Clinical trial NCT04752163
Conditions: Hematopoietic and Lymphoid Cell Neoplasm Recurrent Acute Lymphoblastic Leukemia Recurrent Acute Myeloid Leukemia Recurrent Chronic Myelomonocytic Leukemia Recurrent Myelodysplastic Syndrome Refractory Acute Lymphoblastic Leukemia Refractory Acute Myeloid Leukemia Refractory Chronic Myelomonocytic Leukemia Refractory Myelodysplastic Syndrome
Sponsor: M.D. Anderson Cancer Center
Start date: 2021-03-25; Completion date: 2023-11-08
Enrollment: 17 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase I/II trial studies the effect of DS-1594b with or without azacitidine, venetoclax, or mini-HCVD in treating patients with acute myeloid leukemia or acute lymphoblastic leukemia that has come back (recurrent) or not responded to treatment (refractory). Chemotherapy drugs, such as azacitidine, venetoclax, and mini-HCVD, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. DS-1594b may inhibit specific protein bindings that cause blood cancer. Giving DS-1594b, azacitidine, and venetoclax, or mini-HCVD may work better in treating patients with acute myeloid leukemia or acute lymphoblastic leukemia.

Detailed description:
OUTLINE: This is a phase I, dose-escalation study of DS-1594b followed by a phase II study.

PHASE I: Patients receive DS-1594b orally (PO) twice daily (BID) on days 1-28 in the absence of disease progression or unacceptable toxicity.

PHASE II: Patients are assigned to 1 of 4 cohorts.

COHORT A: Patients with MLLr receive DS-1594b PO BID on days 1-28. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

COHORT B: Patients with NPM1m receive DS-1594b PO BID on days 1-28. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

COHORT C: Patients receive DS-1594b PO BID on days 1-28, venetoclax PO QD on days 1-28, and azacitidine intravenously (IV) or subcutaneously (SC) on days 1-7. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

COHORT D: Patients receive DS-1594b PO BID on days 1-28. For cycles 1, 3, 5, 7, patients also receive cyclophosphamide IV over 3 hours on days 1-3, mesna IV over 24 hours on days 1-3, vincristine IV on days 1 and 11, dexamethasone PO or IV on days 1-4 and 11-14, filgrastim SC on days 1-28, methotrexate intrathecally (IT) on day 2 of cycles 1 and 3, and cytarabine IT on day 7 of cycles 1 and 3. For cycles 2, 4, 6, 8, patients also receive methotrexate IV over 24 hours on day 1, cytarabine BID IV over 3 hours on days 2 and 3, leucovorin IV or PO every 6 hours (Q6H) starting 12 hours after completion of methotrexate, filgrastim SC days 1-28, cytarabine IT on day 5-8 of cycles 2 and 4 and methotrexate IT on days 8-11 of cycles 2 and 4. Patients with CD20 expression may also receive rituximab IV on days 1 and 11 of cycles 1 and 3 and days 1 and 8 of cycles 2 and 4. Cycles repeat every 28 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Patients may then receive DS-1594b PO BID on days 1-28, vincristine IV over 15 minutes on day 7 and prednisone PO BID on days 1-5. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at days 30 and 100.

Arms: arm 1: Patients with MLLr or NPM1m receive DS-1594b PO BID on days 1-28. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive DS-1594b PO BID on days 1-28, venetoclax PO QD on days 1-28, and azacitidine IV or SC on days 1-7. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. arm 3: Patients receive DS-1594b PO BID on days 1-28. For additional information, see trial description. arm 4: Patients receive DS-1594b PO BID on days 1-28 in the absence of disease progression or unacceptable toxicity.

70 mg twice daily. arm 5: Patients receive DS-1594b PO BID on days 1-28 in the absence of disease progression or unacceptable toxicity.

50 mg twice daily. arm 6: Patients receive DS-1594b PO BID on days 1-28 in the absence of disease progression or unacceptable toxicity.

20 mg daily. arm 7: Patients receive DS-1594b PO BID on days 1-28 in the absence of disease progression or unacceptable toxicity.

50 mg daily. arm 8: Patients receive DS-1594b PO BID on days 1-28 in the absence of disease progression or unacceptable toxicity.

100 mg daily.
Interventions: intervention 1: DS-1594b intervention 2: Azacitidine intervention 3: Cyclophosphamide intervention 4: Cytarabine intervention 5: Dexamethasone intervention 6: Filgrastim intervention 7: Leucovorin intervention 8: Mesna intervention 9: Methotrexate intervention 10: Prednisone intervention 11: Rituximab intervention 12: Venetoclax intervention 13: Vincristine
Intervention descriptions: intervention 1: Given DS-1594b PO intervention 2: Given IV or SC intervention 3: Given IV intervention 4: Given IT intervention 5: Given PO or IV intervention 6: Given SC intervention 7: Given IV or PO intervention 8: Given IV intervention 9: Given IT intervention 10: Given PO intervention 11: Given IV intervention 12: Given PO intervention 13: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 1 of 127 
 
MD Anderson IND Sponsor Cover Sheet 
  
Protocol ID 
2020-0946 
Protocol Title 
An Open-label Phase 1/2 Multi-Arm Study of DS-1594b as a Single-
Agent and in Combination with Azacitidine and Venetoclax or mini-
HCVD for the Treatment of Patients with Acute Myeloid Leukemia 
(AML) and Acute Lymphoblastic Leukemia (ALL)  
Protocol Phase 
I/II 
Protocol Version 
5.0 
Version Date 
20 Aug 2021 
  
Protocol PI 
Naval Daver, MD  
Department 
Leukemia 
  
IND Sponsor 
MD Anderson Cancer Center 
IND # 
154785 
  
 
 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 2 of 127 
 
An Open-label Phase 1/2 Multi-Arm Study of DS-1594b as a 
Single-Agent and in Combination with Azacitidine and 
Venetoclax or mini-HCVD for the Treatment of Patients with 
Acute Myeloid Leukemia (AML) and Acute Lymphoblastic 
Leukemia (ALL) 
 
 
 
 
 
Principal Investigator: Naval Daver, MD  
Co-PI: Hagop Kantarjian, MD 
Sponsor: MD Anderson Cancer Center 
 
 
 
University of Texas 
 
 
MD Anderson Cancer Center  
Leukemia Department, Unit 428. 
Information contained in this document is proprietary to the Sponsor and to the holder of the 
Investigational New Drug Application.  The information is provided to you in confidence which 
is requested under an agreed upon and signed Confidentiality and Disclosure Agreement.  Do not 
give this document or any copy of it or reveal any proprietary information contained in it to any 
third party (other than those in your organization who are assisting you in this work and are bound 
by the Confidentiality and Disclosure Agreement) without the prior written permission of an 
authorized representative. 
 
 
 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 3 of 127 
 
TABLE OF CONTENTS 
LIST OF TABLES ........................................................................................................................ 7 
LIST OF FIGURES ...................................................................................................................... 9 
1. 
OBJECTIVES ............................................................................................................... 10 
2. 
BACKGROUND .......................................................................................................... 16 
2.1. 
Acute Myeloid Leukemia .............................................................................................. 16 
2.2. 
Acute Lymphoblastic Leukemia ................................................................................... 16 
2.3. 
MLL rearrangements and NPM1 mutations in AML and ALL ..................................... 16 
2.4. 
DS-1594b ...................................................................................................................... 17 
2.4.1. 
Pharmacodynamics ....................................................................................................... 17 
2.4.2. 
Safety Pharmacology and Toxicology........................................................................... 18 
2.4.3. 
Benefit/Risk Assessment ............................................................................................... 19 
3. 
STUDY DESIGN ......................................................................................................... 19 
3.1. 
Rationale for dose and regimen selection ...................................................................... 20 
3.2. 
Phase 1 Design .............................................................................................................. 21 
3.2.1. 
Operation Characteristics for BOIN Design .................................................................. 24 
3.2.2. 
Dose-Limiting Toxicity Definition ............................................................................... 26 
3.2.3. 
DDI Sub-study with Anti-fungal Agents that are Strong CYP3A Inhibitors ................. 27 
3.2.3.1.  Sub-Study Rationale ..................................................................................................... 27 
3.2.3.2.  Sub-study Design .......................................................................................................... 28 
3.2.3.3.  Sub-Study PK Evaluability Criteria .............................................................................. 29 
3.2.4. 
Food Effect Sub-study .................................................................................................. 29 
3.2.4.1.  Sub-Study Rationale ..................................................................................................... 29 
3.2.4.2.  Sub-Study Design ......................................................................................................... 29 
3.2.4.3.  Sub-Study PK Evaluability Criteria .............................................................................. 30 
3.3. 
Phase 2 Design .............................................................................................................. 30 
3.3.1. 
Rationale for Combination Cohorts (C&D) .................................................................. 32 
4. 
SUBJECT SELECTION ............................................................................................... 32 
4.1. 
Inclusion Criteria .......................................................................................................... 32 
4.2. 
Exclusion Criteria ......................................................................................................... 35 
5. 
TREATMENT PLAN ................................................................................................... 37 
5.1. 
Phase 1 Dose Administration ........................................................................................ 37 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 4 of 127 
 
5.1.1. 
Study Treatment ............................................................................................................ 37 
5.1.2. 
Dose Administration Guidance ..................................................................................... 37 
5.2. 
Phase 2 Cohort A: R/R AML with MLL-rearrangement ............................................... 39 
5.2.1. 
Dose Administration Guidance ..................................................................................... 39 
5.3. 
Phase 2 Cohort B: R/R AML with NPM1 mutation ...................................................... 39 
5.3.1. 
Dose Administration Guidance ..................................................................................... 39 
5.4. 
Phase 2 Cohort C: R/R AML Treated with the Combination of Azacitidine and 
Venetoclax with DS-1594b ........................................................................................... 39 
5.4.1. 
Study Treatment of Study Drug and Other Combination Drugs .................................... 39 
5.4.2. 
Venetoclax Administration ........................................................................................... 42 
5.5. 
Phase 2 Cohort D: R/R ALL treated with miniHCVD with DS-1594b ......................... 42 
5.5.1. 
Treatment Overview ..................................................................................................... 42 
5.5.2. 
Mini-Hyper-CVD Regimen .......................................................................................... 43 
5.5.2.1.  General Considerations ................................................................................................. 43 
5.5.2.2.  Mini-Hyper-CVD [Odd courses 1, 3, 5, 7]: ................................................................... 44 
5.5.2.3.  Methotrexate and Cytarabine [Even courses 2, 4, 6, and 8]: ......................................... 45 
5.5.3. 
Intrathecal Treatments .................................................................................................. 46 
5.5.4. 
Suggested Standard Dose Reductions/Modifications/Discontinuations: ....................... 46 
5.5.5. 
Maintenance .................................................................................................................. 48 
5.6. 
Concomitant Medications ............................................................................................. 48 
5.6.1. 
Concomitant Medications – Subject Supportive and Safety .......................................... 48 
5.6.2. 
Medications that may prolong the QTc interval ............................................................ 49 
5.6.3. 
Concomitant Medications Requiring Caution ............................................................... 49 
5.6.4. 
Prohibited Concomitant Medications: ........................................................................... 50 
5.6.5. 
Supportive Care Measures ............................................................................................ 50 
6. 
DOSING DELAYS / MODIFICATIONS / DISCONTINUATIONS FOR 
POSSIBLY RELATED ADVERSE EVENTS ............................................................. 52 
6.1. 
Toxicity At Least Possibly Related to Study Drugs ...................................................... 52 
6.2. 
Toxicity Grading ........................................................................................................... 52 
6.2.1. 
Dose Adjustments for Hematological Adverse Events (AE) Considered at Least 
Possibly Related to Study Drugs ................................................................................... 53 
6.2.2. 
Dose Adjustments for Non-Hematologic AEs Considered at Least Possibly 
Attributable to Study Drugs .......................................................................................... 54 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 5 of 127 
 
6.2.3. 
DS-1594b AEs of Special interest ................................................................................. 57 
6.2.3.1.  QTc Prolongation, Torsade de Pointes, and Other Ventricular Arrhythmias ................. 57 
6.2.3.2.  Combined Elevations of Aminotransferases and Bilirubin ............................................ 57 
6.2.4. 
Management of AESI ................................................................................................... 58 
6.2.4.1.  QTc Prolongation, TdP, and Other Ventricular Arrhythmias ........................................ 58 
6.2.4.2.  Combined Elevations of Aminotransferases and Bilirubin ............................................ 58 
6.3. 
CYP3A and P-gp Inhibitors: Dose modifications Venetoclax ....................................... 59 
6.4. 
Tumor Lysis Prophylaxis (TLS) ................................................................................... 59 
6.5. 
Differentiation Syndrome ............................................................................................. 59 
6.6. 
Meals and Dietary Requirements .................................................................................. 60 
6.7. 
Modifications of Dose Schedules Other Than the Above Will Be Allowed 
Within the Following Guidelines .................................................................................. 60 
6.8. 
Treatment Interruptions ................................................................................................. 61 
6.9. 
Intra-Patient Dose Escalation (IPDE) ............................................................................ 61 
7. 
AGENT FORMULATION AND PROCUREMENT ................................................... 62 
7.1. 
Potential Indications and Use ........................................................................................ 62 
7.2. 
Ongoing Clinical Trials ................................................................................................. 62 
7.3. 
Dosing and Administration ........................................................................................... 62 
7.4. 
Packaging and Labeling ................................................................................................ 62 
7.5. 
Study Drug Description and Preparation ....................................................................... 62 
7.6. 
Study Drug Storage ....................................................................................................... 62 
7.7. 
Study Drug Accountability ........................................................................................... 62 
8. 
SUBJECT EVALUATION ........................................................................................... 63 
8.1. 
Schedule of Assessments .............................................................................................. 63 
8.2. 
Screening ...................................................................................................................... 64 
8.3. 
Evaluation During Treatment ........................................................................................ 65 
8.4. 
PK Assessment ............................................................................................................. 66 
8.4.1. 
PK Blood Sample Collection and Handling .................................................................. 67 
8.4.2. 
Analytical Methods ....................................................................................................... 75 
8.5. 
Cardiac Assessment (Electrocardiograms) .................................................................... 75 
8.6. 
Correlative Studies (Mandatory for Phase 1) ................................................................ 77 
8.7. 
Outside Physician Participation During Treatment ....................................................... 79 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 6 of 127 
 
8.8. 
CRITERIA FOR RESPONSE: ..................................................................................... 80 
8.8.1. 
Response Criteria for AML ........................................................................................... 80 
8.8.2. 
Response Criteria for ALL ............................................................................................ 81 
8.8.3. 
Transfusion Independence (TI) ..................................................................................... 82 
8.8.4. 
Relapse Definition (AML and ALL) ............................................................................. 82 
8.9. 
DISCONTINUATION OF TREATMENT ................................................................... 82 
8.9.1. 
Discontinuation Criteria for Individual Subjects ........................................................... 82 
8.9.2. 
Study Stopping Rules .................................................................................................... 83 
8.9.3. 
Protocol Violations and Deviations ............................................................................... 83 
8.10. 
ADVERSE EVENT MONITORING, RECORDING, AND REPORTING ................. 84 
8.10.1.  Definitions and Procedures ........................................................................................... 84 
8.10.2.  Serious Adverse Events (SAEs) .................................................................................... 86 
Serious Adverse Event (SAE) Reporting Requirements for M D Anderson Sponsor 
Single Site IND Protocols ............................................................................................. 86 
Adverse Events of Special Interest (AESI) ................................................................................. 87 
8.10.3.  Pregnancy ..................................................................................................................... 87 
8.10.4.  Investigator Communications with MDACC ................................................................ 88 
8.10.5.  MDACC Reporting to Daiichi Sankyo, Inc. .................................................................. 88 
9. 
STATISTICAL CONSIDERATIONS .......................................................................... 88 
9.1. 
Phase 1 .......................................................................................................................... 89 
9.2. 
Phase 2 .......................................................................................................................... 89 
9.3. 
Futility and Toxicity Monitoring ................................................................................... 89 
9.3.1. 
IND Office Futility and Safety Monitoring ................................................................... 91 
9.4. 
Statistical Analysis Plan ................................................................................................ 92 
9.4.1. 
Analysis Sets ................................................................................................................. 92 
9.4.1.1.  Efficacy Analysis Set .................................................................................................... 92 
9.4.1.2.  Safety Analysis Set ....................................................................................................... 92 
9.4.1.3.  DLT Evaluable Set ........................................................................................................ 92 
9.4.1.4.  PK Analysis Set ............................................................................................................ 93 
9.4.2. 
Analysis Convention ..................................................................................................... 93 
9.4.3. 
Analysis of Subject Disposition, Demography and Baseline Characteristics, and 
Medical History ............................................................................................................ 93 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 7 of 127 
 
9.4.4. 
Analysis of Exposure of Study Drug ............................................................................. 93 
9.4.5. 
Analysis of Prior and Concomitant Medications ........................................................... 94 
9.4.6. 
Efficacy Analyses ......................................................................................................... 94 
9.4.7. 
Safety Analyses ............................................................................................................ 95 
9.4.7.1.  Dose-Limiting Toxicities .............................................................................................. 95 
9.4.7.2.  Adverse Events ............................................................................................................. 95 
9.4.7.3.  Vital Signs .................................................................................................................... 97 
9.4.7.4.  ECG .............................................................................................................................. 97 
9.4.8. 
Dosing and Extent of Exposure ..................................................................................... 98 
9.4.9. 
PK Analyses ................................................................................................................. 99 
9.4.9.1.  Food Effect Sub-Study .................................................................................................. 99 
9.4.9.2.  DDI Sub-Study ............................................................................................................. 99 
9.4.10.  PK/PD Analyses ......................................................................................................... 100 
10. 
APPENDICES ............................................................................................................ 101 
11. 
REFERENCES ........................................................................................................... 125 
 
LIST OF TABLES 
Table 1: 
Primary Objectives and Their Endpoints and Category ............................................ 10 
Table 2: 
Secondary Objectives and Their Endpoints and Category ........................................ 11 
Table 3: 
Exploratory Objectives and Their Endpoints and Category ...................................... 13 
Table 4: 
Dose escalation/de-escalation rule for the BOIN design .......................................... 23 
Table 5: 
Operating Characteristics of the BOIN Design ......................................................... 25 
Table 6: 
Dose Levels for Azacitidine, Venetoclax, and DS-1594b......................................... 39 
Table 7: 
Dose levels for miniHCVD, and DS-1594b ............................................................. 42 
Table 8: 
Maintenance Chemotherapy Dose Adjustments ....................................................... 48 
Table 9: 
Recommendations for the use of concomitant medications and therapies ................ 51 
Table 10:  DS-1594b Dose Adjustments for Neutropenia At Least Possibly Related to 
Study Drug ............................................................................................................... 53 
Table 11:  Dose Adjustments of Azacitidine, Venetoclax, and/or DS-1594b for Non-
Hematologic Possibly Related AEs, Clinically Significant in the Opinion of 
the Investigator ......................................................................................................... 55 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 8 of 127 
 
Table 12:  Dose Adjustment for QTc Interval Prolongation ...................................................... 55 
Table 13:  Dose Modification for Clinically Suspected Acute Differentiation Syndrome ......... 56 
Table 14:  DS-1594b PK Blood Collection for Twice a Day (BID) Dosing During 
Phase 1 [Excluding Subjects Enrolled in DDI and Food Effect Sub-Studies] 
Dose Escalation ........................................................................................................ 68 
Table 15:  DS-1594b PK Blood Collection for Daily (QD) Dosing During Phase 1 
[Excluding Subjects Enrolled in DDI and Food Effect Sub-Studies] Dose 
Escalation ................................................................................................................. 69 
Table 16:  DS-1594b PK Blood Collection During Phase 2 Dose Expansion ........................... 71 
Table 17:  DS-1594b PK Blood Collection for DDI Sub-Study with Antifungal Agents 
During Phase 1 After MTD Determination (N ~ 12) ................................................ 71 
Table 18:  DS-1594b PK Blood Collection for DDI Sub-Study with Antifungal Agents 
During Phase 1 Before MTD Determination ............................................................ 73 
Table 19:  DS-1594b PK Blood Collection for Food Effect Sub-Study During Phase 1 
After MTD Determination (N ~ 6) ........................................................................... 74 
Table 20:  ECG Collection During Phase 1 Escalation .............................................................. 75 
Table 21:  ECG Collection During Phase 2 Dose Expansion .................................................... 77 
Table 22:  Stopping Boundaries for Toxicity and Futility Monitoring in Each of 
Cohorts A-D ............................................................................................................. 90 
Table 23:  Operating Characteristics for Futility Monitoring in each of Cohorts A-D .............. 91 
Table 24:  Operating Characteristics for Toxicity Monitoring in each of Cohorts A-D ............. 91 
Table 25:  Overall early stopping probabilities for Futility and Toxicity Monitoring in 
each of Cohorts A-D ................................................................................................ 91 
Table 26:  95% Credible Intervals Under Various Scenarios with Different Numbers of 
Responses ................................................................................................................. 92 
Table 27:  AESI Categories and SMQ Search Criteria .............................................................. 96 
Table 28:  List of Prohibited QT Prolongation Drugs ............................................................. 101 
Table 29:  Prohibited Medications That Are Strong Inhibitors or Inducers of CYP3A, or 
CYP3A/P-Gp and CYP2C19 Substrates with Narrow Therapeutic Indices ............ 102 
Table 30:  List of medications to be used with caution............................................................ 103 
Table 31:  Additional Prohibited Medications for Subjects Enrolled in DDI and Food 
Effect Sub-Studies .................................................................................................. 105 
Table 32:  Phase 1 Dose Escalation Schedule of Events ......................................................... 106 
Table 33:  Phase 2 Cohorts A & B Schedule of Events ........................................................... 112 
Table 34:  Phase 2 Cohort C Schedule of Events .................................................................... 116 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 9 of 127 
 
Table 35:  Phase 2 Cohort D Schedule of Events .................................................................... 120 
LIST OF FIGURES 
Figure 1: 
Study Schema ........................................................................................................... 20 
Figure 2: 
Flowchart for Trial Conduct Using the BOIN Design .............................................. 24 
 
 
 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 10 of 127 
 
1. 
OBJECTIVES 
The Primary, Secondary, and Exploratory Objectives are shown in tabular format in the 
following three tables. See Figure 1Figure 1 for this Phase 1 / 2 Study Diagram. 
Table 1: 
Primary Objectives and Their Endpoints and Category 
Primary Objectives 
Endpoints 
Category 
Phase 1 only: 
To determine the safety, tolerability, 
Maximum Tolerable Dose (MTD), and 
Recommended Phase 2 Dose (RP2D) of DS-
1594b in subjects with relapsed/refractory 
(R/R) Acute Myeloid Leukemia (AML) and 
Acute Lymphoblastic Leukemia (ALL). 
MTD; 
RP2D; 
Safety Profile of DS-1594b; 
Safety 
Phase 2 only (Cohort A): 
To evaluate the safety, tolerability, and 
efficacy defined as Complete Remission 
(CR) and Complete Remission with Partial 
Hematologic Recovery (CRh) rate of DS-
1594b in subjects with R/R AML with 
Mixed-Lineage Leukemia rearrangement 
(MLLr). 
CR/CRh rate with DS-1594b 
monotherapy in R/R AML with MLLr; 
Safety Profile of DS-1594b 
Efficacy 
Safety 
Phase 2 only (Cohort B): 
To evaluate the safety, tolerability, and 
efficacy defined as CR+CRh rate of DS-
1594b in subjects with R/R AML with a 
Nucleophosmin 1 mutation (NPM1m). 
CR/CRh rate with DS-1594b 
monotherapy in R/R AML with 
NPM1m; 
Safety Profile of DS-1594b 
Efficacy 
Safety 
Phase 2 only (Cohort C): 
To evaluate the safety, tolerability, and 
efficacy defined as CR+CRh rate of DS-
1594b in combination with azacitidine and 
venetoclax in R/R MLLr or R/R NPM1m 
AML. 
CR/CRh rate with DS-1594b 
monotherapy in R/R AML with MLLr; 
Safety Profile of DS-1594b in 
combination with azacitidine and 
venetoclax 
Efficacy 
Safety 
Phase 2 only (Cohort D): 
To evaluate the safety, tolerability, and 
efficacy defined as CR+ Complete 
Remission with Incomplete Hematologic 
Recovery (CRi) rate of DS-1594b in 
combination with mini-HCVD in R/R ALL 
with MLLr. 
CR/CRi rate with DS-1594b in 
combination with mini-HCVD in R/R 
ALL with MLLr; 
Safety Profile of DS-1594b in 
combination with mini-HCVD 
Efficacy 
Safety 
Response definitions Section 8.8  
 
Formatted: C-Hyperlink


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 11 of 127 
 
Table 2: 
Secondary Objectives and Their Endpoints and Category 
Secondary Objectives 
Endpoints 
Category 
Phase 1 only:  
To evaluate the combined complete 
remission (CR) and CR with partial 
hematologic recovery (CRh) rate within 3 
months of therapy initiation with DS-1594b 
in subjects with R/R AML or R/R ALL. 
CR/CRh rate in Phase 1 
Efficacy 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 12 of 127 
 
Secondary Objectives 
Endpoints 
Category 
Phases 1 and 2: 
To assess the composite CR (CRc) rate 
defined as CR + complete remission with 
incomplete blood count recovery (CRi), 
morphologic leukemia free survival 
(MLFS), partial remission (PR), and overall 
response rate of subjects with R/R AML and 
R/R ALL treated on single-agent or 
combinations of DS-1594b. 
CRc rate 
MLFS rate 
PR rate 
ORR (CR + CRi + MLFS + PR) rate 
Efficacy 
Phases 1 and 2: 
To determine the:  
 
duration of response (DOR),  
 
time to first response, time to 
best response,  
 
rate of durable transfusion 
independence (TI), 
 
event-free survival (EFS),  
 
overall survival (OS),  
 
measurable residual disease 
(MRD) by multiparameter flow 
cytometry at first response and 
best response,  
 
4- and 8-week mortality, and  
 
number of subjects able to 
proceed to hematopoietic stem 
cell transplantation (HSCT) 
without additional AML therapy 
and median duration to HSCT 
from the initiation of single-
agent or combinations of DS-
1594b in subjects with RR AML 
and R/R ALL 
 
DOR,  
 
time to first response, time 
to best response,  
 
TI rate, 
 
EFS,  
 
OS,  
 
MRD rate by 
multiparameter flow 
cytometry at first response 
and best response,  
 
4- and 8-week mortality 
 
number of subjects able to 
proceed to HSCT without 
additional AML therapy 
and median duration to 
HSCT from the initiation 
of single-agent or 
combinations of 
DS-1594b in subjects with 
R/R AML and R/R ALL 
Efficacy 
Phases 1 and 2: 
To characterize single and multiple-dose 
pharmacokinetics (PK) of DS-1594b and its 
metabolites  
Cmax, Ctrough, Tmax, Tlast, 
AUClast, AUCtau, AUCinf, Kel, t1/2, 
CL/F, Vz/F, AR 
 
PK 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 13 of 127 
 
Secondary Objectives 
Endpoints 
Category 
Phase 1 only: 
In a subset of subjects, to evaluate the effect 
of multiple doses of antifungal agents that 
are strong CYP3A inhibitors on the PK of 
DS-1594b 
Cmax, Ctrough, Tmax, Tlast, 
AUClast, AUCtau, AUCinf, Kel, t1/2, 
CL/F, Vz/F 
 
PK 
Phases 1 only: 
In a subset of subjects, to evaluate the 
relative exposures of DS-1594b when 
administered with a standard meal compared 
to fasted conditions 
Cmax, Ctrough, Tmax, Tlast, 
AUClast, AUCtau, AUCinf, Kel, t1/2, 
CL/F, Vz/F 
 
PK 
 
Table 3: 
Exploratory Objectives and Their Endpoints and Category 
Exploratory Objectives 
Endpoints 
Category 
Phases 1 and 2: 
To investigate correlations of clinical 
benefit to single-agent or combinations of 
DS-1594b with a pre- therapy, on-therapy, 
and progression using an appropriate NGS 
panel of gene mutations in AML and ALL, 
routine cytogenetics/karyotyping, fusion 
panels, immunophenotyping, and 
fluorescence in situ hybridization (FISH), 
when applicable. 
Not applicable 
PD/Biomarker 
Phases 1 and 2: 
To investigate possible relationships 
between response and non-response to 
single-agent or combinations of DS-1594b 
with pretherapy, on-therapy, and 
progression gene expression signatures 
(e.g., MEIS1, MEF2c or HOXA). 
Not applicable 
PD/Biomarker 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 14 of 127 
 
Exploratory Objectives 
Endpoints 
Category 
Phases 1 and 2: 
To investigate the characterization of 
genetic heterogeneity in AML or ALL 
tumor cell populations that are 
longitudinally collected, by performing 
targeted single-cell sequencing using a 
novel microfluidic approach that barcodes 
amplified genomic DNA from thousands of 
individual leukemia cells confined to 
droplets (single cell sequencing). Targeted 
single-cell sequencing is able to sensitively 
identify cells harboring pathogenic 
mutations during complete remission and 
uncover complex clonal evolution within 
AML or ALL tumors that are not 
observable with bulk sequencing. 
Not applicable 
PD/Biomarker 
Phases 1 and 2: 
To identify individual cell populations 
(AML/ALL blasts, T-cells – both bulk and 
T-cell subsets and coreceptor/ligand 
expression, macrophages and their 
coreceptor/ligands) and how their signaling 
state in disease relates to clinical outcomes 
we will perform CyTOF (mass cytometry) 
using a customized CyTOF panel 
specifically developed for this study on 
subjects’ bone marrow samples and 
peripheral blood at diagnosis, remission and 
relapse and potentially other time-points on 
study. 
Not applicable 
PD/Biomarker 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 15 of 127 
 
Exploratory Objectives 
Endpoints 
Category 
Phases 1 and 2: 
To store and/or analyze surplus blood or 
tissue including bone marrow, if available, 
for potential future companion diagnostic 
development or exploratory research into 
factors that may influence development of 
AML/ALL and/or response to therapies 
(where response is defined broadly to 
include efficacy, tolerability or safety). 
Not applicable 
PD/Biomarker 
Phases 1 and 2: 
To assess the relationship between DS-
1594b PK and PD biomarker, safety (e.g. 
QT prolongation) and efficacy endpoints. 
PK parameters vs. PD, AEs, efficacy 
PK 
 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 16 of 127 
 
2. 
BACKGROUND 
2.1. 
Acute Myeloid Leukemia 
Acute Myeloid Leukemia (AML) is a hematologic neoplasm characterized by the proliferation of 
poorly differentiated myeloid progenitor cells. The disease is particularly difficult to treat in 
older adults who account for the majority of subjects; thus, the 5-year overall survival is only 
approximately 27% in newly diagnosed AML1 . In recent years, multiple studies have 
characterized distinct molecular subgroups of AML, leading to the discovery of certain disease-
associated mutations that are now being used to classify disease, dictate prognosis and, in some 
cases, guide therapy2,3. 
Approximately, 30 to 40% of adults with AML fail to achieve CR with 1 or 2 cycles of induction 
chemotherapy and are deemed primary refractory. The outcome of subjects with AML who are 
refractory to induction therapy are dismal, with low response rates (CR/CRi = 15 to 25%) to 
salvage chemotherapy and poor long-term survival4,5,6, median OS 4-7 months . We have 
previously reported a dismal median OS of 3.8 months for subjects with AML who are refractory 
to HiDAC-containing induction therapy (defined as ≥ 1gm/m2 cytarabine per dose7). Salvage 
therapy in such subject populations yielded a response rate of 18% and median response duration 
of 9 months. These results emphasize the need to explore alternate salvage regimens for subjects 
with relapsed/refractory AML. The development of novel and effective anti-AML agents and/or 
combinations is crucial to improving the outcome of AML. 
2.2. 
Acute Lymphoblastic Leukemia 
Acute Lymphoblastic leukemia (ALL) is a malignant transformation and proliferation of 
lymphoid progenitor cells. The incidence of ALL follows a bimodal distribution, with the first 
peak occurring in childhood and a second peak occurring around the age of 508. The 5-year 
overall survival is approximately 90% in children and 30% to 40% in adults and elderly subjects. 
It is known that chromosomal alterations are a hallmark of ALL and include aneuploidy and 
recurring chromosomal translocations9. KMT2A rearrangements occur in about 5% of ALL and 
confer resistance to standard chemotherapy as well as novel agents including blinatumomab and 
inotuzumab.   
2.3. 
MLL rearrangements and NPM1 mutations in AML and ALL 
Two examples of mutations or cytogenetic aberrations are most relevant to our proposed study 
here: 
The first example is the mixed-lineage leukemia (MLL) gene, also known as KMT2A, on 
chromosome 11q23, which is disrupted in a unique group of acute leukemias. Translocations of 
MLL gene, which are found in approximately 5%-10% of acute leukemia subjects, result in an 
aggressive subtype of leukemia, with a 5-year survival rate of only approximately 35%10,11. More 
than 80 different partner genes in these fusions have been described, although the majority of 
leukemias result from MLL fusions with one of about six common partner genes (AF4, AF9, 
ENL, AF10, ELL, PTD) and only 9 specific gene fusions account for more than 90% of all 
aberrant recombinations of the MLL gene12. MLL translocations lead to fusion of the N-terminal 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 17 of 127 
 
fragment of MLL with 1 of the >80 protein partners, resulting in the expression of MLL fusion 
proteins that enhance proliferation and block hematopoietic differentiation, ultimately driving the 
development of leukemia. MLL fusion proteins bind to DNA/chromatin and induce leukemic 
transformation in hematopoietic stem and progenitor cells through transcriptional deregulation of 
fusion protein target genes. The best studied of the target genes include HOXA genes and their 
co-factors MEIS1, which have been shown to be important for leukemia development, cell 
proliferation, and self-renewal.  Because of poor subject outcomes, MLL leukemia represents an 
unmet medical need, necessitating the development of new therapies. 
The second example is one of the most common recurrent driver mutations in AML: mutation 
of the nucleophosmin 1 (NPM1) gene, which is seen in approximately 30% of cases2. NPM1 
mutations most commonly occur in de novo AML and are associated with a normal karyotype. 
NPM1 mutations are associated with the upregulated expression of HOXA and MEIS1 genes as 
do the MLL rearrangements13. AML with mutated NPM1 is associated with a more favorable 
prognosis in the newly diagnosed setting; however, this favorable prognostic effect is lost in the 
presence of concomitant FLT3-ITD mutations, which are seen in 40%-50% of AML with 
mutated NPM1, or in a relapsed/refractory setting14. In addition to FLT3-ITD mutations, 
mutations in genes regulating DNA methylation, including DNMT3A, IDH1, and IDH2, are also 
commonly seen in the presence of NPM1 mutations, and these combined mutations are 
associated with significantly inferior overall survival15, emphasizing the need for new therapies. 
Menin is a scaffold protein encoded by the multiple endocrine neoplasia type 1 (MEN1) gene. In 
the nucleus, menin associates with different proteins that activate or repress the transcription of 
genes involved in multiple cellular processes. Among them, menin interacts with MLL. MLL has 
2 fragments, MBM1 and MBM2, located within the 43-amino acid fragment at the N-terminus of 
MLL16. Because this N-terminus of MLL is retained in MLL fusion proteins, the menin-MLL 
interaction is preserved among wild-type MLL and all MLL fusion proteins. It has been reported 
that menin protein interaction with MLL fusion proteins, which leads to upregulation of HOXA 
and MEIS1 gene expressions, is crucial for the development of acute leukemias with MLL 
rearrangements17,18. Additionally, it has also been reported that menin protein interaction with 
wild-type MLL proteins, which is suggested to lead to upregulation of HOXA and MEIS1 gene 
expressions, is crucial for the development of other types of acute leukemias, such as those with 
NPM1 mutations13. The interaction of MLL1 fusion proteins with menin plays an important role 
to enhance the proliferation and block the differentiation of hematopoietic cells, ultimately 
leading to acute leukemia19,20. Therefore, inhibition of the menin-MLL interaction is expected to 
show efficacy against these acute leukemias. Subjects with MLL-r acute leukemia respond 
poorly to currently available treatments19, emphasizing the urgent need to develop more effective 
therapies directly disrupting the menin-MLL1 complex. 
2.4. 
DS-1594b 
2.4.1. 
Pharmacodynamics 
DS-1594b is the development designation of a novel, potent, orally available small molecule 
inhibitor of the binding of MLL1 fusion proteins and wild-type MLL1 to menin in development 
for the treatment of subjects with hematologic malignancies, including subjects with acute 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 18 of 127 
 
leukemia with MLL1-r and NPM1 mutations. MLL1 is also known as KMT2A (lysine 
methyltransferase 2A). The nonclinical testing strategy was designed to demonstrate and 
characterize the mechanism of action of DS-1594b as well as to support the oral dosing regimen 
planned for the initial clinical studies.  Nonclinical primary pharmacodynamic studies supporting 
development of DS-1594b were designed to provide information on its mechanism of action and 
potential for efficacy in the treatment of hematological tumors.  In vitro studies assessed the 
effects of DS-1594b on the interaction between menin and MLL1, cellular growth of MV-4-11, 
MOLM-13, and K-562 cell lines, and expression levels of MEIS1, HOXA9, and PBX3 genes in 
MV-4-11 and MOLM-13 cell lines.  In vivo studies in mice evaluated the effects of DS-1594b 
on antitumor activity against MV-4-11 xenografts.   
2.4.2. 
Safety Pharmacology and Toxicology 
The safety pharmacology parameters were assessed in mice (CNS) and in monkeys 
(cardiovascular and respiratory systems).  DS-1594b was administered orally by gavage in all in 
vivo studies.  In addition, the effect of DS-1594b on the hERG potassium channel current was 
assessed in vitro. DS-1594b has potent activity on the hERG channel with an IC50 value of 0.3 
µM. In an in vivo cardiovascular study using telemetered male cynomolgus monkeys, QT and 
QTc intervals were prolonged following a single administration of DS-1594b at ≥ 20 mg/kg in a 
dose dependent manner. Based on the exposure-response (ER) analysis, the plasma concentration 
of DS-1594a (free form of DS-1594b) to induce QTc interval prolongation by 10 milliseconds 
was predicted to be around 1000 ng/mL.  No effect on any other cardiovascular or respiratory 
parameters was noted at doses up to 200 mg/kg.  In the 28-day repeated dose toxicity study in 
monkeys, the QTc interval increased on Days 8 and 22 at ≥ 60 mg/kg/day; however, no 
exacerbation of the increased QTc interval was seen on Day 22 compared to that on Day 8. The 
anticipated human equivalent dose of the 60mg/kg/day dose in monkeys is approximately 19.2 
mg/kg/day.   
DS-1594b is highly bound to plasma protein (>97%) in all species. No concentration-
dependency was observed across species. Cytochrome P450 (CYP) 3A4 is the primary CYP 
isoform involved in the metabolism of DS-1594b from the results of experiments using human 
CYP-expressing microsomes and human liver microsomes.  DS-1594b did not inhibit CYP1A2 
or CYP2B6 (IC50 > 50 µM).  The IC50 values of DS-1594b were 19.6 µM for CYP2C8, 48.4 µM 
for CYP2C9, 2.66 µM for CYP2C19, and 27.0 µM for CYP2D6 without preincubation and 
comparable to those with preincubation. In addition, DS-1594b induced time-dependent 
inhibitory effects on CYP3A.  
Results from in vitro studies using Caco-2 cell monolayer systems suggested that DS-1594b is a 
substrate of efflux transporters. In an exploratory PK study after oral dosing of DS-1594b at 3 
mg/kg to rats, AUC increase of DS-1594b was observed by oral pretreatment of elacridar at 50 
mg/kg, a P-gp inhibitor which partially inhibits BCRP. These observations indicated that DS-
1594b is likely transported by P-gp, and BCRP to a lesser extent. 
DS-1594b inhibited OATP1B1 (IC50: 20.5 µM), OATP1B3 (IC50: 32.3 µM), OCT1 (IC50: 0.489 
µM), OCT2 (IC50: 12.8 µM), MATE1 (IC50: 2.78 µM), MATE2-K (IC50: 3.12 µM), P-gp (IC50: 
1.79 µM) and BCRP (IC50: 1.94 µM) to different extent. 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 19 of 127 
 
2.4.3. 
Benefit/Risk Assessment 
DS-1594b is under development for the treatment of hematologic malignancies, including acute 
leukemias with MLL1-r or NPM1-mutations.  No clinical studies have been conducted and 
therefore, no efficacy or safety in humans has been demonstrated. 
Nonclinical studies have demonstrated the potent antitumor activity of DS-1594b in mouse 
models of acute leukemia with MLL1-r or NPM1-mutations.  Therefore, DS-1594b is expected 
to demonstrate efficacy in subjects with MLL1-r or NPM1-mutated acute myeloid leukemia and 
acute lymphoid leukemia. 
Potential risks of DS-1594b, based either on mechanism of action (i.e. differentiation syndrome), 
or nonclinical toxicity studies or clinical studies with other products of the same class include 
QT interval prolongation, gastrointestinal toxicity (i.e., nausea, vomiting), hematological (i.e., 
anemia, neutropenia, and thrombocytopenia), renal, hepatic, skeletal muscle, pulmonary, and 
cardiac toxicities should be surveilled and appropriately managed in clinical studies.  
Based on the nonclinical data, the benefit-risk balance supports clinical development of 
DS-1594b. 
Please see the Investigator Brochure for more information about DS-1594b. 
3. 
STUDY DESIGN 
This will be a Phase 1/2 study of orally administered single agent DS-1594b in subjects with R/R 
AML or ALL, including subjects with or without MLLr or NPM1m (Figure 1Figure 1).  
The Phase 1 portion of the study is open-label, non-randomized, sequential, BOIN escalation. 
Dose Escalation will provide the MTD and/or RP2D for the Phase 2 portion and will include two 
sub-studies to evaluate the drug-drug interaction potential with strong inhibitors of CYP3A and 
the effect of DS-1594b co-administration with food. 
The Phase 2 portion is a four-cohort, open-label, non-randomized study with no crossover 
permitted between the cohorts to evaluate single agent DS-1594b and combinations of DS-1594b 
with azacitidine and venetoclax in AML subjects with MLLr or NPM1m, and with mini-HCVD 
in ALL subjects with MLLr.  
A Safety Review Committee (SRC), comprised of selected Sponsor study team members and 
Investigators, will be responsible for overseeing the safety of dose escalation/de-escalation, 
declaring the RP2D, and recommending whether to open each expansion cohort. The SRC will 
review the emerging safety and PK data (if available) from each cohort to determine if dose 
escalation will occur.   
Formatted: C-Hyperlink


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 20 of 127 
 
Figure 1: 
Study Schema 
 
 
Note: All dose levels after the starting dose are tentative. Alternative doses or dosing regimens may be enrolled 
based on emerging clinical data, including further de-escalation. BID and QD cohorts can be enrolled in parallel and 
will be evaluated independently for DLT. Cohorts A and B (single agent cohorts) will enroll a maximum of 26 
subjects, and Cohorts C and D (combination cohorts) will enroll a maximum of 32 subjects 
3.1. 
Rationale for dose and regimen selection 
The selection of the starting dose level and regimen is based on the extrapolation of data from 
cell line efficacy models and toxicology studies in rodents and monkeys. 
The DS-1594b Severely Toxic Dose in 10% of animals (STD10) in mice was greater than 
300 mg/kg/day and the Highest Non-Severely Toxic Dose (HNSTD) in monkeys was 
60 mg/kg/day.  The human equivalent dose (HED) of 300 mg/kg/day in mice, based on 
allometric scaling by body surface area, is approximately 24.3 mg/kg, and using 1/10th of the 
HED gives a dose of 2.4 mg/kg as the recommended starting human dose for the proposed 
clinical study.  The value of 2.4 mg/kg is lower than a starting dose (3.2 mg/kg) derived from 
1/6th of the HED for the HNSTD (60 mg/kg/day) in monkeys.  The estimated human systemic 
exposure at the starting dose exceeds the IC50 of DS-1594b against MV-4-11 human AML cell 
line (1.97 nM [1.13 ng/mL]), and inhibition of cell proliferation is expected.  Therefore, the 
value of 2.4 mg/kg is considered the appropriate starting dose for the proposed clinical study.  
No supportive data are available at this stage that would suggest body size-based dosing would 
reduce human inter-subject variability in PK. Thus, based on an average body weight of 60 kg 
human, the recommended starting human dose is 140 mg/day. A dosing approach with 70 mg 
given twice a day will be adopted in order to reduce Cmax while maintaining AUC compared to 
once-daily dosing to mitigate potential QT interval prolongation risk, given the observed QTc 
interval prolongation signal seen in monkeys (see Section 2.4.2). In addition, the estimated 
clinical half-life of DS-1594b is ~ 7 to 8 hours, which also supports a twice daily dosing 
regimen.  
Based on emerging clinical data to assess the PK and safety profile of DS-1594b, the frequency 
of dosing may be adjusted to once daily (QD), if deemed appropriate and supported by safety 
data. In this case, dose escalation would follow the same rules as the BID schedule. The SRC 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 21 of 127 
 
may recommend the enrollment of simultaneous QD and BID dosing regimens or may switch 
from BID dosing to QD dosing.   
In case two dosing regimens are enrolling simultaneously, sequentially enrolling subjects will be 
assigned to either regimen in an alternating method. After at least 3 subjects have completed the 
dose-limiting toxicity (DLT) evaluation window for a given cohort, all available clinical data 
(e.g., PK, safety and any other available data) will be assessed by the SRC to determine if a 
single dosing regimen (i.e., QD or BID) should be selected.  If the SRC selects a single dosing 
regimen, simultaneous enrollment into both regimens will stop and the remaining subjects in 
dose-escalation will be enrolled in the subsequent dose level for that selected dosing regimen. 
 
3.2. 
Phase 1 Design 
The primary objective of Phase 1 is to determine the Maximum Tolerated Dose (MTD) and the 
Recommended Phase 2 Dose (RP2D) of DS-1594b when administered as a single agent in 
subjects with relapsed or refractory AML or ALL, including subjects with or without MLLr or 
NPM1m using a Bayesian optimal interval (BOIN) design to find the MTD34,35.  
The BOIN design is implemented in a simple way similar to the traditional 3+3 design but is 
more flexible and possesses superior operating characteristics that are comparable to those of the 
more complex model-based designs, such as the continual reassessment method (CRM)33. 
At least 3 subjects must be enrolled at each dose level. If a dose level is found to be safe by the 
BOIN design we will escalate to the next higher dose level. The SRC can recommend additional 
enrollment of up to 9 additional subjects per dose level for dose levels that have already been 
deemed to be safe with the intent to gain additional information on safety, efficacy and PK at 
different dose levels, and to guide selection of optimal biologically effective RP2D.  These 
additional 9 subjects per dose level will not be considered evaluable for DLTs. It is anticipated 
that approximately 18 subjects will be added in this Phase 1 expansion.  
Although all R/R ALL and R/R AML subjects, irrespective of mutations,  will be allowed during 
the Phase 1 dose-escalation the goal is to treat at least 3 subjects with MLLr or NPM1m are 
included at dose levels that are anticipated to be biologically active to allow for optimal 
evaluation of safety and efficacy in the presumed target population to guide selection of the 
optimal RP2D.   
Treatment during Phase 1 dose escalation phase will follow continuous oral administration under 
a twice-daily schedule or daily schedule on a 28-day dosing cycle. 
The first dose cohort will start at 70 mg twice daily, approximately every 12 hours.  The target 
toxicity rate for the MTD is ߶ൌ 0.2 and the maximum sample size for determining the MTD is 
42. Each cohort will include a minimum of 3 subjects. The DLT evaluation period will be limited 
to the first 28 days of dosing.   DLTs are defined in Section 3.2.2 and only those DLTs that occur 
within the first cycle (28 days) will be used for dose finding. As shown in Figure 2Figure 2, the 
BOIN design uses the following rule, optimized to minimize the probability of incorrect dose 
assignment, to guide dose escalation/de-escalation: 
Formatted: C-Hyperlink


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 22 of 127 
 
 if the observed DLT rate at the current dose is 0.157 or less, escalate the dose to the 
next higher dose level; 
 if the observed DLT rate at the current dose is more than 0.238, de-escalate the dose 
to the next lower dose level; 
 otherwise, stay at the current dose. 
Evaluation by the abovementioned BOIN rule will be done for each dose level separately based 
on the cumulative number of DLT evaluable subjects treated in that dose level and regimen (i.e., 
QD or BID). In case the multiple dosing regimens are initiated simultaneously and parallel 
enrollment is allowed in the multiple dosing regimens, the evaluation by the BOIN rule for each 
dose level and regimen would be made separately. DLT observed after intra-patient dose 
escalation (IPDE) will not be considered in the dose escalation/de-escalation decision (See 
Section 6.9 for details about IPDE). For the purpose of overdose control, doses ݆ and higher 
levels will be eliminated from further examination if Prሺ݌௝൐ 0.2 | data) ൐ 0.95 and at least 3 
subjects have been treated at dose level ݆, where ݌௝ is the true DLT rate of dose level ݆, ݆ൌ 1,⋯, 
6. This posterior probability is evaluated based on the beta-binomial model ݕ௝∣݌௝∼
binomialሺ݌௝ሻ with ݌௝∼uniformሺ0,1ሻ, where ݕ௝ is the number of subjects who experienced 
DLT at dose level ݆. When the lowest dose is eliminated, stop the trial for safety. The probability 
cutoff 0.95 is chosen to be consistent with the common practice that when the target DLT rate 
<=1/6, a dose with 2/3 subjects experienced DLT is eliminated. The above dose escalation/de-
escalation and elimination rule can be equivalently presented in Table 4Table 4, which will be 
used to conduct the trial. 
The steps to implement the BOIN design are described as follows: 
1. Three subjects in the first cohort are treated at dose level 1 (70 mg twice daily). Each 
cohort will include a minimum of 3 subjects. 
2. To assign a dose to the next cohort of subjects, conduct dose escalation/de-escalation 
according to the rule displayed in Table 4Table 4. When using Table 4Table 4, please 
note the following: 
a. “Eliminate” means eliminate the current and higher doses from the trial to prevent 
treating any future subjects at these doses because they are overly toxic. 
b. When we eliminate a dose, automatically de-escalate the dose to the next lower level. 
When the lowest dose is eliminated, stop the trial for safety. In this case, no dose 
should be selected as the MTD. 
c. If none of the actions (i.e., escalation, de-escalation or elimination) is triggered, treat 
the new subjects at the current dose. 
d. If the current dose is the lowest dose and the rule indicates dose de-escalation, treat 
the new subjects at the lowest dose unless the number of DLTs reaches the 
elimination boundary, at which point terminate the trial for safety. 
e. If the current dose is the highest dose and the rule indicates dose escalation, treat the 
new subjects at the highest dose. 
Formatted: C-Hyperlink
Formatted: C-Hyperlink
Formatted: C-Hyperlink


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 23 of 127 
 
3. Repeat step 3 until the maximum sample size of 30 is reached or stop the trial if the 
number of subjects treated at the current dose reaches 9 and the decision according to 
Table 4Table 4 is to stay at the current dose. 
 
Table 4: 
Dose escalation/de-escalation rule for the BOIN design 
Number of subjects treated at current dose 
3 
4 
5 
6 
7 
8 
9 
Escalate if number of DLTs is less than or equal to 
0 
0 
0 
0 
1 
1 
1 
De-escalate if number of DLTs equal to or greater than 
1* 1* 
2 
2 
2 
2 
3 
Eliminate if number of DLTs equal to or greater than 
2 
3 
3 
3 
4 
4 
4 
Note. # of DLT is the number of subjects with at least 1 DLT in the first 28 days of dosing. Observations from IPDE 
will not be considered (Section 6.9). When none of the actions (i.e., escalate, de-escalate or eliminate) is triggered, 
stay at the current dose for treating the next cohort of subjects. *The SRC can decide to enroll an additional 3 
subjects at this dose level.  In case the multiple dosing regimens are initiated simultaneously and parallel enrollment 
is allowed in the multiple dosing regimens, the evaluation for BOIN rule for each dose level and regimen would be 
made separately. 
 
In Table 4Table 4, if 1 out of 3 or 4 subjects experience a DLT in the first cycle of treatment, the 
algorithm recommends dose de-escalation, rather than staying at the current dose. Considering 
only information from 3 to 4 subjects will be initially available, the incidence of 1 DLT does not 
sufficiently establish that the MTD is exceeded. Under this situation, a recently published i3+3 
design recommends staying in the current dose level if the observed number of DLTs is only 1 
greater than the number required for dose escalation32. Therefore, the Safety Review Committee 
could decide to enroll an additional 3 subjects at that dose level, if only 1 of 3 or 4 subjects 
experiences a DLT. 
 
Formatted: C-Hyperlink
Formatted: C-Hyperlink


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 24 of 127 
 
Figure 2: 
Flowchart for Trial Conduct Using the BOIN Design 
 
After the trial is completed, select the MTD based on isotonic regression as specified in Liu and 
Yuan (2015). This computation is implemented by the ‘Shiny App’ “BOIN” available at 
http://www.trialdesign.org. Specifically, select as the MTD the dose for which the isotonic 
estimate of the toxicity rate is closest to the target toxicity rate. If there are ties, select the higher 
dose level when the isotonic estimate is lower than the target toxicity rate and select the lower 
dose level when the isotonic estimate is greater than or equal to the target toxicity rate.  
Up to approximately 18 additional subjects (no more than 9 additional subjects per dose) will be 
enrolled at a safe dose(s) below or at the MTD for additional experience with safety and efficacy. 
We will use the elimination boundaries in Table 4Table 4 for the toxicity monitoring. 
The RP2D will be recommended by the SRC based on efficacy, safety and PK/PD data 
evaluation and may or may not be the same dose as the determined MTD dose. 
3.2.1. 
Operation Characteristics for BOIN Design 
Table 5Table 5 shows the operating characteristics of the trial design based on 1000 simulations 
of the trial using shiny app “BOIN” available at http://www.trialdesign.org. The operating 
characteristics show that the design selects the true MTD, if any, with high probability and 
allocates more subjects to the dose levels with the DLT rate closest to the target of 0.2. 
 
Formatted: C-Hyperlink
Formatted: C-Hyperlink


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 25 of 127 
 
Table 5: 
Operating Characteristics of the BOIN Design 
Dose 
1 
2 
3 
4 
5 
6 
Number of 
Subjects 
% Early 
Stopping 
Scenario 1 
  
  
  
  
  
  
  
  
True DLT Rate 
0.2 
0.34 
0.4 
0.45 
0.5 
0.55 
  
  
Selection % 
57.5 
20.9 
4.9 
2.4 
1 
0.1 
  
13.2 
% Pts Treated 
41.4 
29.8 
14.4 
8 
4.4 
2 
18.2 
  
Scenario 2 
  
  
  
  
  
  
  
  
True DLT Rate 
0.09 
0.2 
0.35 
0.41 
0.48 
0.54 
  
  
Selection % 
24.1 
47.4 
19.2 
5.5 
1 
0.5 
  
2.3 
% Pts Treated 
24.5 
33.5 
22.4 
11.6 
5.8 
2.3 
22 
  
Scenario 3 
  
  
  
  
  
  
  
  
True DLT Rate 
0.02 
0.08 
0.2 
0.37 
0.43 
0.49 
  
  
Selection % 
1.5 
22 
56.4 
16.4 
2.6 
1.1 
  
0 
% Pts Treated 
8.4 
22.4 
33.8 
21.4 
9.6 
4.4 
23.7 
  
Scenario 4 
  
  
  
  
  
  
  
  
True DLT Rate 
0.01 
0.05 
0.09 
0.2 
0.38 
0.51 
  
  
Selection % 
1 
4.2 
22.8 
54.9 
14.7 
2.3 
  
0.1 
% Pts Treated 
6.2 
10.2 
22.1 
32.4 
21.1 
7.9 
23.6 
  
Scenario 5 
  
  
  
  
  
  
  
  
True DLT Rate 
0.01 
0.04 
0.07 
0.1 
0.2 
0.37 
  
  
Selection % 
0.2 
1.4 
6.6 
23.1 
49.5 
19.2 
  
0 
% Pts Treated 
5.4 
7.9 
12.3 
22.8 
31.9 
19.8 
22.9 
  
Scenario 6 
  
  
  
  
  
  
  
  
True DLT Rate 
0.02 
0.04 
0.06 
0.08 
0.1 
0.2 
  
  
Selection % 
0.1 
2 
4 
6.1 
23.3 
64.4 
  
0.1 
% Pts Treated 
6.6 
8.6 
11 
13.9 
23.9 
35.9 
19.7 
  
Note: “% Early Stopping”" refers to early stopping due to excessive DLT. 
 
The SRC will meet when there are a sufficient number of DLT-evaluable subjects to review in 
the current cohort who have completed the Cycle 1, 28-day DLT evaluation period, and before 
proceeding to the next cohort at a higher dose level. 
The dose-escalation recommendation obtained via the BOIN design will be reviewed by the 
SRC, along with the DLT data, other AE data, and available PK/PD and laboratory data before 
implementation of the next dose cohort. 
If a lower dose is recommended by the BOIN method and confirmed by the SRC, then 
enrollment into the next lower dose level may be initiated, and additional cohorts may be opened 
to enroll subjects into a previously tested safe dose level to facilitate the evaluation of the dose-
toxicity relationship. 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 26 of 127 
 
3.2.2. 
Dose-Limiting Toxicity Definition 
Dose-Limiting Toxicity (DLT) is defined in this study as a non-hematologic adverse event or 
abnormal laboratory value assessed as unrelated to disease progression, intercurrent illness, or 
concomitant medications and occurring during the first 28 days on study that meets any of the 
following criteria, using the Common Terminology Criteria for Adverse Events (CTCAE) 
grading system, version 5.0: 
 Hematologic DLT is defined as CTCAE Grade 4 neutropenia (absolute neutrophil 
count <0.5 x10
9
/L) or thrombocytopenia (platelet count <25.0 x10
9
/L) lasting for 
42 days or more from Cycle 1 Day 1 in the absence of residual leukemia (i.e., with 
less than 5% blasts by morphology or residual leukemia by flow-cytometry).  
 Anemia will not be considered for the definition of DLT.  
 CTCAE Grade 3 AST (SGOT) or ALT (SGPT) increased for at least 7 days or 
Grade 3 hyperbilirubinemia for at least 7 days. 
 CTCAE Grade 3 AST (SGOT) or ALT (SGPT) increased accompanied by Grade 2 
bilirubin increase 
 CTCAE Grade 4 AST (SGOT) or ALT (SGPT) increased of any duration 
 Any other non-hematological adverse events that are CTCAE Grade 3 or 4. However, 
the following adverse events are NOT considered DLTs: 
 Grade 3 nausea, vomiting and diarrhea will be considered DLT only if not 
controlled to Grade 2 or lower with optimal therapy within 72 hours (not 
including tube feeding, total parenteral nutrition, and/or hospitalization). Any 
Grade 3 gastrointestinal toxicity requiring tube feeding, total parenteral nutrition, 
and/or hospitalization and any Grade 4 gastrointestinal toxicity will be considered 
DLT. 
 Grade 3 or 4 biochemical abnormalities (e.g., lipase or amylase increased) will 
only be considered DLT if accompanied by clinical consequences.  
 Grade 3 or 4 isolated electrolyte abnormalities must be without clinical 
consequence and resolve, with or without intervention, to less than Grade 2 levels 
within 72 hours. 
 Grade 3 infusion reaction if successfully managed and which resolves within 
72 hours 
 Grade 3 or 4 Tumor Lysis Syndrome if it is successfully managed clinically and 
resolves within 7 days without end-organ damage  
 Grade 3 or 4 Differentiation Syndrome which improves to ≤ Grade 1 within 7 
days of the start date of ≥ Grade 3 Differentiation Syndrome and which is not 
associated with end-organ damage.  Note: Grade 1 is mild, Grade 2 is moderate, 
Grade 3 is serious, and Grade 4 is life-threatening. 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 27 of 127 
 
 CTCAE Grade 3 QTcF prolongation (based on the average of 3 triplicate 12-lead 
readings or Holter monitor reading)  
 Results in dose-reduction or discontinuation of therapy 
 Any treatment-related death;  
 Subjects not considered evaluable due to insufficient dosing (at least 75% of doses of 
study drugs) and who do not develop a toxicity that is considered a DLT will be 
replaced. These subjects may continue therapy on trial after discussion with the 
Principal Investigator if they are having clinical benefit and the reasons for 
continuation and potential benefit/risk profile for the subject must be clearly 
documented in the medical records.  
 Phase 2 only: For subjects in venetoclax- or Mini-HCVD-containing regimens 
(cohorts C and D) who do not receive venetoclax or Mini-HCVD on Day 1 due to 
logistical and/or financial reasons, the DLT period will be extended to 28 days from 
the first dose of venetoclax or Mini-HCVD.  For evaluation of hematologic-related 
DLT, the DLT evaluation period will be 42 days from the first dose of venetoclax or 
Mini-HCVD.  
 Subjects must receive at least 75% of the doses of DS-1594b, azacitidine (Phase 2 
only), venetoclax (Phase 2 only), or miniHCVD (Phase 2) during the first 28 days on 
trial (i.e. during Cycle 1) to be considered evaluable during the DLT evaluation 
period. Subjects who receive less than these planned number of doses of each drug 
during the first 28 days on trial will not be considered evaluable during the DLT 
evaluation period. However, if such subjects develop a toxicity that would normally 
be considered a DLT this will still be captured as a DLT. Any toxicity that meets the 
criteria for DLT during the first 28 days of trial in a subject who has received at least 
one dose of trial medication will constitute a DLT.  
 For subjects who discontinue therapy, the reason for treatment discontinuation will be 
documented.   
 Dose modifications other than the ones mentioned above can be considered after 
discussion with the PI and proper documentation of the rationale. 
3.2.3. 
DDI Sub-study with Anti-fungal Agents that are Strong CYP3A Inhibitors 
3.2.3.1. 
Sub-Study Rationale 
Since AML subjects are at a high risk for fungal infections, to reduce the likelihood and severity 
of fungal infections, azole antifungal agents such as fluconazole, posaconazole and voriconazole 
are commonly administered. However, these azole compounds carry DDI risks because of their 
inhibitory effect on CYP3A enzymes. Based on nonclinical assessment, DS-1594b is a CYP3A 
substrate (see Section 2.4.2 ), thus DDI assessment for DS-1594b and antifungal agents is 
necessary to identify the DS-1594b dosing regimen that can be concomitantly given with 
antifungals and potentially extend to other strong CYP3A inhibitors. This DDI assessment is also 
aligned with the recommendation from the FDA Industry Guidance for developing drugs and 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 28 of 127 
 
biological products for AML treatment (Aug 2020). The guidance recommends studying DDI 
with moderate and strong CYP3A inhibitors early in clinical development if the investigational 
AML drug is a CYP3A substrate, to determine dose modification, if needed, when concomitantly 
administered with moderate and/or strong CYP3A inhibitors.  
3.2.3.2. 
Sub-study Design  
Following dosing in Phase 1 Dose Escalation and MTD declaration, approximately 12 additional 
subjects will be enrolled into a drug-drug interaction (DDI) sub-study within the Phase 1 portion 
of the study at a predetermined dose level (at least 50% below the RP2D, as recommended by the 
SRC) to assess the effect of multiple doses of antifungal agents (i.e. posaconazole [N ~ 6], 
voriconazole [N ~ 6]) that are strong CYP3A inhibitors, on the steady-state PK of DS-1594b. 
Based on preliminary assessment using physiologic-based modeling, the magnitude of PK 
increase of DS-1594b ranges from 30% (with posaconazole) to 2-fold (with voriconazole).  
This estimate will be further assessed based on emerging clinical and nonclinical data and the 
information will be provided to the SRC for consideration in dose selection. Nonetheless, the 
dose will be at least 50% below the declared RP2D. These subjects can be the same subjects 
included in the Phase 1 expansion for RP2D determination.  
This DDI sub-study is a single sequence, crossover design. Enrollment will complete on the 
posaconazole sub-study before enrollment will begin on the voriconazole sub-study. Subjects 
will receive twice-daily or daily oral dosing of DS-1594b alone at the assigned dose from Cycle 
1 Day 1 to Cycle 1 Day 8. On Cycle 1 Day 9 to Cycle 1 Day 18, subjects will receive the same 
assigned DS-1594b dose with either (a) 300 mg oral posaconazole twice on Cycle 1 Day 9 and 
once daily on Cycle 1 Day 10 to Cycle 1 Day 18 or (b) 400 mg oral voriconazole twice on Cycle 
1 Day 9 and 200 mg twice daily from Cycle 1 Day 10 to Cycle 1 Day 18.  
The anti-fungal agents are planned to be given for 10 consecutive days as stated above to ensure 
steady-state is reached in order to maximize inhibitory effect on CYP3A-mediated metabolism of 
DS-1594b. After completion of the sub-study (Cycle 1 Day 18 is the last day of the sub-study), 
subjects will continue with DS-1594b dosing alone starting on Cycle 1 Day 19. PK sampling 
timepoints of DS-1594b are outlined in Table 17Table 17.  
Note: If the use of posaconazole is essential for subject care during the dose escalation phase 
(i.e. prior to MTD/RP2D declaration), the subject can enter the DDI sub-study sooner, starting 
from the third dose escalation cohort. Voriconazole is not allowed as DDI perpetrator prior to 
MTD declaration given it is a more potent CYP3A inhibitor compared to posaconazole. To avoid 
interference with the DLT evaluation period (first 28-day cycle), subjects will receive oral twice 
daily or daily dosing of DS-1594b alone at the assigned dose for the entire Cycle 1. Starting on 
Cycle 2 Day 1 to Cycle 2 Day 10, subjects will receive either the same assigned DS-1594b dose 
provided that dose level has been declared safe from the DLT evaluation, or at one dose level 
lower with 300 mg oral posaconazole twice on Cycle 2 Day 1 and once daily on Cycle 2 Day 2 to 
Cycle 2 Day 10. After completion of the sub-study (Cycle 2 Day 10 is the last day of the sub-
study), subjects will continue with DS-1594b dosing alone starting on Cycle 2 Day 11. PK 
sampling timepoints of DS-1594b for these subjects are outlined in Table 18Table 18. These 
subjects will contribute to the overall sample size of ~ 12 for DDI sub-study. 
Formatted: C-Hyperlink
Formatted: C-Hyperlink, Font: Italic


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 29 of 127 
 
The entry criteria for subjects in DDI sub-study will be the same as all other subjects, except for 
additional concomitant medications restrictions for CYP3A modulators and gastric reducing 
agents (see Section 4.2 ). 
3.2.3.3. 
Sub-Study PK Evaluability Criteria 
Subjects should meet the following minimum criteria to be considered evaluable for the DDI 
assessment. PK non-evaluable subjects will be replaced. 
 On Cycle 1 Day 8 and Cycle 1 Day 18 (or Cycle 2 Day 10 for subjects entering DDI 
sub-study before MTD declaration), subject takes DS-1594b according to the 
assigned dose. 
 Subject has an interpretable PK profile following administration of the assigned dose 
of DS-1594b on Cycle 1 Day 8 and Cycle 1 Day 18 (or Cycle 2 Day 10). 
 Subject does not vomit within 4 hours after receiving either dose of DS-1594b or 
antifungal agents (posaconazole or voriconazole) on PK sampling days. 
 Subject receives at least 5 consecutive twice daily or daily doses of DS-1594b at the 
assigned dose prior to the co-administration with antifungal agents 
 Subject receives at least 5 consecutive twice daily or daily doses of DS-1594b at the 
assigned dose when co-administered with antifungal agents  
 Subject receives the assigned dose and appropriate prandial condition of the 
antifungal agents. 
3.2.4. 
Food Effect Sub-study  
3.2.4.1. 
Sub-Study Rationale 
As DS-1594b is administered orally, the potential impact of food intake on oral bioavailability is 
an important consideration. In addition, potential combination agents, such as venetoclax, require 
administration under fed conditions. Determining the food effect early for DS-1594b will help 
optimize the prandial condition for DS-1594b dosing. Based on in vitro and animal studies, 
minimal food effect has been observed thus far. 
3.2.4.2. 
Sub-Study Design  
Following MTD declaration, approximately 6 additional subjects will be enrolled into a food 
effect sub-study to evaluate the effect of a standard meal on the steady-state PK of DS-1594b. 
This sub-study follows a single sequence, crossover design. Subjects will receive oral twice-daily 
or daily dosing of DS-1594b at a predetermined dose level (at least 50% lower than the RP2D) 
within 0.5 hours after a standard meal (breakfast and dinner), defined as one containing 600 kcal 
and 30% fat (~21g fat), from Cycle 1 Day 1 to Cycle 1 Day 8. Subjects should refrain from food 
and drink, except water, 2 hours before dosing (except for breakfast and dinner) and 2 hours after 
dosing.  


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 30 of 127 
 
From Cycle 1 Day 9 to Cycle 1 Day 18, subjects will receive the same DS-1594b dose under 
fasting conditions (i.e. subjects refrain from food and drink, except water, for 2 hours before 
dosing and for 2 hours after dosing). See Section 5.1.2 (under “food effect sub-study only”) for 
more details regarding dose administration guidance. On days when PK blood samples will be 
taken, DS-1594b dosing and meal regimens will be administered at the investigational site. After 
completion of the sub-study (Cycle 1 Day 18 is the last day of sub-study), subjects will continue 
with DS-1594b dosing under fasting conditions, same as patients not in sub-study (DS-1594b 
dosing at least 1 hour before or 2 hours after a meal) starting on Cycle 1 Day 19. 
Note:   The entry criteria will be the same as the preceding cohorts, except for additional 
concomitant medications restrictions for CYP3A modulators and gastric reducing agents (see 
Section 4.2). PK sampling timepoints of DS-1594b are outlined in Table 19Table 19. 
3.2.4.3. 
Sub-Study PK Evaluability Criteria 
Subjects should meet the following minimum criteria to be considered evaluable for the food 
effect assessment. PK non-evaluable subjects will be replaced. 
 On Cycle 1 Day 8 and Cycle 1 Day 18, subject takes DS-1594b according to the 
assigned dose. 
 Subject has an interpretable PK profile following administration of the assigned dose 
of DS-1594b on Cycle 1 Day 8 and Cycle 1 Day 18. 
 Subject takes DS-1594b under the assigned dose and prandial conditions (first 7 days 
under fed state, then under fasted state afterwards) for at least 5 consecutive days 
prior to full PK sampling days on Cycle 1 Day 8 and Cycle 1 Day 18. 
 Subject does not vomit within 4 hours after DS-1594b dosing on full PK sampling 
days. 
For toxicity monitoring in each group of the DDI sub-study and food effect sub-study we will 
use the elimination boundaries in Table 4Table 4 for BOIN design. 
3.3. 
Phase 2 Design 
Enrollment in Phase 2 will start once the RP2D has been determined in Phase 1. This Phase 2 
study will have four cohorts: 
 Cohort A: DS-1594b monotherapy for R/R AML with MLL-r,  
 Cohort B: DS-1594b monotherapy for R/R AML with NPM1m,  
 Cohort C: DS-1594b in combination with azacitidine and venetoclax for R/R AML 
with NPM1m or MLLr  
 Cohort D: DS-1594b in combination of mini-HCVD for R/R ALL with MLLr 
Subjects enrolled in Cohorts A and B will receive the RP2D dose of DS-1594b determined in 
Phase 1. Cohorts C and D will enroll an initial 6 subjects in a safety run-in at one dose level 
below the RP2D (Dose level 0) with DS-1594b dose titration as specified below. 
Formatted: C-Hyperlink
Formatted: C-Hyperlink


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 31 of 127 
 
Cohorts A and B (single agent cohorts) will enroll a maximum of 26 subjects, and Cohorts C and 
D (combination cohorts) will enroll a maximum of 32 subjects, to allow reasonable 
determination of CRc within 3 months of therapy initiation. 
For the combination cohorts (C & D) there will be a safety-run in evaluation with pre-defined 
toxicity stopping rules to be implemented for early DLT evaluation as per following plan: 
 Safety run-in evaluation by the Safety Review Committee of the first 6 subjects in 
cohorts C and D will occur after 6 subjects have completed at least one cycle of 
treatment (or at least 28 days from the first day of treatment).  
 Enrollment will be paused while the first 6 subjects are evaluated for safety. Each 
combination cohort will be evaluated independently.  
 If ≤ 1 of the 6 subjects experiences DLT in the first cycle of treatment, the 
treatment combination will be considered as safe and the DS-1594b dose can be 
escalated to the RP2D (Dose level 1) for the treatment of the next 6 patients 
(repeat the safety run-in evaluation). If the RP2D (Dose level 1) is considered 
safe, continue enrollment of an additional 20 subjects at the RP2D (i.e. total 
subjects treated at the RP2D will be 26 subjects; total cohort size will be 32 
subjects).  If ≥2 of 6 subjects at the RP2D experiences DLT in the first cycle of 
treatment, de-escalate and continue enrollment of an additional 20 subjects at 
Dose Level 0. 
 If ≥2 of 6 subjects have DLTs in the first cycle of treatment at Dose Level 0, then 
an additional 6 subjects will enroll at a next lower dose level to be determined by 
the Principal Investigator and Safety Review Committee after reviewing the 
safety, efficacy, and PD data from the first 6 subjects enrolled (Table 6Table 6,  
Table 7Table 7). If ≤ 1 of the additional 6 subjects treated at the lower dose level 
experience DLTs, this treatment combination will be considered as safe and 
continue to enroll to a total of 26 subjects (i.e. an additional 20 subjects at the 
lower dose level; total cohort enrollment of 32 subjects). If ≥2 of these 6 
additional subjects experienced DLTs, then enrollment at the current dose level 
will be closed.  
 Subjects must receive at least 75% of the doses of DS-1594b, azacitidine (Phase 2 
only), venetoclax (Phase 2 only), or miniHCVD (Phase 2) during the first 28 days on 
trial (i.e. during Cycle 1) to be considered evaluable during the DLT evaluation 
period. Any subjects who are not evaluable for DLT in either cohort during the 
safety-run in period will be replaced for the assessment of DLT rate. This will allow 
for early identification of significant toxicities and early stoppage in the combination 
cohorts.  
 The Safety Review Committee (SRC) will meet when there are enough 
DLT-evaluable subjects to review in each cohort who have completed the DLT 
evaluation period. The SRC will review the DLT data, other AE data, and available 
PK/PD, ECG, and laboratory data before proceeding to expansion of each of the 
cohorts to enroll the additional 20 subjects. 
Formatted: C-Hyperlink
Formatted: C-Hyperlink


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 32 of 127 
 
3.3.1. 
Rationale for Combination Cohorts (C&D) 
AML and ALL are highly heterogenous diseases and patients often harbor more than one driver 
mutation2.  While recent studies of novel molecularly targeted agents, such as FLT3 inhibitors28 
and IDH1/2 inhibitors29,30, have demonstrated improved response rates and overall survival as 
monotherapy in patients with relapsed or refractory AML, there is still a high unmet medical 
need as patients will ultimately succumb to the disease.  Combination therapies with molecularly 
targeted agents have emerged as an attractive strategy to improve efficacy while maintaining a 
tolerable safety31. 
The primary objective of the Phase 2 combination Cohorts C & D is to evaluate the safety and 
tolerability, as well as efficacy, of DS-1594b administered with standard of care backbone 
regimens. The RP2D will be selected based upon the cumulative safety, efficacy and PK data at 
the end of the Phase 1 portion, as the anticipated optimal dose considering benefit-risk.  Since 
this will be the first evaluation of DS-1594b administered in combination, both Cohorts C & D 
will include a safety run-in period (beginning enrollment at one dose level below the RP2D) with 
pre-specified rules for dose titration under the supervision of the Principal Investigator and the 
Safety Review Committee, as described in Section 3.3. Additionally, all cohorts will be 
monitored for toxicity, with pre-specified criteria for early termination if excessive toxicity is 
predicted, as described in Section 9.3.  
4. 
SUBJECT SELECTION 
4.1. 
Inclusion Criteria 
Each subject must meet all the following inclusion criteria to be enrolled in this study.  
a. Provision of written (signed) informed consent form (ICF) by the subject or legal 
guardian prior to the performance of any study-specific procedures, according to 
International Council on Harmonisation (ICH) and local regulatory requirements. 
Subject must be fully informed about their illness and the investigational nature of the 
study protocol (including foreseeable risks and possible toxicities) and must sign and 
date an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
approved informed consent form (ICF)(including Health Insurance Portability and 
Accountability Act authorization [HIPAA], if applicable) before performance of any 
study-specific procedures or examinations. 
b. Subjects must be willing and able to comply with the protocol.   
c. Subjects with AML or ALL, diagnosed according to the 2016 criteria by the World 
Health Organization (WHO)26,25, who are refractory or relapsed (any salvage) with no 
available therapies or not candidates for available therapies. For subjects with prior 
MDS or chronic myelomonocytic leukemia (CMML) or MPN who transformed to 
AML, therapy received for MDS, CMML, or MPN is NOT considered as prior 
therapy for AML except for MDS or CMML treated with HMAs. Subjects with MDS 
or CMML treated with HMA therapies who progress to AML and have no available 
therapies or are not candidates for available therapies, will be eligible at the time of 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 33 of 127 
 
progression to AML. In Phase 1: all R/R AML or R/R ALL subjects irrespective of 
mutations will be eligible.  In Phase 2 Cohort A only R/R AML with MLLr will be 
eligible. In Phase 2 Cohort B only R/R AML with NPM1m will be eligible.  In Phase 
2 Cohorts C and D: Only R/R AML or R/R ALL subjects with an MLLr or NPM1m 
will be eligible. 
d. Prior therapy with hydroxyurea, chemotherapy, biological or targeted therapy (e.g. 
FLT3 inhibitors, other kinase inhibitors), or hematopoietic growth factors is 
permitted. 
e. Age 18 years or older. 
f. Eastern Cooperative Oncology Group (ECOG) Performance Status 0, 1, or 2.  
g. Adequate hepatic organ function: total bilirubin ≤ 1.5 times upper limit of normal 
(x ULN); aspartate aminotransferase or alanine aminotransferase ≤ 2.5 x ULN 
(aspartate aminotransferase or alanine aminotransferase ≤ 5.0 x ULN if deemed 
related to leukemia by the treating physician) 
h. Creatinine clearance ≥ 50 mL/min as calculated using the modified Cockcroft-Gault 
equation.  
i. Serum electrolytes within the institution’s normal limits: potassium, calcium (total 
calcium, calcium corrected for serum albumin in case of hypoalbuminemia or ionized 
calcium) and magnesium.  If outside of the institution’s normal range, subject will be 
eligible when electrolytes are corrected.  
j. In the absence of rapidly progressive disease, the interval from prior treatment to the 
time of initiation of protocol therapy will be at least 14 days for prior anti-leukemic 
therapy with the exception of hydroxyurea as noted below OR at least 5 half-lives 
for cytotoxic/noncytotoxic agents, whichever is shorter. The half-life for the therapy 
in question will be based on published pharmacokinetic literature (abstracts, 
manuscripts, investigator brochure’s, or drug-administration manuals) and will be 
documented in the protocol eligibility document. Since the effect of therapy may be 
delayed, use of hydroxyurea for subjects with rapidly proliferative disease is allowed 
before the start of study therapy and on study and hydroxyurea will not require a 
washout.  
k. Concurrent therapy for CNS prophylaxis or continuation of therapy for controlled 
CNS disease is permitted. Subjects with a known history of CNS disease or leukemic 
brain metastasis must have been treated locally, have at least 3 consecutive LPs with 
no evidence of CNS leukemia, and must be clinically stable for at least 4 weeks prior 
to enrollment and have no ongoing neurological symptoms that in the opinion of the 
treating physician are related to the CNS disease (sequelae that are a consequence of 
the treatment of the CNS disease are acceptable). 
l. Females must be surgically or biologically sterile or postmenopausal (amenorrheic for 
at least 12 months) or if of childbearing potential, must have a negative serum or 
urine pregnancy test within 72 hours before the start of the treatment. 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 34 of 127 
 
m. Women of childbearing potential must agree to use an adequate method of 
contraception during the study and until 4 months after the last treatment. Males must 
be surgically or biologically sterile or agree to use an adequate method of 
contraception during the study until 3 months after the last treatment. In addition, 
sexually active male subjects must agree to use condoms during the study until 3 
months after the last treatment to prevent the potential transmission of the study drug 
and/or metabolites via semen. Adequate methods of contraception include: 
 Total abstinence when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 
 Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In 
case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment 
 Male sterilization (at least 6 months prior to screening). For female subjects on 
the study, the vasectomized male partner should be the sole partner for that 
subject 
 Combination of any of the two following (a+b or a+c or b+c) 
a. Use of oral, injected or implanted hormonal methods of contraception or 
other forms of hormonal contraception that have comparable efficacy 
(failure rate <1%), for example hormone vaginal ring or transdermal 
hormone contraception. Contraceptives containing ethinyl estradiol should 
be used with caution (Section 5.6.3). 
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS).  
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm 
or cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal 
suppository. 
 In case of use of oral contraception, women should have been stable on the same 
pill before taking study treatment. 
 Note: Oral contraceptives are allowed but should be used in conjunction with a 
barrier method of contraception due to unknown effect of drug-drug interaction. 
Women are considered post-menopausal and not of child-bearing potential if they 
have had 12 months of natural (spontaneous) amenorrhea with an appropriate 
clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had 
surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation 
at least six weeks ago. In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level 
assessment is she considered not of child-bearing potential. 
 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 35 of 127 
 
4.2. 
Exclusion Criteria 
a. Subjects with a known allergy, hypersensitivity, or contraindication to the protocol 
therapies or any of their components to be used in the arm the subject is to be enrolled 
on.  
b. Uncontrolled or significant cardiovascular disease, including any of the following: 
 Bradycardia of less than 50 beats per minute, unless the subject has a pacemaker; 
 QTcF interval >450 msec; 
 Diagnosis of or suspicion of long QT syndrome (including family history of long 
QT syndrome); 
 Systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥110 mmHg; 
 History of clinically relevant ventricular arrhythmias within 6 months prior to 
screening (eg, ventricular tachycardia, ventricular fibrillation, or Torsade de 
Pointes); 
 History of second (Mobitz II) or third-degree heart block (subjects with 
pacemakers are eligible if they have no history of fainting or clinically relevant 
arrhythmias while using the pacemaker); 
 History of uncontrolled angina pectoris, unstable angina or myocardial infarction, 
CABG, CVA, TIA, symptomatic pulmonary emboli within 6 months prior to 
Screening; 
 New York Heart Association Class 3 or 4 heart failure; 
 Left ventricular ejection fraction (LVEF) ≤50or less than the institutional lower 
limit of normal; 
 Complete left bundle branch block (right bundle branch block is permitted, but 
requires manual reading of the QTc interval); 
 Active cardiac dysrhythmias of NCI CTCAE grade ≥ 2 (eg, atrial fibrillation). 
c. Persisting toxicity related to prior therapy of Grade >1 NCI-CTCAE v 5.0; however, 
alopecia and sensory neuropathy Grade 2 or lower is acceptable 
d. Underwent HSCT within 90 days of the first dose of protocol therapy, or subjects 
with clinically significant (Grade 2 or greater) graft-versus-host disease (GVHD) (the 
use of topical steroids for ongoing cutaneous GVHD is permitted) 
e. Subjects with symptomatic CNS leukemia or subjects with poorly controlled CNS 
leukemia.  
f. Active and uncontrolled disease (active infection requiring systemic therapy, fever 
likely secondary to infection within prior 48 hours, uncontrolled hypertension despite 
adequate medical therapy as judged by the treating physician). 
g. Active (uncontrolled, metastatic) other malignancies 
h. Major surgery within 28 days prior to the first dose of protocol therapy  


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 36 of 127 
 
i. Known dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit 
the ingestion or gastrointestinal absorption of drugs administered orally 
j. Known history of testing positive for HIV or known acquired immunodeficiency 
syndrome (test at screening only if required by local regulations)  
k. Known history of Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection with 
active Hepatitis B or C infection at screening (positive HBV surface antigen or HCV 
RNA if anti-HCV antibody screening test positive)  
l. Vaccination with live-attenuated vaccines within 4 weeks of the first dose of study 
drug and while on trials is prohibited (COVID-19 vaccination is permitted) 
m. Subjects who are currently receiving treatment with medication that meet one of the 
following criteria and that cannot be discontinued at least one week prior to the start 
of DS-1594b treatment: 
 Medications that may prolong QTc interval and have a known risk of inducing 
Torsades de Pointes unless it is vital for the care of the subjects (see Appendix 
Table 28Table 28) 
 Strong inhibitors or inducers of CYP3A (see Appendix Table 29Table 29) 
 CYP3A and CYP2C19 substrates with narrow therapeutic index (see Appendix 
Table 29Table 29) 
n. Subjects who consume grapefruit products, Seville oranges, or Star fruit within 3 days 
prior to the first DS-1594b administration and until the last day of DS-1594b is 
completed. 
o. Additional exclusion criteria for the DDI sub-study and food effect sub-study 
(see Appendix Table 31Table 31) 
 Subjects who are currently receiving moderate inhibitors or inducers of CYP3A 
who cannot discontinue at least one week prior to the start of DS-1594b treatment 
till the end of sub-study period (note that strong CYP3A inhibitors or inducers 
still need to be restricted as defined in Section 4.2m). 
 Subjects who are currently receiving proton pump inhibitors who cannot 
discontinue at least 2 days prior to the start of DS-1594b treatment till the end of 
sub-study period. 
p. Other severe acute or chronic medical conditions that is active and not well controlled 
including renal, skeletal muscle, adrenal insufficiency, colitis, inflammatory bowel 
disease, or psychiatric conditions including recent (within the past year) or active 
suicidal ideation or behavior; or laboratory abnormalities that may increase the risk 
associated with study participation or study treatment administration or may interfere 
with the interpretation of study results and, in the judgment of the investigator, would 
make the subject inappropriate for entry into this study. 
q. Subjects unwilling or unable to comply with the protocol, including: 
 Pregnant or breastfeeding women or women of childbearing potential who are 
unable to comply with appropriate contraception as outlined in Section 4.1m or 
Formatted: C-Hyperlink
Formatted: C-Hyperlink
Formatted: C-Hyperlink
Formatted: C-Hyperlink


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 37 of 127 
 
who plan to become pregnant while in the study or for at least 6-7 months after 
last administration of study treatment  
 Known alcohol or drug abuse within the last 1 year 
 In a man whose sexual partner is a woman of childbearing potential, 
unwillingness or inability to use an acceptable contraceptive method for the entire 
study period and for at least 3 months after study completion 
r. Acute promyelocytic leukemia (APL). 
s. Uncontrolled or poorly controlled adrenal or pituitary disease (including adrenal 
insufficiency, Addison’s disease, Cushing’s disease)  
5. 
TREATMENT PLAN 
5.1. 
Phase 1 Dose Administration 
5.1.1. 
Study Treatment 
The orally administered film-coated tablet formulation of DS-1594b will be supplied by Daiichi 
Sankyo and are in 20 mg, 50 mg, and 200 mg dose strengths. 
The first dose cohort will start at 70 mg twice daily, approximately every 12 hours. For 
provisional dose levels beyond the first dose cohort, see Figure 1Figure 1. Alternative doses or 
dosing regimens may be enrolled based on emerging clinical data, including intermediate dose 
levels or dose de-escalation. BID and QD cohorts can be enrolled in parallel and will be 
evaluated independently for DLT.   
5.1.2. 
Dose Administration Guidance 
DS-1594b will be administered orally on a continuous twice daily (or once daily) regimen. In 
this study a complete cycle of treatment is defined as 28 days. The Investigator must instruct the 
subject to take the study drug (DS-1594b) exactly as prescribed: 
1. For BID dosing, subjects should take DS-1594b tablets twice daily at approximately the 
same time each day for morning and evening doses; for QD dosing, subjects should take 
DS-1594b tablets once daily at approximately the same time each day for morning doses. 
2. Each dose of DS-1594b is to be taken with a glass of water (at least 8 ounces – 
approximately 250 mL) and consumed over as short a time as possible (i.e., not slower 
than 1 tablet every 2 minutes). 
3. Subjects should be instructed to swallow the tablets whole and not to chew them. 
4. DS-1594b should be administered under fasting condition, at least 1 hour before or 
2 hours after a meal. 
5. For BID dosing, the morning and evening doses should be taken 12 (± 4) hours apart, 
although 12-hour interval is recommended. If a dose is not taken within 4 hours of the 
planned dosing time, the missed dose should not be replaced. On days when serial PK 
Formatted: C-Hyperlink


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 38 of 127 
 
blood samples are to be collected especially those with 12 hours post-dose timepoint (see 
Section 8.4.1), subjects should keep the 12-hour interval between morning and evening 
doses.  
6. On days when PK blood samples are to be collected, subjects will be instructed to hold 
their dose until arrival at the study center; the site will remind subjects one day before not 
to take the morning dose at home. DS-1594b will be administered at the site in the 
morning after the pre-dose ECG assessment and PK blood draw and prior to the post-
dose PK blood draws. The exact date/time of drug administration should be recorded in 
the eCRF. If a subject vomits within the first 4 hours post-treatment on a full PK 
sampling day, the exact time of vomiting should be recorded on the eCRF. 
7. All pre-dose PK samples should be drawn just before DS-1594b dosing. The sampling 
time of the pre-dose PK sample and the dosing time of DS-1594b must be precisely 
recorded in the eCRF. Furthermore, the dosing time of DS-1594b on the previous day 
must be precisely recorded in the eCRF. 
DDI sub-study only: 
 On days with posaconazole co-administration, DS-1594b will be dosed first under 
fasting condition. One hour later, posaconazole will be dosed (within 0.5 hours) 
following a breakfast. 
 On days with voriconazole co-administration, DS-1594b and voriconazole can be 
administered together since both drugs will be given under fasting conditions. 
Food effect sub-study only: 
 Subjects in this sub-study do not follow bullet (4) above but the bullets below for 
prandial condition. 
 For the morning doses from Cycle 1 Day 1 to Cycle 1 Day 8, DS-1594b will be 
administered immediately (within 0.5 hours) following a standard breakfast 
defined as one containing 600 kcal and 30% fat (~ 21g fat). Subjects should 
refrain from food and drink, except water, for at least 2 hours after dosing; for the 
evening doses (12 hours apart from morning dose) (applicable for BID dosing 
only), DS-1594b will also be administered immediately (within 0.5 hours) 
following a standard dinner (same meal content as breakfast). Subjects should 
refrain from food and drink, except water, for 2 hours before dosing (except for 
breakfast and dinner) and for 2 hours after dosing. 
 Starting from Cycle 1 Day 9 to Cycle 1 Day 18, DS-1594b should be 
administered under fasting condition (i.e. subjects should refrain from food and 
drink, except water, for 2 hours before dosing and for 2 hours after dosing). After 
completion of the sub-study (Cycle 1 Day 18 is the last day of sub-study), 
subjects will continue with DS-1594b dosing under fasting conditions, same as 
patients not in the food effect sub-study (DS-1594b dosing at least 1 hour before 
or 2 hours after a meal) starting on Cycle 1 Day 19. 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 39 of 127 
 
5.2. 
Phase 2 Cohort A: R/R AML with MLL-rearrangement  
5.2.1. 
Dose Administration Guidance 
The general dose administration guidance for DS-1594b as listed in Section 5.1 should be 
followed. 
5.3. 
Phase 2 Cohort B: R/R AML with NPM1 mutation 
5.3.1. 
Dose Administration Guidance 
The general dose administration guidance for DS-1594b as listed in Section 5.1 should be 
followed. 
5.4. 
Phase 2 Cohort C: R/R AML Treated with the Combination of 
Azacitidine and Venetoclax with DS-1594b 
5.4.1. 
Study Treatment of Study Drug and Other Combination Drugs 
Subjects will be treated according to the following dose levels; 
Table 6: 
Dose Levels for Azacitidine, Venetoclax, and DS-1594b 
Dose Level 
Azacitidine 
(mg/m2) 
Venetoclax (400 mg 
or equivalent) 
DS-1594b 
-1  
75 mg/m2 D1-7 
D1-28a, b, c, d 
Lower dose of DS-1594b 
as recommended by SRC 
0 (Starting dose) 
75 mg/m2 D1-7 
D1-28 a, b, c, d 
One dose level below the 
RP2D of DS-1594b from 
Phase 1 
1 
Not applicable 
Not applicable 
RP2D of DS-1594b from 
Phase 1 
Venetoclax: 
a During Cycle 1, venetoclax administered orally will be dose escalated daily to the goal dose of 
400mg daily.  Subjects will receive 100mg on Day 1, 200mg on Day 2 and 400mg on Day 3 and 
onwards, or adjusted ramp up per drug label if on concomitant azoles. The goal is to administer 
28 days of venetoclax in Cycle 1 unless marrow remission with concomitant marrow 
hypocellularity and/or myelosuppression is confirmed earlier than Cycle 1 Day 28. In this case 
the venetoclax may be stopped earlier to avoid venetoclax related myelosuppression or further 
marrow hypo/aplasia after discussion and approval from the PI. Venetoclax dose ramp-up as 
described in Section 5.4.2  
b If a bone marrow remission (<5% blasts) or aplasia/hypoplasia (<10% cellularity or insufficient 
sample) is not confirmed on the Day 21 bone marrow, subjects should continue venetoclax until 
day 28 and have a repeat bone marrow on Day 28 (+/- 5 days). If the Day 28 bone marrow shows 
≥ 5% blasts proceed with cycle 2 if this is in the best interest of the subject (those with C1D28 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 40 of 127 
 
bone marrow ≥ 5% are allowed to receive 21 days of venetoclax in Cycle 2 after discussion and 
approval from the PI). If the Day 28 bone marrow shows < 5% blasts or aplasia/hypoplasia 
follow steps outlined in the Azacitidine administration information “a” and “b” below. 
c Venetoclax will be administered orally daily on Days 1 to 28 of the first cycle; and may be 
reduced to Venetoclax Days 1 to 21 or less for subsequent cycles after PI approval.  
d Results from published in vitro and clinical DDI studies revealed a need to modify the dose of 
venetoclax when it is co-administered with moderate or strong CYP3A inhibitors or P-gp 
inhibitors (VENCLEXTA® USPI). Based on in vitro assessment, DS-1594b has the potential to 
inhibit CYP3A-mediated metabolism and P-gp mediated transport of venetoclax in vivo. Thus, 
dose level(s) of venetoclax should be recommended by the SRC based on emerging DS-1594b 
PK and safety data, and the dose level of venetoclax and DS-1594b may be adjusted after review 
of the data collected during the safety run-in evaluation.  
Azacitidine: 
Azacitidine (75 mg/m2/day) will be administered subcutaneously (SQ) or intravenously (IV) for 
the first 7 days of every cycle. Azacitidine may be given in a 5on - 2off - 2on or 4on - 2off – 3 on 
or other similar modified schedule if the subject is not able to get weekend infusions. Azacitidine 
is administered in the clinic or chemotherapy administration area. Both SQ and IV forms of 
administration are FDA approved and are allowed and considered interchangeable. Subjects may 
start receiving azacitidine by one route and change to the other, and administration schedules 
from one schedule and change to the other at any time as needed based on subject and/or 
physician preference. 
 
In Cycle 1, subjects should undergo a bone marrow aspiration and biopsy on Day 21 (+/- 
4 days). Subjects who achieve a confirmed marrow remission (i.e. bone marrow blasts < 
5% by morphology) or marrow aplasia/hypoplasia (≤ 10% cellularity or insufficient 
sample) may discontinue venetoclax for the remainder of the cycle and be monitored for 
count recovery.  
  If the Day 21 bone marrow shows < 5% blasts, the venetoclax may be held, and 
consider delaying cycle 2 till ANC > 0.5 x 109/L and platelets are > 30 x 109/L 
without platelet transfusion support for > 5 days.  
  If the Day 21 bone marrow shows aplasia/hypoplasia (≤ 10% cellularity or 
insufficient sample), the venetoclax may be held on Day 21 to avoid venetoclax 
related myelosuppression or further marrow hypo/aplasia, and a repeat bone 
marrow should be performed on Day 28 (+/- 4 days) to confirm response and 
MRD assessment. If the Day 28 bone marrow shows ≥ 5% blasts, proceed with 
Cycle 2 if this is in the best interest of the subject (those with C1D28 bone 
marrow ≥ 5% are allowed to receive 21 days of venetoclax in Cycle 2). If the Day 
28 bone marrow shows < 5% blasts, the venetoclax may be continued to be held, 
and consider delaying cycle 2 till ANC > 0.5 x 109/L and platelets are >30 x 109/L 
without platelet transfusion support for > 5 days. If the Day 28 bone marrow 
shows persistent aplasia/hypoplasia (≤ 10% cellularity or insufficient sample) 
venetoclax may be held to avoid venetoclax related myelosuppression or further 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 41 of 127 
 
marrow hypo/aplasia and consider repeating a bone marrow in approximately 10-
14 days. 
 If a bone marrow remission (< 5% blasts) or aplasia/hypoplasia is not noted on 
the Day 21 bone marrow, subjects should continue venetoclax until day 28 and 
have a repeat bone marrow on Day 28 (+/- 5 days). If the Day 28 bone marrow 
shows ≥ 5% blasts proceed with Cycle 2 if this is in the best interest of the subject 
(those with C1D28 bone marrow ≥ 5% are allowed to receive 21 days of 
venetoclax in Cycle 2 after discussion with and approval from the PI). If the Day 
28 bone marrow shows < 5% blasts or aplasia/hypoplasia follow steps outlined in 
“a” and “b” above. 
 Treatment interruptions and dosing schedules other than the ones mentioned 
above can be considered after discussion with the PI and proper documentation of 
the rationale. 
 DS-1594b administration will continue as scheduled and will not be impacted or 
adjusted based on venetoclax dosing schema or venetoclax-related delays. 
 
Physicians should leukoreduce with hydroxyurea to reduce the peripheral white blood 
count to below 10 x 109/L prior to the administration of the first dose of venetoclax. If the 
WBC is more than 10 x 109/L, the venetoclax should not be initiated till the white count 
is brought down to below 10 x 109/L. 
 
The subject will be admitted to the hospital for at least the first 7 days of the 1st cycle of 
concomitant azacitidine-venetoclax-DS-1594b therapy (e.g., Day 1 through Day 7) of 
Cycle 1, potentially admission will be longer if we encounter TLS, infections or other 
complications that would be better managed in the in-patient setting. To mitigate the risk 
for tumor lysis syndrome, subjects must be receiving tumor lysis prophylaxis, including 
hydration (oral, intravenous) and treatment with a uric acid reducing agent (allopurinol, 
rasburicase) prior to the start of venetoclax therapy and continued during Cycle 1.  
 TLS chemistry tests (potassium, uric acid, creatinine, calcium and phosphorus) 
will be obtained prior to dosing and 5 to 8 hours after each new venetoclax dose 
during the venetoclax ramp-up period. TLS chemistry test results will be reviewed 
by the investigator in real time and prior to the subject receiving the next higher 
dose of venetoclax to ensure appropriate and timely management. If a subject 
meets the criteria for clinically significant laboratory or clinical TLS, no 
additional venetoclax should be administered until resolution of the TLS. 
Venetoclax interruption for up to 72 hours following transient (< 48 hours) 
chemical changes and laboratory TLS will be allowed and will not require a dose 
reduction. 
 
See Section 6.4 for details of TLS management.  
 
If azacitidine cycles are delayed, venetoclax therapy may continue on Days 1-21 or Days 
1-28 of a 4-week cycle after discussion with the PI or Co-PI and documentation in the 
medical record.If azacitidine cycles are delayed, DS-1594b may continue without 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 42 of 127 
 
interruption after discussion with the PI or Co-PI and Sponsor, and documentation in the 
medical record. 
5.4.2. 
Venetoclax Administration 
If a dose is missed or vomited, the next dose should not be increased to account for missing a 
dose. The subject should take the next regular dose at the regularly scheduled time. 
Day 1 of each cycle will be counted from the start of the azacitidine infusion. Treatment may be 
prolonged beyond the planned 28 days of each cycle if the start of the next course of azacitidne is 
delayed. However, if there are adverse events that mandate treatment interruption or it is 
considered in the best interest of the subject for safety reasons to interrupt DS-1594b and/or 
venetoclax therapy, DS-1594b and/or venetoclax administration can be transiently discontinued 
and re-started as per guidelines in  Section 6. 
5.5. 
Phase 2 Cohort D: R/R ALL treated with miniHCVD with DS-1594b 
Subjects will be treated according to the following dose levels: 
Table 7: 
Dose levels for miniHCVD, and DS-1594b 
Dose Level 
miniHCVD 
DS-1594b 
-1  
As published21,22 miniHCVD regimen  
Lower dose of DS-1594b as 
recommended by SRC 
0 (Starting dose) 
As published miniHCVD regimen 
One dose level below the RP2D 
of DS-1594b from the Phase 1 
1 
Not applicable 
RP2D of DS-1594b from the 
Phase 1 
DS-1594b orally twice daily (or daily, dependent on results from dose escalation phase). In each 
cycle, DS-1594b will be taken daily continuously. 
Variations in dose reductions of the individual chemotherapy or the administration of venetoclax 
or supportive care dose schedules other than those suggested below are allowed in the best 
interest of subjects. Such subjects should be discussed with the principal investigator. Dose 
escalations of chemotherapy above those outlined in the protocol; however, are not allowed. 
Variations in infusion times due to minor differences in IV bag overfill/underfill and institutional 
procedure on flushing chemotherapy lines will not result in protocol deviation. 
5.5.1. 
Treatment Overview  
DS-1594b will be given orally twice daily (or daily, dependent on results from dose escalation 
phase) in combination with mini-hyper-CVD. Each cycle is 28 days. Mini-hyper-CVD 
chemotherapy regimen consists of a total of 8 cycles of intensive chemotherapy with Mini-
hyper-CVD alternating with high-dose methotrexate and cytarabine administered approximately 
every 28 days (or later to allow for recovery from myelosuppression or infection).  Subjects will 
then receive up to 2 years of maintenance with: DS-1594b, vincristine and corticosteroids. 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 43 of 127 
 
Subjects who are responding, and without any major drug-related toxicity, may continue DS-
1594b until the end of the 2-year maintenance period.  
Cycle 1:  Eligible subjects will receive DS-1594b orally twice daily (or daily) in the in-patient 
setting in combination with Mini-hyper-CVD chemotherapy starting together on Day 1. The 
subjects will remain hospitalized up until the completion of chemotherapy. The hospital stay may 
be prolonged in subjects with infections or other issues requiring an in-patient stay. The 
remainder of the course of DS-1594b can be administered as an out-patient. Dose level 0 is the 
starting dose level and will be one dose level below the RP2D, and dose level -1 will only be 
explored if there is excess toxicity with the starting dose. If dose level 0 is tolerated, escalation to 
the RP2D will be performed as described in Section 3.3.  Each cycle is 28 days, however 
additional days may be needed for subject recovery before starting the next cycle. At the end of 
Cycle 1, subjects will have bone marrow aspirate/biopsy for response assessment.   
Hydroxyurea and/or dexamethasone is allowed prior to the beginning of Mini-hyper-CVD. 
Cycles 2 – 8:  Subjects will continue DS-1594b orally twice daily (or daily) continuously. 
Chemotherapy from the mini-hyper-CVD regimen will be administered in the in-patient setting, 
starting on Day 1 of each of the Cycles 2 through 8. The subjects may remain hospitalized up 
until the completion of chemotherapy. Hospital stay may be prolonged for subjects with 
infections or other issues requiring in-patient stay.  The remainder of the course of DS-1594b can 
be administered as an out-patient. 
Upon completion of the 8 courses of the Mini-hyper-CVD regimen, subjects may continue 
DS-1594b orally twice daily (or daily) continuously of each 28-day cycle for up to 2 years during 
maintenance.  The dose will be according to the dose level administered during Cycles 2 
through 8.  Subjects may be moved from the intensive chemotherapy phase to the maintenance 
phase with vincristine, steroids, DS-1594b orally twice daily (or daily) continuously prior to 
completion of 8 cycles of chemotherapy due to frequent infectious complications, or if the 
subject is intolerant to the chemotherapy (after discussion with the Principal Investigator). If an 
early transition to maintenance phase is planned, subjects should receive at least 2 cycles of 
intensive chemotherapy. The reason for early transition to the maintenance phase must be 
documented in the medical record. 
At any time while enrolled in this trial, subjects may be referred for hematopoietic stem cell 
transplantation at the discretion of the treating physician.  DS-1594b will be discontinued at least 
2 days prior to the start of the conditioning regimen for hematopoietic stem cell transplantation. 
5.5.2. 
Mini-Hyper-CVD Regimen 
5.5.2.1. 
General Considerations 
 The Mini-hyper-CVD (odd cycles) will alternate with methotrexate and cytarabine 
(even courses) administered on Day 28 (if count recovery allows) or later day cycle 
(as count recovery allows).  
 Anti-emetic therapy with each course of intensive chemotherapy as needed.  


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 44 of 127 
 
 Filgrastim (G-CSF) will be administered with each course after the completion of 
chemotherapy.  Peg-filgrastim may replace filgrastim (G-CSF). Biosimilars may be 
used for filgrastim or peg-filgrastim. 
 Next cycle may be started when granulocytes > 1.0 x 109/L and platelets  50 x 109/L. 
Cycles may be started with dose reductions prior to full platelet recovery, if the 
treatment is delayed (e.g., greater than 28 days from last cycle).   
 Prophylactic antibiotics may be given with each course until neutrophil recovery to 
0.5 x 109/L or greater (or other antibiotics if being treated for active infection). 
Suggestions include:  Levaquin 500 mg orally daily; trimethoprim-sulfamethoxazole 
double-strength one tablet orally twice daily; or other appropriate antibacterial agent. 
Caspofungin or another appropriate antifungal agent. Valacyclovir 500 mg orally 
daily; or acyclovir 200 mg orally twice daily; or another appropriate antiviral agent.  
 Omit azoles on Day -1, same day, and day after vincristine. 
 In general, 8 cycles of chemotherapy (4 Mini-hyper-CVAD, 4 methotrexate plus 
cytarabine) will be administered in approximately 28-day intervals (depending on the 
recovery of blood counts.  Thereafter, maintenance therapy with DS-1594b in 
combination with, vincristine and corticosteroids may be continued for up to 2 years 
of maintenance. Modifications thought to be in the best interest of the subject are 
allowed after discussion with the Principal Investigator. Subjects will be followed 
indefinitely for relapse and survival. 
 For subjects with CD20 expression (≥ 20% by flow cytometry) Rituximab 375 mg/m2 
may be added on Days 1 (± 3 days) and 11 (± 3 days) of Cycles 1 and 3, and on Days 
1 (± 3 days) and 8 (± 3 days) of Cycles 2 and 4. For subjects receiving rituximab all 
therapy can be moved back 1 day if needed (i.e. Day 1 starts Day 2, Day 2 starts 
Day 3, etc.). 
 Methotrexate dose regimen will be adjusted as indicated below for pleural effusions. 
5.5.2.2. 
Mini-Hyper-CVD [Odd courses 1, 3, 5, 7]: 
 Cyclophosphamide (CTX) 150 mg/m2 intravenously (IV) over 3 hrs (± 1 hour) every 
12 hrs x 6 doses on Days 1, 2, 3 
 MESNA 300 mg/m2/d IV continuous infusion daily for 24 hrs (± 4 hours), starting 
approximately 1 hour prior to CTX and completing by approximately 12 hrs after the 
last dose of CTX.  
 Vincristine 2 mg IV on Days 1 ( 3 days) and 11 ( 3 days). Vincristine is not 
myelosuppressive and may be given while subjects are receiving a filgrastim product 
(G-CSF); no known adverse effects have been observed with the 2 agents given 
together. Biosimilars may be used for filgrastim or peg-filgrastim. 
 Dexamethasone 20 mg IV or orally daily on Days 1 - 4 ( 3 days) and Days 11 - 14 
( 3 days). 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 45 of 127 
 
 Filgrastim (G-CSF) 10 mcg/kg (rounded) subcutaneously daily (or 5 mcg/kg twice 
daily) until post-nadir granulocytes > 1.0 x 109/L and may be stopped earlier for bone 
pain or other related toxicity. Minimum time allowed between courses is 14 days.  
Peg-filgrastim may replace filgrastim (G-CSF) at a dose of 6 mg SQ on Day 5 
(+ 3 days).  Biosimilars may be used for filgrastim or peg-filgrastim. 
 For subjects with CD20 expression (≥ 20% by flow cytometry) Rituximab 375 mg/m2 
may be added on Days 1 (± 3 days) and 11 (± 3 days) of Cycles 1 and 3. For subjects 
receiving rituximab all therapy can be moved back 1 day if needed (i.e. Day 1 starts 
Day 2, Day 2 starts Day 3, etc.). 
 CNS prophylaxis: Methotrexate 12 mg intrathecally (6 mg via Ommaya reservoir) on 
Day 2 ( 3 days) of Cycles 1 and 3. Cytarabine 100 mg intrathecally on Day 7 ( 3 
days) of Cycle 1 and 3 for a total of 8 intrathecal (IT) doses. These are generally 
given on Cycles 1 - 4 but if one or more IT treatments is missed it can be made up on 
a later cycle. Administer in 3 to 5 cc of preservative-free normal saline.  
5.5.2.3. 
Methotrexate and Cytarabine [Even courses 2, 4, 6, and 8]: 
 Methotrexate (MTX) 50 mg/m2 IV over 2 hrs (± 1 hour) followed by 200 mg/m2 over 
22 hrs on Day 1. Total duration of administration is 24 hours (2 plus 22 hours) 
(± 3 hours). 
 Cytarabine 0.5 g/m2 IV over 3 hrs (± 1 hour) every 12 hrs for 4 doses on Days 2 
and 3. 
 Leucovorin rescue 50 mg IV or oral followed by 15 mg IV or oral every 6 hours for 
8 doses (or until MTX level is less than 0.1 M) beginning 12 hrs ( 3 hrs) post MTX 
completion (i.e. approximately 36 hours from start of MTX). 
 Check MTX levels around time 0h, 24h and 48h post completion of MTX unless 
methotrexate cleared: 
 if > 20 M at Time 0, hold cytarabine and repeat level; if continues to be > 20 M 
reduce cytarabine to 0.25 g/m2 IV over 2 hours every 12 hours for 4 doses on 
Days 2 and 3. Begin leucovorin rescue as described above. 
 if > 1 M at 24hrs or > 0.1 M at 48 hours, increase leucovorin rescue to 50 mg 
IV or oral every 6 hrs until serum methotrexate level is < 0.1 M. Clearance to 
levels 0.15 M or less is acceptable in subjects with normal renal function. 
 Leucovorin rescue may be increased further for elevated methotrexate levels or 
delayed clearance 
 Filgrastim (G-CSF) 10 mcg/kg (rounded) subcutaneously daily (or 5 mcg /kg twice 
daily) until post-nadir granulocytes ≥ 1.0 x 109/L and may be stopped earlier for bone 
pain or other related toxicity. Minimum time allowed between courses is 14 days 
(e.g., Day 14).  Peg-filgrastim may replace filgrastim (G-CSF) at 6 mg SQ on Day 4 
(± 3 days). Biosimilars may be used for filgrastim or peg-filgrastim. 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 46 of 127 
 
 For subjects with CD20 expression (≥ 20% by flow cytometry) Rituximab 375 mg/m2 
may be added on Days 1 (± 3 days) and 8 (± 3 days) of Cycles 2 and 4. For subjects 
receiving rituximab all therapy can be moved back 1 day if needed (i.e. Day 1 starts 
Day 2, Day 2 starts Day 3, etc.). 
 CNS prophylaxis: cytarabine 100 mg day 5 + 3 days and methotrexate 12 mg 
intrathecal (IT) (6 mg via Ommaya reservoir) Day 8 + 3 days of Cycle 2 and 4 for a 
total of 8 IT doses. These are generally given on Cycles 1- 4 but if one or more IT 
treatments is missed it can be made up on a later cycle.  Administer in 3 to 5 mL of 
preservative-free normal saline 
5.5.3. 
Intrathecal Treatments 
If the subject has been previously treated, and has had prior intrathecal therapy, or prior CNS 
disease, discuss management of CNS with the Principal Investigator.  
If active CNS disease: Consider methotrexate alternating with cytarabine twice weekly until 
cerebrospinal fluid (CSF) clear; then once weekly for 4 weeks, then every other week for 4 
weeks, then monthly for 4 months. Alternative methods of treating CNS disease are allowed if 
appropriate for the subject (e.g., intrathecal liposomal cytarabine, or others).  
Concomitant intrathecal chemotherapy should be avoided, if possible, on the days of 
administration of intravenous methotrexate and cytarabine (even courses). 
 
5.5.4. 
Suggested Standard Dose Reductions/Modifications/Discontinuations: 
 Vincristine 1 mg IV Days 1 and 11 (50% reduction) if: 
 Bilirubin > 2 mg/dl and ≤ 3 mg/dl 
 Clinically significant grade 2 peripheral neuropathy persisting greater than 
2 weeks. 
 Eliminate vincristine for Grade 3-4 peripheral neuropathy, including Grade 3-4 
ileus suspected to be related to vincristine, or bilirubin > 3 mg/dL. 
 Methotrexate: 
 Consider reduction by 25% to 50% for Grade 3 or worse mucositis with previous 
methotrexate course. 
 Reduce by 50% for calculated creatinine clearance 10-50 mL/min, if < 10 ml/min, 
hold methotrexate. 
 Reduce by 25% to 75% for delayed excretion and/or nephrotoxicity with previous 
methotrexate course. 
 Reduce by 50% for pleural effusion or ascites (drain effusion if possible).  
 Non-hematological toxicity  


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 47 of 127 
 
 If Grade 3 or 4 non-hematologic toxicity is at least possibly attributable to DS-
1594b, dose interruption of DS-1594b is required. Subjects who experience drug-
related Grade 3 non-hematological toxicity may be given a subsequent course one 
dose level below the previous course, but the subject must have recovered to 
Grade ≤1 before start of the next course. If a subject has drug-related Grade 4 
non-hematological toxicity, he/she may receive a subsequent courses at one 
reduced dose level after resolution of toxicity to Grade ≤1, only if approved by 
the PI based on the clinical significance of the toxicity and only if subject has had 
derived a benefit from the therapy. The dose of DS-1594b can be decreased 
during a cycle, at the discretion of treating physician and PI, for chronic Grade 2 
non-hematological toxicity. Other dose modifications may be considered as 
clinically indicated with documentation and approval of the PI.  
 Hematologic toxicity 
 Dose interruptions or modifications will be made for Grade 4 hematological 
toxicities, only if considered at least possibly related to DS-1594b and not related 
to underlying disease or the use of chemotherapy, as determined by the treating 
physician and the study PI. Subjects with baseline neutropenia or those who have 
significant bone marrow involvement may be particularly at high risk.  
 If a subject achieves CRi or has a morphologically leukemia free bone marrow 
after completion of a cycle, DS-1594b may be interrupted from Day 21 for up to 
14 days or until recovery of ANC ≥ 0.5 x 109/L. The next cycle administration 
will also be delayed until ANC ≥ 0.5 x 109/L. If DS-1594b is interrupted then the 
next cycle administration of chemotherapy will also be delayed. The next cycle 
with both DS-1594b and chemotherapy will resume on the same day after the 
interruption.  
 If a subject presents with new onset Grade 4 neutropenia for more than 1 week 
during subsequent cycles, unless it is thought to be due to the underlying disease, 
DS-1594b dosing may be interrupted until ANC recovery to >0.5 x 109/L in 
consultation with the study PI. DS-1594b may be re-initiated at a lower dose per 
discussion between the treating physician and the study PI.  
 Other modifications of drug schedules may be implemented if judged to be in the best 
clinical interest of the subject after discussion with PI or at the discretion of the 
treating physician.  This includes delays in chemotherapy cycles because of persistent 
myelosuppression, other side effects, subject request, or other reasons. Missed doses 
of DS-1594b do not need to be made up. 
 Dose reductions exceeding those above or in other agents, e.g., leucovorin, 
antibiotics, antiemetics, etc., are allowed after discussion with the Principal 
Investigator. 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 48 of 127 
 
5.5.5. 
Maintenance 
Maintenance chemotherapy with vincristine, DS-1594b, and prednisone for approximately 24 
months beginning at Dose level 0 or lower dose level if prior toxicity required dose reduction of 
agents (titrate to keep ANC > 0.5 x 109/L and platelet count ≥ 30 x 109/L) (See Table 8Table 8 
below): 
 Vincristine 2 mg IV on Day 1 approximately every 28 days. 
 Prednisone 50 mg orally daily on Days 1 to 5 approximately every 28 days with 
vincristine. 
 DS-1594b continuously, twice daily (or daily) every 28 days at the same dose 
received during induction/consolidation. 
 For DS-1594b dose adjustments, see Section 6.  
 Suggested maintenance chemotherapy dose adjustments are in Table 8Table 8 below.   
Table 8: 
Maintenance Chemotherapy Dose Adjustments 
Level 
 Vincristine (mg) 
Prednisone (mg) 
0 
2 
50 
-1 
1 
40 
-2 
0 
30 
 Prednisone 
 Dose should remain at 50 mg unless steroid myopathy or other significant toxicity 
occurs. 
 Prednisone is not required to be dose adjusted for hyperglycemia. 
 Further reductions beyond what is shown in Table 8Table 8 may be allowed if 
recommended by the treating physician and after discussion with the PI. 
 Vincristine 
 Decrease by one dose level for Grade 2 peripheral neuropathy persisting longer 
than 2 weeks and bilirubin >2 mg/dL and ≤ 3 mg/dL. 
 Discontinue for Grade 3 or greater peripheral neuropathy persisting longer than 
2 weeks, including Grade 3-4 ileus suspected to be related to vincristine, or 
bilirubin > 3 mg/dL. 
5.6. 
  Concomitant Medications 
5.6.1. 
Concomitant Medications – Subject Supportive and Safety 
The use of any concomitant medication/therapies deemed necessary for subject supportive care 
and safety are permitted, with the exception of those outlined below.  Other leukemia directed 
therapy including systemic chemotherapyor biologic response modifiers are not permitted during 
Formatted: C-Hyperlink
Formatted: C-Hyperlink
Formatted: C-Hyperlink


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 49 of 127 
 
the study except for those specified in the eligibility criteria. A course of radiation therapy as 
required in the best interest of the patient if approved by the PI/Co-PI. No other investigational 
agent for the treatment of AML is allowed during the study. Antiemetics may be used for the 
prevention or treatment of nausea and vomiting.  
Administration of other antineoplastic agents is prohibited for subjects while on this study with 
the following exceptions:  
 intrathecal (IT) therapy for subjects with controlled CNS leukemia at the discretion of 
the PI, 
 Since the effect of DS-1594b may be mediated by differentiation, this effect may be 
delayed, use of hydroxyurea (any dose) for subjects with rapidly proliferative disease 
is allowed on study and before the start of study therapy and will not require a 
washout. These medications will be recorded in the case-report form. 
5.6.2. 
Medications that may prolong the QTc interval 
Medications that may prolong QTc interval and have a known risk of inducing Torsades de 
Pointes should be avoided unless it is vital for the care of the subjects: 
 Concomitant use of DS-1594b with drugs known to have a high risk of increasing the 
QTc interval, and drugs known to increase the QTc interval that are also primarily 
metabolized by CYP3A should be avoided. See Appendix Table 28Table 28.  
5.6.3. 
Concomitant Medications Requiring Caution 
 Based on nonclinical assessment, DS-1594b is primarily metabolized by CYP3A. 
Caution should be exercised with concomitant use of drugs that are moderate 
inhibitors or inducers of CYP3A (Appendix Table 30Table 30). The actual dose, 
actual start/end date and time of dosing for these concomitant medications should be 
recorded on the eCRF. 
 DS-1594b is shown to inhibit P-gp activity in vitro with estimated IC50 value of 
1.79 µM. Alternative therapies that are not P-gp substrates should be considered.  If 
concomitant use of DS-1594b and P-gp substrates is unavoidable, separate DS-1594b 
administration by at least 6 hours before or after the administration of oral narrow 
therapeutic index P-gp substrates (e.g. digoxin, tacrolimus) to minimize the potential 
for interactions. 
 DS-1594b was shown to inhibit BCRP and OCT1 activities in vitro with estimated 
IC50 value of 1.94 µM and 0.489 µM, respectively.  Alternative therapies that are not 
BCRP or OCT1 substrates should be considered.  If concomitant use of DS-1594b 
and BCRP or OCT1 substrates is unavoidable, caution should be exercised when co-
administered with DS-1594b (Appendix Table 30Table 30). 
 The concurrent use of a H2-antagonist or an antacid is allowed, but the H2-antagonist 
must be administered 10 hours before or 2 hours after the DS-1594b dose, and the 
antacid must be administered 2 hours before or 2 hours after the DS-1594b dose. 
Formatted: C-Hyperlink
Formatted: C-Hyperlink
Formatted: C-Hyperlink


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 50 of 127 
 
 Caution is advised with concurrent use of proton pump inhibitors, as exposure of DS-
1594b may be reduced. The dose, start/end date of dosing for these concomitant 
medications should be recorded on the eCRF. 
 Caution is advised with concurrent use of ethinyl estradiol containing contraceptives, 
as in vitro studies of DS-1594b have demonstrated the potential for time-dependent 
inhibition of CYP3A.  If ethinyl estradiol containing contraceptives are used, counsel 
subjects and monitor for adverse events related to potential increased ethinyl estradiol 
exposure, such as venous thromboembolism.  
 Drugs that should be used with caution are included in Appendix Table 30Table 30.  
5.6.4. 
Prohibited Concomitant Medications: 
 Co-administration of DS-1594b with drugs that are CYP3A and CYP2C19 substrates 
known to have narrow therapeutic index should be avoided, unless there are no 
alternative therapies or if the drugs are considered by the investigators as vital for the 
care of the subjects. 
 Strong inhibitors or inducers of CYP3A may affect the clearance of DS-1594b, and 
this may impact its potential efficacy or increase the risk of side effects.  Therefore, 
strong CYP3A inhibitors (e.g. posaconazole, voriconazole) or inducers (e.g. rifampin) 
should be restricted in the initial stage of the study until DDI assessments have been 
conducted post-MTD/RP2D determination to characterize this risk.  
 P-gp substrates that have narrow therapeutic indices should be avoided. 
 Drugs that should be restricted is included in Appendix Table 29Table 29.  
 For the DDI sub-study with anti-fungal agents, medications known to induce or 
inhibit CYP3A (moderate/strong inhibitors/inducers) must be discontinued or 
substituted one week prior to the first dose of DS-1594b, or must be temporarily 
interrupted during the course of the DDI sub-study of 17 day duration (Appendix 
Table 28Table 28 and Table 31Table 31). 
 For the food effect sub-study, gastric reducing agents such as proton pump inhibitors 
should be discontinued one week prior to the first dose of DS-1594b or must be 
temporarily interrupted during the sub-study of 14-day duration (Appendix 
Table 31Table 31).  
 Refer to the package inserts of venetoclax and azacitidine for prohibited concomitant 
medications related to venetoclax and azacitidine (Cohort C). 
5.6.5. 
Supportive Care Measures  
Supportive care measures including blood products, infection prophylaxis and growth factors 
will be administered according to standard practice at the investigational site (See 
Recommendations in Table 9Table 9 ). 
Formatted: C-Hyperlink
Formatted: C-Hyperlink
Formatted: C-Hyperlink
Formatted: C-Hyperlink
Formatted: C-Hyperlink
Formatted: C-Hyperlink


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 51 of 127 
 
Table 9: 
Recommendations for the use of concomitant medications and therapies 
Category of Use 
Medication 
Comment on Use 
Restriction on Use 
Recommended 
Prophylactic 
antibiotics, antifungal 
agents, and antiviral 
agents 
Strongly encouraged 
Refer to Appendix 
Table 22Table 22, 
Table 23Table 23, 
Table 25Table 25 for 
restrictions, and 
Section 5.3. 
 
Antiemetic agents 
According to standard 
of care at the site 
Avoid QTc prolonging 
antiemetics 
(Section 10) 
Allowed 
Oral allopurinol or 
rasburicase 
According to standard 
of care at the site 
 
None 
 
Leukapheresis 
According to standard 
of care at the site 
 
Before first dose on 
Day 1 = 1 only 
 
Red blood cell 
transfusion 
None 
 
 
None 
 
Platelet transfusion 
None 
 
 
None 
 
White blood cell 
transfusion 
At Investigators 
discretion according to 
standard of care at the 
site 
 
None 
 
Myeloid growth factors 
or platelet growth 
factor 
At Investigators 
discretion according to 
standard of care at the 
site 
 
None 
 
Erythropoietin or 
darbepoetin 
 
At Investigators 
discretion according to 
standard of care at the 
site 
 
None 
 
Any other medication 
for supportive care 
 
 
At Investigators 
discretion according to 
standard of care at the 
site 
None 
 
Consistent with subject safety and comfort, administration of any prescription or over-the-
counter drug products other than study medication should be minimized during the study period. 
Subjects should be discouraged from use of street drugs, herbal remedies, self-prescribed drugs, 
tobacco products, or excessive alcohol during the clinical study. 
Formatted: C-Hyperlink, Font: 11 pt
Formatted: C-Hyperlink, Font: 11 pt
Formatted: C-Hyperlink, Font: 11 pt


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 52 of 127 
 
If considered necessary for the subject’s wellbeing, drugs for concomitant medical conditions or 
for symptom management may be given at the discretion of the investigator. The investigator’s 
decision to authorize the use of any drug other than study drug should take into account subject 
safety, the medical need, the potential for drug interactions, the possibility for masking 
symptoms of a more significant underlying event, and whether use of the drug will compromise 
the outcome or integrity of the study. 
Subjects should be instructed about the importance of the need to inform the clinic staff of the 
use of any drugs or remedies (whether prescribed, over-the- counter, or illicit) before and during 
the study. 
Recommendations for specific types of concomitant therapies, supportive care; diet and other 
interventions are as follows: 
 Infections secondary to myelosuppression are common in subjects with AML, and 
may be related to underlying disease, chemotherapy, or both. Therefore, the use of 
prophylactic antibiotics, antifungal agents, and antiviral agents is recommended 
according to institutional standards. The use of strong CYP3A inhibitors is not 
allowed. Therefore, the use of antifungal, antiviral and antibiotics agents listed in 
Appendix Table 29Table 29 are prohibited until DDI assessments based on DDI sub-
study have been conducted to fully characterize the risk. 
 All ongoing medications and therapies (including herbal products, nutritional 
supplements, and nontraditional medications) at screening will be considered prior 
medications. All prior medications (within 30 days of enrollment) and concomitant 
medications will be recorded in the case report form.  
 If a prohibited medication is inadvertently administered/ taken by the subject, the 
subject may remain on study as long as the prohibited medication is discontinued as 
soon as feasible. If a prohibited medication is considered essential for the subject 
well-being, continuation on study with concomitant administration of such 
medication(s) will need to be discussed with and approved by the principal 
investigator and sponsor. 
6. 
DOSING DELAYS / MODIFICATIONS / DISCONTINUATIONS 
FOR POSSIBLY RELATED ADVERSE EVENTS 
6.1. 
Toxicity At Least Possibly Related to Study Drugs 
Subjects experiencing unacceptable toxicity at least possibly related to the study drugs should 
temporarily stop treatment according to the guidelines in the dose adjustment schema. 
6.2. 
Toxicity Grading 
Toxicity grading will be according to the NCI CTCAE, v5.0.  To prevent unnecessary morbidity, 
the following guidelines for dose adjustment for toxicities at least possibly related to study drugs 
are recommended.  
Formatted: C-Hyperlink


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 53 of 127 
 
6.2.1. 
Dose Adjustments for Hematological Adverse Events (AE) Considered at Least 
Possibly Related to Study Drugs 
Dose reduction/interruption/discontinuation decisions should be based on the CTCAE version 
5.0 and the guidelines provided below. 
Subjects with acute leukemias usually present with abnormal peripheral blood counts at the time 
therapy is started, and myelosuppression is an expected event during the course of therapy for 
acute leukemia. Thus, subsequent courses may be administered regardless of peripheral blood 
counts during the first 3 cycles and/or in the presence of residual leukemia. After Cycle 3, 
treatment interruptions and dose adjustments may be considered according to the following 
guidelines when there is no evidence of active leukemia: 
 Subjects with a response (no evidence of any residual leukemia on bone marrow 
and/or peripheral blood by morphology or flow-cytometry) will have dose 
modifications for hematological toxicities as specified in the azacitidine and 
venetoclax PIs and in Section 5.4.15.4.1.1 and Section 5.4.2. See Table 10Table 10 
for recommended dose modifications for DS-1594b for hematologic adverse events 
that are considered at least possibly related (see Section 5.1 for preliminary dose 
levels).  
 If there are persistent peripheral blood blasts, or the bone marrow shows ≥ 5% blasts 
or any evidence of residual leukemia by morphology or flow, treatment may be 
continued regardless of neutrophil and platelet count with supportive care as needed. 
Dose-interruptions of individual drugs in these subjects should be considered on an 
individual case-by-case basis and discussed with the PI and sponsors. 
 Investigators should, whenever possible, determine which medication is causing the 
toxicity and interrupt or dose reduce, as applicable.  
Table 10: 
DS-1594b Dose Adjustments for Neutropenia At Least Possibly Related to 
Study Drug 
Grade 
Occurrence 
Dose Modification 
1 or 2 
Any 
No modification 
3 (without infection or 
febrile neutropenia) 
Any 
No modification 
≥ 3 (with infection or 
febrile neutropenia) or  
4 
1st 
Interrupt dosing until resolution to ≤ Grade 2 or baseline 
 
If recovery occurs ≤14 days of holding DS-
1594b: resume dosing at the same dose level the 
subject was on at the time of the interruption 
 
If recovery occurs >14 days of holding DS-
1594b: resume dosing at one dose level lower 
than the dose level the subject was on at the 
time of the interruption (Dose level -1) 
Formatted: C-Hyperlink


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 54 of 127 
 
Grade 
Occurrence 
Dose Modification 
2nd  
Interrupt dosing until resolution to ≤ Grade 2 or baseline  
 
If recovery occurs ≤14 days of holding DS-
1594b: resume dosing at the same dose level the 
subject was on at the time of the interruption 
 
If recovery occurs >14 days of holding DS-
1594b: resume dosing at one dose level lower 
than the dose level the subject was on at the 
time of the interruption (Dose level -1 or -2, 
depending on the dose level the subject was on 
at the time of the interruption)  
3rd  
 
If the subject is on Dose level -2 at the time of 
the event, permanently discontinue therapy. 
 
If the subject is not on Dose level -2 at the time 
of the event, interrupt the dosing until resolution 
to ≤ Grade 2 or baseline and resume dosing at 
one dose level lower than the dose level the 
subject was on at the time of the interruption 
(Dose level -1 or -2, depending on the dose level 
the subject was on at the time of the 
interruption).  
4th  
 
Permanently discontinue therapy. 
Note: Treatment interruptions and dose modifications other than the ones mentioned above can be considered after 
discussion with the PI and proper documentation of the rationale.  
6.2.2. 
Dose Adjustments for Non-Hematologic AEs Considered at Least Possibly 
Attributable to Study Drugs 
Investigators should, whenever possible, determine which medication is causing the toxicity and 
interrupt or dose reduce azacitidine, venetoclax, and/or interrupt DS-1594b, see 
Table 11Table 11.  
Dose reductions of azacitidine will be as follows: Baseline dose level: 75 mg/m2 x 7 days, dose 
level -1 of azacitidine: 50 mg/m2 x 7 days, dose level -2: 37.5 mg/m2 x 7 days, dose level -3: 25 
mg/m2 x 7 days. Further reductions or modifications to schedule beyond what is shown above or 
alternative reductions (e.g. 75mg/m2 x 5 days) may be allowed if deemed in the subject’s best 
interest by the treating physician after approval from the PI and Sponsors. 
Dose reductions of venetoclax will be as follows: Baseline dose level of venetoclax: 400mg, 
dose level -1 of venetoclax: 200mg, dose level -2: 100mg, dose level -3, 50mg. Alternatively, the 
duration of venetoclax administration can be decreased (e.g. decrease from 28-days per cycle to 
21-days per cycle to 14-day per cycle to 10 days per cycle) rather the dose being reduced. 
Dose reductions for DS-1594b will be allowed if warranted by Investigator and after discussion 
and approval by PI and Sponsors and will follow the Phase 1 doses used for DS-1594b 
(Table 6Table 6).  
Formatted: C-Hyperlink
Formatted: C-Hyperlink


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 55 of 127 
 
 Table 11: 
Dose Adjustments of Azacitidine, Venetoclax, and/or DS-1594b for Non-
Hematologic Possibly Related AEs, Clinically Significant in the Opinion of 
the Investigator 
Grade 
Occurrence 
Dose modification 
1 or 2 
Any time 
No dose reduction 
3 
 
(Persistent Grade 2: Consider 
similar dose adjustments if 
persistent and not responding to 
optimal management in the 
opinion of PI and treating 
physician) 
1st and 2nd time 
Hold suspected drug. 
-Resume the held drug at prior dose if 
recovery to ≤ Grade 1 occurs within 14 
days. 
-If toxicity persists for 15-28 days, hold 
the drug and resume at prior dose if 
recovery to ≤ Grade 1 OR resume the 
drug at ONE dose level below current 
dose if recovery to ≤ Grade 2. 
-If toxicity persists for >28 days, hold the 
drug; resume the drug at ONE dose level 
below current dose if recovery to ≤ Grade 
2. 
 
Dose re-escalation to prior dose of the 
drug is permitted in accordance with the 
dose-escalation guidelines in Section 5 . 
3rd.  
 
Hold suspected drug. 
Follow until toxicity ≤ Grade 2. 
Resume the held drug at ONE dose level 
below current dose. 
Dose re-escalation of the drug to prior 
dose is permitted in  
accordance with the dose-escalation 
guidelines outlined below Subjects who 
are experiencing ongoing dose delays >8 
weeks due to unresolved grade ≥3 adverse 
events should be taken off treatment. 
4th time 
Discontinue therapy 
4 
Any time 
Discontinue therapy 
Note: For dose adjustments to DS-1594b for QTc Interval Prolongation or Acute Differentiation Syndrome, refer to 
Table 12Table 12 and Table 13Table 13.  
Table 12: 
Dose Adjustment for QTc Interval Prolongation  
For all QTc interval prolongations (average of the triplicate 12-lead readings or by Holter): 
Check serum electrolyte levels (including magnesium, potassium, and calcium) and correct 
any abnormalities. If possible, stop any medications that may prolong the QTc interval.  
Formatted: C-Hyperlink
Formatted: C-Hyperlink


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 56 of 127 
 
Subjects who experience Grade ≥2 QTcF prolongation and undergo dose interruption and/or 
reduction must be monitored closely with ECGs, performed twice weekly for the first week of 
the QTcF prolongation and then weekly thereafter until the QTcF prolongation is resolved. 
 
Grade 2: QTcF (average of triplicate 
ECG readings) > 480ms and ≤ 500ms 
Reduce the dosage of one dose level without interrupt the 
administration  
To resume the treatment at the previous dose level if the QTcF has 
decreased to within 30 ms of baseline or <450 ms 
Grade 3: QTcF (average of triplicate 
ECG readings) > 500ms for the first 
time; >60 ms change from baseline 
Interrupt DS-1594b administration. 
 If QTcF returns to within 30 ms of baseline or <450 ms within 14 days, 
study drug administration may be resumed at ONE dose level below the 
current dose. 
QTcF (average of triplicate ECG 
readings) > 500ms repeatedly 
  
Permanently discontinue DS-1594b administration if QTcF recurs 
despite appropriate dose reduction and correction/elimination of other 
risk factors (eg serum electrolyte abnormalities, discontinuation of a 
concomitantly administered drug susceptible to prolong QT)  
Grade 4:  Torsade de pointes or 
polymorphic ventricular tachycardia 
or signs/symptoms of serious 
arrhythmia 
Permanently discontinue DS-1594b administration 
 
Table 13: 
Dose Modification for Clinically Suspected Acute Differentiation Syndrome  
Occurrence 
Action  
DS-1594b dose modification 
1st  
Interrupt If severe pulmonary 
symptoms (requiring intubation or 
ventilatory support), and/or renal 
dysfunction persisting more than 48 
hours after initiation of 
corticosteroids 
Resume when until signs and 
symptoms no longer severe (i.e. 
improve to Grade 2* or lower);  
Start treatment with systemic 
corticosteroids  
If signs and symptoms improve to 
Grade 2* or lower within 7 days, 
resume at ONE dose level below 
current dose. 
 
Escalate back to current dose after 
7 days, if the reduced dose is 
tolerated after. 
If syndrome persists for ≥7 days 
despite supportive management, 
discontinue permanently. 
2nd  
Discontinue DS-1594b 
permanently; start systemic 
corticosteroid treatment 
Not applicable. 
*Grade 1 is mild, Grade 2 is moderate, Grade 3 is serious, Grade 4 is life-threatening. 
 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 57 of 127 
 
6.2.3. 
DS-1594b AEs of Special interest 
6.2.3.1. 
QTc Prolongation, Torsade de Pointes, and Other Ventricular Arrhythmias 
Subjects who experience >480 ms QTcF prolongation and undergo dose interruption and/or 
reduction must be monitored closely with ECGs, performed twice weekly for the first week of 
the QTcF prolongation and then weekly thereafter until the QTcF prolongation is resolved 
(Table 12Table 12) . 
QTcF prolongation of Grade 3 or higher, either serious or non-serious and whether or not 
causally related, must be recorded as AE or SAE in the Electronic Data Capture (EDC) system 
within 24 hours of awareness of the central ECG laboratory reading, with the investigator’s 
assessment of seriousness, causality, and a detailed narrative. The central ECG reading 
confirming QTcF prolongation ≥ Grade 3 is to be recorded in the EDC system. 
Regarding the detailed narrative(s): 
 Serious AESI: The narrative will be captured directly in the EDC system. 
 Non-Serious AESI:  The narrative will be captured on a form outside of the EDC 
system (paper form). 
6.2.3.2. 
Combined Elevations of Aminotransferases and Bilirubin 
Combined elevations of aminotransferases and bilirubin, either serious or non-serious and 
whether or not causally related, meeting the laboratory criteria of a potential Hy’s Law case 
[ALT or AST ≥3 × ULN with simultaneous TBL ≥2 × ULN] should always be recorded as an 
AE or SAE within 24 hours of awareness, with the investigator’s assessment of seriousness, 
causality, and a detailed narrative.  
Regarding the detailed narrative(s): 
 Serious AESI: The narrative will be captured directly in the EDC system. 
 Non-Serious AESI:  The narrative will be captured on a form outside of the EDC 
system (paper form). 
For liver elevation, workup elevations meeting FDA DILI criteria below: 
Elevation of liver enzymes that meet the criteria below should be investigated and the cause 
identified when possible: 
 ALT >8 × ULN; or 
 AST or ALT >5 x ULN for more than two weeks; or 
 ALT or AST >3 x ULN, but not reaching the limits in the above criteria, in 
combination with clinical symptoms suggestive of hepatitis; or 
 ALT or AST >3 x ULN with TBL >2 x ULN. 
Once the cause of liver enzyme elevation is identified, remove or treat the contributing cause.  
Formatted: C-Hyperlink


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 58 of 127 
 
If the above criteria are met and the elevation is considered to be related or possibly related to 
DS-1594b, dosing should be interrupted. 
Liver enzyme level testing will be repeated at least weekly, or more frequently, based on degree 
of hepatic laboratory abnormality. If the liver enzyme levels return to baseline levels, DS-1594b 
may be resumed at ONE dose level below the current dose level. If toxicity does not 
improve/resolve within 28 days, then DS-1594b will be discontinued. Upon resumption of DS-
1594b, if liver enzyme elevations recur, treatment must be permanently discontinued. 
 
6.2.4. 
Management of AESI 
6.2.4.1. 
QTc Prolongation, TdP, and Other Ventricular Arrhythmias 
Electrolytes (potassium, calcium, and magnesium) should be checked and supplementation given 
to correct any values outside the normal range. 
 Concomitant medications should be reviewed to identify and, if appropriate, discontinue any 
medication with known QT prolonging effects (Table 28Table 28).  
Subjects who experience >480 msec QTcF prolongation and undergo dose interruption and/or 
reduction must be monitored closely with ECGs, performed twice weekly for the first week of 
the QTcF prolongation and then weekly thereafter until the QTcF prolongation is resolved. 
6.2.4.2. 
Combined Elevations of Aminotransferases and Bilirubin 
Combined elevations of aminotransferases and bilirubin, either serious or non-serious and 
whether or not causally related, meeting the laboratory criteria of a potential Hy’s Law case 
[ALT or AST ≥3 x ULN with simultaneous TBL ≥2 x ULN] should always be recorded as an AE 
or SAE within 24 hours of awareness, with the Investigator’s assessment of seriousness, 
causality, and a detailed narrative. Subjects will be monitored as described in Section 8.10.  
Evaluation may include the following depending on the clinical situation: 
 Medical history and physical exam, including focus on medications and substances 
used: alcohol, acetaminophen, azole antifungals, change in medication dosages, new 
medications added, over the counter medication use and recreational drug use. Check 
for change in diet or use of dietary supplements; 
 Abdominal ultrasound; 
 Hepatitis A, B, C, and E screening (anti-hepatitis A virus immunoglobulin M, 
hepatitis B surface antigen, anti-hepatitis C virus plus viral titer, and 
evaluation for Hepatitis E), antinuclear antibody and anti-Smith antibody, 
cytomegalovirus, Epstein Barr virus; 
 Additional evaluations as deemed appropriate by the Investigator to exclude other 
causes of liver enzyme and bilirubin elevations; 
 All laboratory results, including local laboratory reference ranges are to be recorded. 
Formatted: C-Hyperlink


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 59 of 127 
 
6.3. 
CYP3A and P-gp Inhibitors: Dose modifications Venetoclax 
Venetoclax should be administered at 50% dose reduction in the setting of moderate CYP3A 
inhibitor and at 75% dose reduction in the setting of strong CYP3A inhibitor for the duration of 
co-administration. The venetoclax dose will be reduced to 70mg by mouth once daily if subject 
is on posaconazole.  
In the event the co-administered CYP3A inhibitor is discontinued, the assigned venetoclax dose 
should be resumed 3 days after discontinuation. 
Every effort should be made to adhere venetoclax dose reduction. Variations in schedule of 
events such as late/missed interventions that do not affect the rights and safety of the subject will 
not be considered as deviations.   
P-gp substrates: Concomitant use of venetoclax increases Cmax and AUCinf of P-gp substrates, 
which may increase toxicities of these substrates (please see Venetoclax US prescribing 
information). Avoid concomitant use of venetoclax with a P-gp substrate. If a concomitant use is 
unavoidable, separate dosing of the P-gp substrate at least 6 hours before venetoclax.  
6.4. 
Tumor Lysis Prophylaxis (TLS) 
The venetoclax dose titration scheme utilized in the AML studies performed to date to mitigate 
the risk of Tumor Lysis Syndrome (TLS) will be employed. All subjects will be hospitalized for 
the entirety of the venetoclax dose escalation starting at least on Day 1 of treatment initiation and 
until 24 hours after the completion of venetoclax dose escalation. During Cycle 1, venetoclax 
will be dose escalated daily to the goal dose regimen of 400 mg daily.  Subjects will receive 
100 mg on Day 1, 200 mg on Day 2, and 400 mg on Day 3 and onwards, or adjusted dose if on 
concomitant azoles (discussed below in Section 6.7).  
To mitigate the risk for TLS, subjects must be receiving tumor lysis prophylaxis, including 
hydration (oral, intravenous) and treatment with a uric acid reducing agent (allopurinol, 
rasburicase) prior to start of venetoclax and at least during the first cycle of therapy.  
TLS chemistry tests (potassium, uric acid, creatinine, calcium and phosphorus) will be obtained 
prior to dosing and 5 to 8 hours after each day of a new venetoclax dose. TLS chemistry test 
results will be reviewed by the investigator in real time and prior to the subject’s next dose to 
ensure appropriate management. If a subject meets the criteria for clinically significant 
laboratory or clinical TLS, no additional venetoclax should be administered until resolution. 
Venetoclax interruption for up to 72 hours following transient (< 48 hours) chemical changes and 
laboratory TLS will be allowed and will not require a dose reduction. 
6.5. 
Differentiation Syndrome 
DS-1594b may result in terminal differentiation of leukemic blast cells in subjects with relapsed 
or refractory disease, which may be associated with the development of differentiation syndrome 
(also known as retinoic acid syndrome) and may be life-threatening or fatal if not treated. 
It is important to promptly recognize the signs and symptoms of differentiation syndrome and 
implement appropriate treatment. Symptoms of differentiation syndrome could include dyspnea, 
unexplained fever, peripheral edema, unexplained hypotension, weight gain >5 kg, pulmonary 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 60 of 127 
 
infiltrates, pleuro-pericardial effusion, acute renal failure, musculoskeletal pain, and 
hyperbilirubinemia.  Less commonly, differentiation syndrome might present with pulmonary 
hemorrhage or acute febrile neutrophilic dermatosis.   
The diagnosis of differentiation syndrome requires the presence of at least 2 of the following 
signs or symptoms: dyspnea, unexplained fever ≥38°C, weight gain >5 kg, unexplained 
hypotension, acute renal failure, or a chest radiograph demonstrating pulmonary infiltrates or 
pleuro-pericardial effusion36 or multiple organ dysfunction.37 No single sign or symptom is 
sufficient to make a diagnosis of the syndrome. It is important to rule out other conditions with 
similar symptoms, such as sepsis, pneumonia, heart failure, pulmonary embolism, and diffuse 
alveolar hemorrhage.  
For subjects at an increased risk for severe differentiation syndrome (white blood cell count > 5 x 
109/L or serum creatinine > 1.4 mg/dL), consider the administration of prophylactic systemic 
glucocorticoids.38 For subjects with a white blood cell count > 10 x 109/L, administer 
hydroxyurea 1-3g per day.  
Subjects with suspected differentiation syndrome should promptly start treatment with 
intravenous or oral dexamethasone 10 mg every 12 hours or equivalent and hemodynamic 
monitoring until improvement. If symptoms do not improve after 24 hours of therapy, increase 
dexamethasone dosing to 10 mg every 6 hours. If severe pulmonary symptoms (requiring 
intubation or ventilatory support), and/or renal dysfunction persisting more than 48 hours after 
initiation of steroids, interrupt DS-1594b until signs and symptoms no longer severe 
(Table 13Table 13). Hospitalization for subjects with severe pulmonary or renal manifestation is 
recommended.  
 
6.6. 
Meals and Dietary Requirements 
Each dose of venetoclax should be taken with approximately 240 mL of water within 30 minutes 
after the completion of a meal, preferably breakfast. 
Subjects should not consume grapefruit or grapefruit products, Seville oranges, or Star fruit 
within the 3-day period prior to the first DS-1594b or venetoclax administration and until the last 
day of DS-1594b or venetoclax is completed due to possible CYP3A-mediated metabolic 
interaction. 
6.7. 
Modifications of Dose Schedules Other Than the Above Will Be 
Allowed Within the Following Guidelines 
 Dose adjustments by more than 1 dose level at a time for azacitidine or venetoclax 
(e.g., from azacitidine 75 mg/m2 to 25 mg/m2) can be considered when judged in the 
best interest of the subject (e.g. severe myelosuppression) when toxicity has resolved. 
The reason for this reduction will be discussed with the PI or Co-PI and documented 
in the medical record. 
 A subject who has had a dose reduction because of any of the reasons mentioned 
above may have their dose escalated provided the subject has remained free of 
Formatted: C-Hyperlink


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 61 of 127 
 
toxicity requiring dose adjustments as defined above in Table 11Table 11 for at least 
1 month. Escalation will be made by 1 dose-level increment only, and not more 
frequent than every month. The dose of any agent must not exceed the RP2D dose for 
that agent in this protocol (i.e. azacytidine dose cannot exceed 75mg/m2 x 7 days, 
venetoclax dose cannot exceed 400 mg/day, and established RP2D for DS-1594b 
from Phase 1). 
 Treatment interruptions and dose modifications other than the ones mentioned above 
can be considered after discussion with the PI and proper documentation of the 
rationale. This includes delays in chemotherapy cycles because of persistent 
myelosuppression, other side effects, subject request, or other reasons. Missed doses 
of DS-1594b do not need to be made up. Dose adjustment/delay/interruptions of only 
one of the agents is permissible if the toxicity is most likely judged to be related to 
one of the agents by the investigator (e.g., in subjects with Differentiation Syndrome 
(Table 13Table 13) this would be likely secondary to the DS-1594b, in subjects with 
neutropenia this would be likely secondary to azacitidine and venetoclax).  Subjects 
in whom one agent is interrupted/discontinued for potential toxicity may be able to 
continue treatment on protocol if it is in the best interest of the subject to continue on 
protocol. 
6.8. 
Treatment Interruptions 
Treatment interruptions and dose modifications or delays other than the ones mentioned above 
can be considered after discussion with the PI or Co-PI and clear documentation of the rationale 
in the medical records. 
6.9. 
Intra-Patient Dose Escalation (IPDE) 
Intra-patient dose escalation (IPDE) of DS-1594b is permitted for subjects enrolled in the dose 
escalation portion of the study who may benefit from IPDE after approval from the PI or Co-PI, 
provided the subject meets all of the following criteria: 
 The subject has failed to achieve a complete remission (CR) or has experienced 
disease progression on treatment with DS-1594b, 
 The subject has not experienced a DLT or treatment related adverse event requiring 
DS-1594b dose reduction or interruption. 
The dose may be escalated up to a dose level that has previously been established to be safe and 
tolerable in at least 3 DLT evaluable subjects (for example, a subject enrolled at 50mg BID may 
be dose escalated to 70mg BID only after the 70mg BID dose level has been declared safe and 
tolerable in at least 3 DLT evaluable subjects).   
Additionally, a subject may be switched to an alternative DS-1594b dosing regimen (BID vs. 
QD) once they have completed the DLT evaluation period in Phase I, if that dosing regimen has 
been found to be safe and tolerable in at least 3 DLT evaluable subjects (for example, from 50 
mg BID to 100 mg QD). 
Formatted: C-Hyperlink
Formatted: C-Hyperlink


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 62 of 127 
 
7. 
AGENT FORMULATION AND PROCUREMENT 
7.1. 
Potential Indications and Use 
DS-1594b is being developed for the treatment of relapsed or refractory AML or ALL with 
MLL1-r or AML with NPM1-mutations. 
7.2. 
Ongoing Clinical Trials  
This is the first clinical study for DS-1594b. There are no other ongoing studies. 
7.3. 
Dosing and Administration 
See Section 5.1.2 for DS-1594b dosing and administration information.  
7.4. 
Packaging and Labeling 
DS-1594b is packaged as 35 tablets per bottle, in high-density polyethylene (HDPE) bottles with 
desiccant. The labeling complies with the requirements of the applicable regulatory agencies. 
7.5. 
Study Drug Description and Preparation 
DS-1594b tablets are formulated in 3 strengths: 20 mg, 50 mg, and 200 mg.  The dose strength of 
the tablet is expressed as the free form of DS-1594b.  DS-1594b tablets are supplied as grayish-
red, film-coated round-shaped tablets (20 mg) and grayish-red, film-coated oblong-shaped tablets 
(50 mg and 200 mg). 
DS-1594b is supplied as tablets that need no further preparation at the study sites.  
7.6. 
Study Drug Storage 
DS-1594b must be stored appropriately in a locked cabinet/room with limited and controlled 
access under the recommended storage conditions.  The required storage conditions are provided 
in the investigational medicinal product labeling. 
NOTE: If storage conditions go outside of the recommended storage conditions, the Study 
Center must not dispense the affected supplies (affected supplies should be placed in 
quarantine).  Proper notification processes must be followed immediately after receipt of 
DS-1594b identified as having a temperature excursion. 
7.7. 
Study Drug Accountability 
A Drug Accountability Record must be kept current and must contain the dates and quantities of 
study drug received, the subject’s identification number and/or initials or supply number (as 
applicable), the date and quantity of DS-1594b dispensed and remaining (in tablets), as well as 
the initials of the dispenser. 
Azacitidine: It is commercially available and will be handled as per the packet insert and 
standards in the site pharmacy.  


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 63 of 127 
 
Venetoclax: It is commercially available and will be handled as per the packet insert and 
standards in the site pharmacy 
International Non-proprietary name venetoclax (formerly ABT-199) 
Manufacturer Abbvie/Genentech 
Dose 70 - 400 mg daily 
Route of Administration oral 
Formulation Capsule formulation (10 mg, 50 mg and 100 mg) 
Venetoclax will be obtained from commercial source. For further details, please refer to the 
prescribing information (Appendix G). 
Mini-HCVD: It is commercially available and will be handled as per the packet insert and 
standards in the site pharmacy. cyclophosphamide, vincristine, methotrexate, cytarabine, 
rituximab, MESNA, filgrastim, peg-filgrastim, dexamethasone, and prednisone will be obtained 
from commercial source. Biosimilars may be used for filgrastim or peg-filgrastim. For further 
details on each drug, please refer to the prescribing information . 
Disposition of unused drug:  all unused drug will be disposed of per institutional guidelines and 
procedures. 
Variations in infusion times of drugs due to minor differences in IV bag overfill/under fill and 
institutional procedure on flushing chemotherapy lines will not result in protocol deviation. All 
infusion times are considered approximate. 
For further details on drug formulation, reconstitution, administration, infusion related 
instructions, concern and plan of management for infusion related topics please the respective 
agents IB or package insert. 
8. 
SUBJECT EVALUATION 
Every effort will be made to adhere to the schedule of events and all protocol requirements.  
8.1. 
Schedule of Assessments 
All Assessment Schedule Tables are in the Appendix: 
Phase 1 
Dose Escalation 
Table 32Table 32  
Phase 2 
Cohorts A & B 
Table 33Table 33  
Cohort C 
Table 34Table 34  
Cohort D 
Table 35Table 35  
  
Formatted: C-Hyperlink
Formatted: C-Hyperlink
Formatted: C-Hyperlink
Formatted: C-Hyperlink


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 64 of 127 
 
8.2. 
Screening 
The Screening period begins up to 14 days prior to treatment.  It is anticipated that subjects will 
recently have had some, or all, of the screening tests done as part of routine care outside the 
auspices of this study.  Results of some tests done as part of routine care, outside the auspices of 
this study, may be used to qualify the subject. All pretreatment studies should be obtained within 
14 days of first dose, unless otherwise stated. Written informed consent must be obtained before 
any study-specific procedure is performed.   
All study procedures, risks, and benefits must be explained to the subject and/or their legal 
guardians; the Study Informed Consent Form must be reviewed with the subject and/or their  
legal guardians; all the subject’s and/or their legal guardians' questions must be answered; the 
subject and/or their legal guardians must sign the Informed Consent Form.  Subjects and/or their 
legal guardians must receive a copy of their Informed Consent Form.  
All subjects will be assigned a unique identification number upon signing the informed consent 
form. 
At screening, the following will be performed: 
 A complete history and physical, medical and acute leukemia disease history 
(including classification per the latest WHO criteria for AML or ALL), disease state 
(primary refractory, untreated relapse, refractory relapse), number of prior lines of 
therapy, best response to most recent line of therapy, duration of most recent 
remission (if applicable), prior medications, non-drug therapies, and radiotherapy 
within 28 days of Cycle 1 Day 1, prior transfusions (red blood cell and platelet) 
within 28 days of Cycle 1 Day 1, concomitant medications, non-drug therapies, and 
radiotherapy, and performance status. 
 Complete blood count (CBC), platelet count, differential (differential can be omitted 
if WBC is ≤0.4 x109/L), and international normalized ratio (INR). 
 Serum chemistry panel (including creatinine, electrolytes, glucose, uric acid, calcium, 
magnesium, BUN).  
 Hepatic panel (AST, ALT, Alk phosphatase, total bilirubin [fractionated]) 
 Creatinine Kinase (fractionated if > ULN) 
 Troponin 
 Alpha-Melanocyte stimulating hormone (alpha-MSH)  
 Fasting morning adrenocorticotropic hormone (ACTH), aldosterone, renin, and 
cortisol levels. If results are abnormal, consult an endocrinologist. Perform an ACTH 
stimulation test if adrenal insufficiency is suspected. 
 Urinalysis (by dipstick) to include appearance, bilirubin, blood, specific gravity, 
glucose, ketones, pH, and protein. 
 Pregnancy test (urine or plasma) in females of childbearing potential should be 
performed within 72 hours before initiation of protocol therapy. 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 65 of 127 
 
 Bone marrow aspirate/biopsy  
 Cytogenetics and molecular tests for MLLr or NPM1m performed by MDACC 
laboratories must be obtained  
 Height, weight, and BSA calculated by the Mosteller formula.  
 HIV antibody test (if required by local regulations) 
 Hepatitis B (HBsAG) test, and Hepatitis C antibody test  
 Blood oxygen levels (SpO2).  
 Vital signs, including blood pressure, pulse rate, respiratory rate, and temperature 
(taken 5 min prior to the electrocardiogram [ECG]).  
 Triplicate Electrocardiogram (ECG) by 12-lead or Holter measurement at baseline. 
See Section 8.5  for the details of ECG monitoring.   
 Pretreatment correlative studies (Section 8.6). 
 MUGA or Echocardiogram 
8.3. 
Evaluation During Treatment 
 Physical exam at the start of each cycle (± 4 days). 
 Hematology/coagulation labs: CBC with differential, platelet count, INR pre-dose on 
Cycle 1, Day 1 and at least 3 times per week for the first cycle, then 2 times per week 
for Cycles 2 and 3, then one to two times per week in subsequent cycles (differential 
can be omitted if WBC is ≤ 0.5 x109/L). Lower frequency of laboratory evaluations 
may be considered on a case by case basis after Cycle 6 in subjects in remission, after 
discussion and approval from PI (e.g, at least once every 2 weeks). 
 Serum chemistry labs: serum creatinine, electrolytes, glucose, uric acid, calcium, 
magnesium, BUN pre-dose on Cycle 1, Day 1 and at least 3 times per week for the 
first cycle, then 2 times per week for Cycles 2 and 3, then one to two times per week 
in subsequent cycles. Lower frequency of laboratory evaluations may be considered 
on a case by case basis after Cycle 6 in subjects in remission, after discussion and 
approval from PI (e.g, at least once every 2 weeks) 
 Hepatic labs: AST, ALT, alkaline phosphatase, total bilirubin, direct bilirubin, and 
indirect bilirubin pre-dose on Cycle 1, Day 1 and at least 3 times per week for the first 
cycle, then 2 times per week for Cycles 2 and 3, then one to two times per week in 
subsequent cycles. Lower frequency of laboratory evaluations may be considered on a 
case by case basis after Cycle 6 in subjects in remission, after discussion and approval 
from PI (e.g, at least once every 2 weeks). 
 Creatinine kinase (fractionated if > ULN) pre-dose on Cycle 1, Day 1 and at least 
once weekly in Cycles 1-3, then monthly.  Lower frequency of laboratory evaluations 
may be considered on a case by case basis after Cycle 6 in subjects in remission, after 
discussion and approval from PI. 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 66 of 127 
 
 Urinalysis pre-dose on Cycle 1, Day 1 and monthly during treatment. 
 Pregnancy test (urine or plasma) in females of childbearing potential should be 
performed monthly during treatment.  
 Tumor lysis syndrome chemistry tests (potassium, uric acid, creatinine, calcium and 
phosphorus) will be obtained same day prior to dosing and 5-8 hours on each day 
after a new venetoclax dose during cycle 1 (Cohort C). 
 Troponin during treatment as clinically indicated.  
 Plasma alpha-melanocyte stimulating hormone (alpha-MSH), fasting morning 
adreno-corticotropic hormone (ACTH), aldosterone, renin, and cortisol levels on 
Cycle 1 Day 28 (± 4 days), then once every 3 cycles beginning at Cycle 3 (eg, Cycles 
3, 6, 9) and at End of Treatment. If results are abnormal, consult an endocrinologist. 
Perform an ACTH stimulation test if adrenal insufficiency is suspected. 
 Bone marrow aspiration/biopsy on Cycle 1 Day 28 (± 4 days), then on Day 28 (± 4 
days) of Cycles 2, 3, 6, 9 and progression. Bone marrow tests can be ordered more 
frequently if mandated by development of peripheral blood counts. No repeat bone 
marrow is necessary if nonresponse or progressive disease can be unequivocally 
diagnosed from peripheral blood tests or, in subjects with a WBC < 0.3 if the bone 
marrow test is considered noncontributory by the investigator at any time point. For 
subjects in Cohort C, the initial bone marrow aspiration/biopsy in Cycle 1 will be on 
Day 21 (± 4 days).  
 For subjects that remain on study with no significant toxicity for more than 6 months, 
subsequent evaluations during study may be modified after discussion with the 
principal investigator. These include a decrease in frequency of bone marrow 
aspiration and biopsy to every 6-12 months (or as clinically indicated), correlative 
studies to every 6-12 months (or suspension of sample collection for correlative 
studies), other laboratory tests to once every cycle. 
8.4. 
PK Assessment 
Blood samples for PK analysis of DS-1594b and metabolites (if appropriate) will be collected 
during the study from all subjects receiving DS-1594b. PK parameters using standard non-
compartmental method will be generated. Plasma concentration-versus-time data will be 
summarized using summary statistics by dose/study day/time  
 On Cycle 1 Day 1 (dose escalation and dose expansion): Cmax, Tmax, Tlast, 
AUClast, AUCtau, AUCinf*, Kel*, t1/2*, CL/F*, Vz/F* 
 On Cycle 1 Day 8 (dose escalation and dose expansion): Cmax, Cavg, Ctrough, 
Tmax, Tlast, AUClast, AUCtau, Kel*, t1/2*, CLss/F, Vz/F*, AR**, t1/2,ar*** 
 Food effect sub-study: 
 On Cycle 1 Day 1: Cmax, Tmax, Tlast, AUClast, AUCtau, AUCinf*, Kel*, t1/2*, 
CL/F*, Vz/F* 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 67 of 127 
 
 On Cycle 1 Day 8 and Cycle 1 Day 15: Cmax, Ctrough, Tmax, Tlast, AUClast, 
AUCtau, Kel*, t1/2*, CLss/F, Vz/F* 
 DDI sub-study: 
 On Cycle 1 Day 1: Cmax, Tmax, Tlast, AUClast, AUCtau, AUCinf*, Kel*, t1/2*, 
CL/F*, Vz/F* 
 On Cycle 1 Day 8 and Cycle 1 Day 18 (or Cycle 2 Day 10 for subjects who 
enrolled to sub-study prior to MTD/RP2D determination): Cmax, Ctrough, Tmax, 
Tlast, AUClast, AUCtau, Kel*, t1/2*, CLss/F, Vz/F* 
*:   To be calculated only if possible. 
**: Accumulation ratio (AR) calculated as AUCtau at steady state /AUCtau following first dose, where 
tau is the dosing interval of 12 hour 
*** Effective half-life can be calculated from AR: ln2 • tau/ ln(AR / (AR-1)) 
8.4.1. 
PK Blood Sample Collection and Handling 
Time points of PK blood sample collection are outlined in Table 14Table 14 (BID dosing) and 
Table 15Table 15 (QD dosing) for Dose Escalation and Table 16Table 16 for Dose Expansion in 
Phase 1.  Time points of PK blood sample collection for DDI sub-study and food effect sub-
study are outlined in Table 17Table 17, Table 18Table 18  and Table 19Table 19, respectively. 
On PK sampling days, DS-1594b will be administered during the clinic visit as instructed by 
study personnel. Complete dosing and sampling information, including the exact dates and times 
of PK blood draw and exact dates and times of the last study drug dose prior to PK sampling and 
the study drug dose on the day of PK sampling (i.e. dose after pre-dose PK sampling), will be 
obtained on all PK sampling days and recorded on eCRF and on the CRO requisition form(s). If 
vomiting occurs within 4 hours of dose administration, the vomiting time should be documented 
on the eCRF. No re-dosing of the subject will be permitted during that period. 
An unscheduled PK sample should be collected if a subject experiences an adverse event that 
results in an unscheduled visit or fits the criteria of a SAE, or if the triplicate ECG reading shows  
QTcF interval prolongation of > 60 msec change from baseline or new absolute QTcF ≥ 500 
msec. 
Residual PK samples may also be used for exploratory analysis to further characterize the PK of 
DS-1594b and all of its metabolite(s). This may include using leftover samples for protein 
binding analysis or metabolite profiling (e.g. other metabolites and markers for metabolic 
enzyme activity such as 4-beta hydroxy cholesterol levels), if there is sufficient sample 
remaining. 
For the food effect sub-study, meal records will be collected including the start and end time of 
the meal associated with each DS-1594b dose administered in the clinic on PK sampling days 
(Cycle 1 Day 1 and Cycle 1 Day 8). Compliance with prandial conditions for non-PK sampling 
days (fed or fasting conditions) will be confirmed by the study personnel during study visits.  
For the DDI sub-study, the actual dose, starting date/time and stopping date/time for the anti-
fungal agents (posaconazole or voriconazole) must be recorded on the eCRF. If vomiting of 
Formatted: C-Hyperlink
Formatted: C-Hyperlink
Formatted: C-Hyperlink
Formatted: C-Hyperlink
Formatted: C-Hyperlink
Formatted: C-Hyperlink


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 68 of 127 
 
these agents occurs within 5 hours of dose administration, the vomiting time should be 
documented on the eCRF.  
All blood samples will be taken by either direct venipuncture or venous catheter or indwelling 
cannula inserted in a forearm vein. Instructions for the handling of blood samples and shipping 
of plasma PK samples are included in a separate document (eg, laboratory manual).   
 
Table 14: 
DS-1594b PK Blood Collection for Twice a Day (BID) Dosing During Phase 1 
[Excluding Subjects Enrolled in DDI and Food Effect Sub-Studies] Dose 
Escalation 
Cycle 
Day 
Scheduled Time Point 
1 
1 
Pre-dose/0ha 
1 
1 
Post-dose 0.5h (± 5 min) 
1 
1 
Post-dose 1h (± 10 min) 
1 
1 
Post-dose 2h (± 10 min) 
1 
1 
Post-dose 3h (± 10 min) 
1 
1 
Post-dose 4h (± 10 min) 
1 
1 
Post-dose 6h (± 10 min) 
1 
1 
Post-dose 8h (± 10 min) 
1 
1 
Post-dose 12h (± 60 min) (i.e. pre-dose of Cycle 1 
Day 1 evening dose) 
1 
2 
Pre-dose/0ha 
1 
5 
Pre-dose/0ha 
1 
8 
Pre-dose/0ha 
1 
8 
Post-dose 0.5h (± 5 min) 
1 
8 
Post-dose 1h (± 10 min) 
1 
8 
Post-dose 2h (± 10 min) 
1 
8 
Post-dose 3h (± 10 min) 
1 
8 
Post-dose 4h (± 10 min) 
1 
8 
Post-dose 6h (± 10 min) 
1 
8 
Post-dose 8h (± 10 min) 
1 
8 
Post-dose 12h (± 60 min) (i.e. pre-dose of Cycle 1 
Day 8 evening dose) 
1 
15 
Pre-dose/0ha 
1 
15 
Post-dose 2h (± 10 min) 
1 
15 
Post-dose 4h (± 10 min) 
1 
15 
Post-dose 6h (± 10 min) 
1 
15 
Post-dose 8h (± 10 min) 
1 
21 
Pre-dose/0ha 
1 
21 
Between 2-4 hours post-dose 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 69 of 127 
 
Cycle 
Day 
Scheduled Time Point 
2 
1 
Pre-dose/0ha 
3 
1 
Pre-dose/0ha 
4 
1 
Pre-dose/0ha 
5 
1 
Pre-dose/0ha 
6 
1 
Pre-dose/0ha 
7 
1 
Pre-dose/0ha 
8 
1 
Pre-dose/0ha 
Unscheduled 
Anytime 
After intra-patient dose escalation (see Section 6.9): 
Cycle X of the new higher 
dose level or different 
dosing regimen (frequency) 
8 
Pre-dose/0ha 
Cycle X of the new higher 
dose level or different 
dosing regimen (frequency) 
8 
Between 2-4 hours post-dose 
Unscheduled 
Anytime 
All measurement times are relative to dose of DS-1594b unless otherwise specified 
a PK sample should be taken immediately prior to the next administration of DS-1594b 
 
Table 15: 
DS-1594b PK Blood Collection for Daily (QD) Dosing During Phase 1 
[Excluding Subjects Enrolled in DDI and Food Effect Sub-Studies] Dose 
Escalation 
Cycle 
Day 
Scheduled Time Point 
1 
1 
Pre-dose/0ha 
1 
1 
Post-dose 0.5h (± 5 min) 
1 
1 
Post-dose 1h (± 10 min) 
1 
1 
Post-dose 2h (± 10 min) 
1 
1 
Post-dose 3h (± 10 min) 
1 
1 
Post-dose 4h (± 10 min) 
1 
1 
Post-dose 6h (± 10 min) 
1 
1 
Post-dose 8h (± 10 min) 
1 
2 
Pre-dose/0hb 
1 
5 
Pre-dose/0ha 
1 
8 
Pre-dose/0ha 
1 
8 
Post-dose 0.5h (± 5 min) 
1 
8 
Post-dose 1h (± 10 min) 
1 
8 
Post-dose 2h (± 10 min) 
1 
8 
Post-dose 3h (± 10 min) 
1 
8 
Post-dose 4h (± 10 min) 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 70 of 127 
 
Cycle 
Day 
Scheduled Time Point 
1 
8 
Post-dose 6h (± 10 min) 
1 
8 
Post-dose 8h (± 10 min) 
1 
9 
Pre-dose/0hc 
1 
15 
Pre-dose/0ha 
1 
15 
Post-dose 2h (± 10 min) 
1 
15 
Post-dose 4h (± 10 min) 
1 
15 
Post-dose 6h (± 10 min) 
1 
15 
Post-dose 8h (± 10 min) 
1 
16 
Pre-dose/0hd 
1 
21 
Pre-dose/0ha 
1 
21 
Between 2-4 hours post-dose 
2 
1 
Pre-dose/0ha 
3 
1 
Pre-dose/0ha 
4 
1 
Pre-dose/0ha 
5 
1 
Pre-dose/0ha 
6 
1 
Pre-dose/0ha 
7 
1 
Pre-dose/0ha 
8 
1 
Pre-dose/0ha 
Unscheduled 
Anytime 
After intra-patient dose escalation (see Section 6.9): 
Cycle X of the new higher 
dose level or different 
dosing regimen (frequency) 
8 
Pre-dose/0ha 
Cycle X of the new higher 
dose level or different 
dosing regimen (frequency) 
8 
Between 2-4 hours post-dose 
Unscheduled 
Anytime 
All measurement times are relative to dose of DS-1594b unless otherwise specified. 
a PK sample should be taken immediately prior to the next administration of DS-1594b. 
b Predose C1D2 PK sample is the same as 24 hours (± 2h) C1D1 post-dose PK sample; it will be collected immediately 
prior the administration of DS-1594b. 
c Predose C1D9 PK sample is the same as 24 hours (± 2h) C1D8 post-dose PK sample; it will be collected immediately 
prior the administration of DS-1594b. 
d Predose C1D16 PK sample is the same as 24 hours (± 2h) C1D15 post-dose PK sample; it will be collected 
immediately prior the administration of DS-1594b. 
 
 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 71 of 127 
 
Table 16: 
DS-1594b PK Blood Collection During Phase 2 Dose Expansion 
Cycle 
Day 
Scheduled Time Point 
Comment 
1 
1 
Pre-dose/0ha 
 
1 
1 
Post-dose 0.5h (± 5 min) 
Optional pending Phase 1data 
1 
1 
Post-dose 1h (± 10 min) 
 
1 
1 
Post-dose 2h (± 10 min) 
 
1 
1 
Post-dose 4h (± 10 min) 
 
1 
1 
Post-dose 6h (± 10 min) 
 
1 
1 
Post-dose 8h (± 10 min) 
 
1 
2 
Pre-dose/0hb 
For daily (QD) dosing only 
1 
8 
Pre-dose/0ha 
 
1 
8 
Post-dose 0.5h (± 5 min) 
Optional pending Phase 1 data 
1 
8 
Post-dose 1h (± 10 min) 
 
1 
8 
Post-dose 2h (± 10 min) 
 
1 
8 
Post-dose 4h (± 10 min) 
 
1 
8 
Post-dose 6h (± 10 min) 
 
1 
8 
Post-dose 8h (± 10 min) 
 
1 
9 
Pre-dose/0hc 
For daily (QD) dosing only 
1 
15 
Pre-dose/0ha 
 
1 
15 
Between 2-4 hours post-dose 
 
2 
1 
Pre-dose/0ha 
 
3 
1 
Pre-dose/0ha 
 
4 
1 
Pre-dose/0ha 
 
5 
1 
Pre-dose/0ha 
 
6 
1 
Pre-dose/0ha 
 
Unscheduled 
Anytime 
 
All measurement times are relative to dose of DS-1594b unless otherwise specified 
a PK sample should be taken immediately prior to the next administration of DS-1594b 
b Predose C1D2 PK sample is the same as 24 hours (± 2h) C1D1 post-dose PK sample; it will be collected immediately 
prior the administration of DS-1594b 
c Predose C1D9 PK sample is the same as 24 hours (± 2h) C1D8 post-dose PK sample; it will be collected immediately 
prior the administration of DS-1594b 
 
 
Table 17: 
DS-1594b PK Blood Collection for DDI Sub-Study with Antifungal Agents 
During Phase 1 After MTD Determination (N ~ 12) 
Cycle 
Day 
Scheduled Time Point 
Comment 
1 
1 
Pre-dose/0ha 
 
1 
1 
Post-dose 1h (± 10 min) 
 
1 
1 
Post-dose 2h (± 10 min) 
 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 72 of 127 
 
Cycle 
Day 
Scheduled Time Point 
Comment 
1 
1 
Post-dose 4h (± 10 min) 
 
1 
1 
Post-dose 6h (± 10 min) 
 
1 
1 
Post-dose 8h (± 10 min) 
 
1 
8 
Pre-dose/0ha 
Full PK profile in the absence of 
antifungal agents 
1 
8 
Post-dose 0.5h (± 5 min) 
1 
8 
Post-dose 1h (± 10 min) 
1 
8 
Post-dose 2h (± 10 min) 
1 
8 
Post-dose 3h (± 10 min) 
1 
8 
Post-dose 4h (± 10 min) 
1 
8 
Post-dose 6h (± 10 min) 
1 
8 
Post-dose 8h (± 10 min) 
1 
8 
Post-dose 12h (± 60 min) (i.e. pre-dose of Cycle 
1 Day 8 evening dose) [for BID dosing only] 
1 
9 
Pre-dose/0hb [for daily dosing only] 
1 
18 
Pre-dose/0ha 
Full PK profile in the presence of 
antifungal agents 
1 
18 
Post-dose 0.5h (± 5 min) 
1 
18 
Post-dose 1h (± 10 min) 
1 
18 
Post-dose 2h (± 10 min) 
1 
18 
Post-dose 3h (± 10 min) 
1 
18 
Post-dose 4h (± 10 min) 
1 
18 
Post-dose 6h (± 10 min) 
1 
18 
Post-dose 8h (± 10 min) 
1 
18 
Post-dose 12h (± 60 min) (i.e. pre-dose of Cycle 
1 Day 18 evening dose) [for BID dosing only] 
1 
19 
Pre-dose/0hc [for daily dosing only] 
2 
1 
Pre-dose/0ha 
 
3 
1 
Pre-dose/0ha 
 
4 
1 
Pre-dose/0ha 
 
Unscheduled 
Anytime 
 
All measurement times are relative to dose of DS-1594b unless otherwise specified 
a PK sample should be taken immediately prior to the next administration of DS-1594b 
b Predose C1D9 PK sample is the same as 24 hours (± 2h) C1D8 post-dose PK sample; it will be collected immediately 
prior the administration of DS-1594b 
c Predose C1D19 PK sample is the same as 24 hours (± 2h) C1D18 post-dose PK sample; it will be collected 
immediately prior the administration of DS-1594b 
 
 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 73 of 127 
 
Table 18: 
DS-1594b PK Blood Collection for DDI Sub-Study with Antifungal Agents 
During Phase 1 Before MTD Determination 
Cycle 
Day 
Scheduled Time Point 
Comment 
1 
1 
Pre-dose/0ha 
 
1 
1 
Post-dose 0.5h (± 5 min) 
 
1 
1 
Post-dose 1h (± 10 min) 
 
1 
1 
Post-dose 2h (± 10 min) 
 
1 
1 
Post-dose 3h (± 10 min) 
 
1 
1 
Post-dose 4h (± 10 min) 
 
1 
1 
Post-dose 6h (± 10 min) 
 
1 
1 
Post-dose 8h (± 10 min) 
 
1 
1 
Post-dose 12h (± 60 min) (i.e. pre-dose of 
Cycle 1 Day 1 evening dose) [for BID 
dosing only] 
 
1 
2 
Pre-dose/0ha 
 
1 
5 
Pre-dose/0ha 
 
1 
8 
Pre-dose/0ha 
Full PK profile in the absence of 
antifungal agents 
1 
8 
Post-dose 0.5h (± 5 min) 
1 
8 
Post-dose 1h (± 10 min) 
1 
8 
Post-dose 2h (± 10 min) 
1 
8 
Post-dose 3h (± 10 min) 
1 
8 
Post-dose 4h (± 10 min) 
1 
8 
Post-dose 6h (± 10 min) 
1 
8 
Post-dose 8h (± 10 min) 
1 
8 
Post-dose 12h (± 60 min) (i.e. pre-dose of 
Cycle 1 Day 8 evening dose) [for BID 
dosing only] 
1 
9 
Pre-dose/0hb [for daily dosing only] 
2 
10 
Pre-dose/0ha 
Full PK profile in the presence of 
antifungal agents   
2 
10 
Post-dose 0.5h (± 5 min) 
2 
10 
Post-dose 1h (± 10 min) 
2 
10 
Post-dose 2h (± 10 min) 
2 
10 
Post-dose 3h (± 10 min) 
2 
10 
Post-dose 4h (± 10 min) 
2 
10 
Post-dose 6h (± 10 min) 
2 
10 
Post-dose 8h (± 10 min) 
2 
10 
Post-dose 12h (± 60 min) (i.e. pre-dose of 
Cycle 2 Day 10 evening dose) [for BID 
dosing only] 
2 
11 
Pre-dose/0hc [for daily dosing only] 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 74 of 127 
 
Cycle 
Day 
Scheduled Time Point 
Comment 
3 
1 
Pre-dose/0ha 
 
4 
1 
Pre-dose/0ha 
 
5 
1 
Pre-dose/0ha 
 
6 
1 
Pre-dose/0ha 
 
Unscheduled 
Anytime 
 
All measurement times are relative to dose of DS-1594b unless otherwise specified 
a PK sample should be taken immediately prior to the next administration of DS-1594b 
b Predose C1D9 PK sample is the same as 24 hours (± 2h) C1D8 post-dose PK sample; it will be collected immediately 
prior the administration of DS-1594b 
c Predose C2D11 PK sample is the same as 24 hours (± 2h) C2D10 post-dose PK sample; it will be collected 
immediately prior the administration of DS-1594b 
 
 
 
Table 19: 
DS-1594b PK Blood Collection for Food Effect Sub-Study During Phase 1 
After MTD Determination (N ~ 6) 
Cycle 
Day Scheduled Time Point 
Comment 
1 
1 
Pre-dose/0ha 
 
1 
1 
Post-dose 1h (± 10 min) 
 
1 
1 
Post-dose 2h (± 10 min) 
 
1 
1 
Post-dose 4h (± 10 min) 
 
1 
1 
Post-dose 6h (± 10 min) 
 
1 
1 
Post-dose 8h (± 10 min) 
 
1 
8 
Pre-dose/0ha 
Full PK profile under fed 
condition with standard 
breakfast 
1 
8 
Post-dose 0.5h (± 5 min) 
1 
8 
Post-dose 1h (± 10 min) 
1 
8 
Post-dose 2h (± 10 min) 
1 
8 
Post-dose 3h (± 10 min) 
1 
8 
Post-dose 4h (± 10 min) 
1 
8 
Post-dose 6h (± 10 min) 
1 
8 
Post-dose 8h (± 10 min) 
1 
8 
Post-dose 12h (± 60 min) (i.e. pre-dose of Cycle 
1 Day 8 evening dose) [for BID dosing only] 
1 
9 
Pre-dose/0hb [for daily dosing only] 
1 
18 
Pre-dose/0ha 
Full PK profile under fasting 
condition  
1 
18 
Post-dose 0.5h (± 5 min) 
1 
18 
Post-dose 1h (± 10 min) 
1 
18 
Post-dose 2h (± 10 min) 
1 
18 
Post-dose 3h (± 10 min) 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 75 of 127 
 
Cycle 
Day Scheduled Time Point 
Comment 
1 
18 
Post-dose 4h (± 10 min) 
1 
18 
Post-dose 6h (± 10 min) 
1 
18 
Post-dose 8h (± 10 min) 
1 
18 
Post-dose 12h (± 60 min) (i.e. pre-dose of Cycle 
1 Day 18 evening dose) [for BID dosing only] 
1 
19 
Pre-dose/0hc [for daily dosing only] 
2 
1 
Pre-dose/0ha 
 
3 
1 
Pre-dose/0ha 
 
4 
1 
Pre-dose/0ha 
 
Unscheduled 
Anytime 
 
All measurement times are relative to dose of DS-1594b unless otherwise specified 
a PK sample should be taken immediately prior to the next administration of DS-1594b 
b Predose C1D9 PK sample is the same as 24 hours (± 2h) C1D8 post-dose PK sample; it will be collected immediately 
prior the administration of DS-1594b 
c Predose C1D19 PK sample is the same as 24 hours (± 2h) C1D18 post-dose PK sample; it will be collected 
immediately prior the administration of DS-1594b 
 
 
8.4.2. 
Analytical Methods 
Plasma DS-1594b and metabolites (if appropriate) will be measured at a laboratory designated 
by Daiichi Sankyo using a validated LC/MS assay. 
8.5. 
Cardiac Assessment (Electrocardiograms) 
A standard 12-lead ECG or Holter monitor will be used to collect the ECG timepoints described 
in Table 20Table 20 and Table 21Table 21 of Phase 1 and Phase 2, respectively. At all scheduled 
timepoints, ECGs must be performed in triplicate. The triplicate ECGs must be taken 
approximately ≥1 minute apart, with the subject in the supine/semi-recumbent position. All 
ECGs recorded for each time point must be transmitted electronically to a central laboratory and 
must be centrally reviewed by an independent reviewer. Any original ECG not transmitted 
electronically to the central laboratory must be forwarded for central review. All ECGs must be 
performed within 15 mins prior to the collection of all PK samples. 
The ECG collection plan is described in Table 20Table 20 and Table 21Table 21 , respectively, 
for Phase 1 Dose Escalation and Phase 1 Dose Expansion / Phase 2. 
Table 20: 
ECG Collection During Phase 1 Escalation 
Cycle 
Day 
Time 
Comment 
Screening 
-28 to -1  
Anytime 
 
1 
1 
Pre-dose/0ha 
 
1 
1 
Post-dose 2h 
 
1 
1 
Post-dose 4h 
 
1 
1 
Post-dose 6h 
 
1 
1 
Post-dose 8h 
 
Formatted: C-Hyperlink
Formatted: C-Hyperlink
Formatted: C-Hyperlink
Formatted: C-Hyperlink


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 76 of 127 
 
1 
1 
Post-dose 12hb (or Cycle 1 Day 1 pre-
evening dose) 
 
1 
2 
Pre-dose/0ha (Post-dose 12h from 
evening dose on Cycle 1, Day 1 [if BID 
dosing], or post-dose 24h from morning 
dose on Cycle 1, Day 1 [if QD dosing]) 
 
1 
5 
Pre-dose/0ha 
 
1 
8 
Pre-dose/0ha 
 
1 
8 
Post-dose 2h 
 
1 
8 
Post-dose 4h 
 
1 
8 
Post-dose 6h 
 
1 
8 
Post-dose 8h 
 
1 
8 
Post-dose 12hb (or Cycle 1 Day 8 pre-
evening dose) 
For BID dosing only 
1 
9 
Pre-dose/0ha (same as post-dose 24 h of 
C1D8) 
For daily (QD) 
dosing only 
1 
15 
Pre-dose/0ha 
 
1 
15 
Post-dose 2h 
 
1 
15 
Post-dose 4h 
 
1 
18 
Pre-dose/0ha 
DDI sub-study onlyd 
1 
18 
Post-dose 2h 
DDI sub-study onlyd 
1 
18 
Post-dose 4h 
DDI sub-study onlyd 
1 
18 
Post-dose 6h 
DDI sub-study onlyd 
1 
18 
Post-dose 8h 
DDI sub-study onlyd 
1 
18 
Post-dose 12hb (or Cycle 1 Day 18 pre-
evening dose) 
DDI sub-study onlyd 
For BID dosing only 
1 
19 
Pre-dose/0ha (same as post-dose 24 h of 
C1D18) 
DDI sub-study onlyd 
For QD dosing only 
1 
21 
Pre-dose/0ha 
 
1 
21 
Between 2-4 hours post-dose 
 
2 
1 
Pre-dose/0ha 
 
2 
10 
Pre-dose/0ha 
DDI sub-study onlye 
2 
10 
Post-dose 2h 
DDI sub-study onlye 
2 
10 
Post-dose 4h 
DDI sub-study onlye 
2 
10 
Post-dose 6h 
DDI sub-study onlye 
2 
10 
Post-dose 8h 
DDI sub-study onlye 
2 
10 
Post-dose 12hb (or Cycle 2 Day 10 pre-
evening dose) 
DDI sub-study onlye 
For BID dosing only 
2 
11 
Pre-dose/0ha (same as post-dose 24 h of 
C2D10)  
DDI sub-study onlye 
For QD dosing only 
3-8 
1 
Pre-dose/0ha 
 
During treatment after 
Cycle 6 
Any dayc 
Anytime 
 
After intra-patient dose escalation (see Section 6.9): 
Cycle X of the new 
higher dose level 
8 
Pre-dose/0ha 
 
Cycle X of the new 
higher dose level 
8 
Between 2-4 hours post-dose 
 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 77 of 127 
 
End of Treatment 
-- 
-- 
 
All measurement times are relative to dose of DS-1594b unless otherwise specified 
a Pre-dose assessment should be taken prior to the next administration of DS-1594b and within 15 mins prior to PK 
collection 
b12-hour assessment must be performed prior to the next dose and within 15 mins prior to PK collection 
c ECG should be performed only if clinically indicated 
d For subjects participating in the DDI sub-study AFTER MTD declaration (N ~ 12), additional triplicate ECGs will 
be performed on Cycle 1 Day 18 and Day 19 to coincide with PK assessments in which DS-1594b is co-
administered with antifungal agents (posaconazole, voriconazole) that are potent CYP3A inhibitors 
e For subjects participating in the DDI sub-study BEFORE MTD declaration, additional triplicate ECGs will be 
performed on Cycle 2 Day 10 and Day 11 to coincide with PK assessments in which DS-1594b is co-administered 
with antifungal agents (posaconazole) that are potent CYP3A inhibitors 
 
Table 21: 
ECG Collection During Phase 2 Dose Expansion 
Cycle 
Day 
Time 
Comment 
Screening 
-28 to -1 
Anytime 
 
1 
1 
Pre-dose/0ha 
 
1 
1 
Post-dose 2h 
 
1 
1 
Post-dose 4h 
 
1 
8 
Pre-dose/0ha 
 
1 
8 
Post-dose 2h 
 
1 
8 
Post-dose 4h 
 
1 
15 
Pre-dose/0ha 
 
1 
15 
Between 2-4 hours post-dose 
 
2-6 
1 
Pre-dose/0ha 
 
During 
treatment 
after Cycle 6 
Any dayb 
Anytime 
 
End of 
Treatment 
-- 
-- 
 
All measurement times are relative to dose of DS-1594b unless otherwise specified. 
a Pre-dose assessment should be taken prior to the next administration of DS-1594b and within 15 minutes prior to PK 
collection. 
b ECG should be performed only if clinically indicated. 
8.6. 
Correlative Studies (Mandatory for Phase 1)  
Tumor tissue, blood samples and bone marrow aspirate/biopsy for correlative research will be 
collected. Correlative laboratory studies will be conducted under this clinical trial as described:   
 Peripheral blood up to 40 mL (within 24 hours) will be collected for testing of 
biomarkers at Baseline (prior to day 1 dose of drug), and on Cycle 1 Days 8 (± 2), 
15(± 2), 21(± 2),  28(± 2), and on Cycle 2, Day 15(± 2), and Cycles 3 and 4, Day 
1(± 2) and at end of treatment / progression (if possible). Additional timepoints may 
be collected as needed. 
 Bone marrow samples will be collected for testing of biomarkers at baseline, on Day 
28 (+/-4 days), at Day 28 (+/- 4 days) of Cycles 2, 3, 6, 9, and at end of treatment or 
progression (if possible). Additional timepoints may be collected as needed. 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 78 of 127 
 
 All subjects are also routinely monitored for MRD by multiparametric flow 
cytometry and RT-PCR or NGS (in some cases, when applicable) at the time of bone 
marrow assessments. This will allow an analysis of response beyond hematologic 
criteria and correlation with long-term outcome.  
 All subjects will be evaluated by a pre-therapy and on-treatment NGS molecular 
panels, FISH, routine karyotyping, immunophenotyping and by a leukemia fusion 
panel (as applicable), to investigate correlations of gene alterations with long-term 
outcome, and to identify molecular characteristics of residual or recurrent clones.  
 Identification of clonal subsets in AML almost entirely been done using genomics, in 
which cellular populations are inferred. In order to effectively characterize and 
ultimately treat these cells, we need tools to identify therapy resistant cell populations 
as they arise in subjects. Flow cytometry is a useful tool for tracking cells in subjects 
but traditional fluorescent cytometry is limited by panel size and scope.  CyTOF 
(Cytometry by Time of Flight), is a variation of flow cytometry in which antibodies 
are labeled with heavy metal ion tags rather than fluorochromes.  This allows for the 
combination of many more antibody specificities in a single cell with greater depth 
and breadth of phenotypic and functional cytometric profiling. CyTOF will enable us 
to identify individual treatment-resistant cell populations and their signaling state in 
disease relate to clinical outcomes. CyTOF will be performed on bone marrow 
samples and peripheral blood at screening, remission, longitudinal samples on study, 
and relapse (where possible).  
 To enable the characterization of genetic heterogeneity in tumor cell populations, we 
will use novel microfluidic approach that barcodes amplified genomic DNA from 
thousands of individual leukemia cells confined to droplets. The barcodes are then 
used to reassemble the genetic profiles of cells from next-generation sequencing data. 
By using this approach, we will sequence longitudinally collected AML tumor 
populations from subjects and genotype disease relevant loci across thousands of 
individual cells. Targeted single-cell sequencing is able to sensitively identify cells 
harboring pathogenic mutations during complete remission and uncovered complex 
clonal evolution within AML tumors that are not observable with bulk sequencing. 
We anticipate that this approach will make feasible the routine analysis of AML 
heterogeneity, leading to improved stratification and therapy selection for the 
subjects. Single cell sequencing will be performed on bone marrow samples at 
screening, remission, longitudinal samples on study, and relapse (where possible). 
 Additional analysis including but not limited to bulk RNA sequencing to include 
Menin dependent genes (MEIS1, PBX3, MEF2C, and others), single cell RNA 
sequencing, IHC for differentiation markers on bone marrow slides/blocks, plasma 
inhibitory activity (PIA), RT-MLP, genomic break point sequencing may be 
performed on the subjects’ bone marrow samples and peripheral blood at screening, 
remission, longitudinal samples on study, and relapse (where possible). 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 79 of 127 
 
8.7. 
Outside Physician Participation During Treatment 
 The first cycle (28 days) of DS-1594b must be administered at the site, either 
in-patient or out-patient. The first 7 days of azacitidine and first cycle of mini-HCVD 
infusions must be administered at the site. Subsequently, subjects will have the option 
of receiving azacitidine injections or mini-HCVD infusions at the site out-patient 
clinic or the local ambulatory treatment center/outside physician’s office. We do not 
intend for the subjects to receive DS-1594b at any time at an outside physician’s 
office. During the first cycle in both Dose Escalation and Dose Expansion of Phase 1 
all the laboratory evaluations will be done at the site and the subjects must stay 
locally within easy access of the site. Subsequently, the subject may have the 
laboratory work done at a local clinic and the results reported and filed by the site 
research nurse for the study. The laboratory work done at the local clinic will be 
forwarded to the investigator or PI of the study, who will sign off on the labs to verify 
that the results have been reviewed. 
 Investigator communication with the outside physician is required prior to the subject 
returning to the local physician.  
 This will be documented in the subject record. 
 A letter to the local physician outlining the subject’s participation in a clinical trial 
will request local physician agreement to supervise the subject’s care. 
 Protocol required evaluations outside of the site will be documented by telephone, fax 
or e-mail. Fax and/or e-mail will be dated and signed by the Investigator, indicating 
that they have reviewed it. Changes in drug dose and/or schedule must be discussed 
with and approved by the Investigator, or they’re representative prior to initiation, and 
will be documented in the subject record. 
 A copy of the informed consent, and treatment schema and evaluation during 
treatment will be provided to the local physician. 
 Documentation to be provided by the local physician will include progress notes, 
reports of protocol required laboratory and diagnostic studies and documentation of 
any hospitalizations. 
 The home physician will be requested to report to the Investigator all life-threatening 
events within 24 hours of documented occurrence.  
 All protocol required follow-up visits will be performed at the site.  
 Changes in drug dose and/or schedule must be discussed with and approved by the 
investigator, or they’re representative prior to initiation, and will be documented in 
the subject record. 
 Subjects with an objective response at completion of active study treatment will be 
followed for survival at the site every 3 to 6 months for up to 5 years after completion 
of active treatment and while still on study. If the subject is unable to return to the 
site, the duration visits may be conducted via telephone.  


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 80 of 127 
 
 Data regarding adverse events will be collected during the study. Protocol specific 
data will be entered into the electronic case report form (eCRF). The eCRF used for 
this protocol will be Prometheus. AEs will be recorded in the Case Report Form.  
 Treatment may be discontinued for a variety of reasons, including subject withdrawal, 
investigator decision, and reasons specified by the protocol. Reasons for 
discontinuation of treatments are described in section 10.0. 
8.8. 
CRITERIA FOR RESPONSE: 
8.8.1. 
Response Criteria for AML 
Responses will be assessed by the criteria below, adapted from the International Working Group 
for AML and the European Leukemia Net Guidelines23,24. Responders are subjects who obtain a 
CR, CRh, CRi, or PR, with or without cytogenetic response, or a morphologic leukemia-free 
state.  
Complete remission (CR) 
 Peripheral blood counts: No circulating blasts. 
 Neutrophil count:  >1.0 x109/L  
 Platelet count >100 x109/L. 
 Bone marrow aspirate and biopsy:  < 5% blasts.  
 No Auer rods. 
 No extramedullary leukemia 
Complete remission with incomplete blood count recovery (CRi) 
 Peripheral blood counts:  No circulating blasts 
 Neutrophil count:  <1.0 x109/L, OR  
 Platelet count:  <100 x109/L 
 Bone marrow aspirate and biopsy: <5% blasts 
 No Auer rods 
 No extramedullary leukemia 
Complete Remission with Partial Hematological Recovery (CRh) 
 Peripheral blood counts:  No circulating blasts 
 Neutrophil count:  ≥ 0.5 x109/L  
 Platelet count:  ≥ 50 x109/L 
 Bone marrow aspirate and biopsy: < 5% blasts 
 No Auer rods 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 81 of 127 
 
 No extramedullary leukemia 
Partial remission (PR) 
 Neutrophil count:  >1.0 x109/L  
 Platelet count >100 x109/L  
 ≥ 50 % reduction in bone marrow blast from pretreatment baseline, but still ≥ 5% 
Morphologic leukemia-free state (MLFS): 
 Bone marrow < 5% myeloblasts,  
 No Auer rods,  
 No extramedullary leukemia,  
 Neutrophil or platelet recovery is not required 
8.8.2. 
Response Criteria for ALL  
Complete Remission (CR) 
 No circulating lymphoblasts or extramedullary disease 
 No lymphadenopathy, splenomegaly, skin/gum infiltration/testicular mass/CNS 
involvement 
 Trilineage hematopoiesis (TLH) and <5% blasts 
 Neutrophil count:  >1.0 x109/L  
 Platelet count >100 x109/L 
 No recurrence for 4 weeks 
Complete Remission with Partial Hematological Recovery (CRh) 
 No circulating lymphoblasts or extramedullary disease 
 No lymphadenopathy, splenomegaly, skin/gum infiltration/testicular mass/CNS 
involvement 
 Neutrophil count:  ≥ 0.5 x109/L  
 Platelet count:  ≥ 50 x109/L 
 Trilineage hematopoiesis (TLH) and <5% blasts 
 No recurrence for 4 weeks 
Complete Remission with Incomplete Hematologic Recovery (CRi) 
 Meets all criteria for CR except platelet count or ANC 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 82 of 127 
 
8.8.3. 
Transfusion Independence (TI)  
TI is defined as the absence of red blood cell and platelet transfusions for a consecutive 56-day 
period during continued treatment.  
TI will be assessed as a response achieved in the subgroup of subjects who were transfusion 
dependent (TD) at baseline (conversion from TD to TI with treatment) separately from the 
subgroup of subjects who were TI at baseline (maintenance of TI with treatment). Transfusion 
dependence at baseline is based on the receipt of any red blood cell or platelet transfusions 
within at least 28 days prior to the start of study treatment. Analyses of red blood cell TI and 
platelet TI will also be assessed separately. 
8.8.4. 
Relapse Definition (AML and ALL) 
Hematological relapse is defined as marrow blasts ≥ 5% by morphology, persistent reappearance 
of blasts in the peripheral blood by morphology, or the occurrence of extramedullary disease 
after achieving remission (CR, CRh, CRi, or MLFS). 
When relapse is suspected on the basis of the follow-up physical examination or peripheral blood 
counts, additional testing may be performed to confirm the finding, but the date of relapse is set 
to the date of the first test that suggests relapse. 
8.9. 
DISCONTINUATION OF TREATMENT 
8.9.1. 
Discontinuation Criteria for Individual Subjects 
Subject Withdrawal 
Subjects may voluntarily withdraw consent to participate in the clinical study at any time and 
without giving any reason. For subjects who withdraw consent, the Investigator may search 
publicly available records (where permitted) to ascertain survival status. Their withdrawal will 
not jeopardize their relationship with their healthcare providers or affect their future care. 
Subjects may also choose to withdraw from study treatment but agree to remain in the study for 
follow-up procedures.  
Investigator Discontinuation of Subject 
The Investigator may exercise medical judgment to discontinue study treatment if clinically 
significant changes in clinical status or laboratory values are noted. 
Criteria for Protocol-Defined Required Discontinuation of Treatment 
The protocol requires discontinuation of study treatment for the following reasons: 
 Lack of clinical benefit (defined as failure to achieve a PR or ≥ 50 % reduction in bone 
marrow blast from pretreatment baseline within 6 cycles of treatment) 
 Subject requests discontinuation. 
 Unacceptable toxicity that in the opinion of the investigator makes it unsafe to     
continue therapy.  
 Clinically significant progressive disease.  


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 83 of 127 
 
 Investigator discretion. 
Follow-Up at Treatment Discontinuation or Early Withdrawal 
Subjects who discontinue treatment for any reason should complete end-of-treatment procedures 
when possible. End of treatment procedures will include a physical examination, CBC with 
differential and platelets, triplicate ECG, and full chemistry panel with ALT, AST, bilirubin 
(fractionated), alkaline phosphatase, potassium, magnesium, creatinine kinase (fractionated if 
>ULN), blood urea nitrogen (BUN), serum creatinine, troponin. A bone marrow aspiration and 
biopsy may be recommended only if non-response or progressive disease cannot be 
unequivocally diagnosed from peripheral blood. Although treatment will be discontinued at that 
time, all subjects who do not withdraw consent for follow-up, die, or become lost to follow-up, 
will remain on study for follow-up evaluations. Subject will be followed for toxicity for at least 
30 days after the last protocol treatment. The 100-day follow-up visit (+ or – 5 days) will be 
scheduled as a clinic visits for clinical evaluation and physical examinations. If the subject 
cannot make it to the site for this visit, the required follow up treatment procedures may be done 
with a local physician and the records forwarded to Investigator. The Investigator or delegate 
will contact the subject by telephone and get a verbal assessment of the subject’s condition. The 
phone conversation will then be documented in the subject’s charts.  
8.9.2. 
Study Stopping Rules 
The Principal Investigator and  the Sponsor have the right to terminate this clinical study at any 
time. The principal investigator will be involved in any decisions regarding terminating the 
study, temporarily suspending enrollment, or stopping ongoing treatment with study treatment. 
Reasons for terminating the clinical study or a study site’s participation include, but are not 
limited to, the following: 
 The incidence or severity of an adverse reaction related to treatment in this study or 
other studies indicates a potential health hazard to subjects 
 Data recording is significantly inaccurate or incomplete 
 Study site personnel are noncompliant with study procedures 
 Pattern of noncompliance is observed 
8.9.3. 
Protocol Violations and Deviations 
Protocol violations are defined as significant departures from protocol-required processes or 
procedures that affect subject safety and benefit potential or confound assessments of safety or 
clinical activity. A protocol deviation is a departure from the protocol that does not meet the 
above criteria. Protocol violations or deviations may be grouped into the following classes: 
 Enrollment criteria 
 Study activities (missed evaluations or visits)  
 Noncompliance with dose or schedule, including dose calculation, administration, 
interruption, reduction, or delay; or discontinuation criteria 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 84 of 127 
 
 Investigational product handling, including storage and accountability 
 Informed consent and ethical issues 
8.10. 
ADVERSE EVENT MONITORING, RECORDING, AND 
REPORTING 
8.10.1. 
Definitions and Procedures 
Adverse Event (AE) is any untoward medical occurrence that may present during treatment with 
a pharmaceutical product, but which does not necessarily have a causal relationship with this 
treatment. Adverse drug reaction (ADR) is a response to a drug which is noxious and 
unintended, and which occurs at doses normally used in man for prophylaxis, diagnosis, or 
therapy of disease or for the modification of physiologic function.  
Assessing causal connections between agents and disease is fundamental to the understanding of 
adverse drug reactions. In general, a drug may be considered a contributory cause of an adverse 
event if, had the drug not been administered, 1) the event would not have happened at all, 2) the 
event would have occurred later than it actually did, or 3) the event would have been less severe. 
All subjects will be monitored for AEs during the study. AEs will be recorded in the subject’s 
source documents from the first dose through 30 days after the last dose. All Grade 1-5 AEs will 
be captured within the Prometheus, irrespective of relatedness to study drug(s). Hematologic lab 
abnormalities will not be recorded or reported as adverse except for prolonged myelosuppression 
as defined by the NCI-CTCAE criteria specific for leukemia, e.g. marrow hypocellularity on day 
42 or later (6 weeks) from start of therapy without evidence of leukemia (< 5% blasts), or that 
results in dose modifications, interruptions or meets the protocol definition of DLT or SAE.  
Adverse Events Attribution 
Attribution is the determination of whether an adverse event is related to a medical treatment or 
procedure.  
Definite - the adverse event is clearly related to the investigational agent(s). 
Probable - the adverse event is likely related to the investigational agent(s). 
Possible - the adverse event may be related to the investigational agent(s). 
Unlikely - The adverse event is doubtfully related to the investigational agent(s). 
Unrelated - The adverse event is clearly NOT related to the investigational agent(s). 
Adverse Events Severity 
The severity of the adverse events (AEs) will be graded according to the U.S. Department of 
Health and Human Services, National Institutes of Health, National Cancer Institute, Common 
Terminology Criteria for Adverse Events (CTCAE), Version 5.0.   
Events not included in the NCI CTCAE will be scored as follows: 
 Grade 1: Mild: discomfort present with no disruption of daily activity, no treatment 
required beyond prophylaxis. 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 85 of 127 
 
 Grade 2: Moderate: discomfort present with some disruption of daily activity, require 
treatment. 
 Grade 3: Severe: discomfort that interrupts normal daily activity, not responding to 
first line treatment.  
 Grade 4: Life Threatening: discomfort that represents immediate risk of death 
The investigator (or physician designee) is responsible for verifying and providing source 
documentation for all adverse events, assigning the attribution and assessing the severity of the 
AE, the causal relationship between any events and the clinical study procedure, activities or 
device.  Additionally, the Investigator is responsible for providing appropriate treatment for the 
event and for adequately following the event until resolution for all adverse events for subjects 
enrolled. 
The Principal Investigator will sign and date the AE log per each subject at the completion of 
each course. Following signature, the AE log will be used as source documentation for the 
adverse events for attribution. 
All participants will be registered in the Clinical Oncology Research System (CORe) 
The Leukemia-specific Adverse Event Recording and Reporting Guidelines will be followed 
for the recording and reporting of adverse and serious adverse events. 
Baseline events will be recorded in the medical history section of the case report form and will 
include the terminology event name, grade, and start date of the event.  The medical history 
section of the case report form will serve as the source document for baseline events once signed 
and dated by the principal investigator.   
Baseline events are any medical condition, symptom, or clinically significant lab abnormality 
present before the informed consent is signed 
Hematologic laboratory abnormalities will not be recorded as baseline events for subjects with 
acute leukemia, myelodysplastic syndrome, chronic lymphocytic leukemia, or chronic myeloid 
leukemia in blast phase. 
If exact start date is unknown, month and year or year may be used as the start date of the 
baseline event. 
All grades of the adverse event will be captured per course or protocol defined visit date.  For 
adverse events that increase or decrease in grade, the stop date should reflect the date that the 
event changed grade and a new start date should be added for the new grade. 
Hematologic adverse events will not be recorded or reported for studies in subjects with acute 
leukemia, except for: 
 Prolonged myelosuppression as defined by the NCI-CTCAE criteria specific for 
leukemia, e.g. marrow hypocellularity on day 42 or later (6 weeks) from start of 
therapy without evidence of leukemia (< 5% blasts), or that results in dose 
modifications, interruptions or meets the protocol definition of DLT or SAE. 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 86 of 127 
 
Overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important.  All occurrences of overdose must be 
reported to the Sponsor within 24 hours of awareness.  Overdose will be reported via eCRF. 
An “excessive and medically important” overdose includes any overdose in which either an 
SAE, a non-serious AE, or no AE occurs and is considered by the Investigator as clinically 
relevant, ie, poses an actual or potential risk to the subject. 
Occupational exposures of DS-1594b must be reported to Daiichi Sankyo. 
Serious adverse events will be reported according to institutional policy. 
Protocol specific language regarding the recording and reporting of adverse and serious adverse 
events will be followed in the event of discordance between the protocol and Leukemia-specific 
adverse event recording and reporting guidelines. 
8.10.2. 
Serious Adverse Events (SAEs) 
Serious Adverse Event (SAE) Reporting Requirements for M D Anderson Sponsor Single 
Site IND Protocols 
 An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or the sponsor, it results in any of the following outcomes:  
 Death 
 A life-threatening adverse event 
 Inpatient hospitalization or prolongation of existing hospitalization 
 A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
 A 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 upon appropriate medical judgment, they 
may jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse (21 CFR 312.32).  
Important medical events as defined above, should be considered serious adverse events. Any 
important medical event can and should be reported as an SAE if deemed appropriate by the 
Principal Investigator or the IND Sponsor, IND Office. 
All events occurring during the conduct of a protocol and meeting the definition of a SAE must 
be reported to the IRB in accordance with the timeframes and procedures outlined in “The 
University of Texas M. D. Anderson Cancer Center Institutional Review Board Policy on 
Reporting Adverse Events for Drugs and Devices”. 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 87 of 127 
 
Serious adverse events will be captured from the time of the first protocol-specific intervention, 
until 30 days after the last dose of drug, unless the participant withdraws consent.  
Serious adverse events must be followed until clinical recovery is complete and laboratory tests 
have returned to baseline, progression of the event has stabilized, or there has been acceptable 
resolution of the event. 
All SAEs, expected or unexpected/ initial or follow up, must be reported to the IND Office 
within 5 working days of knowledge of the event regardless of the attribution. 
Death or life-threatening events that are unexpected, possibly, probably or definitely related to 
drug must be reported (initial or follow up) to the IND Office within 24 hours of knowledge of 
the event. 
Additionally, any serious adverse events that occur after the 30 day time period that are related to 
the study treatment must be reported to the IND Office. This may include the development of a 
secondary malignancy. 
The electronic SAE application (eSAE) will be utilized for safety reporting to the IND Office 
and MD Anderson IRB.  
All events reported to the supporting company must also be reported to the IND Office  
 Reporting to FDA: 
Serious adverse events will be forwarded to FDA by the IND Sponsor according to 21 CFR 
312.32.  
It is the responsibility of the PI and the research team to ensure serious adverse events are 
reported according to the Code of Federal Regulations, Good Clinical Practices, the protocol 
guidelines, the sponsor’s guidelines, and Institutional Review Board policy. 
Adverse Events of Special Interest (AESI) 
Additionally, the following events regardless of seriousness should be reported as outlined in 
Sections 6.2.3.1 and 6.2.3.2: 
 QTc prolongation ≥ Grade 3, either serious or non-serious and whether or not 
causally related. 
 Hepatic events meeting combination abnormalities [ALT or AST ≥3 × ULN with 
simultaneous TBL ≥2 × ULN] (potential Hy's Law case), both serious and non-
serious and whether or not causally related. 
8.10.3. 
Pregnancy 
IND Sponsor must be notified of any female subject or partner of a male subject who becomes 
pregnant while receiving or within 3 months of discontinuing DS-1594b. 
Although pregnancy is not technically an AE, all pregnancies must be followed to conclusion to 
determine their outcome.  If a pregnancy is reported, the Investigator should inform the Sponsor 
within 24 hours of learning of the pregnancy. 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 88 of 127 
 
This information is important for both drug safety and public health concerns.  It is the 
responsibility of the Investigator, or designee, to report any pregnancy in a female subject or 
partner of a male subject.  The Investigator should make every effort to follow the female subject 
or partner of a male subject (upon obtaining written consent from partner) until completion of the 
pregnancy and obtain complete pregnancy outcome information, including normal delivery and 
induced abortion.  Any adverse pregnancy outcome, either serious or non-serious, should be 
reported in accordance with study procedures.  If the outcome of the pregnancy meets the criteria 
for immediate classification as an SAE (ie, post-partum complications, spontaneous or induced 
abortion, stillbirth, neonatal death, or congenital anomaly, including that in an aborted fetus), the 
Investigator should follow the procedures for reporting SAEs. 
8.10.4. 
Investigator Communications with MDACC 
Serious Adverse Events (SAEs) will be captured starting from the date of consent, irrespective 
of relatedness to study drug(s). 
Serious adverse events will be captured from the time of the first protocol-specific intervention, 
until 30 days after the last dose of drug, unless the participant withdraws consent.  
Serious adverse events must be followed until clinical recovery is complete and laboratory tests 
have returned to baseline, progression of the event has stabilized, or there has been acceptable 
resolution of the event. 
All events reported to the supporting company must also be reported to the IND Office. 
All events reported to DSI, must be reported to MDACC IND Office as well. 
8.10.5. 
MDACC Reporting to Daiichi Sankyo, Inc. 
All Serious Adverse Events, Adverse Events of Special Interest, overdoses and pregnancies must 
be reported by MDACC to the DSI Clinical Safety and Pharmacovigilance (CSPV) according to 
the terms outlined in the Alliance Pharmacovigilance Agreement. 
DSI CSPV may query MDACC regarding cases in order to ensure appropriate documentation. 
9. 
STATISTICAL CONSIDERATIONS 
This is an open-label Phase 1/2 multi-arm study. The primary objective in Phase 1 is to 
determine the Maximum Tolerable Dose (MTD) and identify the Recommended Phase 2 Dose 
(RP2D) of DS-1594b.  
Phase 2 will evaluate the safety and  response rate within 3 months of therapy initiation with 
single agent or combinations of DS-1594b at the RP2D in the following 4 cohorts: 
 Cohort A: R/R AML with MLL-rearrangement,  
 Cohort B: R/R AML with NPM1 mutation,  
 Cohort C: R/R AML treated with the combination of azacitidine and venetoclax with 
DS-1594b 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 89 of 127 
 
 Cohort D: R/R ALL treated with the combination of miniHCVD with DS-1594b. 
Up to 182 subjects will be enrolled in the study (approximately 66 subjects in Phase 1 (i.e. up to 
42 for dose titration-BOIN design, 6 for food effect sub-studies, and up to 18 for refining RP2D 
at safe doses below or at the MTD and DDI sub-studies) and up to 26 subjects per cohort in 
Cohorts A-and B and up to 32 subjects per cohort in Cohorts C and D in Phase 2). 
9.1. 
Phase 1 
The primary objective of Phase 1 is to determine the MTD and RP2D of DS-1594b when 
administered as a single agent in subjects with R/R AML or R/R ALL, including subjects with or 
without MLLr or NPM1m using a Bayesian optimal interval (BOIN) design (Liu and Yuan, 
2015; Yuan et al., 2016) to find the MTD. The details of the BOIN design to be used in the Phase 
1 are outlined in Section 3.2.  
According to the BOIN design, cohorts of 3 subjects will be treated at each dose level. If a dose 
level is found to be safe by the BOIN design we will escalate to the next higher dose level. 
Evaluation for above mentioned BOIN rule will be done for each dose level and dosing regimen 
(i.e., QD vs BID) separately based on the cumulative number of DLT evaluable subjects treated 
in that dose level. In case the multiple dosing regimens are initiated simultaneously and parallel 
enrollment is allowed in the multiple dosing regimens, the evaluation for BOIN rule for each 
dose level and dosing regimen would be made separately. Up to 9 additional subjects may be 
enrolled at each dose level that has already been deemed to be safe with the intent to gain 
additional information on safety and efficacy at different dose levels, to guide selection of 
optimal biologically effective RP2D. Although all R/R ALL and R/R AML subjects, irrespective 
of mutations, will be allowed during the Phase 1 dose-escalation it is suggested that at least 3 
subjects with MLLr or NPM1m are included at each dose level that is anticipated to be clinically 
active, to allow for optimal evaluation of safety and efficacy in the presumed target population to 
guide selection of the optimal RP2D. As described in Section 3.2, we will use the same the 
elimination boundaries in  Table 4 for the toxicity monitoring in the expansion cohort(s). 
9.2. 
Phase 2 
The primary endpoint of cohorts A-C is the achievement of CR + CRh within 3 months of 
therapy initiation in subjects with R/R AML with MLLr or NPM1m. The primary endpoint of 
cohort D is the achievement of CR + CRi within 3 months of therapy initiation in subjects with 
R/R ALL with MLLr. Up to 26 subjects will be enrolled per cohort in Cohorts A and B and up to 
32 subjects will be enrolled per cohort in Cohorts C and D. Each cohort will be analyzed 
separately. Treatment will be considered encouraging if the CR/CRh rate (Cohorts A, B, and C) 
or CR/CRi rate (Cohort D) rate would reach at least 40%, an improvement over the historical 
rate by more than 15%. The study will monitor futility and toxicity using the Bayesian method of 
Thall, Simon and Estey27. 
9.3. 
Futility and Toxicity Monitoring  
The historical data suggest a response rate of 25% in subjects with R/R AML or R/R ALL with 
NPM1m or MLLr using a variety of different therapies4,10, 19, 22, and the target response rate is 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 90 of 127 
 
40% with acceptable safety. The response rate is defined as CR + CRh rate within 3 months of 
therapy initiation in cohorts A, B and C and CR/CRi rate within 3 months of therapy initiation in 
Cohort D. The cohort will be stopped early if the data suggest that:  
Pr(PE <=  0.40| data) > 0.95, or 
Pr(PT > 0.2 | data) >0.85. 
where PE is the response rate and PT is the probability of DLT for experimental treatments, 
respectively. We assume PE and PT follow a priori ~ beta (0.5, 0.5).  That is, if at any time during the 
study we determine that there is more than 95% chance that the response rate would be at less 
than 40%, the cohort will be stopped due to futility. Or if at any time during the study, we 
determine that there is more than 85% chance that the toxicity rate is more than 20%, the cohort 
will be stopped due to toxicity. DLT observations from IPDE will not be used in toxicity 
monitoring. 
The futility and toxicity monitoring will be conducted separately for each of four cohorts, 
starting once the 10th subject in a cohort has been evaluated, and thereafter in groups of 5 
subjects, except the last group. The design parameters are set the same for cohorts A-D, each 
with a maximum of 26 subjects per cohort, excluding the safety run-in period for the first 6 
subjects in each of Cohorts C and D (Section 3.3). 
The stopping boundaries for futility and toxicity based on these assumptions and monitoring 
conditions are provided in Table 22Table 22. The operating characteristics are summarized in 
Table 23Table 23 and in Table 24Table 24  for futility and toxicity monitoring, respectively. 
Table 25Table 25 presents the overall early stopping probabilities for futility and toxicity 
monitoring. Bayesian Toxicity Monitoring software and Bayesian Efficacy monitoring with 
Posterior Probability software on https://trialdesign.org were used for the design of toxicity and 
futility monitoring. 
If the study arm is not stopped early and 26 subjects have been treated and evaluated in each 
cohort, assuming 11 of the 26 subjects achieve CR+CRh (Cohorts A, B, C) or CR+CRi (Cohort 
D), then the 95% credible interval for CR+CRh (Cohorts A-C) or CR+CRi (Cohort D) rate will 
be (25%, 61.3%). 
Table 22: 
Stopping Boundaries for Toxicity and Futility Monitoring in Each of Cohorts 
A-D 
 
Toxicity Stopping Boundaries 
Futility Early Stopping Boundaries 
Number of  
Subjects 
(inclusive) 
Num DLTs 
(inclusive) are 
considered too toxic 
Actions for 
toxicity 
monitoring 
Num. Responses 
(inclusive) are 
considered futile 
Actions for 
futility 
monitoring 
10 
4 - 10 
Early stopping 
0 - 1 
Early stopping 
15 
5 - 15 
Early stopping 
0 - 2 
Early stopping 
20 
6 - 20 
Early stopping 
0 - 4 
Early stopping 
26 
8 - 26 
Reach to Nmax 
0 - 6 
Reach to Nmax 
Formatted: C-Hyperlink
Formatted: C-Hyperlink
Formatted: C-Hyperlink
Formatted: C-Hyperlink


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 91 of 127 
 
9.3.1. 
IND Office Futility and Safety Monitoring 
Safety oversight will be performed by the SRC, the meeting minutes will be submitted to the 
IND Office Medical Affairs & Safety group upon availability. 
Table 23: 
Operating Characteristics for Futility Monitoring in each of Cohorts A-D 
True Response Rate 
Early stop probability for futility 
Average sample size 
0.1 
0.9633 
12.29 
0.2 
0.6713 
17.72 
0.3 
0.2906 
22.57 
0.4 
0.0811 
25.00 
0.5 
0.0153 
25.79 
0.6 
0.002 
25.97 
Table 24: 
Operating Characteristics for Toxicity Monitoring in each of Cohorts A-D  
True DLT rate 
Probability of Early Stop for toxicity 
Average Sample size 
0.1 
0.0235 
25.70 
0.2 
0.2509 
22.92 
0.3 
0.636 
17.84 
0.4 
0.8954 
13.53 
0.5 
0.9834 
11.22 
Table 25: 
Overall early stopping probabilities for Futility and Toxicity Monitoring in 
each of Cohorts A-D 
True DLT rate 
True Response Rate 
Overall probability of early stop 
0.1 
0.2 
0.6790  
0.1 
0.4 
0.1027  
0.1 
0.6 
0.0255  
 0.2 
0.2 
0.7538  
 0.2 
0.4 
0.3117  
 0.2 
0.6 
0.2524  
 0.4 
0.2 
0.9656  
 0.4 
0.4 
0.9039  
 0.4  
0.6 
0.8956  


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 92 of 127 
 
Table 26Table 26 presents the estimation precision (e.g., 95% credible intervals) under various 
scenarios with different numbers of observed responses, given that a cohort is not stopped early 
and 26 subjects have been enrolled. For example:  
 if 11 of the 26 subjects achieve the response (CR + CRh for Cohorts A-C and CR+Cri 
for Cohort D), the 95% credible interval of the response rate will be (25%, 61.3%).  
 if 8 of the 26 subjects achieve the response, the 95% credible interval of the response 
rate will be (15.8%, 49.8%). 
Table 26: 
95% Credible Intervals Under Various Scenarios with Different Numbers of 
Responses 
Number of responses 
Empirical  response rate 
95% Credible interval 
6 
23.1% 
(10.3%, 41.5%) 
8 
30.8% 
(15.8%, 49.8%) 
10 
38.5% 
(21.8%, 57.6%) 
11 
42.3% 
(25.0%, 61.3%) 
12 
46.2% 
(28.2%, 64.9%) 
14 
53.8% 
(35.1%, 71.8%) 
16 
61.5% 
(42.4%, 78.2%) 
18 
69.2% 
(50.2%, 84.2%) 
9.4. 
Statistical Analysis Plan 
9.4.1. 
Analysis Sets 
9.4.1.1. 
Efficacy Analysis Set 
The efficacy analysis set is all subjects with MLLr or NPM1m who received at least one dose of 
DS-1594b. Each cohort will be analyzed separately for efficacy.  
9.4.1.2. 
Safety Analysis Set 
Safety analysis set is all subjects who received at least one dose of DS-1594b.  
9.4.1.3. 
DLT Evaluable Set 
The DLT Evaluable Set will include all subjects in the Safety Analysis Set from Dose Escalation 
who experienced a DLT during the DLT evaluation period (first 28-day cycle), or who has not 
had a DLT and has received at least 42 out of the 56 DS-1594b doses and has completed the 
DLT evaluation period. 
Formatted: C-Hyperlink


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 93 of 127 
 
9.4.1.4. 
PK Analysis Set 
The Pharmacokinetic Analysis Set (PAS) will include all subjects who receive at least one dose 
of DS-1594b and have at least one evaluable PK sample. The PAS will be used for summaries of 
PK data as well as for listing of derived PK parameters. The definition of PK evaluability for the 
DDI sub-study and food effect sub-study are described in Section 3.2.3.3 and Section 3.2.4.3, 
respectively. 
9.4.2. 
Analysis Convention 
General rule 
Baseline is defined as the last non-missing value before the first dosing of study drug. The day of 
treatment would be considered as Day 1. Both the scheduled and unscheduled assessments will 
be used in the scope of analysis. For Phase 1, results will be presented by dose level and in total 
excluding subjects enrolled in the two sub-studies. The results from the DDI sub-study and food 
effect sub-study will be presented separately. For Phase 2, results will be presented by Cohort 
and in total, unless otherwise stated.  
Visit window 
For the summary at scheduled post-treatment visits, a continuous visit window would be used. 
For example, for visit scheduled at Day X, the visit window starts on day prior to XL 
=[(X+Y)/2]+  and ends on Day XU =[(X+Z)/2]+ where Y is the   scheduled day of prior visit, Z is 
the scheduled day of next visit and [x]+ is the least integer greater than or equal to x. The visit 
window for a given scheduled post-treatment visit can be different for different assessments 
depending on schedule assessments as not all the assessments are planned at each visit.  
Multiple assessments 
For multiple assessments within a particular visit window the assessment closest to the scheduled 
day of visit would be used. If there are multiple equi-distant assessments within a visit window, 
the assessment collected after the scheduled day of visit would be used. If there are multiple 
assessments, on a particular day, the worst value would be used. 
9.4.3. 
Analysis of Subject Disposition, Demography and Baseline Characteristics, and 
Medical History 
Subjects disposition (e.g., number of subjects screened, treated, completed study drug, 
completion of study, reason for discontinuation) will be summarized using counts and 
percentages. Subject demography and relevant baseline characteristics and medical history will 
be summarized descriptively for all treated subjects (i.e., the safety analysis set).   
9.4.4. 
Analysis of Exposure of Study Drug 
Study treatment exposure and treatment duration will be summarized using descriptive statistics 
for the Safety Analysis Set. In addition, the total number of cycles initiated will be summarized 
using descriptive statistics.  Number and percentage of subjects with and without dose reductions 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 94 of 127 
 
or interruptions will also be summarized. In addition, cumulative dose and dose intensity will 
also be summarized. 
The following definitions would be used: 
Exposure (in days): last dose date – first dose date + 1 
Treatment duration (in days): last dose date – first dose date + 30 
Cumulative dose: Total amount dose actually taken 
Dose intensity: Cumulative dose/ Exposure 
9.4.5. 
 Analysis of Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization drug 
dictionary (WHO-DD).  Concomitant medications will be summarized by ATC2 class and 
preferred term for the Safety Analysis Set.  Prior medications will be summarized for the Safety 
Analysis Set. Within each level of summarization, a subject will be counted once if he/she takes 
one or more medications.  
Prior medications are defined as those with a start date prior to the date of first dose of study 
drug.  Concomitant medications are defined as those with a start date greater than or equal to the 
date of first dose of study drug, or with a start date prior to the date of first dose of study drug 
and a stop date either after the date of first dose of study drug or marked as “ongoing” or 
“continuing”.  Medications taken prior to the first dose of study drug, but with a missing stop 
date or with a stop date either on or after the date of the first dose of study drug or marked as 
“ongoing” or “continuing” will also be considered concomitant medications for the summary. 
Medications started after the 40-day visit or after start of new anticancer therapy are not 
considered as concomitant medications. A listing of prior and concomitant medications by 
subject will also be provided. 
9.4.6. 
Efficacy Analyses 
The efficacy analyses will be carried out for both the Efficacy Analysis Set and the Safety 
Analysis Set. Subjects with prior treatment with other menin inhibitors will be analyzed 
separately for efficacy. 
For the primary efficacy analysis, the primary efficacy outcome (CR + CRh rate for Cohorts A, 
B, C and CR+CRi rate for Cohort D) will be estimated along with the 95% credible interval for 
each cohort. If the study cohort is not stopped early, assuming 11 of the 26 subjects achieve the 
response (CR + CRh for Cohorts A, B, C and CR+CRi for Cohort D), the 95% credible interval 
for the response rate will be (25%, 61.3%).   The same method will be used for other binary 
efficacy outcomes in Phase 1 and Phase 2, including rate of durable transfusion independence, 
the 4- and 8-week mortality rates, the rate of subjects able to proceed to HSCT, and the MRD 
rate at the first response and at the best response. The time to event outcomes, including DOR, 
time to first response, time to best response, median duration to HSCT. EFS and OS, will be 
estimated using the Kaplan-Meier method. For the exploratory analysis, logistic regression 
models and Cox proportional hazards models will be fitted to correlate clinical factors, 
expressions of immune markers with efficacy outcomes.  OS time will be calculated from the 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 95 of 127 
 
date of the treatment start to the date of death or to the date of last follow-up if patients are alive 
at the time of data collection. Patients alive will be censored at the analysis. EFS will be 
calculated from the date of start treatment to the date of disease relapse or date of death 
whichever occurs first, or to the date of last follow-up for patients who are alive and have no 
relapsed disease at the time of data collection. Patients who are alive and have no relapsed 
disease will be censored at the analysis. 
9.4.7. 
Safety Analyses 
Safety analyses will be performed in the safety population.  AEs that occur or worsen relative to 
the pre-treatment state after the start of study treatment and within 30 days of the last dose of 
study drug (TEAEs) will be tabulated. AEs will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) terminology and tabulated by body organ group using the 
MedDRA system organ class (SOC) and by AE term using preferred terms (PTs).  
Safety evaluation will include DLTs, serious adverse events, treatment-emergent adverse events, 
physical examination findings (including ECOG performance status), vital signs measurements, 
standard clinical laboratory parameters, and ECG parameters (including QTcF). 
Safety analyses in general will be descriptive and will be presented in tabular format with the 
appropriate summary statistics by dose level and in total for Phase 1, and by cohort and in total 
for Phase 2, unless otherwise stated. Only the treatment emergent assessments (i.e., assessments 
within the 30 days of last study drug dose) would be used in the analyses unless otherwise 
specified.  
The summary of DLTs in the Dose Escalation parts will be performed based on the DLT 
Evaluable Set. All other safety summaries and analyses will be performed based on the Safety 
Analysis Set and subjects will be analyzed according to the actual treatment they received.  
9.4.7.1. 
Dose-Limiting Toxicities 
For Phase 1 (Dose Escalation), the number of DLTs identified among the DLT evaluable 
subjects in the DLT Evaluable Set will be listed and summarized for each dose cohort and in 
total by the worst NCI-CTCAE grade, system organ class (SOC), and preferred term (PT). 
9.4.7.2. 
Adverse Events 
Adverse events will be assigned grades based on NCICTCAE v5.0. 
A TEAE is defined as those AEs with start or worsening date during the treatment period (from 
first dose date until 30 days after the last dose of study medication). It includes AEs having been 
absent at pre-treatment; or reemerges during treatment, having been present at baseline, but 
stopped prior to treatment; or worsens in severity after starting treatment relative to the pre-
treatment state, when the AE is continuous. 
9.4.7.2.1. Summary of Treatment-Emergent Adverse Events 
The number and percentage of subjects with the following TEAEs will be summarized:  
1. TEAEs by SOC, preferred term, and worst CTCAE grade; 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 96 of 127 
 
2. Study-drug-related TEAEs by SOC, preferred term, and worst CTCAE grade; 
3. Serious TEAEs by SOC, preferred term, and worst CTCAE grade; 
4. Study-drug-related serious TEAEs by SOC, preferred term, and worst CTCAE grade; 
5. TEAEs associated with drug discontinuation by SOC and preferred term 
6. TEAEs associated with dose reduced by SOC and preferred term 
7. TEAEs associated with drug interrupted by SOC and preferred term 
8. TEAEs associated with death by SOC and preferred term 
The number and percentage of subjects with AEs will be also summarized by PT only, if 
applicable. A by-subject TEAE data listing including, but not limited to, verbatim term, preferred 
term, SOC, CTCAE grade, and relationship to study drug will be provided.  
Listings will be provided for deaths, SAEs, and AEs associated with discontinuation of study 
drug. A by-subject AE (including treatment-emergent) data listing including, but not limited to, 
verbatim term, preferred term, system organ class, NCI-CTCAE grade, and relationship to study 
drug will be provided. 
9.4.7.2.2. Adverse Events of Special Interest 
The adverse events of special interest (AESI) will be categorized by Standardized MedDRA 
Queries (SMQs) or grouping of MedDRA terms in this study and will include the following two 
categories: TdP/other ventricular arrhythmias and Hepatotoxicity. The search criteria for each 
AESI category are specified in Table 27Table 27.  
Table 27: 
AESI Categories and SMQ Search Criteria  
AESI Category 
 SMQ Search Criteria 
TdP/other ventricular arrhythmias 
All PTs from Torsade de pointes/QT prolongation SMQ (broad) 
plus PTs Fall, presyncope, agonal rhythm, arrhythmia, cardiac 
flutter, paroxysmal arrhythmia 
Hepatotoxicity 
All PTs from: 
Cholestasis and jaundice of hepatic origin (SMQ) (narrow) 
Hepatic failure, fibrosis and cirrhosis and other liver damage-
related conditions (SMQ) (narrow) 
Hepatitis, non-infectious (SMQ) (narrow) 
Liver related investigations, signs and symptoms (SMQ) 
(narrow) 
The preferred terms (PT) in each AESI category, as well as the AESI categories in the table may 
be updated. A complete list of AESI categories with PT terms will be reported in the CSR. 
Formatted: C-Hyperlink


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 97 of 127 
 
The following AESI summaries will be provided: 
 TEAEs by AESI category and PT (any TEAEs, Grade ≥3, fatal, associated with study 
drug discontinuation) 
 Time to onset of earliest TEAEs by AESI category 
9.4.7.2.3. Clinical Laboratory Evaluations 
Descriptive statistics will be provided for selected clinical laboratory test results (hematology 
and blood chemistry) and changes from baseline by scheduled time of evaluation, including the 
End-of-Treatment Visit, maximum post-treatment value, and minimum post-treatment value. 
Both scheduled and unscheduled post-treatment values will be considered for the summaries of 
the maximum and minimum post-treatment values. 
Abnormal laboratory results will be graded according to NCI-CTCAE Version v5.0, if 
applicable. A shift table, presenting the 2-way frequency tabulation for baseline and the worst 
post-treatment value according to the NCI-CTCAE grade, will be provided for selected clinical 
laboratory tests (ALT, AST, Total Bilirubin, ALP, and Creatinine). Both scheduled and 
unscheduled post-treatment values during the treatment period will be considered. 
The number and percentage of subjects with the following potentially clinically relevant 
abnormal liver function test will be summarized by dose cohort and in subtotal for each part: 
 ALT ≥3 x ULN, ≥5 x ULN, ≥10 x ULN, and ≥20 x ULN 
 AST ≥3 x ULN, ≥5 x ULN, ≥10 x ULN, and ≥20 x ULN 
 Total bilirubin  ≥2 x ULN 
 Potential Hy’s Law cases: ALT or AST >3 x ULN, total bilirubin ≥2 x ULN, and ALP 
<2 x ULN  
Mean absolute neutrophil count and platelet count over time by dose cohort for Part 1 as well as 
individual absolute neutrophil count and platelet count over time for Part 1A subjects will be 
plotted. 
All clinical laboratory data will be listed, and values deemed clinically significance will be 
flagged. 
9.4.7.3. 
Vital Signs 
Descriptive statistics will be provided for the vital signs measurements by scheduled time of 
evaluation (including the EOT visit), as well as for the change from baseline. In addition, the 
change from baseline will be presented for the maximum and minimum post-treatment values.  
9.4.7.4. 
ECG 
Electrocardiogram parameters (PR, RR, QRS, QT, QTcB, and QTcF) will be summarized using 
descriptive statistics for actual values and for changes from baseline by scheduled time of 
evaluation, including the EOT Visit and the maximum post-treatment value.  Both scheduled and 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 98 of 127 
 
unscheduled post-treatment values will be considered for summaries of the maximum 
post-treatment values. The corrected QT intervals using Bazett’s and Fridericia’s formula will be 
calculated as follows: QTcB = QT/(RR)1/2 and QTcF = QT/(RR)1/3. 
The incidence of notable ECG changes in maximum absolute QT, QTcF, and QTcB over all post-
treatment evaluations will be summarized using the following intervals: 
 New > 450 and ≤ 480 ms; 
 New > 480 and ≤ 500 ms; 
 New > 500 ms. 
The incidence of notable ECG changes in QT, QTcF, and QTcB maximum changes from baseline 
over all post-treatment evaluations will be summarized with the following intervals: 
1. 30 and ≤ 60 ms; 
2. > 60 ms; 
All triplicate ECG measurements at a particular timepoint will be averaged prior to analysis and 
summarization. 
 
9.4.8. 
Dosing and Extent of Exposure 
The following items of DS-1594b administration will be summarized. 
1. Treatment duration (day) 
= Last dose date – First dose date + 1 
2. Study duration (day) 
= Date of the Follow-up visit – First dose date + 1 
3. Total amount of DS-1594b taken (mg) 
4. Dose intensity (mg) 
= Total amount of doses taken / (Treatment duration) 
5. Relative dose intensity (%) 
= Actual Dose intensity / Planned dose intensity * 100   
In addition, the total number of cycles initiated will be summarized using descriptive statistics.  
In Phase 2, DS-1594b dosing status will be summarized to show the number and percentage of 
subjects with and without dose reductions or interruptions. For subjects with dose reductions or 
interruptions, the reasons will be provided. A listing of dose escalation subjects with dose 
reductions or interruptions will be provided. 
For the combination-treatment cohorts C & D in Phase 2, the exposure of the combination drugs 
azacitidine and venetoclax, and mini-HCVD will be summarized separately.  
All study drug administration data will be listed by subject by study Phase. 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 99 of 127 
 
9.4.9. 
PK Analyses 
DS-1594b PK parameters will be determined using non-compartmental method(s) and fitting of 
the actual values to a population PK model. The single-dose dose and multiple dose PK 
parameters listed in Section 8.4 will be estimated and reported, as appropriate. 
Descriptive statistics (n, mean, SD, CV%, median, minimum, and maximum) will be performed 
on all PK parameters by cohort and study day. Geometric means and geometric CV% will be 
presented for Cmax, AUClast, AUCinf, AUCtau, Ctrough, Cavg, CL/F, CLss/F, Vz/F and AR. 
Medians and ranges will be presented for Tmax, Tlast, t1/2, and t1/2,ar.  
Descriptive statistics (n, mean, SD, median, geometric mean, CV%, geometric CV%, minimum, 
and maximum) will be presented for plasma concentrations by cohort. 
A graphical presentation of the plasma concentration profiles will also be provided by cohort 
using the arithmetic mean (+/- SD) and geometric mean values at each scheduled time point for 
full PK collection profile on Cycle 1 Day 1, Cycle 1 Day 8, Cycle 1 Day 15 (food effect sub-
study), Cycle 1 Day 18 (DDI sub-study) and Cycle 2 Day 10 (DDI sub-study). The trough 
concentration -time profile will also be plotted by cohort.  
Concentration values below the lower limit of quantitation (LLOQ) will be displayed in listings 
as zero with a flag and handled as zero in any calculations of summary statistics but handled as 
missing for the calculation of the geometric means and their CV%. Any missing PK parameter 
data will not to be imputed. 
9.4.9.1. 
Food Effect Sub-Study 
The effect of meal on the steady-state PK of DS-1594b will be evaluated in the food effect sub-
study when: 
 DS-1594b is administered orally twice daily or daily with a standard meal from Cycle 
1 Day 1 to Cycle 1 Day 8. 
 DS-1594b is administered orally twice daily or daily under fasting condition from 
Cycle 1 Day 9 to Cycle 1 Day 18.  
The analysis will consider the primary PK parameters AUCtau and Cmax of DS-1594b on Cycle 
1 Day 8 and Cycle 1 Day 18. A mixed-effects model will be used with treatment period (fed vs. 
fasting) as a fixed effect and subject as a random effect on log-transformed PK parameter data, 
and the results will be presented at original scale after back-transformation. The geometric mean 
of DS-1594b PK parameters (as estimated by the mixed effect model) will be calculated and the 
geometric mean ratio of DS-1594b PK parameters (Cycle 1 Day 18 relative to Cycle 1 Day 8) 
will be reported with 90% CIs.  
9.4.9.2. 
DDI Sub-Study 
The effect of multiple doses of strong CYP3A inhibitor on the steady-state PK of DS-1594b will 
be evaluated in the DDI sub-study when: 
 DS-1594b is administered orally twice daily or daily alone from Cycle 1 Day 1 to 
Cycle 1 Day 8. 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 100 of 127 
 
 DS-1594b is administered oral twice daily or daily with strong CYP3A inhibitor 
(posaconazole or vericonazole) from Cycle 1 Day 9 to Cycle 1 Day 18 (or Cycle 2 
Day 1 to Cycle 2 Day 10).  
The analysis will consider the primary PK parameters AUCtau and Cmax of DS-1594b on Cycle 
1 Day 8 and Cycle 1 Day 18 (or Cycle 2 Day 10). A mixed-effects model will be used with 
treatment period (with CYP3A inhibitor vs. without CYP3A inhibitor) as a fixed effect and 
subject as a random effect on log-transformed PK parameter data, and the results will be 
presented at original scale after back-transformation. The geometric mean of DS-1594b PK 
parameters (as estimated by the mixed effect model) will be calculated and the geometric mean 
ratio of DS-1594b PK parameters (Cycle 1 Day 18 (or Cycle 2 Day 10) relative to Cycle 1 Day 
8) will be reported with 90% CIs.  
9.4.10. 
PK/PD Analyses 
Additional exploratory analyses may be conducted to identify possible relationships of 
appropriate observed or population PK-derived PK parameters with clinical efficacy, safety 
variables, biomarkers, or dosing change as appropriate.  
To assess the effect of DS-1594b on the QT interval, QTc changes from baseline will be plotted 
against the time-matched PK concentration, for each QTc parameter. In addition, a linear mixed 
effects model may be used to analyze changes from baseline QTc versus DS-1594b PK 
concentrations, including covariates such as baseline QTc, age, gender, race. Details will be 
described in a separate modeling plan. 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 101 of 127 
 
10. 
APPENDICES 
Table 28: 
List of Prohibited QT Prolongation Drugs 
Prohibited medications causing QTc prolongation 
Antiarrhythmic: 
Anticancer: 
Antibiotic: 
Antianginal: 
amiodarone 
arsenic trioxide 
azithromycin 
bepridil 
disopyramide 
vandetanib 
clarithromycin* 
 
dofetilide 
oxaliplatin 
erythromycin* 
Antipsychotic: 
flecainide 
Antihistamine: 
moxifloxacin 
chlorpromazine 
ibutilide 
astemizole* 
sparfloxacin 
haloperidol* 
procainamide 
terfenadine* 
levofloxacin 
mesoridazine  
quinidine* 
 
ciprofloxacin 
pimozide 
sotalol 
Antimalarial: 
grepafloxacin 
thioridazine 
dronedarone* 
chloroquine 
Antinausea: 
sulpiride 
 
halofantrine 
domperidone  
levomepromazine 
Antilipemic: 
hydroxychloroquine 
droperidol 
Opiate agonist: 
probucol 
 
ondansetron 
levomethadyl 
Antidepressant: 
 
GI stimulant:  
methadone 
citalopram 
Anti-infective: 
cisapride* 
cocaine 
escitalopram 
pentamidine 
 
Other: 
 
 
 
anagrelide 
 
 
 
sevoflurane 
 
 
 
cilostazol 
 
 
 
donepazil 
 
 
 
papaverine 
 
 
 
propofol 
Note: *CYP3A substrate 
Source: The most updated list is available on website https://www.crediblemeds.org/healthcare-providers/drug-
list  
 
 
 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 102 of 127 
 
Table 29: 
Prohibited Medications That Are Strong Inhibitors or Inducers of CYP3A, 
or CYP3A/P-Gp and CYP2C19 Substrates with Narrow Therapeutic Indices 
CYP3A4/5 substrates and/or P-gp substrates with narrow therapeutic index 
astemizole* 
diergotamine 
pimozide* 
alfentanil 
cisapride* 
ergotamine 
quinidine* 
terfenadine* 
cyclosporine 
fentanyl 
tacrolimus 
sirolimus 
digoxin 
paclitaxel 
 
 
CYP2C19 substrates with narrow therapeutic index 
(S)-mephenytoin 
 
 
 
Strong CYP3A inhibitors 
Macrolide antibiotics: 
Antivirals: 
Antifungals: 
Others: 
clarithromycin** 
indinavir 
itraconazole** 
conivaptan 
telithromycin 
lopinavir/ritonavir 
ketoconazole 
 
troleandomycin 
nelfinavir 
posaconazole 
mibefradil 
 
ritonavir** 
voriconazole 
nefazodone 
 
indinavir/ritonavir** 
 
 
 
saquinavir 
 
 
 
saquinavir/ritonavir** 
 
 
 
telaprevir** 
 
 
 
tipranavir/ritonavir** 
 
 
 
danoprevir/ritonavir** 
 
 
 
elvitegravir/ritonavir** 
 
 
 
boceprevir 
 
 
 
cobicistat 
 
 
Strong CYP3A/5 inducers 
avasimibe 
carbamazepine 
phenobarbital 
phenytoin 
rifabutin 
rifampin 
St. John’s wort 
mitotane 
* Compounds known to increase QTc interval that are also primarily metabolized by CYP3A4/5. 
** Compounds known to have P-gp inhibitory effect 
Reference:   
University of Washington’s Drug Interaction Database 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLab
eling/ucm093664.htm#4  
 
 
 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 103 of 127 
 
Table 30: 
List of medications to be used with caution 
Moderate CYP3A4/5 inhibitors* 
netupitant 
darunavir 
grapefruit juice 
crizotinib 
atazanavir/ritonavir 
darunavir/ritonavir 
aprepitant 
tofisopam 
amprenavir 
diltiazem 
casopitant 
lomitapide 
atazanavir 
verapamil 
cimetidine 
 
 
imatinib 
nilotinib 
 
Moderate CYP3A4/5 inducers* 
bosentan 
efavirenz 
etravirine 
modafinil 
nafcillin 
lersivirine 
talviraline 
tipranavir 
 
lopinavir 
 
 
P-gp inhibitors (not strong CYP3A inhibitors) 
carvedilol 
lapatinib 
propafenone 
ranolazine 
verapamil 
 
 
 
BCRP substrates 
atorvastatin 
daunorubicin 
doxorubicin 
imatinib 
methotrexate 
mitoxantrone 
pitavastatin 
rosuvastatin 
SN-38 (irinotecan) 
ethinyl estradiol 
simvastatin 
sulfasalazine 
sofosbuvir 
topotecan 
 
 
OCT1/2 substrates 
 
 
 
metformin 
phenformin 
6-beta-hydroxycortisol 
amantadine 
carboplatin 
cisplatin 
histamine 
lamivudine 
linagliptin 
oxaliplatin 
oxybutynin 
picoplatin 
pramsorafenib 
tropisetron 
trospium 
varenicline 
umeclidinium 
 
 
 
P-gp substrates 
 
 
 
aliskiren 
ambrisentan 
atorvastatin 
azithromycin 
cerivastatin 
colchicine 
cyclosporine 
dabigatran 
docetaxel 
domperidone 
doxorubicin 
fexofenadine 
lapatinib 
linezolid 
loperamide 
maraviroc 
nevirapine 
proguanil 
ritonavir 
ranolazine 
simvastatin 
sofosbuvir 
ticagrelor 
voclosporin 
 
 
 
 
 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 104 of 127 
 
Table 30: 
List of medications to be used with caution (Continued) 
Gastric reducing agents (proton pump inhibitors) 
 
esomeprazole 
lansoprazole 
omeprazole 
pantoprazole 
rabeprazole 
 
 
 
*Subjects enrolled in DDI and food effect sub-studies will have moderate CYP3A inhibitors and 
inducers prohibited (see Appendix Table 31Table 31). 
References:   
University of Washington’s Drug Interaction Database 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLab
eling/ucm093664.htm#4  
 
 
 
Formatted: C-Hyperlink


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 105 of 127 
 
Table 31: 
Additional Prohibited Medications for Subjects Enrolled in DDI and Food 
Effect Sub-Studies 
Moderate CYP3A4/5 inhibitors 
netupitant 
darunavir 
grapefruit juice 
crizotinib 
atazanavir/ritonavir 
darunavir/ritonavir 
aprepitant 
tofisopam 
amprenavir 
diltiazem 
casopitant 
lomitapide 
atazanavir 
verapamil 
cimetidine 
 
fluconazole 
imatinib 
nilotinib 
 
Moderate CYP3A4/5 inducers 
bosentan 
efavirenz 
etravirine 
modafinil 
nafcillin 
lersivirine 
talviraline 
tipranavir 
 
lopinavir 
 
 
Gastric reducing agents (proton pump inhibitors) 
esomeprazole 
lansoprazole 
omeprazole 
pantoprazole 
rabeprazole 
 
 
 
References:   
University of Washington’s Drug Interaction Database 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLab
eling/ucm093664.htm#4  
 
 
 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
 
Page 106 of 127 
 
 
Table 32: 
Phase 1 Dose Escalation Schedule of Events  
Phase 1 Dose Escalation Schedule of Events 
Procedure 
SCR 
C1 
C2 
C3 
C4 
Cx 
EOT 
30D 
FU 
LT 
FU 
Comment 
Day 
-14 
1 
2 
5 
8 
9 
15 
16 
21 
28 
1 
8 
15 
21 
28 
1 
15 
28 
1 
15 
1 
Window 
 
 
 
±1D ±1D ±1D ±1D ±1D ±1D ±4D ±4D ±1D ±1D ±1
D 
±4D ±4D ±1D ±4D ±4D ±1D 
±4D 
±3D 
+7D 
±14D  
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior to study 
procedures 
Bone Marrow 
Aspirate/Biopsy 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X* 
X 
 
 
*Day 28 (±4) of 
Cycles 1, 2, 3, 
6, 9, and EOT 
Eligibility  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, 
Medical History, 
Disease History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WHO 
classification, 
cytogenetics, 
mutations, prior 
therapy 
Vital Signs 
X 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
 
X 
 
X 
X 
 
 
Blood pressure, 
pulse rate, 
respiratory rate, 
and temperature 
taken ~5 min 
prior to ECG 
measurements 
ECG (in 
triplicate) by 
12-lead or Holter 
X 
X 
X 
X 
X 
X* 
X 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
X** 
X 
 
 
*For daily 
dosing only 
**Cycles 5 to 8 
only. 
Triplicate ECGs 
≥1 minute 
apart, 
supine/semi-
recumbent.  
Prior to PK 
Section 8.5 and 
Table 20Table 
Formatted: C-Hyperlink, Font: 8 pt


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
 
Page 107 of 127 
 
Phase 1 Dose Escalation Schedule of Events 
Procedure 
SCR 
C1 
C2 
C3 
C4 
Cx 
EOT 
30D 
FU 
LT 
FU 
Comment 
Day 
-14 
1 
2 
5 
8 
9 
15 
16 
21 
28 
1 
8 
15 
21 
28 
1 
15 
28 
1 
15 
1 
Window 
 
 
 
±1D ±1D ±1D ±1D ±1D ±1D ±4D ±4D ±1D ±1D ±1
D 
±4D ±4D ±1D ±4D ±4D ±1D 
±4D 
±3D 
+7D 
±14D  
20 for timing of 
ECGs 
(additional 
ECGs required 
for DDI 
substudy). 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening 
procedures 
should be done 
3 days before 
C1D1. 
Weight 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
X 
 
 
BSA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Calculate by 
Mosteller 
formula  
SpO2 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
X 
 
 
 
Physical Exam 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
X 
 
 
 
ECOG PS 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
X 
 
 
 
ECHO/MUGA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
≤30 days prior 
to first dose 
SAEs 
X 
Continuously 
 
 
AEs 
 
Continuously 
 
 
Prior 
Medications, Non-
Drug Therapies, 
and Radiotherapy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medications, Non-
Drug Therapies, 
and Radiotherapy 
 
Continuously 
 
 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
 
Page 108 of 127 
 
Phase 1 Dose Escalation Schedule of Events 
Procedure 
SCR 
C1 
C2 
C3 
C4 
Cx 
EOT 
30D 
FU 
LT 
FU 
Comment 
Day 
-14 
1 
2 
5 
8 
9 
15 
16 
21 
28 
1 
8 
15 
21 
28 
1 
15 
28 
1 
15 
1 
Window 
 
 
 
±1D ±1D ±1D ±1D ±1D ±1D ±4D ±4D ±1D ±1D ±1
D 
±4D ±4D ±1D ±4D ±4D ±1D 
±4D 
±3D 
+7D 
±14D  
Hematology,  
Coagulation, 
Chemistry 
X 
X 
≥ 3 times weekly 
≥ 2 times weekly 
1-2 times weekly 
X 
 
 
Screening 
procedures 
should be done 
3 days before 
C1D1. 
CBC with 
Differential, 
PLT, Serum 
Creatinine, 
Electrolytes, 
Glucose, Uric 
acid, calcium, 
magnesium, 
BUN  
After C6, less 
frequent at 
guidance of PI 
Hepatic Labs 
X 
X 
≥ 3 times weekly 
≥ 2 times weekly 
1-2 times weekly 
X 
 
 
AST, ALT, Alk 
phos, Total 
Bilirubin 
(fractionated) 
Creatinine Kinase 
X 
X 
Weekly 
≥ 1 per cycle 
X 
 
 
Fractionated if 
>ULN 
Troponin  
X 
 
 
 
 
 
 
Monitor on 
treatment, if 
clinically 
indicated  
Urinalysis 
X 
X 
≥ 1 per cycle 
X 
 
 
Screening 
procedures 
should be done 
3 days before 
C1D1. 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
 
Page 109 of 127 
 
Phase 1 Dose Escalation Schedule of Events 
Procedure 
SCR 
C1 
C2 
C3 
C4 
Cx 
EOT 
30D 
FU 
LT 
FU 
Comment 
Day 
-14 
1 
2 
5 
8 
9 
15 
16 
21 
28 
1 
8 
15 
21 
28 
1 
15 
28 
1 
15 
1 
Window 
 
 
 
±1D ±1D ±1D ±1D ±1D ±1D ±4D ±4D ±1D ±1D ±1
D 
±4D ±4D ±1D ±4D ±4D ±1D 
±4D 
±3D 
+7D 
±14D  
Pregnancy Test 
 
X 
≥ 1 per cycle 
X 
X 
 
For women of 
childbearing 
potential, 
document the 
results of a 
negative urine 
or serum 
pregnancy test 
within 72 hours 
before C1D1 
and monthly 
while on 
treatment.  
Plasma alpha-
MSH  
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X* 
 
 
X* 
X 
 
 
* Once every 3 
cycles 
beginning at 
Cycle 3 
Fasting morning 
ACTH, 
aldosterone, 
renin, and cortisol 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X* 
 
 
X* 
X 
 
 
* Once every 3 
cycles 
beginning at 
Cycle 3 
HIV Ab Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If required by 
local 
regulations; ≤28 
days of first 
dose 
HBsAg, HC Ab 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
≤28 days of 
first dose 
PK 
 
X 
X 
X 
X 
X* 
X 
X* 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
X** 
 
 
 
*For daily 
dosing only 
**Cycles 5 to 8 
only. 
See 
Table 14Table 
14 (BID 
Formatted: C-Hyperlink, Font: 8 pt


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
 
Page 110 of 127 
 
Phase 1 Dose Escalation Schedule of Events 
Procedure 
SCR 
C1 
C2 
C3 
C4 
Cx 
EOT 
30D 
FU 
LT 
FU 
Comment 
Day 
-14 
1 
2 
5 
8 
9 
15 
16 
21 
28 
1 
8 
15 
21 
28 
1 
15 
28 
1 
15 
1 
Window 
 
 
 
±1D ±1D ±1D ±1D ±1D ±1D ±4D ±4D ±1D ±1D ±1
D 
±4D ±4D ±1D ±4D ±4D ±1D 
±4D 
±3D 
+7D 
±14D  
dosing) and 
Table 15Table 
15 (QD dosing) 
for timing of 
sampling, 
Table 19Table 
19  for food-
effect sub-
study, and 
Table 17Table 
17 and 
Table 18Table 
18 for DDI sub-
study. Visit 
windows not 
applicable for 
PK sub-studies. 
Assess Response 
and Relapse  
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X* 
X 
 
 
*Day 28 (±4) of 
each cycle.  
Biomarker/ PD 
Blood Sample 
X 
X 
 
 
X 
 
X 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Dispense  
DS-1594b 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
X 
 
 
 
Continuous 
Dosing Every 
12h (+/- 4h); 
Administer 
morning dose in 
clinic on PK 
days 
Administer 
morning dose of 
DS-1594b at site 
 
X 
X 
X 
X 
X* 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
X** 
 
 
 
*For daily 
dosing only 
** Cycles 5 and 
6 only.  
Additional 
instruction for 
sub-studies: 
Formatted: C-Hyperlink, Font: 8 pt
Formatted: C-Hyperlink, Font: 8 pt
Formatted: C-Hyperlink, Font: 8 pt
Formatted: C-Hyperlink, Font: 8 pt


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
 
Page 111 of 127 
 
Phase 1 Dose Escalation Schedule of Events 
Procedure 
SCR 
C1 
C2 
C3 
C4 
Cx 
EOT 
30D 
FU 
LT 
FU 
Comment 
Day 
-14 
1 
2 
5 
8 
9 
15 
16 
21 
28 
1 
8 
15 
21 
28 
1 
15 
28 
1 
15 
1 
Window 
 
 
 
±1D ±1D ±1D ±1D ±1D ±1D ±4D ±4D ±1D ±1D ±1
D 
±4D ±4D ±1D ±4D ±4D ±1D 
±4D 
±3D 
+7D 
±14D  
For DDI sub-
study, 
administer 
morning dose 
on-site on PK 
days (C1D18, 
C1D19, C2D10, 
C2D11). See 
Table 17Table 
17 and 
Table 18Table 
18. For food 
effect sub-
study, 
administer 
morning dose 
on-site on PK 
days (C1D18, 
C1D19); see 
Table 19Table 
19. 
Collect Returned 
DS-1594b 
Assess 
Compliance 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
X 
 
 
 
Survival FU, 
Subsequent 
Antileukemic 
Treatments & 
Outcomes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Every 3 months 
in LTFU 
Formatted: C-Hyperlink, Font: 8 pt
Formatted: C-Hyperlink, Font: 8 pt
Formatted: C-Hyperlink, Font: 8 pt


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 112 of 127 
 
Table 33: 
Phase 2 Cohorts A & B Schedule of Events 
Phase 2 Cohorts A & B 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Procedure 
SCR 
C1 
C2 
C3 
C4 
Cx 
EOT 30D 
FU 
LT 
FU 
Comment 
 
Day 
-14 
1 
2 
8 
9 
15 
28 
1 
28 
1 
28 
1 
28 
1 
28 
 
 
 
Window 
 
 
±1D ±1D ±1D ±1D ±4D ±4D ±4D ±4D ±4D ±4D ±4D 
±4D 
±4D 
±3D 
+7D 
±14D 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior to study procedures 
Bone Marrow 
Aspirate/Biopsy 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
X* 
X 
 
 
*Day 28 (±4) of Cycles 1, 2, 3, 
6, 9, and EOT 
Confirm NPM1-m or 
MLL-r 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, Medical 
& Disease History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WHO classification, 
cytogenetics, mutations, prior 
therapy 
Vital Signs 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Blood pressure, pulse rate, 
respiratory rate, and temperature 
taken ~5 min prior to ECG 
measurements 
ECG (in triplicate) by 
12-lead or Holter 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X* 
 
X 
 
 
*Cycles 5 and 6 only. 
Triplicate ECGs ≥1 minute 
apart, supine/semi-recumbent.  
Prior to PK. See Section 8.5 and 
Table 21Table 21 for timing of 
ECGs. 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening procedures should be 
done 3 days before C1D1. 
Weight 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
BSA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Calculate by Mosteller formula 
SpO2 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Physical Exam 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Formatted: C-Hyperlink, Font: 8 pt


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 113 of 127 
 
Phase 2 Cohorts A & B 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Procedure 
SCR 
C1 
C2 
C3 
C4 
Cx 
EOT 30D 
FU 
LT 
FU 
Comment 
 
Day 
-14 
1 
2 
8 
9 
15 
28 
1 
28 
1 
28 
1 
28 
1 
28 
 
 
 
Window 
 
 
±1D ±1D ±1D ±1D ±4D ±4D ±4D ±4D ±4D ±4D ±4D 
±4D 
±4D 
±3D 
+7D 
±14D 
ECOG PS 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
ECHO/MUGA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
≤30 days prior to first dose 
SAEs 
X 
Continuously 
 
 
AEs 
 
Continuously 
 
 
Prior Medications, Non-
Drug Therapies, and 
Radiotherapy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medications, Non-Drug 
Therapies, and 
Radiotherapy 
X 
Continuously 
 
 
 
Hematology,  
Coagulation, Chemistry 
X 
X 
≥ 3 times weekly 
≥ 2 times weekly 
1-2 times weekly 
X 
 
 
Screening procedures should be 
done 3 days before C1D1. 
CBC with Differential, PLT, 
Serum Creatinine, Electrolytes, 
Glucose, Uric acid, calcium, 
magnesium, BUN  
After C6, less frequent at 
guidance of PI 
Hepatic Labs 
X 
X 
≥ 3 times weekly 
≥ 2 times weekly 
1-2 times weekly 
X 
 
 
AST, ALT, Alk phos, Total 
Bilirubin (fractionated) 
Creatinine Kinase 
X 
X 
Weekly 
≥ 1 per cycle 
X 
 
 
Fractionated if >ULN 
Troponin  
X 
 
 
 
 
Monitor on treatment, if 
clinically indicated  
Urinalysis 
X 
X 
≥ 1 per cycle 
X 
 
 
Screening procedures should be 
done 3 days before C1D1. 
Pregnancy Test 
X 
≥ 1 per cycle 
X 
X 
 
For women of childbearing 
potential, document the results 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 114 of 127 
 
Phase 2 Cohorts A & B 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Procedure 
SCR 
C1 
C2 
C3 
C4 
Cx 
EOT 30D 
FU 
LT 
FU 
Comment 
 
Day 
-14 
1 
2 
8 
9 
15 
28 
1 
28 
1 
28 
1 
28 
1 
28 
 
 
 
Window 
 
 
±1D ±1D ±1D ±1D ±4D ±4D ±4D ±4D ±4D ±4D ±4D 
±4D 
±4D 
±3D 
+7D 
±14D 
of a negative urine or serum 
pregnancy test within 72 hours 
before C1D1 and monthly while 
on treatment.  
Plasma alpha-MSH  
X 
 
 
 
 
 
X 
 
 
X* 
 
 
X* 
 
X 
 
 
* Once every 3 cycles beginning 
at Cycle 3 
Fasting morning ACTH, 
aldosterone, renin, and 
cortisol 
X 
 
 
 
 
 
X 
 
 
X* 
 
 
X* 
 
X 
 
 
* Once every 3 cycles beginning 
at Cycle 3 
HIV Ab Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If required by local regulations; 
≤28 days of first dose 
HBsAg, HC Ab 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
≤28 days of first dose 
PK 
 
X 
X* 
X 
X* 
X 
 
X 
 
X 
 
X 
 
X** 
 
 
 
 
*For daily dosing only 
**Cycles 5 and 6 only 
See Table 16Table 16  for 
sampling times  
Assess Response and 
Relapse  
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X* 
X 
 
 
*Day 28 (±4) of each cycle. 
Biomarker/ PD Blood 
Sample 
X 
X 
 
X 
 
X 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
Dispense DS-1594b 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Continuous Dosing Every 12h 
(+/- 4h); Administer morning 
dose in clinic on PK days 
Administer morning 
dose of DS-1594b at site 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X* 
 
 
 
 
*Cycles 5 and 6 only 
Collect Returned DS-
1594b,  Assess 
Compliance 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Formatted: C-Hyperlink, Font: 8 pt


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 115 of 127 
 
Phase 2 Cohorts A & B 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Procedure 
SCR 
C1 
C2 
C3 
C4 
Cx 
EOT 30D 
FU 
LT 
FU 
Comment 
 
Day 
-14 
1 
2 
8 
9 
15 
28 
1 
28 
1 
28 
1 
28 
1 
28 
 
 
 
Window 
 
 
±1D ±1D ±1D ±1D ±4D ±4D ±4D ±4D ±4D ±4D ±4D 
±4D 
±4D 
±3D 
+7D 
±14D 
Survival FU, Subsequent 
Anti-leukemic 
Treatments & Outcomes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Every 3 months in LTFU 
 
 
 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 116 of 127 
 
Table 34: 
Phase 2 Cohort C Schedule of Events 
Phase 2 Cohort C 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Procedure 
SCR 
C1 
C2 - C3 
C4 
Cx 
EOT 30D 
FU 
LT 
FU 
Comment 
Day 
-14 
1 
2-7 
8 
9 
15 
21 
28 
1 
2-7 
28 
1 
2-7 
28 
1 
2-7 
28 
 
 
 
Window 
 
 
±1D ±1D ±1D ±1D ±4D ±4D ±4D 
 
±4D ±4D 
 
±4D ±4D 
 
±4D 
±3D +7D ±14D 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior to study procedures 
Bone Marrow 
Aspirate/Biopsy 
X 
 
 
 
 
 
X 
X 
 
 
X 
 
 
 
 
 
X* 
X 
 
 
Adjust venetoclax 
administration per Section 5.4 
based on Cycle 1 Day 21 bone 
marrow evaluation 
*Day 28 (±4) of Cycles 1, 2, 3, 
6, 9, and EOT 
Confirm NPM1-m or 
MLL-r 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, 
Medical History, 
Disease History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WHO classification, 
cytogenetics, mutations, prior 
therapy 
Vital Signs 
X 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Blood pressure, pulse rate, 
respiratory rate, and 
temperature taken ~5 min 
prior to ECG measurements 
ECG (in triplicate) by 
12-lead or Holter 
X 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X* 
 
 
X 
 
 
*Cycles 5 and 6 only 
Triplicate ECGs ≥1 minute 
apart, supine/semi-recumbent.  
Prior to PK 
Section 8.5 and 
Table 21Table 21 for timing 
of ECGs. 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening procedures should 
be done 3 days before C1D1. 
Weight 
X 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Formatted: C-Hyperlink, Font: 8 pt


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 117 of 127 
 
Phase 2 Cohort C 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Procedure 
SCR 
C1 
C2 - C3 
C4 
Cx 
EOT 30D 
FU 
LT 
FU 
Comment 
Day 
-14 
1 
2-7 
8 
9 
15 
21 
28 
1 
2-7 
28 
1 
2-7 
28 
1 
2-7 
28 
 
 
 
Window 
 
 
±1D ±1D ±1D ±1D ±4D ±4D ±4D 
 
±4D ±4D 
 
±4D ±4D 
 
±4D 
±3D +7D ±14D 
BSA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Calculate by Mosteller 
formula  
SpO2 
X 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Physical Exam 
X 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
ECOG PS 
X 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
ECHO/MUGA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
≤30 days prior to first dose 
SAEs 
X 
Continuously 
 
 
AEs 
 
Continuously 
 
 
Prior Medications, 
Non-Drug Therapies, 
and Radiotherapy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medications, Non-
Drug Therapies, and 
Radiotherapy 
X 
Continuously 
 
 
 
Hematology,  
Coagulation, 
Chemistry 
X 
X 
≥ 3 times weekly 
≥ 2 times weekly 
1-2 times weekly 
X 
 
 
Screening procedures should 
be done 3 days before C1D1. 
CBC with Differential, PLT, 
Serum Creatinine, 
Electrolytes, Glucose, Uric 
acid, calcium, magnesium, 
BUN  
After C6, less frequent at 
guidance of PI 
Hepatic Labs 
X 
X 
≥ 3 times weekly 
≥ 2 times weekly 
1-2 times weekly 
X 
 
 
AST, ALT, Alk phos, Total 
Bilirubin (fractionated) 
Creatinine Kinase 
X 
X 
Weekly 
≥ 1 per cycle 
X 
 
 
Fractionated if >ULN 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 118 of 127 
 
Phase 2 Cohort C 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Procedure 
SCR 
C1 
C2 - C3 
C4 
Cx 
EOT 30D 
FU 
LT 
FU 
Comment 
Day 
-14 
1 
2-7 
8 
9 
15 
21 
28 
1 
2-7 
28 
1 
2-7 
28 
1 
2-7 
28 
 
 
 
Window 
 
 
±1D ±1D ±1D ±1D ±4D ±4D ±4D 
 
±4D ±4D 
 
±4D ±4D 
 
±4D 
±3D +7D ±14D 
Troponin  
X 
 
 
 
 
 
Monitor on treatment, if 
clinically indicated  
Urinalysis 
X 
X 
≥ 1 per cycle 
X 
 
 
Screening procedures should 
be done 3 days before C1D1. 
Pregnancy Test 
X 
≥ 1 per cycle 
X 
X 
 
For women of childbearing 
potential, document the results 
of a negative urine or serum 
pregnancy test within 72 hours 
before C1D1 and monthly 
while on treatment.  
Plasma alpha-MSH  
X 
 
 
 
 
 
 
X 
X* 
 
 
 
X* 
X 
 
 
* Once every 3 cycles 
beginning at Cycle 3 (Not 
required in Cycle 2) 
Fasting morning 
ACTH, aldosterone, 
renin, and cortisol 
X 
 
 
 
 
 
 
X 
X* 
 
 
 
X* 
X 
 
 
* Once every 3 cycles 
beginning at Cycle 3 (Not 
required in Cycle 2) 
HIV Ab Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If required by local 
regulations; ≤28 days of first 
dose 
HBsAg, HC Ab 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
≤28 days of first dose 
PK 
 
X X* X 
X* 
X 
 
 
X 
 
 
X 
 
 
X** 
 
 
 
 
 
*For daily dosing only 
**Cycles 5 and 6 only. 
See Table 16Table 16 for 
timing of sampling  
Assess Response and 
Relapse  
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X* 
X 
 
 
*Day 28 (±4) of each cycle. 
Biomarker/ PD Blood 
Sample 
X 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
Dispense  
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
Continuous oral dosing every 
12h (+/- 4h); Administer 
Formatted: C-Hyperlink, Font: 8 pt


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 119 of 127 
 
Phase 2 Cohort C 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Procedure 
SCR 
C1 
C2 - C3 
C4 
Cx 
EOT 30D 
FU 
LT 
FU 
Comment 
Day 
-14 
1 
2-7 
8 
9 
15 
21 
28 
1 
2-7 
28 
1 
2-7 
28 
1 
2-7 
28 
 
 
 
Window 
 
 
±1D ±1D ±1D ±1D ±4D ±4D ±4D 
 
±4D ±4D 
 
±4D ±4D 
 
±4D 
±3D +7D ±14D 
DS-1594b 
morning dose in clinic on PK 
days 
Dispense venetoclax 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
Continuous oral dosing daily; 
schedule adjustments per 
Section 5.4 
Administer azacitidine 
 
Daily* 
 
 
 
 
 
X* 
 
 
X* X* 
 
X* 
X* 
 
 
 
 
*Administer azacitidine SQ or 
IV in clinic on Day 1-7 of 
each cycle; schedule  per 
Section 5.4 
Administer morning 
dose of DS-1594b at 
site 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X* 
 
 
 
 
 
*Cycles 5 and 6 only 
Collect Returned DS-
1594b 
Assess Compliance 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Survival FU, 
Subsequent 
Antileukemic 
Treatments & 
Outcomes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Every 3 months in LTFU 
 
 
 
 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 120 of 127 
 
Table 35: 
Phase 2 Cohort D Schedule of Events 
Phase 2 Cohorts D 
Procedure 
SCR 
C1 
C2 
C3 
C4 
Cx 
Mainte
nance 
C1-C24 
EOT 30D 
FU 
LT 
FU 
Comment 
 
Day 
-14 
1 
2 
5 
8 
9 
15 
21 
28 
1 
8 
15 21 28 
1 
15 
28 
1 
15 
1 
1 
 
 
 
 
Window 
 
 
 
 
 
 
 
 
 
±4D 
 
 
 
 
±4D 
 
 
±4D 
 
±4D 
 
±3D 
+7D 
±14D  
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior to study 
procedures 
Bone Marrow 
Aspirate/Biopsy 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X* 
 
X 
 
 
*Day 28 (±4) of 
Cycles 1, 2, 3, 
6, 9, and EOT 
Eligibility  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, 
Medical History, 
Disease History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WHO diag., 
cytogenetics, 
mutations, prior 
therapy 
Vital Signs 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
X 
 
X 
 
X 
X 
X 
 
 
Blood pressure, 
pulse rate, 
respiratory rate, 
and temperature 
taken ~5 min 
prior to ECG 
measurements 
ECG (in 
triplicate) by 12-
lead or Holter 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
X* 
X 
X 
 
 
*Cycles 5 and 6 
only.  
Triplicate ECGs  
obtained at least 
1 minute apart, 
in a 
supine/semi-
recumbent 
position.  
Obtain prior to 
PK 
Section 8.5 and 
Table 21Table 2
Formatted: C-Hyperlink, Font: 8 pt


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 121 of 127 
 
Phase 2 Cohorts D 
Procedure 
SCR 
C1 
C2 
C3 
C4 
Cx 
Mainte
nance 
C1-C24 
EOT 30D 
FU 
LT 
FU 
Comment 
 
Day 
-14 
1 
2 
5 
8 
9 
15 
21 
28 
1 
8 
15 21 28 
1 
15 
28 
1 
15 
1 
1 
 
 
 
 
Window 
 
 
 
 
 
 
 
 
 
±4D 
 
 
 
 
±4D 
 
 
±4D 
 
±4D 
 
±3D 
+7D 
±14D  
1 for timing of 
ECGs. 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening 
procedures 
should be done 
3 days before 
C1D1. 
Weight 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
X 
X 
 
 
BSA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Calculate by 
Mosteller 
formula  
SpO2 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
X 
X 
 
 
 
Physical Exam 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
X 
X 
 
 
 
ECOG PS 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
X 
X 
 
 
 
ECHO/MUGA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
≤30 days prior 
to first dose 
SAEs 
X 
Continuously 
 
 
Non SAEs 
X 
Continuously 
 
 
Prior Meds, Non-
Drug Therapies, 
and 
Radiotherapy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medications, 
Non-Drug 
Therapies, and 
Radiotherapy 
 
Continuously 
 
 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 122 of 127 
 
Phase 2 Cohorts D 
Procedure 
SCR 
C1 
C2 
C3 
C4 
Cx 
Mainte
nance 
C1-C24 
EOT 30D 
FU 
LT 
FU 
Comment 
 
Day 
-14 
1 
2 
5 
8 
9 
15 
21 
28 
1 
8 
15 21 28 
1 
15 
28 
1 
15 
1 
1 
 
 
 
 
Window 
 
 
 
 
 
 
 
 
 
±4D 
 
 
 
 
±4D 
 
 
±4D 
 
±4D 
 
±3D 
+7D 
±14D  
Hematology,  
Chemistry Tests; 
Coagulation  
X 
X 
≥ 3 times weekly 
≥ 2 times weekly 
1-2 times weekly 
X 
X 
 
 
Screening 
procedures 
should be done 
3 days before 
C1D1. 
CBC with 
Differential, 
PLT, Serum 
Creatinine, 
Electrolytes, 
Glucose, Uric 
acid, calcium, 
magnesium, 
BUN  
After C6, less 
frequent at 
guidance of PI 
Hepatic Labs 
X 
X 
≥ 3 times weekly 
≥ 2 times weekly 
1-2 times weekly ≥ 1 per 
cycle 
X 
 
 
AST, ALT, Alk 
phos, total 
Bilirubin 
(fractionated) 
Creatinine 
Kinase 
X 
X 
Weekly 
≥ 1 per cycle 
≥ 1 per 
cycle 
X 
 
 
Fractionated if 
>ULN 
Troponin  
X 
 
 
 
 
 
 
 
Monitor on 
treatment, if 
clinically 
indicated  
Urinalysis 
X 
X 
≥ 1 per cycle 
≥ 1 per 
cycle 
X 
 
 
Screening 
procedures 
should be done 
3 days before 
C1D1. 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 123 of 127 
 
Phase 2 Cohorts D 
Procedure 
SCR 
C1 
C2 
C3 
C4 
Cx 
Mainte
nance 
C1-C24 
EOT 30D 
FU 
LT 
FU 
Comment 
 
Day 
-14 
1 
2 
5 
8 
9 
15 
21 
28 
1 
8 
15 21 28 
1 
15 
28 
1 
15 
1 
1 
 
 
 
 
Window 
 
 
 
 
 
 
 
 
 
±4D 
 
 
 
 
±4D 
 
 
±4D 
 
±4D 
 
±3D 
+7D 
±14D  
Pregnancy Test 
 
X 
≥ 1 per cycle 
≥ 1 per 
cycle 
X 
 
 
For women of 
childbearing 
potential, 
document the 
results of a 
negative urine 
or serum 
pregnancy test 
within 72 hours 
before C1D1 
and monthly 
while on 
treatment.  
Plasma alpha-
MSH  
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X* 
 
 
X* 
X* 
X 
 
 
* Once every 3 
cycles 
beginning at 
Cycle 3  
Fasting morning 
ACTH, 
aldosterone, 
renin, and 
cortisol 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X* 
 
 
X* 
X* 
X 
 
 
* Once every 3 
cycles 
beginning at 
Cycle 3  
HIV Ab Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
As required by 
local 
regulations, to 
be done within 
28 days prior to 
Enrollment. 
HBsAg, HC Ab 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
To be done 
within 28 days 
prior to 
Enrollment. 
PK 
 
X 
X* 
 
X X* 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
X** 
 
 
 
 
*For daily 
dosing only 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 124 of 127 
 
Phase 2 Cohorts D 
Procedure 
SCR 
C1 
C2 
C3 
C4 
Cx 
Mainte
nance 
C1-C24 
EOT 30D 
FU 
LT 
FU 
Comment 
 
Day 
-14 
1 
2 
5 
8 
9 
15 
21 
28 
1 
8 
15 21 28 
1 
15 
28 
1 
15 
1 
1 
 
 
 
 
Window 
 
 
 
 
 
 
 
 
 
±4D 
 
 
 
 
±4D 
 
 
±4D 
 
±4D 
 
±3D 
+7D 
±14D  
**Cycles 5 and 
6 only. 
See 
Table 16Table 1
6 for timing of 
sampling 
Assess Response 
and Relapse  
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
X 
X 
 
 
 
 
Biomarker/ PD 
Blood Sample 
X 
X 
 
 
X 
 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
TBD after the 
phase I 
Dispense  
DS-1594b 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
X 
 
 
 
Continuous 
Dosing Every 
12h (+/- 4h); 
Administer 
morning dose in 
clinic on PK 
days 
Administer 
morning dose of 
DS-1594b at site 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
X* 
 
 
 
 
*Not required 
after Cycle 6 
Collect Returned 
DS-1594b, Assess 
Compliance 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
X 
X 
 
 
 
Survival FU, 
Subsequent 
Antileukemic 
Treatments & 
Outcomes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Every 3 months 
in LTFU 
 
 
 
Formatted: C-Hyperlink, Font: 8 pt


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 125 of 127 
 
11. 
REFERENCES 
1. Winer ES and Stone RM. Novel therapy in acute myeloid leukemia (AML): moving 
toward targeted approaches. Ther Adv Hematol. 2019;10:1-18. 
2.  Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND, et al. 
Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 
2016;374:2209-21. 
3. Metzeler KH, Herold T, Thurley MR, Amler S, Sauerland MC, Gorlich D, et al. 
Spectrum and prognostic relevance of driver gene mutations in acute myeloid leukemia. 
Blood. 2016;128:686-98. 
4. Estey EH. Treatment of relapsed and refractory acute myelogenous leukemia. Leukemia 
2000;14:476-9. 
5. Ravandi F, Cortes J, Faderl S, et al. Characteristics and outcome of subjects with acute 
myeloid leukemia refractory to 1 cycle of high-dose cytarabine-based induction 
chemotherapy. Blood 2010;116:5818-23. 
6. Stanisic S, Kalaycio M. Treatment of refractory and relapsed acute myelogenous leukemia. 
Expert Rev Anticancer Ther 2002;2:287-95. 
7. Ravandi F, Cortes J, Faderl S, et al. Characteristics and outcome of subjects with acute 
myeloid leukemia refractory to 1 cycle of high-dose cytarabine-based induction 
chemotherapy. Blood 2010;116:5818-23. 
8. Paul S, Kantarjian H, Jabbour EJ. Adult acute lymphoblastic leukemia. Mayo Clin Proc 
2016;91:1645-66 
9. Pui CH, Robinson LL, Look AT. Acute lymphoblastic leukemia. Lancet. 2008;371:1030-
43. 
10. Dimartino JF and Cleary ML. Mll rearrangements in haematological malignancies: 
lessons from clinical and biological studies. Br J Haematol. 1999;106:614-26. 
11. Marschalek R. Mechanisms of leukemogenesis by MLL fusion proteins. Br J Haematol. 
2011;152:141-54. 
12. Meyer C, Burmeister T, Groger D, et al. The MLL recombinome of acute leukemias in 
2017. Leukemia. 2018;32: 273–84. 
13. Kuhn MW, Song E, Feng Z, Sinha A, Chen CW, Deshpande AJ et al. Targeting 
chromatin regulators inhibits leukemogenic gene expression in NPM1 mutant leukemia. 
Cancer Discov. 2016;6:1166-81. 
14. Thiede C, Koch S, Creutzig E, et al. Prevalence and prognostic impact of NPM1 
mutations in 1485 adult subjects with acute myeloid leukemia (AML). Blood. 
2006;107:4011-20. 


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 126 of 127 
 
15.  Dunlap JB, Leonard J, Rosenberg M, et al. The combination of NPM1, DNMT3A, and 
IDH1/2 mutations leads to inferior overall survival in AML. Am J Hematol. 2019; 
94:913-20. 
16. Grembecka J, Belcher AM, Hartley T and Cierpicki T. Molecular basis of the mixed 
lineage leukemia-menin interaction: implications for targeting mixed lineage leukemias. J 
Biol Chem. 2010;285:40690-8. 
17. Yokoyama A, Somervaille TC, Smith KS, et al. The menin tumor suppressor protein is an 
essential oncogenic cofactor for MLL-associated leukemogenesis. Cell. 2005;123:207-18. 
18. Borkin D et al. Pharmacologic inhibition of the Menin-MLL interaction blocks 
progression of MLL leukemia in vivo. Cancer Cell. 2015;27:589-602. 
19. Slany RK. When epigenetics kills: MLL fusion proteins in leukemia. Hematol Oncol. 
2005;23:1-9. 
20. Tomizawa D, Koh K, Sato T, et al. Outcome of risk-based therapy for infant acute 
lymphoblastic leukemia with or without an MLL gene rearrangement, with emphasis on 
late effects: a final report of two consecutive studies, MLL96 and MLL98, of the Japan 
Infant Leukemia Study Group. Leukemia. 2007;21:2258-63. 
21. Jabbour E et al, JAMA Onc 2018 Feb 1;4(2):230-4. 
22. Jabbour E et al, Cancer 2018 Oct 15;124(20):4044-55. 
23. Cheson B et al, J Clin Oncol. 2003 Dec 15;21(24):4642-9. 
24. Dohner H et al, Blood. 2017 Jan 26;129(4):424-47 
25. Arber DA, Orazi A, Hasserjian R, etal. The 2016 revision to the World Health 
Organization classification of myeloid neoplasms and acute leukemia. Blood. 
2016;127(20):2391-2405. 
26. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health 
Organization classification of lymphoid neoplasms.  
27. Thall PF, Simon R, Etsey EH. Bayesian sequential monitoring designs for single-arm 
clinical trials with multiple outcomes. Stat Med 1995;14:357-9. 
28. Perl AE, Martinelli G, Cortes JE, et al. Gilteritinib or Chemotherapy for Relapsed or 
Refractory FLT3-Mutated AML. N Engl J Med. 2019;381(18):1728-40. 
29. DiNardo CD, Stein EM, de Botton S, et al. Durable Remissions with Ivosidenib in IDH1-
Mutated Relapsed or Refractory AML. N Engl J Med. 2018;378(25):2386-98. 
30. Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or 
refractory acute myeloid leukemia. Blood. 2017;130(6):722-31. 
31. Daver N, Wei AH, Pollyea DA, et al. New directions for emerging therapies in acute 
myeloid leukemia: the next chapter. Blood Cancer J. 2020;10(10):107. 
32. Liu M, Wang SJ, Ji Y. The i3+3 design for phase I clinical trials. J Biopharm Stat. 2020 
Mar;30(2):294-304.  


Protocol 2020-0946 
20 Aug 2021 
Version 5.0 
 
Page 127 of 127 
 
33. Zhou H, Murray TA, Pan H, Yuan Y. Comparative review of novel model-assisted 
designs for phase I clinical trials. Stat Med. 2018 Jun 30; 37(14):2208-22. 
34. Liu S and Yuan Y. Bayesian optimal interval designs for phase I clinical trials. Journal of 
the Royal Statistical Society. Series C (Applied Statistics). 2015; 64(3): 507-23. 
35. Yuan Y, Hess KR, Hilsenbeck SG, Gilbert MR. Bayesian Optimal Interval Design: A 
Simple and Well-Performing Design for Phase I Oncology Trials. Clin Cancer Res. 2016; 
22(17): 4291-301. 
36. Montesinos P, Bergua JM, Vellenga E, Rayón C, Parody R, de la Serna J, 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 Jan 22;113(4):775-83. 
37. Norsworthy KJ, Mulkey F, Scott EC, Ward AF, Przepiorka D, Charlab R, et al. 
Differentiation Syndrome with Ivosidenib and Enasidenib Treatment in Patients with 
Relapsed or Refractory IDH-Mutated AML: A U.S. Food and Drug Administration 
Systematic Analysis. Clin Cancer Res. 2020 Aug 15;26(16):4280-8. 
38. Stahl M, Tallman MS. Differentiation syndrome in acute promyelocytic leukaemia. Br J 
Haematol. 2019 Oct;187(2):157-62.