing day and missing 
month, the imputed date is the subject start study date if AE or CM start year is the same as 
study start year. Otherwise, the imputed start date is the first day of the year. For stop date 
with both missing day and missing month, the imputed date is the subject end of study date if 
AE or CM stop year is the same as the study end year. Otherwise, the imputed stop date is the 
last day of the year. 
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2.4. Statistical Methods 
2.4.1. General Overview and Plan of Analysis 
 
All data will be analyzed using Statistical Analysis System (SAS Version 9.4 or higher for 
Windows, SAS Institute, Cary, NC). Continuous variables will be summarized using number, 
mean, standard deviation, median, minimum, and maximum. Categorical variables will be 
summarized using frequencies and percentages.  
2.4.2. Hypothesis Testing 
 
No formal hypothesis tests are planned.  
2.4.3. Modeling 
 
 
Not Applicable in this study. 
2.4.4. Multiplicity Issues/Multiple Comparisons  
 
There is no planned Multiplicity Issues/Multiple Comparisons analysis for this study. 
2.4.5. Project Center Effects  
 
The study will be conducted at The University of Texas M.D. Anderson Cancer Center 
(Guillermo Garcia-Manero, M.D.), Study Chair and Case Comprehensive Cancer Center 
(Mikkael Sekeres, M.D.). Other sites may be added to ensure timely accrual to the study. 
2.4.6. Interim Analysis  
 
No formal interim analysis is planned. AE listings and appropriate summary tables will be 
generated for Scientific Review Committee meetings and Development Safety Update 
Reports (DSURs). 
2.4.7. Pharmacokinetic and Pharmacodynamic Analyses 
 
 
Pharmacokinetic and Pharmacodynamic data will be summarized in a separate report. 
 
3. Statistical Analysis 
 
Data will be presented for clinical review and interpretation. Categorical variables will be summarized 
using frequency counts and percentages. Continuous variables will be summarized using descriptive 
statistics (n, mean, SD, median, minimum, and maximum). All listings will be presented for the FAS 
population except for PK and PD data.  
3.1. Enrollment and Disposition of Subjects 
 
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Enrolled individuals are referred to as “subjects”. Subjects with acute myelogenous leukemia 
(AML), myelodysplastic syndrome (MDS), and chronic myelomonocytic leukemia (CMML) will 
be included. 
 
Major selection criteria are: age ≥ 18 years, confirmed high risk MDS/CMML or AML with 
documented disease progression following previous therapy, or subjects with AML ≥ 60 years of 
age who are not candidates for other therapies. Subjects must be ≥ 3 weeks beyond chemotherapy, 
radiotherapy, major surgery, or other experimental treatments, and recovered from all acute 
toxicities (≤ Grade 1), have adequate renal and hepatic function, and no known history of 
significant cardiac disease. 
 
The analyses of subject disposition will be performed on the FAS population for subjects in Phase 
1 dose escalation phase by dose cohort and for subjects in Phase 2a phase by MDS/CMML disease 
cohort. The number and percentage of subjects will be presented. The number of subjects treated, 
and treated subjects who completed follow-up and those who terminated early from treatment and 
the study, along with their reasons for early termination, will be presented.  
3.2. Baseline Characteristics 
3.2.1. Demographic 
 
Summary statistics for demographic characteristics will be presented for subjects in Phase 1 
dose escalation phase by dose cohort and for subjects in Phase 2a phase by MDS/CMML 
disease cohort using the full analysis set (FAS) population. Tabulations will be performed for 
age, sex (male or female), ethnicity (Hispanic/Latino or other), and race (American Indian or 
Alaska Native, Black or African American, White, Asian, Native Hawaiian or Other Pacific 
Islander, Unknown, or other). Age will be calculated as the number of complete years 
between a subject’s date of birth and the date of screening visit. 
3.2.2. Physical Characteristics  
 
Summary statistics will be presented for height (cm) and weight (kg) at screening for subjects 
in phase 1 by dose cohort and for subjects in phase 2a by disease cohort treated at RP2D using 
the FAS population. ECOG performance status at screening will be summarized. 
3.2.3. Disease Characteristics 
 
The baseline disease assessment (AML and MDS/CMML) will be summarized for phase 1 
subjects by dose cohort and for phase 2a subjects treated at RP2D and schedule using the 
FAS population. 
 
3.2.4. Concomitant Medications at Entry  
Concomitant medications coded using WHO Drug Dictionary will be summarized using 
descriptive statistics for phase 1 subjects by dose cohort and for phase 2a subjects by 
MDS/CMML disease cohort using the FAS population. Medication start and stop dates will 
be compared to the date of first dose of medication to allow medications to be classified as 
either Prior or Concomitant. Medications that start and stop prior to the date of first dose of 
study medication will be classified as Prior medications. If a medication starts before the date 
of first dose of study medication or starts on or after the first dose of study medication, and 
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stops on or after the date of first dose of study medication, then the medication will be 
classified as Concomitant.  
3.3. Analysis of Efficacy  
 
All efficacy analyses will be conducted for Phase 1 subjects by dose cohort, if applicable, and for 
Phase 2a subjects by MDS/CMML disease cohort at the RP2D and schedule (400 mg/m2 BID x 21 
days, repeated every 28 days) using the Per Protocol Population (PPS dataset). 
3.3.1. Primary Endpoints 
 
The primary efficacy endpoint is the proportion of subjects with objective response 
achieved within 3 cycles of treatment with FF-10501-01 (i.e., within 3 months) in subjects 
with relapsed/refractory AML or relapsed/refractory high-risk MDS or CMML. 
3.3.2. Secondary Endpoints 
 
The proportion of subjects with MDS who have hematologic improvement in peripheral 
blood or bone marrow blast count at any time after initiation of treatment with FF-10501-01. 
Hematologic improvement in blast count is defined as ≥ 50% reduction in peripheral blood 
or bone marrow blast count when compared with the baseline value. 
 
Progression-Free Survival: length of time from the date of first administration of study drug 
to the first objective evidence of disease progression or death, whichever is earlier. 
 
Overall Survival: length of time from the date of first administration of study drug to the date 
of death from any cause. 
3.3.3. Exploratory/Other Analyses 
 
Pharmacokinetic and pharmacodynamic analyses will be provided by an outside laboratory. 
3.4. Analysis of Safety and Tolerability  
3.4.1. Study Drug Administration 
 
Overall duration of exposure, dose intensity, and relative dose intensity will be summarized 
using descriptive statistics by dose cohort for Phase 1 subjects and by MDS/CMML disease 
cohort for Phase 2a subjects. Duration of exposure to study drug in each cycle will be 
calculated as the date of last dose minus the date of first dose plus one if there are no drug 
interruptions. For drug interruptions, the number of days in each cycle will be calculated as 
date of last dose minus the date of first dose plus one times the actual dose taken (in mg) 
divided by the dose prescribed (in mg) during the cycle. The number of days in all such cycles 
will be added within each dose cohort to calculate overall duration. The total dose taken will 
be calculated based on the actual dose information collected in the CRF. Dose intensity will 
be calculated as the total dose divided by the number of scheduled days on drug. Relative 
dose intensity will be calculated by dividing the dose intensity by starting dose.  
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3.4.2. Adverse Events 
 
 
 
All safety endpoints will be summarized using descriptive statistics and will be by dose 
cohort for phase 1 subjects and by MDS/CMML disease cohort for phase 2a subjects treated 
at RP2D and schedule using the FAS population. 
 
All AEs will be coded based on the Medical Dictionary for Regulatory Affairs (MedDRA; 
Version 17.0 or higher). An AE will be considered a treatment emergent adverse event 
(TEAE) if the onset is after the first dose of study drug or if the condition was present at 
baseline but worsened after the first dose. All other AEs will be considered preexisting 
events.  
 
All AEs for each subject will be listed, including Treatment Emergent status, intensity 
grading, relationship to study drug, action taken and outcome. Subject listings of deaths, 
serious TEAEs, and TEAEs leading to treatment discontinuation will be provided. Summary 
tables will be prepared to examine TEAE severity and relationship to study treatment. 
 
TEAE summaries will be produced separately for each dose cohort for subjects in Phase 1 
and by MDS/CMML disease cohort for subjects in Phase 2a. All TEAE summaries will show 
the number and percentage of subjects experiencing at least 1 TEAE for each preferred term, 
arranged by system organ class, and the number of unique occurrences of the event. Separate 
summaries will be produced by relationship to study medication, and by severity, and for 
those events with an incidence of at least 2% in any group or overall. Subjects with multiple 
events will be counted only once per SOC and preferred term. For each level of 
summarization, the event with the highest level of severity, grade, or strongest drug 
relationship will be presented. TEAEs with Grade 3 or Grade 4 and drug-related TEAES with 
Grade 3 or Grade 4 will be summarized. TEAEs leading to study drug interruption or 
discontinuation, Grade 3 and 4 TEAEs, Serious TEAEs will be provided in a separate listing. 
3.4.3. Clinical Laboratory Results 
 
Laboratory data will be listed by subject. Values above and below normal ranges will be 
indicated. All laboratory values will be graded according to the NCI-CTCAE version 4.03 
criteria. Laboratory data will be summarized by actual value and change from baseline using 
number of non-missing observations, mean, standard deviation, median, minimum, 
maximum, and Grade 3 and 4 by dose cohort and by disease cohort treated at RP2D and 
schedule. In addition, shift tables will be presented. 
3.4.4. Vital Signs 
 
Vital signs will be listed by subject. Vital sign data will be summarized by actual value and 
change from baseline using number of non-missing observations, mean, standard deviation, 
median, minimum and maximum by dose cohort for Phase 1 subjects and by MDS/CMML 
disease cohort for Phase 2a subjects treated at RP2D and schedule. 
3.4.5. Physical/Other Examinations  
 
Data collected for physical examinations, ECGs and related measures will be listed. ECGs 
change from baseline will be summarized by dose cohort for Phase 1 subjects and by 
MDS/CMML disease cohort for Phase 2a subjects. 
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3.4.6. Treatment Discontinuation, Project Termination, and Death 
 
The participants who discontinued (with reasons) and deaths will be listed. The treatment 
emergent adverse events leading to permanent discontinuation from study will be presented. 
 
4. Proposed Summary Tables, Graphs and Listings 
4.1. Mock Tables 
The following tables will be presented by dose cohort for subjects in Phase 1 dose escalation 
phase, and by disease cohort for subjects in Phase 2a. 
4.1.1. Subject Disposition 
 
 
Subject Disposition 
4.1.2. Demographics and Baseline Characteristics 
 
 
Demographics and Baseline Characteristics (Ethnic, Race, Sex, Age at Study Entry, 
Weight, Height and ECOG) 
 
Baseline Disease Assessment - AML 
 
Baseline Disease Assessment - MDS/CMML 
4.1.3. Prior and Concomitant Medication 
 
Summary of Prior Medications 
 
Summary of Concomitant Medications 
4.1.4. Primary Efficacy Summaries 
 
 
Summary of Subject’s Disease Response and 90% Confidence Intervals - AML 
 
Summary of Subject’s Disease Response and 90% Confidence Intervals - MDS/CMML 
4.1.5. Secondary Efficacy Summaries 
 
 
Summary of Subjects With Hematologic Improvement   
 
Progression Free Survival (PFS) 
 
Overall Survival (OS) 
4.1.6. Safety Summaries 
4.1.6.1. Study Drug Administration  
 
 
Summary of Study Drug Exposure  
4.1.6.2. Adverse Events Summaries 
 
 
Summary of Treatment Emergent Adverse Events 
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 
Treatment Emergent Adverse Events by System Organ Class and Preferred Term 
 
Treatment Emergent Adverse Events by Relationship to Study Drug 
 
Summary of Treatment Emergent Adverse Events by Severity 
 
Grade 3 and Grade 4 Treatment Emergent Adverse Events 
 
Drug-related Grade 3 and Grade 4 Treatment Emergent Adverse Events 
 
Treatment Emergent Adverse Events by System Organ Class and Preferred Term 
with at least 2% Incidence in any Group or overall 
4.1.6.3. Laboratory Assessments 
 
 
Summary of Laboratory Assessments by Visit 
 
Change From Baseline in Laboratory Assessments by Visit 
 
Shift Table from Baseline to Most Extreme Post-Baseline Result by CTC Grade 
4.1.6.4. Other Safety Summaries 
 
 
Summary of Vital Sign Results 
 
Change From Baseline in Vital Sign Results  
 
Change From Baseline in 12-Lead Electrocardiogram Results 
4.2. Mock Graphs 
 
 
Progression Free Survival 
 
Overall Survival 
4.3. Mock Listings 
 
The following listings will be presented for subjects in Phase 1 dose escalation phase and for 
subjects in Phase 2a. 
 
 
Inclusion Criteria not Met 
 
Exclusion Criteria not Met 
 
Protocol Violations/Deviations/Exemptions 
 
Demographics 
 
End of Treatment 
 
End of Study 
 
Baseline Disease Assessment - AML 
 
Baseline Disease Assessment - MDS/CMML 
 
Medical History 
 
Prior Cancer Surgery 
 
Physical Examination  
 
Prior Medications 
 
Concomitant Medications 
 
Study Drug Administration - Drug Dispensation 
 
Study Drug Administration – Patient Medication Diary 
 
Pharmacokinetic (PK) Sample Collection 
 
Pharmacodynamic (PD) Sample Collection 
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 
Disease Response - AML 
 
Disease Response - MDS/CMML 
 
Bone Marrow Assessment (BMA) 
 
Treatment Emergent Adverse Events (TEAE) 
 
Serious Treatment Emergent Adverse Events 
 
Treatment Emergent Adverse Events Leading to Dose Adjustment, Temporary Interruption, 
and Permanent Discontinuation of Study Drug 
 
Treatment Emergent Adverse Events Leading to Permanent Discontinuation from Study 
 
Dose Limiting Toxicities 
 
Deaths 
 
Hematology 
 
Chemistry 
 
Urinalysis 
 
Pregnancy Test 
 
Vital Signs 
 
12-lead Electrocardiogram 
 
Blood Transfusion 
 
Other Procedures 
 
Long Term Follow-up 
 
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