Clinical trial NCT03176277
Conditions: Acute Leukemia Myelodysplastic Syndromes
Keywords: Leukemia Leukemia, Myeloid Leukemia, Myeloid, Acute MER MERTK TYRO3 AXL AML Relapsed/ Refractory AML TAM MDS Myelodysplastic Syndrome Relapsed/ Refractory MDS
Sponsor: Ono Pharmaceutical Co. Ltd
Start date: 2017-06-26; Completion date: 2023-01-20
Enrollment: 42 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
\[Updated\]: To assess the safety and tolerability of ONO-7475 monotherapy in patients with relapsed or refractory acute myeloid leukemia or relapsed or refractory myelodysplastic syndromes and to assess: i) safety and tolerability and ii) preliminary efficacy of the combination of ONO-7475 and venetoclax in patients with relapsed or refractory acute myeloid leukemia.

Detailed description:
Part A is a dose escalation study of ONO-7475 in patients with acute myeloid leukemia or relapsed or refractory myelodysplastic syndromes.

Part D is a dose escalation study of ONO-7475 in combination with venetoclax. ONO-7475 starting dose is selected following safety and tolerability outcome of Part A.

Arms: arm 1: Part A Initial dose level arm 2: Part A 2nd dose level arm 3: Part A 3rd dose level arm 4: Part D ONO-7475 + Venetoclax combination
Interventions: intervention 1: ONO-7475 3mg once daily intervention 2: ONO-7475 6mg once daily intervention 3: ONO-7475 10mg once daily intervention 4: ONO-7475 6mg + Venetoclax (70-400mg)
Intervention descriptions: intervention 1: Part A initial dose level intervention 2: Part A 2nd dose level intervention 3: Part A 3rd dose level intervention 4: Part D ONO-7475 + Venetoclax Combination

Protocol documents:
Prot_SAP_000.pdf: 
 
Study Number: ONO-7475-01 
Version: 10.0 [incorporating 
Amendments #1–9] 
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CLINICAL STUDY PROTOCOL 
 
Title: 
A Phase I/II open label study to evaluate the safety, 
tolerability, pharmacokinetics, pharmacodynamics and 
preliminary clinical efficacy of ONO-7475 in patients with 
acute leukemias or myelodysplastic syndromes 
 
Version: 
10.0 [incorporating Amendments #1–9] 
Version Date: 
9 February 2022  
Study Number: 
ONO-7475-01 
Phase: 
I/II 
 
 
 
SPONSOR 
Ono Pharmaceutical Co., Ltd. 
 
CONFIDENTIAL 
The information contained in this document is the property of Ono Pharmaceutical 
Co., Ltd. and may not be reproduced, published or disclosed to others without 
written authorization from Ono Pharmaceutical Co., Ltd. 
NCT03176277


 
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SPONSOR SIGNATURE PAGE 
 




 
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SAFETY CONTACT INFORMATION 
 
Role 
Company/Person 
Name 
Address 
Telephone/ 
Mobile (Cell) Number 
Fax Number 
Email Address 




 
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INVESTIGATOR SIGNATURE PAGE 
I agree to conduct this study in accordance with the requirements of this document 
(the Clinical Study Protocol), the Study Procedures Manual and also in accordance 
with the following: 
• The ethical principles founded in the Declaration of Helsinki  
• The International Council for Harmonization harmonized tripartite guideline 
regarding Good Clinical Practice (E6 Consolidated Guidance, Revision 1, 
Jun 1996) 
• US Code of Federal Regulations, Chapter 21: Parts 11, 50, 54, 312, and 
314 plus Amendments 
 
I acknowledge the confidential nature of the documentation generated as part of 
this study and that the Sponsor of the study (Ono Pharmaceutical Co., Ltd.) has 
the right to discontinue the study at any time. 
 
 
 
Investigator Name 
 
 
 
 
 
Affiliation 
 
 
 
 
 
Investigator Signature 
 
Date 


 
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COORDINATING INVESTIGATOR INFORMATION PAGE 
Role 
Name and Title 
Contact Number 
Fax Number/Email 
Street Address 
 


 
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TABLE OF CONTENTS 
PAGE 
SPONSOR SIGNATURE PAGE ........................................................................ 2 
SAFETY CONTACT INFORMATION ................................................................ 4 
INVESTIGATOR SIGNATURE PAGE ............................................................... 6 
COORDINATING INVESTIGATOR INFORMATION PAGE ............................... 7 
TABLE OF CONTENTS .................................................................................... 8 
ABBREVIATIONS ........................................................................................... 13 
IMPORTANT NOTE TO READERS ................................................................ 15 
PROTOCOL SUMMARY ................................................................................. 16 
1 
INTRODUCTION ...................................................................................... 20 
1.1 
Background ................................................................................................ 20 
1.1.1 
Disease Area and Current Medical Need ..................................... 21 
1.1.2 
Name and Description of the Investigational Drugs ...................... 22 
1.1.2.1 
ONO-7475 .................................................................. 22 
1.1.2.2 
Venetoclax ................................................................. 22 
1.1.3 
Non-clinical Studies ..................................................................... 22 
1.1.3.1 
Non-clinical Pharmacology ......................................... 22 
1.1.3.2 
Preclinical Pharmacokinetics ...................................... 23 
1.1.3.3 
Toxicology and Safety Pharmacology ......................... 23 
1.1.4 
Clinical Experience with ONO-7475 ............................................. 24 
1.1.5 
Clinical Experience with Venetoclax (VENCLEXTA®) ................... 24 
1.1.5.1 
Clinical Efficacy in Study M14-358 .............................. 25 
1.1.5.2 
Clinical Efficacy in Study M14-387 .............................. 25 
1.2 
Rationale .................................................................................................... 25 
1.2.1 
Study Rationale ........................................................................... 25 
1.2.2 
Study Design Rationale ............................................................... 26 
1.2.3 
Dose Rationale ............................................................................ 26 
1.2.3.1 
Starting Dose in Part A ............................................... 26 
1.2.3.2 
Starting Dose in Part D ............................................... 28 
1.3 
Risk/Benefit Assessment ............................................................................ 29 
1.4 
Study Conduct ............................................................................................ 33 
2 
STUDY OBJECTIVES AND ENDPOINTS ................................................ 33 
3 
STUDY DESIGN ...................................................................................... 36 
3.1 
Overview of Study Design ........................................................................... 36 
3.1.1 
Description of Study Design ......................................................... 37 
3.1.2 
Dose Escalation ........................................................................... 41 
3.1.2.1 
Part A ......................................................................... 41 
3.1.2.2 
SA group in Part D...................................................... 42 
3.1.3 
Dose Adjustments during Study ................................................... 43 


 
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3.1.3.1 
Dose Adjustments for ONO-7475 for Part A ............... 43 
3.1.3.2 
Dose Adjustments for ONO-7475 for Part D ............... 43 
3.1.3.3 
Dose Adjustments for Treatment Emergent 
Adverse Events for Part A and Part D ........................ 46 
3.1.3.4 
Dose Adjustment for Venetoclax ................................. 46 
3.2 
Dose-Limiting Toxicities .............................................................................. 48 
3.2.1 
Part A .......................................................................................... 48 
3.2.2 
Part D .......................................................................................... 49 
3.3 
Dose-Limiting Toxicity Evaluability Criteria .................................................. 50 
3.3.1 
Part A .......................................................................................... 50 
3.3.2 
Part D .......................................................................................... 51 
3.4 
Stopping Rules ........................................................................................... 51 
3.4.1 
Study Stopping Rules .................................................................. 51 
3.4.2 
Individual Stopping Rules ............................................................ 52 
3.5 
Blinding and Randomization ....................................................................... 54 
3.6 
Duration of Patient Participation .................................................................. 54 
4 
STUDY POPULATION ............................................................................. 55 
4.1 
Number of Patients ..................................................................................... 55 
4.2 
Patient Population ....................................................................................... 55 
4.3 
Eligibility Criteria ......................................................................................... 55 
4.3.1 
Inclusion Criteria .......................................................................... 55 
4.3.2 
Exclusion Criteria ......................................................................... 57 
4.4 
Lifestyle and/or Contraception .................................................................... 58 
5 
STUDY ASSESSMENTS AND PROCEDURES ....................................... 58 
5.1 
Protocol Flexibility ....................................................................................... 59 
5.2 
Medical History and Baseline Characteristics ............................................. 59 
5.3 
Screening Evaluations ................................................................................ 60 
5.4 
Visit Schedule ............................................................................................. 61 
5.5 
Clinical Response Efficacy Assessments .................................................... 61 
5.6 
Pharmacokinetic Procedures ...................................................................... 62 
5.7 
Biomarkers and Pharmacodynamics Procedures ........................................ 64 
5.7.1 
Pharmacodynamic Marker ........................................................... 64 
5.7.2 
Exploratory Biomarkers ................................................................ 66 
5.8 
 ............................................... 69 
5.9 
Safety Procedures ...................................................................................... 69 
5.9.1 
Electrocardiogram ........................................................................ 72 
5.9.2 
Multigated Acquisition Scan/Echo ................................................ 72 
5.9.3 
Vital Signs .................................................................................... 72 
5.9.4 
Laboratory Assessments ............................................................. 72 
5.9.5 
Ophthalmology Assessments ....................................................... 73 
5.9.6 
Pregnancy of Female Partners of Male Patients .......................... 75 
5.10 
Total Blood Volume .................................................................................... 75 
5.11 
 ........................................... 75 
6 
INVESTIGATIONAL PRODUCTS ............................................................ 76 
6.1 
Dosage and Administration of ONO-7475 ................................................... 76 
6.1.1 
Assessment of the Effect of Food on the Pharmacokinetics 
of  ONO-7475 (Part A) ................................................................ 77 
6.2 
Dosage and Administration of Venetoclax................................................... 77 


 
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6.3 
Treatment Assignment ................................................................................ 77 
6.4 
Packaging and Labelling ............................................................................. 78 
6.5 
Preparation of Investigational Drugs ........................................................... 78 
6.6 
Handling and Storage ................................................................................. 78 
6.7 
Product Accountability and Assessment of Compliance .............................. 78 
6.8 
Treatment of Investigational Product Overdose .......................................... 79 
7 
CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES ........... 79 
7.1 
Permitted Medications and Supportive Therapies ....................................... 79 
7.2 
Prohibited Medications ................................................................................ 80 
7.3 
Medications to be Used with Caution .......................................................... 80 
8 
PATIENT COMPLETION AND WITHDRAWAL ........................................ 81 
8.1 
Patient Completion ..................................................................................... 81 
8.2 
Study Completion ....................................................................................... 81 
8.3 
Patient Withdrawal ...................................................................................... 81 
8.3.1 
Patient Withdrawal from Study ..................................................... 81 
8.4 
Screen and Baseline Failures ..................................................................... 82 
9 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ....................... 82 
9.1 
Adverse Events........................................................................................... 82 
9.1.1 
Adverse Event Severity ................................................................ 82 
9.1.2 
Adverse Event Relationship to Investigational Product(s) ............ 83 
The possible relationships for Part D are: ................................................... 84 
9.1.3 
Adverse Event Reporting ............................................................. 84 
9.2 
Serious Adverse Events .............................................................................. 85 
9.2.1 
Definition...................................................................................... 85 
9.2.2 
Serious Adverse Event Reporting by the Investigator or 
Designee ..................................................................................... 85 
9.2.3 
Serious Adverse Event Processing and Reporting by the 
Study Sponsor or Designee ......................................................... 86 
9.2.4 
Reference Safety Information ...................................................... 87 
9.2.5 
Reporting of Pregnancy ............................................................... 87 
9.2.6 
Adverse Events of Special Interest .............................................. 87 
9.2.7 
Events Not To Be Reported as Serious Adverse Events .............. 87 
9.3 
Progression of Underlying Malignancy ........................................................ 88 
10 DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ..................... 88 
10.1 
Study Design Considerations ...................................................................... 88 
10.1.1 
Sample Size Assumptions and Design Considerations ................ 88 
10.2 
Data Analysis Considerations ..................................................................... 89 
10.2.1 
Analysis Populations .................................................................... 89 
10.2.2 
Key Elements of Analysis Plan .................................................... 90 
10.2.2.1 
Efficacy analyses ........................................................ 91 
10.2.2.2 
Pharmacokinetic 
and 
Pharmacodynamic 
Analyses ..................................................................... 93 
10.2.2.3 
Biomarker Analyses .................................................... 93 
10.2.2.4 
Safety Analyses .......................................................... 94 
10.2.3 
Interim Analysis (Part D only) ....................................................... 95 
10.2.3.1 
Safety Assessment Group Analysis ............................ 95 






 
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ABBREVIATIONS
AE 
Adverse event 
ALL 
Acute Lymphoblastic Leukemia 
ALT 
Alanine aminotransferase 
AML 
Acute Myeloid Leukemia 
 
 
AST 
Aspartate aminotransferase 
 
 
AUC 
Area under the curve 
BA 
Bioavailability 
 
 
BM 
Bone marrow 
CBC 
Complete blood count 
Cmax 
Maximum observed plasma concentration 
COVID-19 
Coronavirus Disease 2019 
CR 
Complete remission 
CrCl 
Creatinine clearance 
CRh 
Complete remission with partial hematologic recovery 
CRi 
Complete remission with incomplete hematologic recovery 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
 
 
DLT 
Dose limiting toxicity 
DoR 
Duration of response 
DMP 
Data management plan 
 
 
EA 
Expansion efficacy assessment 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture system 
EFS 
Event-free survival 
ELN 
European Leukemia Net 
ERG 
Electroretinogram 
ETDR 
Early Treatment Diabetic Retinopathy 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
 
 
GCP 
Good Clinical Practice 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HMA 
Hypomethylating agent 
HNSTD 
Highest non severely toxic dose 
HSCT 
Hematopoietic stem cell transplantation 
IB 
Investigator’s Brochure 
IC50 
Half maximal inhibitory concentration 


 
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ICH 
International Council for Harmonization 
Ig 
Immunoglobulin 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ITD+ 
internal tandem duplication positive 
IWG 
International Working Group 
MDS 
Myelodysplastic Syndromes 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRD 
Minimal residual disease 
 
 
MTD 
Maximum tolerated dose 
MUGA 
Multigated acquisition scan  
NCCN 
NCI 
National Comprehensive Cancer Network 
National Cancer Institute 
 
 
OBD 
Optimal biological dose 
 
 
ORR 
Overall response rate 
OS 
Overall survival  
PD 
Pharmacodynamic(s) 
 
 
PIA 
Plasma inhibitory activity 
PK 
Pharmacokinetic(s) 
PR 
Partial remission 
PT 
Prothrombin time 
QTcF 
QT interval corrected according to Fredericia’s formula 
R/R 
Relapsed/Refractory 
RBC 
Red blood cell 
 
 
SA 
Safety assessment 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SOP 
Standard operating procedure 
SRC 
Study Review Committee 
 
 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TAM 
Tyro3, Axl and Mer 
TLS 
Tumor lysis syndrome 
Tmax 
Time to reach Cmax 
TTR 
Time to response 
T1/2 
Elimination half-life 
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell 
WHO 
World Health Organization  
 
 






















 
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1.1.5.1 Clinical Efficacy in Study M14-358 
The efficacy and safety of VENCLEXTA was studied in a non-randomized, open 
label clinical trial of VENCLEXTA in combination with azacitidine (N=84) or 
decitabine (N=31) in patients with newly-diagnosed AML. Sixty-seven patients who 
received the azacitidine combination and 13 who received decitabine combination 
were aged 75 years or older, or had comorbidities that precluded the use of 
intensive induction chemotherapy. CR and CR with partial hematologic recovery 
(CRh) in patients who received the VENCLEXTA plus azacitidine combination 
were 37% and 24%, respectively. CR and CRh in patients who received the 
VENCLEXTA plus decitabine combination were 54% and 7.7%, respectively. The 
median follow-up was 7.9 months (range: 0.4 to 36 months) for VENCLEXTA in 
combination with azacitidine. The median follow-up was 11 months (range: 0.7 to 
21 months) for VENCLEXTA in combination with decitabine. 
1.1.5.2 Clinical Efficacy in Study M14-387 
The efficacy and safety of VENCLEXTA was studied in a non-randomized, open 
label clinical trial of VENCLEXTA in combination with low dose cytarabine (N=82) 
in patients with newly-diagnosed AML, including patients with previous exposure 
to an HMA for an antecedent hematologic disorder. Sixty-one patients aged 
75 years or older had comorbidities that precluded the use of intensive induction 
chemotherapy based on at least one of the following criteria: baseline Eastern 
Cooperative Oncology Group (ECOG) performance status of 2–3, severe cardiac 
or pulmonary comorbidity, moderate hepatic impairment, creatinine clearance ≥30 
to <45 mL/min, or another comorbidity. CR and CRh in patients who received 
VENCLEXTA in combination with low-dose cytarabine were both 21%. The median 
follow-up was 6.5 months (range: 0.3 to 34 months).  
1.2 Rationale 
1.2.1 Study Rationale 
This 
first-in-patient 
study 
aims 
to 
determine 
the 
safety, 
tolerability, 
pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of oral 
doses of ONO-7475 given as monotherapy in patients with AML and MDS and in 
combination with venetoclax in patients with AML.  
The rationale for investigating ONO-7475 in AML and MDS is based on preclinical 
data, the nature of the disease, and the significant unmet need in these indications.  
The rationale for investigating the combination of ONO-7475 with venetoclax in 
AML is based on preclinical data showing efficacy of ONO-7475 plus venetoclax 
in mouse AML disease models and the significant unmet need in R/R AML. 


















 
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Secondary Objectives 
Secondary Endpoints 
To select an optimal dose of ONO-7475 
for further clinical evaluation  
Maximum tolerated dose (MTD) and/or 
recommended pharmacological dose 
based on clinical response or 
pharmacodynamics (PD) markers  
To assess the pharmacokinetics (PK) of 
ONO-7475 in in patients with R/R AML 
and R/R MDS  
PK parameters: maximum observed 
plasma concentration (Cmax), time to 
reach Cmax (Tmax), area under the 
plasma concentration-time curves (AUC) 
on Days 1 and 28, elimination half-life 
(T1/2) plasma concentration prior to next 
dose  
To evaluate food effect on the PK of 
ONO-7475 
The PK of the food effect on ONO-7475 
(Cmax, Tmax, AUC, T1/2, and plasma 
concentration prior to next dose) 
To assess the PD activity of ONO-7475 
in patients with R/R AML and R/R MDS 
PD biomarkers of response: plasma 
inhibitory activity (PIA) assay (pAxl/pMer 
inhibition) 
To assess the preliminary clinical 
efficacy of ONO-7475 in patients with 
R/R AML and R/R MDS 
• 
Overall response rate (ORR), duration 
of response (DoR), event-free survival 
(EFS)  
• 
Complete remission (CR) without 
minimal residual disease (MRD) 
Part D – Combination with Venetoclax 
Primary Objectives 
Primary Endpoints 
SA group: 
To assess the safety and tolerability of 
ONO-7475 in combination with 
venetoclax 
EA group: 
To assess the preliminary efficacy of 
ONO-7475 in combination with 
venetoclax 
SA group: 
Incidence, nature, and severity of AEs and 
SAEs 
EA group:  
CR/CR with partial hematologic recovery 
(CRh) rate 
Secondary Objectives 
Secondary Endpoints 
Both groups: 
• 
To assess the PK of ONO-7475 in 
combination with venetoclax in 
patients with R/R AML 
• 
To assess the PK of venetoclax 
alone or in combination with ONO-
7475 in patients with R/R AML 
 
SA group: 
Both groups: 
PK parameters (Cmax, AUC, Tmax, T1/2 
for ONO-7475 and venetoclax) 
 
SA group: 
Recommended Phase 2 dose (RP2D) 
 
 
EA group: 




 
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3 STUDY DESIGN 
3.1 Overview of Study Design 


















 
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2. Written informed consent by the patient (or their legal representative) prior to 
admission to this study. In addition, any locally required authorization (Health 
Insurance Portability and Accountability Act in the US), must be obtained from 
the patient prior to performing any protocol-related procedures, including 
screening evaluations.  
3. Adequate renal and hepatic function defined as: 
a. Total bilirubin within 1.5 x upper limit of normal (ULN), except those with 
Gilberts syndrome for whom this must be <3 x ULN 
b. AST and ALT <2.5 x ULN  
c. Calculated creatinine clearance ≥45 mL/min 
d. Serum albumin ≥2.5 g/dL 
For any patient with laboratory values outside the ranges outlined above that are 
considered due to the patient’s underlying disease (AML or MDS), the patient may 
be enrolled into the study following consultation between the Investigator and the 
Sponsor’s Medical Officer, if the patient is likely to benefit from receiving ONO-
7475 (based on the Investigator’s assessment). 
4. ECOG performance status 0–2 as assessed during the screening period and 
then again anytime during the 2-day period immediately preceding the start of 
dosing in Parts A and D.  
5. Life expectancy of at least 3 months. 
6. Sexually active female patients of childbearing potential and sexually active 
male patients must agree to use an effective method of birth control (e.g., 
barrier methods with spermicides, oral or parenteral contraceptives and/or 
intrauterine devices) during the entire duration of the study and for 4 months 
after final administration of study drug. Note that sterility in female patients must 
be confirmed in the patients’ medical records and be defined as any of the 
following: surgical hysterectomy with bilateral oophorectomy, bilateral tubular 
ligation, natural menopause with last menses >1 year ago, radiation-induced 
oophorectomy with last menses >1 year ago, chemotherapy-induced 
menopause with last menses >1 year ago. 
Disease-specific Inclusion Criteria for Relapsed/ Refractory AML or MDS 
(Part A): 
1. Diagnosis of AML or MDS according to World Health Organization (WHO) 
criteria 201612. 
2. Either criterion is met: 
a. Patients with R/R AML with at least 5% blasts by BM biopsy or 
aspirate, or at least 1% blasts in peripheral blood, not likely to benefit 
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b. Patients with R/R MDS who are either not eligible for (or unlikely to 
benefit from) other forms of therapy, including HSCT, according to 
the treating Physician/Investigator  
3. All patients must have received at least 1 previous line of therapy  
Disease-specific Inclusion Criteria for R/R AML (Part D): 
1. Diagnosis of AML according to WHO criteria (2016)12. 
2. Patients with R/R AML who have no standard-of-care options known to provide 
clinical benefit in patients with R/R AML  
a. Refractory AML: Patients who have not achieved complete remission 
after two cycles of induction chemotherapy (i.e., anthracycline 
containing regimen), four cycles of hypomethylating agents, or two 
cycles of other AML therapy 
b. Relapsed AML: Patients who have ≥5% BM blasts in BM, or 
reappearance of blasts in the peripheral blood not attributable to 
another 
cause 
(e.g., 
recovery 
of 
normal 
cells 
following 
chemotherapy-induced aplasia) or (re)appearance of extramedullary 
disease after CR of prior AML therapy.  
3. Patients must have measured BM aspirate blast counts at Screening. Where 
the aspirate is hypo cellular or inaspirable a biopsy would be considered. 
4. Patients who were refractory to or relapsed after their 1st line treatment for 
AML must have received 2 or less additional lines of intensive / aggressive 
chemotherapy, which also includes a venetoclax-based regimen, as per the 
latest National Comprehensive Cancer Network (NCCN) Guidelines. 
4.3.2 Exclusion Criteria 
1 Patients with active central nervous system leukemia. 
2 QT interval corrected according to Fredericia’s formula (QTcF) prolongation 
defined as a QTcF interval >470 msec or other significant ECG abnormalities 
including second degree (type II) or third degree atrioventricular block or 
bradycardia (ventricular rate <50 beats/min). 
3 Clinically significant liver disease, including active viral or other hepatitis, 
current alcohol abuse, or severe cirrhosis. 
4 Human immunodeficiency virus (HIV), active hepatitis B (HBV) or C (HCV) 
infection. 
5 Retinal disease (e.g., retinitis pigmentosa including Mertk mutations), retinal 
hemorrhage or any disorder which may inhibit follow up for retinal toxicity. 
6 Serious intercurrent medical or psychiatric illness that will prevent participation 
or compliance with study procedures, including serious active infection 
(including COVID-19).  
7 Acute promyelocytic leukemia (the French-American-British M3 classification). 


 
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8 Patients not recovered to Grade 1 or stabilized from the effects (excluding 
alopecia) of any prior therapy for their malignancies. 
9 Concurrent treatment with other investigational drugs.  
10 Daily requirement of ≥10 mg/day of prednisone or equivalent dose of other 
corticosteroids. 
11 Prior HSCT within 12 weeks of the first dose of study treatment or ongoing 
immunosuppressive therapy for graft-versus-host disease. 
12 Participation in another clinical trial with any investigational drug within 14 days 
or with any licensed drug within five half-lives, prior to the first ONO−7475 
dosing (for Part A) or prior to the first venetoclax dosing (for Part D). 
13 Prior AML or MDS therapy (non-experimental) within 14 days or 5 half−lives, 
whichever is longer, prior to the first dose of ONO-7475 (for Part A) or prior to 
the first venetoclax dosing (for Part D) (except those permitted in Section 7.1) 
and no residual toxicity from the prior therapy hindering of the ONO-7475 
dosing (for Part A) or ONO-7475 plus venetoclax dosing (for Part D). 
14 Prior radiotherapy within 21 days of screening, with the exception of localized 
palliative radiotherapy.  
15 Patients undergoing current treatments for other cancers. 
16 Pregnant or lactating women. 
17 Proliferative disease (white blood cell [WBC] counts >30 x 109/L) confirmed 
prior to the first dose of ONO-7475 (for Part A) or WBC >25 x 109/L in Part D. 
18 Active malignancy, other than AML (Parts A and D) or MDS (Part A), requiring 
systemic therapy except for those patients who have been diagnosed with 
either prostate or breast cancer and who have received a stable dose of 
hormone therapy for a minimum of 6 months prior to entering this study. 
19 Known hypersensitivity to venetoclax (Part D only). 
20 Calculated creatinine clearance <45 mL/min 
4.4 Lifestyle and/or Contraception 
Sexually active female patients of childbearing potential and sexually active male 
patients must agree to use an effective method of birth control (e.g., barrier 
methods with spermicides, oral or parenteral contraceptives and/or intrauterine 
devices) during the entire duration of the study and for 
 after final 
administration of study drug. 
5 STUDY ASSESSMENTS AND PROCEDURES 
The schedule of study events during each period of the study is presented in 
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In the event that an unexpected and extenuating situation which impacts on study 
conduct develops (e.g., a public health emergency such as a pandemic disease), 
certain protocol deviations (e.g., administering the study drug or adhering to 
protocol-mandated visits and laboratory/diagnostic testing) may be unavoidable. 
In this situation, the Investigator must inform the Sponsor that the patient may not 
meet pre-specified protocol requirements.  
In the above situation, the Sponsor should evaluate whether alternative methods 
for performing safety assessments (e.g., phone contact, virtual visit, and 
alternative location for assessment, including local labs or imaging centers) could 
be implemented and if they would be sufficient to assure the safety of patients. The 
Sponsor will determine if a protocol amendment is required to implement the 
alternative methods. 
Furthermore, the Sponsor will determine if in-person visits are necessary to fully 
assure the safety of patients enrolled in the trial (for example to carry out 
procedures to assess patient safety or to ensure safe use of the study drugs); in 
making the decision to continue administration of the study drugs, the Sponsor and 
the Investigator should discuss and consider whether the safety of trial participants 
can be assured with the implementation of the altered monitoring approach.  
5.1 Protocol Flexibility 
The following flexibilities will be allowed in this protocol: 
• Where an enrolled patient is unable to attend the site due to an extenuating 
circumstance(s) such as a public health emergency and associated 
restrictions the following may occur at the discretion of the Investigator after 
consultation with the Sponsor’s Medical Officer: 
o The visit may be scheduled outside the protocol-defined window 
o Procedures may be performed, where possible, at the patient’s home 
or remotely via telephone or video call 
Further details will be provided in the Study Reference Manual. 
5.2 Medical History and Baseline Characteristics 
The following demographic parameters will be recorded as in Section 13.1 and 
Section 13.3. The collection of some of this information may be restricted 
depending on local/country data guidelines: 
• Date of birth 
• Sex 
• Race and ethnicity 
Medical history including AML/MDS diagnosis and all previous therapies e.g., 
HSCT will also be recorded.  








 
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same process will apply for those patients who have their dose increased (or 
decreased).  
6.4 Packaging and Labelling 
All packaging and labels will be prepared in accordance with 21 Code of Federal 
Regulations 312.6 − Labelling of an investigational new drug and any local 
regulatory requirements. 
6.5 Preparation of Investigational Drugs 
ONO-7475 
No further preparation of ONO-7475 tablets is needed. 
Venetoclax 
No further preparation of venetoclax tablets is needed. 
6.6 Handling and Storage 
ONO-7475 should be stored 
 and a temperature log will be 
maintained during the conduct of the study. All study drugs must be stored in a 
secure location and may only be dispensed by the Investigator or by a member of 
staff who is authorized by the Investigator, or by a pharmacist, as appropriate. 
Venetoclax should be stored as per the approved label of VENCLEXTA22. 
6.7 Product Accountability and Assessment of Compliance 
In accordance with GCP, all supplies of ONO-7475 and venetoclax will be 
accounted for by the investigational site. 
The dispensing and return of the study drug will be carefully recorded on 
appropriate drug accountability forms and an accurate accounting will be available 
for verification and assessment of compliance by the clinical research associate at 
each monitoring visit. 
Investigational product accountability records will include: 
• Details of receipt 
• Storage 
• Administration, and  
• Return or destruction 
The unit of accountability for the study is 1 tablet. At the end of the study, following 
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Grade 5 
Death related to AE. 
 
9.1.2 Adverse Event Relationship to Investigational Product(s) 
The Investigator must classify the relationship of the AE to ONO-7475 (both Parts) 
and venetoclax (Part D only).  
The possible relationships for Part A are: 
Not related/ 
unlikely related 
The temporal sequence between the AE and drug 
administration is such that the drug is not likely to have had 
any reasonable association with the observed event; or 
underlying disease, other drugs or chemicals provide 
plausible explanations. 
Possibly related 
The AE follows a reasonable time relationship from drug 
administration;  
 
and 
 
The AE could also be explained by concurrent disease or 
other drugs or chemicals. 
 
Note: Information on drug withdrawal may be lacking or 
unclear. 
Probably related 
The AE follows a reasonable time relationship from drug 
administration; 
 
The AE is unlikely to be attributed to concurrent disease or 
other drugs or chemicals;  
 
and 
 
Follows a clinically reasonable response upon withdrawal 
(dechallenge); 
Note: rechallenge positive data are not required to fulfill 
this definition. 
Definitely related 
The AE follows a reasonable time relationship from drug 
administration (i.e., occurs in a plausible time relationship 
to drug administration); 
 
The AE cannot be explained by concurrent disease or 
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The AE abates or follows a clinically reasonable response 
upon withdrawal (dechallenge positive);  
 
and 
 
The AE is confirmed by reappearance of the reaction on 
repeat exposure (rechallenge positive). 
The possible relationships for Part D are: 
Not related 
The temporal sequence between the AE and drug 
administration is such that the drug is not likely to have had 
any reasonable association with the observed event; or 
underlying disease, other drugs or chemicals provide 
plausible explanations. 
Related 
The AE follows a reasonable time relationship from drug 
administration (i.e. occurs in a plausible time relationship 
to drug administration); 
 
The AE cannot be explained by concurrent disease or 
other drugs or chemicals; 
 
The AE abates or follows a clinically reasonable response 
upon withdrawal (dechallenge positive);  
 
or 
 
The AE is confirmed by reappearance of the reaction on 
repeat exposure (rechallenge positive). 
9.1.3 Adverse Event Reporting 
The Investigator, or authorized designee, should regularly ask the patients how 
they are feeling to encourage AE reporting. The person approaching the patients 
should use a non-leading question such as “How are you feeling?”. 
All observed or volunteered AEs, regardless of suspected causal relationship to 
study drug, will be recorded on the AE page(s) of the eCRF. 
In addition, abnormal objective test findings (e.g., ECG changes, abnormal 
laboratory test results) that result in a change in the study drug dosage or in 
discontinuation of the drug, or require intervention or diagnostic evaluation to 
assess the risk to the patient, should be recorded as AEs. Clinically significant 
changes in physical examination findings and objective test findings should also 
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Adverse events will be collected from the time informed consent is given until the 
patient has completed the study. 
Any AEs that are ongoing at the time the patient completes the study will be 
followed by the Investigator until the AEs are resolved, the patient’s condition is 
stable or persistent, the patient’s death, or until the patient is lost to follow-up. Any 
pregnancies reported after completion of the study must also be reported as per 
Section 9.2.5. 
9.2 Serious Adverse Events 
9.2.1 Definition 
An SAE is any untoward medical occurrence that at any dose:  
• Results in death 
• Is life-threatening 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Is medically important 
Medical and scientific judgement should be exercised in deciding whether 
reporting is appropriate in other situations, such as important medical events that 
may not reach the above definition but may jeopardize the patient or may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definition. These events are referred to as “important medical events” and 
should also be considered serious. Examples of such events are the emergence 
of any secondary cancers unrelated to AML or MDS, intensive treatment in an 
accident and emergency department or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse. 
9.2.2 Serious Adverse Event Reporting by the Investigator or Designee 
All SAEs, regardless of suspected relationship to study drug, must be reported by 
the Investigator or their authorized designee to designated service provider 
immediately, and in no case later than 24 hours, following knowledge of the SAE. 
All SAEs are documented in the SAE form and reported electronically through the 
designated service provider’s electronic data capture (EDC) system. 
If the event meets serious criteria and it is not possible to access the EDC system, 
the Investigator or their authorized designee should contact the designated service 
provider, either by e-mail or telephone, and fax the completed paper SAE form to 
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information must be entered into the EDC system within 24 hours of the system 
becoming available. 
Safety Contact Information 
 
 
 
 
 
The initial report of an SAE must not be delayed by the investigational site beyond 
24 hours in order to collect additional information. Any medical information relevant 
to the reported SAE which becomes available to the investigational site staff 
following the initial SAE report should be reported to designated service provider 
as part of a follow-up SAE report. The reporting procedure should be referred to 
the outlined above for initial reporting of SAEs. Medical records transmitted as part 
of the SAE report must not disclose study patients’ personal data, such as patient 
name, any contact information, name of patients’ relatives, etc. The study patient 
is to be identified by the unique study-specific subject number only.  
As for AEs, SAEs will be collected from the time informed consent is given until the 
follow-up visit, or until voluntary withdrawal of a clinical study patients’ consent 
(refer to Section 8.3). SAEs that occur after the SAE reporting period and that are 
considered related to study drug will be reported to the Sponsor, if the Investigator 
becomes aware of them. 
Unless they withdraw consent for further follow-up, patients who discontinue study 
therapy will be followed for acquisition of safety information through 30 days after 
the last dose of study treatment (or initiation of new anti-cancer therapy, whichever 
occurs first), and for collection of information regarding survival. 
9.2.3 Serious Adverse Event Processing and Reporting by the Study 
Sponsor or Designee 
All SAEs will be processed by the study Sponsor or contracted designee according 
to study-specific SAE processing guidelines. 
The Sponsor, or contracted designee, will be responsible for submitting suspected, 
unexpected, serious adverse reactions (SUSARs) involving the study drug to the 
applicable regulatory authorities according to ICH guidelines and applicable 
regulations. In addition, the Sponsor, or designee, will be responsible for the 
submission of safety letters to the central IRB and to the Investigator of all SUSARs 
involving the active study drug according to applicable regulations. For clinical sites 


 
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that use a local IRB, it is the responsibility of the Investigator to promptly notify the 
local IRB of all SUSARs involving risk to human patients. 
These reports should be submitted within 7 calendar days of the Sponsor being 
notified of the event for fatal or life-threatening events, or 15 calendar days for all 
other events. 
9.2.4 Reference Safety Information 
The Sponsor or designee is responsible for determining the expectedness of the 
reported event(s) as per the applicable Reference Safety Information. The 
Reference Safety Information is contained in the IB for ONO-747525 and in the 
approved Product Labelling for venetoclax (VENCLEXTA)22. 
9.2.5 Reporting of Pregnancy 
Information on pregnancy of a study patient (or partner) will be collected until the 
follow-up visit or until voluntary withdrawal of a clinical study patient’s or partner’s 
consent. 
If the patient or female partner of a male patient participating in the study becomes 
pregnant during the study or within 90 days of discontinuing study drug, the 
Investigator should report the pregnancy to Medpace Clinical Safety within 
24 hours of being notified. Medpace Clinical Safety will then forward the “Exposure 
In Utero” form to the Investigator for completion. Provided consent is obtained, the 
designated service provider will follow up on the outcome of all pregnancies until 
delivery or the end of pregnancy (i.e., delivery, still birth, miscarriage, termination), 
and also on the health status of the newborn. This also applies to pregnancies 
reported to the designated service provider after the required reporting period. 
9.2.6 Adverse Events of Special Interest 
ONO-7475 
Adverse events of special interest have yet to be defined for ONO-7475. 
Venetoclax 
Adverse events of special interest for venetoclax when taken in combination with 
ONO-7475 have yet to be defined. 
9.2.7 Events Not To Be Reported as Serious Adverse Events 
The following events do not qualify as SAEs as defined in Section 9.2.1. 
Any planned hospitalizations or hospitalizations purely for diagnostic purposes (as 
required by the protocol) do not qualify as AEs or SAEs and do not require 
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analyses. For Part A, the efficacy summaries will focus on the subset of the FAS 
who are diagnosed with AML. For Part D, patients in the FAS may be replaced if 
the efficacy analysis is compromised by extenuating circumstances (for example, 
a pandemic in which patient site visits are not possible and therefore clinical 
response cannot be evaluated). 
The Response Evaluable Analysis Set for Part D will be based on all patients who 
received at least 1 dose of venetoclax and/or ONO-7475 and whose response has 
been determined by the Revised Recommendations of the IWG for Response 
Criteria, in Acute Myeloid Leukemia (Section 13.8). Patients in the Response 
Evaluable Analysis Set will be grouped by the dose level as assigned at the study 
entry. 
The PK Analysis Set will include patients who are administered ONO-7475 for Part 
A or ONO-7475 or venetoclax for Part D, and from whom results of plasma 
concentrations are obtained for at least 1 sampling point. Patients in the PK 
analysis set will be grouped based on the dose level received during the PK sample 
collection period. If necessary, there will be 2 PK Analysis Sets in Part D; 1 for 
ONO-7475 and 1 for venetoclax. 
The PD Analysis Set will include patients who have received at least 1 dose of 
ONO-7475 for Part A or ONO-7475 or venetoclax for Part D, and from whom 
results of PD collection assays are obtained for at least 1 sampling point which is 
suitable for analysis. Patients in the PD analysis set will be grouped based on the 
initial dose they actually received. 
Detailed definitions of the analysis sets will be provided in the Statistical Analysis 
Plan (SAP). 
10.2.2 Key Elements of Analysis Plan 
All data will be presented in the most appropriate manner allowing for type and 
distribution.  
Where appropriate, summaries will be made for each dose level.  
Details of summaries and analyses of the data, including where patients may have 
changed their ONO-7475 dose level, will be provided in the SAP. 
Continuous variables will be summarized using mean, standard deviation, median, 
minimum and maximum, and categorical variables will be summarized using 
frequencies and percentages. 
Baseline and demographic characteristics (e.g., age, sex etc.) will be summarized 
as continuous or categorical variables, as appropriate.  
Statistical analysis, including the PK analysis for after database lock, will be 
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10.2.2.1 Efficacy analyses 
The CR/CRh rate in Part D is defined as the proportion of patients who have a best 
overall response in AML of CR or CRh. 
ORR is defined as the proportion of patients who achieve responder status, i.e, 
having a best overall response in AML and MDS including: 
[AML] 
• CR 
• CRh (Part D only) 
• CRi (note for Part D this will constitute CRi patients who did not meet the 
requirements for CRh) 
• Morphologic leukemia-free state  
• PR  
[MDS] 
• CR 
• Marrow CR 
• PR 
Patients who do not have sufficient baseline or on-study efficacy status information 
to be adequately assessed for response status (i.e., those with best overall 
response of not evaluable) or received anti-leukemic therapy other than the study 
treatment prior to becoming a responder (per the definition above) will be 
considered as non-responders. Patients with a best overall response of treatment 
failure (Parts A and D patients with AML), failure or stable disease (Part A patients 
with MDS), progression (per the definition given below), or missing response 
assessments, will be considered non-responders. 
Best Overall Response is defined as the best response assessment assigned to 
a patient at any time-point during the study up to and including progression, prior 
to the patient’s study completion and prior to initiation of any other anti-leukemic 
therapy.  
Time to Response (TTR) is defined as the duration in months from the date of 
first study treatment to the date of first documentation of responder status (per 
definition above). TTR is not defined for patients who do not achieve a best overall 
response of PR or better.  
DoR is defined as duration in months from the date of first documentation of 
responder status (per definition above) to the date of disease progression or death 
due to any cause, whichever is earlier. DoR is not defined for patients who do not 
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If the specified event does not occur, the DoR will be censored at the date of last 
adequate efficacy assessment. If there is no adequate assessment available after 
the first documentation of responder status (per definition above), the DoR will be 
censored at the date when responder status is first recorded. 
The date of definitive progression will be the time point at which progression is first 
identified. Progression is defined as disease recurrence for AML in Parts A and D, 
relapse after CR or PR and disease progression in MDS (per IWG criteria for 
MDS).  
An adequate tumor assessment is defined as one with an outcome other than “Not 
Evaluable”.  
EFS is defined as the duration in months from the date of first study treatment to 
treatment failure (for AML patients in Parts A and D), failure (for MDS patients in 
Part A), progression (per definition above), or patient death from any cause. 
If the specified event does not occur, the EFS will be censored at the date of last 
adequate efficacy assessment. If there is no adequate assessment available, the 
EFS will be censored at the date of first study treatment. 
OS is defined as duration in months from the date of first study treatment to death 
from any cause. OS will be censored at the date last known to be alive for patients 
who are still alive. 
The primary efficacy variables will be listed and summarized using descriptive 
statistics based on the FAS for each part of the study.  
The CR/CRh rate (for Part D only) and ORR will be calculated using the FAS. The 
2-sided 95% exact confidence intervals of the CR/CRh rate and ORR will be 
estimated using the Clopper-Pearson method.  
The rate of CR/CRh without MRD will be provided for patients in Part D. 
 
The rates of CR and CRh will also be provided separately for patients in Part D. 
TTR will be summarized descriptively as a continuous variable for those patients 
who achieve PR or better. 
DoR will be characterized using the Kaplan-Meier method for patients who achieve 
PR or better (in Part A) and CR/CRh (in Part D). Medians, 25th percentile (Q1), 
75th percentile (Q3), minimum and maximum will be provided along with the 95% 
confidence intervals for the median. Kaplan-Meier curves will be provided. 
OS and EFS will be analyzed for all patients in a similar manner to DoR. 
For Part A, the efficacy endpoint summaries will focus on AML patients only. 




 
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10.2.2.4 Safety Analyses 
The SAF will be used for all safety analyses by default. 
Safety will be evaluated by monitoring all AEs and SAEs.  
All AEs will be tabulated and graded according to NCI CTCAE version 4.03 for 
each patient cohort. Verbatim descriptions of AEs reported during the study period 
will be mapped to Medical Dictionary for Regulatory Activities (MedDRA) preferred 
terms and body systems.  
Treatment-emergent AEs are defined as: 
• Any AEs with an onset date on or after the study drug start date and no later 
than 30 days after permanent discontinuation of study drug (or initiation of 
new anti-cancer therapy, whichever occurs first) 
All treatment-emergent AEs will be summarized in frequency tables.  
For any AE summary showing the AEs by NCI CTCAE grade, the highest grade 
will be used for those AEs that occurred more than once in an individual patient 
during the study. 
The DLTs will be summarized in frequency tables and also listed.  
Laboratory safety assessments will include regular, routine monitoring of 
hematology and blood chemistry, and urinalysis.  
Laboratory data collected during the study will be analyzed and summarized using 
both quantitative and qualitative methods. Summaries of laboratory data will be 
provided and will include data collected up to the last dose of study drug plus 
30 days for patients who have permanently discontinued study drug.  
Laboratory NCI CTCAE grades at baseline and worst post baseline will be 
summarized in shift tables.  
Body weight and vital signs and their change from baseline will be summarized. 
Descriptive statistics will be used to summarize ECOG performance status.  
A summary of ECG parameters will be provided for each scheduled time point and 
categorical summaries of maximum observed and change from baseline values 
will be presented for QTcF.  
Prior and concomitant medications will be summarized. 
Full details will be provided in the SAP. 




 
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11 STUDY ADMINISTRATION 
11.1 Regulatory and Ethical Considerations 
11.1.1 Regulatory Authorities 
Approval from the Regulatory Authorities will be obtained prior to study-specific 
screening of the first patient, according to applicable national and international 
regulations and guidelines. 
11.1.2 Institutional Review Board 
Before initiating the trial, the Investigator must have written and dated approval 
from the IRB for the trial protocol, the written informed consent form, consent form 
updates, and any other written information to be provided to the patients. As part 
of the Investigator's written application to the IRB, the Investigator must provide 
the IRB with a current copy of the IB. If the IB is updated during the trial, the 
Investigator must supply a copy of the updated IB to the IRB.  
The Investigator is required to obtain approval from the IRB if changes to the 
protocol, written informed consent form, written information to be provided to the 
patients and/or other documents are classed as substantial amendments. 
The Investigator is required to report promptly to the IRB any new information that 
may adversely affect the safety of the patients or the conduct of the trial. 
If required by local regulations the Investigator should submit written summaries 
of the trial status to the IRB on an annual basis and upon completion of the trial, 
the Investigator should complete and send the End of Trial Notification form.  
11.1.3 Protocol Adherence 
The protocol must be read thoroughly and the instructions followed exactly. Any 
deviations should be agreed by both the Sponsor and the Investigator and where 
appropriate, written protocol amendments will be made to reflect the changes 
agreed upon. Where a deviation is necessary for the well-being of a patient, the 
ONO Medical Officer must be informed of the action as soon as possible and 
amendments submitted to IRB. 
A protocol amendment requires IRB and regulatory approval if it constitutes a 
substantial amendment. 
In the event that an unexpected and extended situation which impacts on study 
conduct develops (e.g., a public health emergency such as a pandemic disease), 
certain protocol deviations may be unavoidable. In this circumstance, any protocol 
deviations must be recorded along with the specific reason for the deviation as per 
usual practice but additional information must be recorded regarding the root 
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alternative study procedures are required to ensure the patient’s safety. Where the 
Investigator determines a deviation is necessary to maintain patient safety, the 
Sponsor/Clinical Research Associate or the Medical Monitor must be informed of 
the action as soon as possible and it must be appropriately documented. 
11.1.4 Patient Information and Consent 
The Investigator, or person designated by the Investigator, must obtain written 
informed consent prior to the patient undertaking any study-related activity. The 
Investigator or an authorized designee must explain the nature of the study and 
the treatment in such a manner that the patient is aware of his/her rights and 
responsibilities, as well as potential benefits and risks. The Investigator is also 
responsible for answering any questions the patient may have throughout the 
study and for sharing any new information that may be relevant to the patient’s 
willingness to continue his/her participation in the trial in a timely manner. 
Patients must also be informed that participation is voluntary and that they may 
withdraw from the study at any time, without prejudice to their current or future 
care. Documentation of the discussion and the date of informed consent must be 
recorded. Once all of their questions have been answered and the patient has 
voluntarily agreed to participate in the study, patients will be asked to sign and date 
the informed consent form. 
Each patient’s original consent form, signed and dated by the patient and by the 
person who conducted the informed consent discussion, will be retained by the 
Investigator and a copy will be given to the patient for their records. In obtaining 
and documenting informed consent, the Investigator must comply with the applicable 
regulatory requirements and must adhere to GCP and to the ethical principles that 
have their origin in the Declaration of Helsinki. 
11.1.5 Indemnity and Compensation  
In the event that it can be demonstrated that a patient suffers any significant 
deterioration in health or well-being or any harmful susceptibility or toxicity as a 
direct result of their participation in this study, 
 will agree 
to abide by the applicable local guidelines with regard to compensation payable to 
the patient. The amount of compensation will be calculated by reference to the 
level of damages commonly awarded in laws of the state in the US for similar 
injuries at the time when such injury occurred. The Investigator and their employer 
have insurance cover for the malpractice and/or negligence of their employees and 
agents. 
11.2 Reporting of Urgent Safety Measures 
Urgent safety measures may be implemented to protect patients against any 
immediate hazard to their health and safety. The Investigator must notify the 
Sponsor immediately (<24 hours) to discuss the hazard and any actions taken or 
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inform the appropriate competent authorities, Investigators and IRBs immediately 
and in any event no later than 3 calendar days of any urgent safety measures 
implemented during the study. 
11.3 Study Monitoring 
Study monitoring will be performed by a Service Provider (Medpace). Monitoring 
procedures will be followed in order to comply with GCP guidelines and applicable 
SOPs. 
The purposes of trial monitoring are to verify that: 
• The rights and well-being of patients are protected 
• The reported trial data are accurate, complete and verifiable from source 
documents 
• The conduct of the trial is in compliance with the currently approved 
protocol/amendment(s), with GCP, and with applicable regulatory 
requirements 
Study data recorded on source documents will be made available to the study 
monitors for source document verification. The site monitors will perform source 
document verification in compliance with GCP and the respective SOPs. 
11.3.1 Access to Source Data 
The Investigator(s), as outlined in GCP, must provide direct access to source data 
for study-related monitoring, audits, ethics review, and regulatory inspection(s). 
11.3.2 Quality Control and Quality Assurance 
The Sponsor, or its designee, may audit the study at any time during or after its 
completion as part of their Quality Assurance program. The Investigator must 
provide access to source data, eCRFs, and study files for Sponsor-accredited 
auditors or Regulatory Authority or IRB inspectors. If the Investigator is notified of 
a scheduled Regulatory Authority inspection, they must notify the Sponsor 
immediately (within 24 hours of notice). The same applies to unannounced audits 
and inspections. 
11.3.3 Data Handling and Record Keeping 
The Investigator is responsible for filing and archiving appropriate essential 
documents as outlined in the ICH-GCP Section 8. 
All data derived from the study will remain the property of the Sponsor. The study 
CSR will be compiled by order of the Sponsor. Records of patients, source 
documents, eCRFs and drug inventory records, pertaining to the study must be 
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Paper files should be kept in a rodent-proof, fire-proof and water-proof 
environment. 
If the Investigator moves, withdraws from an investigation or retires, the 
responsibility for maintaining the Investigator records may be transferred to 
another person who will accept responsibility. Notice of transfer must be made to 
and agreed by the Sponsor and documented in writing. 
Essential documents must be stored securely for a minimum period, depending on 
the country-specific requirements. 
11.4 Provision of Study Results and Information to Investigators 
No publication or disclosure of study results will be permitted except under the 
terms and conditions of a separate written agreement between the Sponsor and 
the Investigator and/or the Investigator’s institution. 
The Investigators will be provided with an electronic copy of the eCRF data for 
their patients after completion of the study. 
On finalization of the CSR, a copy will be provided to the Investigator(s). 
11.5 Data Management 
Data management for all study data will be conducted by Medpace designated 
staff.  
An EDC system 
 will be used to collect data for this study. 
Trained Investigator site staff will enter the data required by the protocol into the 
EDC system by completing an eCRF from source documents (e.g., medical 
records and study-specific data capture tools as needed). All information in the 
eCRFs must be traceable to these source documents. Data management 
processes will be described in a Data Management Plan (DMP). The DMP will be 
reviewed and approved by the Sponsor and made final prior to study start.  
The EDC system will keep track of all data entry, alterations, and query resolution 
in an audit trail. The audit trail will form an integral part of the application and will 
be archived alongside the data. 
Automatic validation programs within the EDC system will check for data 
discrepancies during and after data entry and, by generating appropriate error 
messages, allow the data to be confirmed or corrected online by the designated 
site staff. The system will keep track of all data entry, alteration, and query 
resolution via an audit trail. The Investigator must certify that the data entered are 
complete and accurate by provision of an electronic signature for each eCRF. If 
any changes are made to the eCRF after a form has been locked and electronically 
signed, the Investigator will be required to repeat the electronic signature process 
to authorize agreement with any new information or changes. 






 
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12 REFERENCES  
1. Park IK, et al. Inhibition of the receptor tyrosine kinase Axl impedes 
activation of the FLT3 internal tandem duplication in human acute myeloid 
leukemia: implications for Axl as a potential therapeutic target. Blood. 2013; 
121: 2064-2073. 
2. Yasuhiro T, et al. Development of an Axl/Mer Dual Inhibitor, ONO-9330547: 
Promising Single Agent Activity in an Acute Myeloid Leukemia (AML) Model. 
ASH Annual Meeting San Francisco, CA December 2014. 
3. Cheson B, et al. The 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; 21:4642-4649. 
4. Yoshizawa T, et al. Development of Axl/Mer inhibitor, ONO-9330547: 
preclinical evidence supporting the combination with immunotherapeutics. 
AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. 
2016. 76, 14 Suppl): LB-218. 
5. NCCN Clinical Practice Guidelines in Oncology; Myelodysplastic 
Syndromes Version 2. 2019 (October 18, 2018). 
6. Linger RM, Keating AK, Earp HS, Graham DK. Taking aim at Mer and Axl 
receptor tyrosine kinases as novel therapeutic targets in solid tumors. 
Expert Opin Ther Targets. 2010; 14(10):1073-90. 
7. International Conference on Harmonisation: Guidance for Industry: S9 
Nonclinical Evaluation for Anticancer Pharmaceuticals (March 2010). From 
URL: 
https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/s9-nonclinical-evaluation-anticancer-pharmaceuticals. 
8. Lemke G. Biology of the TAM receptors. Cold Spring Harb Perspect Biol. 
2013; 5(11):a009076. 
9. Linger RM, Keating AK, Earp HS, Graham DK. TAM receptor tyrosine 
kinases: biologic functions, signaling, and potential therapeutic targeting in 
human cancer. AdvCancerRes. 2008;100:35-83. 
10. Graham DK, DeRyckere D, Davies KD, Earp HS. The TAM family: 
phosphatidylserine sensing receptor tyrosine kinases gone awry in cancer. 
Nat Rev Cancer. 2014; 14(12):769-85. 
11. Ueno Y, et al Gilteritinib (ASP2215), a Novel FLT3/AXL Inhibitor: Preclinical 
Evaluation in Combination with Azacitidine in Acute Myeloid Leukemia. 
Blood 2016; 128 (22): 2830. 
12. Arber DA, et al. The 2016 revision to the World Health Organization 
classification of myeloid neoplasms and acute leukemia. Blood 2016; 
127:2391-2405. 


 
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13. Greenberg PL, et al. Revised International Prognostic Scoring System for 
Myelodysplastic Syndromes. Blood 2012; 120: 2454-2465. 
14. International Committee of Medical Journal Editors. Recommendations for 
the Conduct, Reporting, Editing, and Publication of Scholarly Work in 
Medical 
Journals. 
2015. 
Accessed 
online: 
http://www.icmje.org/recommendations/ 
15. Ma X. Epidemiology of myelodysplastic syndromes. Am J Med. 2012;125(7 
Suppl):S2–S5.  
16. Steensma DP. Myelodysplastic syndromes current treatment algorithm 
2018. Blood Cancer Journal 2018; 8(5): 47.  
17. Cheson BD, et al and World Health Organization(WHO) international 
working group. Clinical application and proposal for modification of the 
International Working Group (IWG) response criteria in myelodysplasia. 
Blood 2006; 108(2), 419–425.  
18. Montesinos P, et al. Differentiation syndrome in patients with acute 
promyelocytic leukemia treated with all-trans retinoic acid and anthracycline 
chemotherapy: characteristics, outcome, and prognostic factors. Blood 
2009; 113(4): 775–783.  
19. Sanz, MA, & Montesinos, P. How we prevent and treat differentiation 
syndrome in patients with acute promyelocytic leukemia. Blood 2014; 
123(18): 2777–2782.  
20. Montesinos P, & Sanz MA. The differentiation syndrome in patients with 
acute promyelocytic leukemia: Experience of the pethema group and review 
of the literature. Mediterranean Journal of Hematology and Infectious 
Diseases 2011; 3(1).  
21. Howlader N, Noone AM, Krapcho M, Miller D, Brest A, Yu M, Ruhl J, 
Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). 
SEER Cancer Statistics Review, 1975–2017, National Cancer Institute. 
Bethesda, 
MD, 
https://seer.cancer.gov/csr/1975_2017/, 
based 
on 
November 2019 SEER data submission, posted to the SEER web site, April 
2020. 
22. VENCLEXTA 
(venetoclax) 
Initial 
US 
approval 
2016 
https://www.rxabbvie.com/pdf/venclexta.pdf  
23. Post S, et al. AXL/Mertk inhibitor ONO-7475 potently synergizes with BCL2 
inhibitor ABT-199, overcomes ABT-199 resistance mechanisms and kills 
FLT3 ITD AML cells. Blood 2019; 134 (Supplement_1): 2550. 
24. Ruvolo P, et al. Anexelekto/MER tyrosine kinase inhibitor ONO-7475 
arrests growth and kills FMS-like tyrosine kinase 3-internal tandem 
duplication mutant acute myeloid leukemia cells by diverse mechanisms. 
Haematologica 2017; 102(12): 2048–2057. 
25. ONO-7475 Investigator’s Brochure 


 
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26. Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin 
Trials. 1989; 10(1):1-10.  
27. Döhner H, et al. Diagnosis and management of AML in adults: 2017 ELN 
recommendations from an international expert panel. Blood 2017; 129(4): 
424–447.   
28. Norsworthy K, et al. FDA Approval Summary: Ivosidenib for Relapsed or 
Refractory Acute Myeloid Leukemia with an Isocitrate Dehydrogenase-1 
Mutation. Clin Cancer Res. 2019; 25(11):3205-3209.  
29. Fathi AT, et al. Differentiation Syndrome Associated With Enasidenib, a 
Selective Inhibitor of Mutant Isocitrate Dehydrogenase 2: Analysis of a 
Phase 1/2 Study. JAMA Oncol. 2018; 4(8):1106-1110.  
 


 
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13 APPENDICES  
13.1 Appendix 1 Time and Events Table (Part A) 


 
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13.2 Appendix 2 Visit Schedule (Part A) 


 
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13.3 Appendix 3 Time and Events Table (Part D) 


 
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13.4 Appendix 4 Visit Schedule (Part D) 


 
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13.6 Appendix 6 Protocol Amendments 


 
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13.7 Appendix 7 ECOG Performance Status 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction  
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, e.g., light house work, office work  
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours  
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed 
or chair  
5 
Dead  
Oken MM, et al. Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am 
J Clin Oncol. 1982; 5(6):649–655. 
 
 


 
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13.8 Appendix 8 Revised Recommendations of the International 
Working Group for Response Criteria in Acute Myeloid Leukemia 
Journal of Clinical Oncology, Vol 21, No 24 (December 15), 2003 
Response Criteria AML 
 
Treatment failure includes: (1) resistant disease, (2) aplasia, (3) indeterminate 
cause and recurrence due to (4) morphologic relapse, (5) molecular or cytogenetic 
relapse. 
Definitions of Endpoints for Clinical Trial 
 
 
 




 
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MDS indicates myelodysplastic syndromes; Hgb, hemoglobin; CR, complete remission; HI, hematologic improvement; 
PR, partial remission; FAB, French-American-British; AML, acute myeloid leukemia; PFS, progression-free survival; 
DFS, disease-free survival. 
* Dysplastic changes should consider the normal range of dysplastic changes (modification).  
† Modification to IWG response criteria. 
‡ In some circumstances, protocol therapy may require the initiation of further treatment (eg, consolidation, 
maintenance) before the 4-week period. Such patients can be included in the response category into which they fit at 
the time the therapy is started. Transient cytopenias during repeated chemotherapy courses should not be considered 
as interrupting durability of response, as long as they recover to the improved counts of the previous course. 
 
 


 
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13.10 
Appendix 10 NCI CTCAE Version 4.03 
In the present study, toxicities will be graded according to the NCI CTCAE, version 
4.03.  
At the time this protocol was issued, the full CTC document was available on the 
NCI web site, at the following address: http://ctep.cancer.gov.  
Investigators will receive a copy prior to the start of the study. 
 
 


 
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13.11 
Appendix 11 Calculation of Creatinine Clearance (CrCl) 
Donald W Cockcroft and M. Henry Gault. Nephron. 1976:16:31-41 
 
Standard Cockcroft and Gault Formula  
For Male: 
CrCl = 
(140–age) x (wt) 
72 x serum creatinine (mg/dL) 
 
 
For Female:  
CrCl = 
(140–age) x (wt) x 0.85 
72 x serum creatinine (mg/dL) 
 
Age in years, Weight (wt) in kilograms  
 
 


 
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13.12 
Appendix 12 Fundus Photography (Part A only) 
From URL: https://www.ophth.wisc.edu//wp-content/uploads/2017/03/7Std-D.pdf 
 
 


 
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13.13 
Appendix 13 Drug-Interactions List 
Lists of drugs with potential for interaction below have been taken from FDA HP 
Drug Development and Drug Interactions: Table of Substrates, Inhibitors and 
Inducers (Content current as of 10/MAR/2020). 
FDA HP link: https://www.fda.gov/drugs/drug-interactions-labeling/drug-
development-and-drug-interactions-table-substrates-inhibitors-and-
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13.14 
Appendix 14 Breakfast Recommendation for the 
Assessment of Food on the Pharmacokinetics of ONO-7475 
(Part A Only) 
According to the FDA guidance, a high-fat (approximately 50 percent of total 
caloric content of the meal) and high-calorie (approximately 800 to 1000 calories) 
meal is recommended as a test meal for food effect assessment. This test meal 
should derive approximately 150, 250, and 500–600 calories from protein, 
carbohydrate, and fat, respectively. An example test meal would be 2 eggs fried in 
butter, 2 strips of bacon, 2 slices of toast with butter, 4 ounces of hash brown 
potatoes and 8 ounces of whole milk. Substitutions in this test meal can be made 
as long as the meal provides a similar amount of calories from protein, 
carbohydrate, and fat and has comparable meal volume and viscosity.