Clinical trial NCT04214860
Conditions: Myeloid Malignancy
Sponsor: Aprea Therapeutics
Start date: 2019-12-13; Completion date: 2022-01-14
Enrollment: 51 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
This clinical trial is a Phase I, open-label, dose-finding and cohort expansion study to determine the safety and preliminary efficacy of APR-246 in combination with venetoclax and azacitidine in patients with myeloid malignancies.

Detailed description:
This study will enroll adult male and female patients of age ≥ 18 years with documented diagnosis of AML, according to WHO classification, and documented TP53 mutation which is not benign or likely benign, who also meet the eligibility requirements of this protocol.

The study will include a safety lead-in dose-finding portion followed by expansion portion. During the safety lead-in portion of the study, two cohorts will independently enroll patients following a 3 + 3 design. Each cohort will enroll up to 6 patients.

The expansion portion will begin once the recommended phase II dose (RP2D) of APR-246 in combination with venetoclax and in combination with venetoclax and azacitidine have been determined in order to assess the antitumor activity of these combinations.

Arms: arm 1: APR-246 4.5 g/day
Interventions: intervention 1: APR-246 intervention 2: Venetoclax intervention 3: Azacitidine
Intervention descriptions: intervention 1: APR-246 4.5 g/day intervention 2: Venetoclax 400 mg once daily intervention 3: Subcutaneous injection, or intravenous infusion

Protocol documents:
Prot_SAP_000.pdf: 
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Phase I Study of APR-246 in Combination with Venetoclax and Azacitidine in 
TP53-Mutant Myeloid Malignancies 
 
Protocol No.: 
A19-11184  
IND No.: 
139738 
 
 
 
Sponsor: 
Aprea Therapeutics, Inc. 
 
 
 
 
Responsible Medical Officer: 
Eyal C. Attar, M.D. 
 
 
Medical Monitor: 
  
 
 
 
 
 
 
Protocol Version: 
5.0 
 
Replaces: 
 
4.0 / 28 September 2020 
Date: 
28 October 2021 
 
 
 
 
 
 
 
CONFIDENTIAL 
 
This document contains strictly confidential information and cannot be disclosed or 
used, unless authorized in writing by Aprea Therapeutics. 
 


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Name: 
 
 
Telephone: 
 
 
 
 
 
 
Address: 
 
 
 
 
 
 
 
 
 
Signature: 
 
 
Date: 
 
 
 
 
 
Sponsor/Representative: 
 
S
 
 
INVESTIGATOR’S STATEMENT 
1. 
I have carefully read this protocol entitled “Phase I Study of APR-246 in Combination with 
Venetoclax and Azacitidine in TP53-Mutant Myeloid Malignancies” and agree that it 
contains all the necessary information required to conduct the study. I agree to conduct 
this study as outlined in the protocol. 
2. 
I understand that this study will not be initiated without approval of the appropriate 
Institutional Review Committee/Independent Ethics Committee (IRB/IEC), and that all 
administrative requirements of the governing body of the Institution will be complied with 
fully. 
3. 
Informed written consent will be obtained from all participants in accordance with 
institutional guidelines, FDA requirements as specified in Title 21 CFR, Part 50, the 
European Union Directive 2001/20/EC and its associated Detailed Guidances, European 
Union GCP Directive 2005/28/EC, the International Counsel for Harmonisation (ICH) 
Guideline for Good Clinical Practice (GCP), Section 4.8, and the terms of the Declaration of 
Helsinki (2013). 
4. 
I will enroll participants who meet the protocol criteria for entry. 
5. 
I understand that my signature on each completed Case Report Form (CRF) indicates that 
I have carefully reviewed the complete set of CRFs and accept full responsibility for the 
contents thereof. 
6. 
I understand that the information presented in this study protocol is confidential, and I 
hereby assure that no information based on the conduct of the study will be released 
without prior consent from the Sponsor unless this requirement is superseded by the 
Food and Drug Administration (FDA), a Competent Authority of the European Union or 
another Regulatory Authority. 
 
Protocol Version 5.0: 28 October 2021 


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TABLE OF CONTENTS 
 
        Page No. 
 
INVESTIGATOR’S STATEMENT .................................................................................................. 2 
TABLE OF CONTENTS ............................................................................................................... 3 
CLINICAL STUDY SYNOPSIS ..................................................................................................... 8 
LIST OF ABBREVIATIONS ........................................................................................................ 19 
1.0 
GENERAL INFORMATION ......................................................................................... 23 
1.1 Protocol Number and Title of the Study ...................................................................... 23 
1.2 Sponsor ........................................................................................................................... 23 
1.3 Monitor ............................................................................................................................ 23 
1.4 Signature Authorization ................................................................................................ 23 
2.0 
BACKGROUND INFORMATION ................................................................................ 24 
2.1 Introduction .................................................................................................................... 24 
2.1.1 Acute Myeloid Leukemia ................................................................................... 24 
2.1.2 TP53 Mutations in Myeloid Malignancies ........................................................ 24 
2.2 APR-246 ........................................................................................................................... 25 
2.3 Venetoclax ....................................................................................................................... 25 
2.4 Azacitidine ....................................................................................................................... 26 
2.5 Combination of Venetoclax with Azacitidine .............................................................. 27 
2.6 APR-246 Preclinical Studies ........................................................................................... 27 
2.6.1 Pharmacology and Mode of Action ................................................................. 27 
2.6.2 Safety Pharmacology......................................................................................... 28 
2.6.3 Pharmacokinetics and Metabolism in Animals .............................................. 29 
2.6.4 Toxicology ........................................................................................................... 30 
2.7 APR-246 Clinical Studies ................................................................................................ 31 
2.7.1 Phase I/II Study in Solid and Hematological Malignancies ........................... 31 
2.7.2 Phase I/II Study in TP53-Mutant Advanced Ovarian Cancer ......................... 31 
2.7.3 Phase I/Ib Study in Refractory Hematologic Malignancies ........................... 32 
2.7.4 Phase Ib/II Study in TP53-Mutant Myeloid Neoplasms ................................. 33 
2.7.5 Phase III Multicenter, Randomized, Open Label Study of APR-246 in 
Combination with Azacitidine ...................................................................................... 33 
2.7.6 APR-246 CNS Safety Overview ......................................................................... 33 
2.7.7 APR-246 Cardiac Safety Overview .................................................................... 33 
2.8 Dose Rationale for APR-246 in Combination with Venetoclax and/or Azacitidine . 35 
2.8.1 APR-246 and Azacitidine ................................................................................... 35 
2.8.2 Venetoclax and Azacitidine ............................................................................... 35 
2.8.3 Venetoclax and APR-246 ................................................................................... 35 
2.8.4 Expansion Cohorts in Front Line AML ............................................................. 36 


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2.9 Potential Risks and Benefits .......................................................................................... 37 
2.9.1 Potential Risks .................................................................................................... 37 
2.9.2 Potential Benefits .............................................................................................. 38 
2.10 Characteristics of a Well-Conducted Trial ................................................................... 38 
2.11 Patient Population ......................................................................................................... 39 
3.0 
TRIAL OBJECTIVES AND PURPOSE ........................................................................... 39 
4.0 
TRIAL DESIGN ............................................................................................................ 40 
4.1 Overview of Trial Design ................................................................................................ 40 
4.2 End of Study .................................................................................................................... 43 
4.3 Drug Products ................................................................................................................. 43 
4.3.1 APR-246 ............................................................................................................... 43 
4.3.2 Venetoclax .......................................................................................................... 43 
4.3.3 Azacitidine .......................................................................................................... 44 
4.4 Duration of Therapy....................................................................................................... 44 
4.5 Trial Discontinuation ...................................................................................................... 45 
4.6 Drug Accountability/Disposition of Clinical Trial Supplies ......................................... 45 
4.7 Registration ..................................................................................................................... 45 
5.0 
SELECTION AND WITHDRAWAL OF PATIENTS ....................................................... 46 
5.1 Inclusion Criteria for Patients in Safety Lead-In Cohorts ........................................... 46 
5.2 Exclusion Criteria for Patients in Safety Lead-In Cohorts .......................................... 46 
5.3 Inclusion Criteria for Patients in Expansion Cohorts ................................................. 47 
5.4 Exclusion Criteria for Patients in Expansion Cohorts ................................................ 47 
5.5 Inclusion of Women, Minorities and Children ............................................................ 48 
5.6 Withdrawal Criteria ........................................................................................................ 48 
5.6.1 Study Treatment Discontinuation ................................................................... 48 
5.6.2 Study Completion .............................................................................................. 49 
5.6.3 Withdrawn Patients ........................................................................................... 49 
5.7 Noncompliance .............................................................................................................. 49 
6.0 
TREATMENT OF PATIENTS ........................................................................................ 49 
6.1 Drug Preparation and Administration ......................................................................... 49 
6.1.1 APR-246 ............................................................................................................... 49 
6.1.2 Venetoclax .......................................................................................................... 50 
6.1.3 Azacitidine .......................................................................................................... 50 
6.1.4 Dose-Limiting Toxicity ....................................................................................... 51 
6.1.5 Recommended Phase II Dose (RP2D) .............................................................. 52 
6.2 Dose Interruptions/Withholding .................................................................................. 52 
6.3 Supportive Management ............................................................................................... 53 
6.3.1 APR-246 ............................................................................................................... 53 
6.3.2 Management of CNS Adverse Events .............................................................. 54 
6.3.3 Management of Nausea and Vomiting ........................................................... 55 
6.3.4 Management of Infusion Reactions ................................................................ 56 


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6.3.5 Management of Infection and/or Infestation Event(s) .................................. 56 
6.3.6 Management of Neutropenia with or without Fever .................................... 57 
6.3.7 APR-246 Dose Modification in the Setting of Moderate Renal Impairment 57 
6.3.8 Venetoclax Dose Adjustments ......................................................................... 57 
6.3.9 Azacitidine Dose Adjustments ......................................................................... 58 
6.3.10 Antifungal Prophylaxis ...................................................................................... 58 
6.4 Concomitant Treatment ................................................................................................ 58 
6.5 Monitoring Patient Compliance .................................................................................... 59 
7.0 
STUDY EVALUATIONS ............................................................................................... 59 
7.1 Schedule of Study Evaluations ...................................................................................... 59 
7.2 Pre-Study Assessments ................................................................................................. 65 
7.2.1 Screening ............................................................................................................ 65 
7.2.2 Cycle 1 ................................................................................................................. 66 
7.2.3 Cycle 2 Day 1 ±3 Day and Onwards (Cycle 3+) ............................................... 68 
7.2.4 End of Odd Numbered Cycles .......................................................................... 70 
7.2.5 End of Even Numbered Cycles ......................................................................... 70 
7.3 End of Treatment Visit ................................................................................................... 70 
7.4 Long-Term Follow-Up .................................................................................................... 70 
8.0 
STUDY ASSESSMENTS ............................................................................................... 71 
8.1 Safety Assessments ....................................................................................................... 71 
8.1.1 Safety Analysis ................................................................................................... 71 
8.1.2 Reporting of Adverse Events ............................................................................ 71 
8.2 Efficacy Assessments ..................................................................................................... 75 
8.2.1 Complete Remission Rate ................................................................................. 75 
8.2.2 Duration of Response ....................................................................................... 75 
8.2.3 Overall Response Rate ...................................................................................... 75 
8.2.4 Overall Survival .................................................................................................. 75 
8.2.5 Stem Cell Transplant ......................................................................................... 75 
8.3 Progression-Free Survival (PFS) .................................................................................... 75 
8.4 Pharmacokinetics ........................................................................................................... 75 
8.5 Electrocardiographic Assessment ................................................................................ 77 
8.6 TP53 Testing .................................................................................................................... 78 
9.0 
STATISTICS ................................................................................................................. 78 
9.1 Sample Size ..................................................................................................................... 78 
9.2 Analysis Populations ...................................................................................................... 79 
9.3 Endpoints ........................................................................................................................ 79 
9.3.1 Primary ............................................................................................................... 79 
9.3.2 Secondary ........................................................................................................... 79 
9.3.3 Exploratory ......................................................................................................... 80 
9.4 Safety ............................................................................................................................... 80 
9.5 Efficacy ............................................................................................................................. 80 
9.6 Pharmacokinetic Analysis.............................................................................................. 81 


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9.7 Exploratory analyses ...................................................................................................... 81 
10.0 
QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES ............................ 82 
10.1 Monitoring of the Study and Regulatory Compliance ................................................ 82 
10.2 Curricula Vitae and Financial Disclosure of Investigators ......................................... 82 
10.3 Protocol Modifications ................................................................................................... 82 
10.4 Publication Policy ........................................................................................................... 82 
11.0 
ETHICAL CONSIDERATIONS ..................................................................................... 83 
11.1 Informed Consent .......................................................................................................... 83 
11.2 Institutional Review Board/Independent Ethics Committee ..................................... 83 
11.3 Patient Privacy ................................................................................................................ 83 
12.0 
DATA HANDLING AND RECORD KEEPING .............................................................. 83 
12.1 Data to be Entered Directly in the Case Report Form................................................ 83 
12.2 Recording of Data .......................................................................................................... 84 
12.3 Study Records ................................................................................................................. 84 
13.0 
REFERENCES .............................................................................................................. 85 
APPENDIX I – Response Criteria Based on Modified Recommendations of the 
International Working Group for Diagnosis, Standardization of Response Criteria, 
Treatment Outcomes, and Reporting Standards in Acute Myeloid Leukemia59 ........... 91 
APPENDIX II - Cockcroft-Gault Equation ............................................................................. 93 
APPENDIX III - ECOG Performance Status ........................................................................... 94 
APPENDIX IV - Acceptable Contraceptive Methods ........................................................... 95 
APPENDIX V - New York Heart Association (NYHA) Classification .................................. 97 
APPENDIX VI - Study Drug Diaries ........................................................................................ 98 
APPENDIX VII - Patient Handout: Prohibited Medications (For Patients Enrolled in 
Cohorts with Venetoclax) ................................................................................................... 100 
APPENDIX VIII - Dose Modifications for Use with CYP3A and P-gp Inhibitors .............. 102 
 
List of In-text Tables 
Table 1. Study Treatment and Prior Therapy by Cohort .............................................................. 8 
Table 2. APR-246 Dose Levels ....................................................................................................... 41 
Table 3. Study Treatment and Prior Therapy by Cohort ............................................................ 41 
Table 4. Management of CNS Adverse Events (Dizziness, Dyskinesia and Ataxia) ................. 55 
Table 5. Medications for Managements of Nausea and Vomiting ............................................ 55 
Table 6. Recommendations for prevention and treatment of cancer-related infections ...... 56 
Table 7: APR-246 Dose Modification in the Setting of Moderate Renal Impairment .............. 57 
Table 8: Study Calendar ................................................................................................................. 60 
Table 9. PK Blood Sampling Timepoints for APR-246 ................................................................. 76 
Table 10. PK Blood Sampling Timepoints for Venetoclax in Cycle 1 ......................................... 76 


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Table 11. PK Blood Sampling Timepoints for Venetoclax in Cycles 2-5 ................................... 77 
Table 12. ECG Assessment Requirements ................................................................................... 77 
Table 13. CYP3A Inhibitors and Inducers 1 ................................................................................. 103 
 
List of In-text Figures 
Figure 1. Dose-Finding Study Design .............................................................................................. 9 
Figure 2. Structure of APR-246 ...................................................................................................... 25 
 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
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CLINICAL STUDY SYNOPSIS 
Title 
Phase I of APR-246 in Combination with Venetoclax and/or Azacitidine in Myeloid 
Malignancies 
Sponsor 
Aprea Therapeutics 
Monitor/Contr
act Research 
Organization 
(CRO) 
 
Number of 
Study Centers 
Multicenter 
Clinical Phase 
I 
Investigational 
Agent 
APR-246 
Study Design 
This clinical trial is a Phase I, open-label, dose-finding and cohort expansion study to 
determine the safety and preliminary efficacy of APR-246 in combination with 
venetoclax and/or azacitidine in patients with myeloid malignancies. The study 
includes a safety lead-in dose-finding portion followed by expansion portion (Table 
1).  
Table 1. Study Treatment and Prior Therapy by Cohort 
Cohort 
Disease 
Study 
Treatment 
Prior Therapy Permitted 
 
 
 
VEN 
HMA 
LDAC 
APR-
246 
SCT 
IC 
Safety Lead-In Cohorts 
Cohort 
1 
F/L AML 
APR-246 + 
VEN 
no 
≥1 prior for 
MDS 
required 
no 
no 
yes for 
MDS 
no 
Cohort 
2 
F/L AML 
APR-246 + 
VEN + AZA 
no 
no 
no 
no 
no 
no 
Expansion Cohorts 
Cohort 
1 
F/L AML 
APR-246 + 
VEN 
no 
yes for 
MDS 
no 
no 
yes for 
MDS 
no 
Cohort 
2 
F/L AML 
APR-246 + 
VEN + AZA 
no 
no 
no 
no 
no 
no 
Cohort 
3 
R/R AML 
APR-246 + 
VEN 
yes 
yes 
yes 
yes for 
MDS 
yes 
yes 
Cohort 
4 
R/R AML 
APR-246 + 
VEN + AZA 
yes 
no 
no 
yes for 
MDS 
yes 
≤1 prior 
Cohort 
5 
F/L AML 
APR-246 + 
AZA 
no 
no 
no 
no 
no 
no 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
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Abbreviations: AZA = azacitidine; F/L = front line; HMA = hypomethylating agent; IC = intensive chemotherapy; 
LDAC = low-dose cytarabine; MDS = myelodysplastic syndrome; R/R = refractory or relapsed; SCT = stem cell 
transplant; VEN = venetoclax  
During the safety lead-in portion of the study, two parallel cohorts will independently 
enroll patients following a 3 + 3 design, as outlined in Figure 1.  
 
 
Figure 1. Dose-Finding Study Design  
Dose-finding study design will be applied to each cohort of the safety lead-in portion 
(Figure 1). Each cohort will enroll up to a maximum of 6 patients. Dose-limiting 
toxicity (DLT) will be assessed after three patients have been enrolled in respective 
cohort and the last enrolled patient has completed the 4-week safety assessment 
period (i.e., one cycle of combination regimen). A patient that discontinues therapy 
during Cycle 1 without DLT is considered evaluable for the purpose of safety only if 
at least 80% of scheduled doses of APR-246 in combination with venetoclax with and 
without azacitidine were administered in the first cycle. At the first dose level of 4.5 
g/day of APR-246, if ≤1 patient out of 3 experiences a DLT, 3 additional patients will 
be enrolled. If ≤1 patient out of 6 experiences DLT, the dose level (4.5 g/day of 
APR-246) will be deemed the recommended Phase II dose (RP2D) for that cohort. If 
≥2 patients out of the total 3 – 6 patients in the cohort experience DLT, the study will 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
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continue enrollment at Dose Level -1 (4.0 g/day of APR-246). If ≤1 patient out of 6 
experiences DLT at this dose level, the dose level (4.0 g/day of APR-246) will be 
deemed the RP2D for that cohort. If ≥2 patients out of the total 3 – 6 patients at that 
dose level experience DLT, the study will continue enrollment at Dose Level -2 (3.5 
g/day of APR-246). If ≤1 patient out of 6 experiences DLT at this dose level, the dose 
level (3.5 g/day of APR-246) will be deemed the RP2D for that cohort. If ≥2 patients 
out of the total 3 – 6 patients at this dose level experience DLT, no additional patients 
will be enrolled at this dose. The trial will be halted, and the Data Review Team (DRT) 
will consider potential future dosing modifications. 
 
The expansion portion will begin once the recommended Phase II dose (RP2D) of 
APR-246 in combination with venetoclax and azacitidine has been determined in 
order to assess the antitumor activity of these combinations. Approximately 70 
patients with TP53-mutant myeloid malignancies will be enrolled in up to five cohorts, 
as outlined in Table 1. 
 
The two Data Review Meetings (DRMs) to assess Safety Lead-in Cohort 2 were held 
on 27 February 2020 (first cohort of 3 patients in Cohort 2) and 26 June 2020 (second 
cohort of 3 patients at Dose Level 1 in Cohort 2). After review of the 6 patients with 
AML treated for at least 1 cycle with the combination of APR-246, venetoclax, and 
azacitidine, it was concluded by the DRT that no DLTs were observed, and that the 
RP2D of APR-246 in this combination is 4.5 g/day.  
 
The two DRMs to assess Safety Lead-in Cohort 1 were held on 17 March 2020 and 7 
August 2020. After review of the 6 patients with AML treated for at least 1 cycle with 
the combination of APR-246 and venetoclax, it was concluded by the DRT that no 
DLTs were observed, and that the RP2D of APR-246 in this combination is 4.5 g/day.  
Study 
Objectives 
Primary objective: To evaluate the safety and tolerability of administration of 
APR-246 in combination with venetoclax and/or azacitidine in patients with 
TP53-mutant myeloid malignancies. 
 
Secondary objectives: 
1. To assess the clinical activity of APR-246 in combination with venetoclax 
and/or azacitidine in patients with myeloid malignancies by determination of 
complete remission (CR) rate. 
2. To assess the clinical activity of APR-246 in combination with venetoclax 
and/or azacitidine in patients with myeloid malignancies by determination of 
CR plus complete remission with incomplete hematologic recovery (CRi) rate.  
3. To assess the clinical activity of APR-246 in combination with venetoclax 
and/or azacitidine in patients with myeloid malignancies by determination of 
CR plus complete remission with partial hematologic recovery (CRh) rate. 
4. To assess the clinical activity of APR-246 in combination with venetoclax 
and/or azacitidine in patients with myeloid malignancies by determination of 
overall response rate (ORR). 
5. To assess the clinical activity of APR-246 in combination with venetoclax 
and/or azacitidine in patients with AML by determination of progression-free 
survival (PFS). 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
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6. To assess the clinical activity of APR-246 in combination with venetoclax 
and/or azacitidine in patients with AML by determination of transition rate to 
hematopoietic stem cell transplant (HSCT). 
7. To assess the clinical activity of APR-246 in combination with venetoclax 
and/or azacitidine in patients with AML by determination of overall survival 
(OS). 
8. To assess clinical activity of APR-246 in combination with venetoclax and/or 
azacitidine in patients with AML by determining the rate of red blood cell 
(RBC) and/or platelet transfusion independence (TI) for at least 56 days. 
9. To determine the pharmacokinetic profile of APR-246 and venetoclax. 
 
Exploratory objectives: 
1. To investigate molecular biomarkers for response prediction and disease 
monitoring in baseline and serial bone marrow or blood samples. 
Study 
Endpoints 
Primary endpoints:  
1. DLTs, classified and graded according to the National Cancer Institute’s 
Common Terminology Criteria for Adverse Events (NCI CTCAE, version 5.0). 
2. Frequency of treatment-emergent adverse events (TEAEs), and serious 
adverse events (SAEs) related to APR-246 in combination with venetoclax 
and/or azacitidine during the trial. 
3. The RP2D of APR-246 (the dose at which <2 out of 6 patients experience 
dose-limiting toxicity during the safety assessment period). 
 
Secondary endpoints: 
1. CR rate, defined as the proportion of patients who achieve CR. 
2. CR + CRi rate, defined as the proportion of patients who achieve CR or CRi. 
3. CR + CRh rate, defined as the proportion of patients who achieve CR or CRh. 
4. Overall response rate (ORR), defined as the proportion of patients achieving 
CR, complete remission with incomplete hematologic recovery (CRi), 
complete remission with incomplete platelet recovery (CRp), partial 
remission (PR) and morphologic leukemia-free state (MLFS) by the IWG 2003 
criteria (APPENDIX I). The complete remission with partial hematologic 
recovery (CRh) rate will also be determined and is defined as bone marrow 
blasts <5%, ANC >0.5 × 109/L and platelets >50 × 109/L. 
5. Overall survival (OS), measured from the date of initiating study treatment to 
the date of death. Patients who have not died by the analysis data cut-off 
date will be censored at their last date of contact. 
6. Rate of red blood cell (RBC) and/or platelet transfusion independence (TI) for 
at least 56 days. 
7. Progression-free survival (PFS), defined from the date of initiating study 
treatment to the date of disease progression or death as a result of any 
cause. 
8. Proportion of patients who transition to HSCT. 
9. Pharmacokinetic parameters: maximum concentration (Cmax), area under 
curve (AUC), Vd and clearance (CL) of APR-246 and time of maximum 
concentration (Tmax), Cmax and AUC of venetoclax. 
 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
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Exploratory endpoints: 
1. Exploratory molecular analyses may include, but are not limited to: TP53 VAF 
by NGS, p53 immunohistochemistry (IHC), mutations in other genes by NGS, 
RNA expression. 
 
Eligibility 
Criteria for 
Patients in 
Safety Lead-In 
Cohorts 
Inclusion Criteria: 
1. Signed informed consent form (ICF) and ability to comply with protocol 
requirements. 
2. Documented diagnosis of initial or relapsed AML according to World Health 
Organization (WHO) classification.  
3. Adequate organ function as defined by the following laboratory values: 
a. Creatinine clearance >30 mL/min (by Cockcroft-Gault method; 
APPENDIX II), 
b. Total serum bilirubin <1.5 × ULN unless due to Gilbert’s syndrome, 
leukemic organ involvement, hemolysis or considered an effect of 
regular blood transfusions, 
c. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
<3 × ULN, unless due to leukemic organ involvement. 
4. Age ≥18 years at the time of signing the ICF. 
5. At least one TP53 mutation which is not benign or likely benign. 
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 
(APPENDIX III). 
7. Projected life expectancy of ≥12 weeks. 
8. Negative serum or urine pregnancy test prior to study treatment initiation in 
female patients of childbearing potential. 
9. Females of childbearing potential and males with female partners of 
childbearing potential must be willing to use an effective form of 
contraception such as latex condom, hormonal birth control, intrauterine 
device or double barrier method (APPENDIX IV) during chemotherapy 
treatment and for at least six months thereafter. 
 
Exclusion Criteria: 
1. Prior treatment for TP53-mutant acute myeloid leukemia (AML) not permitted 
per Table 1. 
2. Known history of human immunodeficiency virus (HIV) or active hepatitis B 
or active hepatitis C infection. 
3. Any of the following cardiac abnormalities: 
a. Myocardial infarction within six months prior to registration; 
b. New York Heart Association Class III or IV (APPENDIX V) heart failure or 
known left ventricular ejection fraction (LVEF) <40%; 
c. A history of familial long QT syndrome; 
d. Symptomatic atrial or ventricular arrhythmias not controlled by 
medications; 
e. QTcF ≥470 msec, unless due to underlying bundle branch block and/or 
pacemaker and with approval of the medical monitor. 
4. Concomitant malignancies for which patients are receiving active therapy at 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
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the time of signing consent. For example, patients with adequately treated 
basal or squamous cell carcinoma of the skin, adequately treated carcinoma 
in situ (e.g. cervix), or breast cancer receiving adjuvant endocrine therapy may 
enroll irrespective of the time of diagnosis with Medical Monitor approval. 
5. Known active CNS involvement from AML. A diagnostic lumbar puncture is 
not required in the absence of suspicion for CNS disease. 
6. Malabsorption syndrome or other condition that precludes enteral route of 
administration. 
7. Pregnancy or lactation. 
8. Active uncontrolled systemic infection (viral, bacterial or fungal). 
Eligibility 
Criteria for 
Patients in 
Expansion 
Cohorts 
Inclusion Criteria: 
1. Signed ICF and ability to comply with protocol requirements. 
2. Newly diagnosed or R/R AML according to WHO classification with permitted 
prior therapy, as per Table 1. For patients with newly diagnosed AML bone 
marrow and/or blood evidence of AML with ≥20% blasts is required. For 
patients with newly diagnosed AML, prior therapy with HMA and/or any 
chemotherapeutic agent for MDS is excluded. 
3. Adequate organ function as defined by the following laboratory values: 
a. Creatinine clearance >30 mL/min (by Cockcroft-Gault method; 
APPENDIX II), 
b. Total serum bilirubin <1.5 × ULN unless due to Gilbert’s syndrome, 
leukemic organ involvement, hemolysis or considered an effect of 
regular blood transfusions, 
c. ALT and AST <3 × ULN, unless due to leukemic organ involvement. 
4. Age ≥18 years at the time of signing the ICF. 
5. At least one TP53 mutation which is not benign or likely benign, based on 
central TP53 testing results. If local TP53 mutation and/or p53 IHC results 
become available before central TP53 mutation results, enrollment may be 
made based on local results with Medical Monitor approval.  
6. ECOG performance status of 0, 1 or 2 (APPENDIX III). 
7. Projected life expectancy of ≥12 weeks. 
8. Negative serum pregnancy test prior to study treatment initiation in female 
patients of childbearing potential. 
9. Females of childbearing potential and males with female partners of 
childbearing potential must be willing to use an effective form of 
contraception such as latex condom, hormonal birth control, intrauterine 
device or double barrier method (APPENDIX IV) during chemotherapy 
treatment and for at least six months thereafter. 
Exclusion Criteria: 
1. Known history of myeloproliferative neoplasm (MPN) (i.e., polycythemia vera, 
essential thrombocythemia and primary myelofibrosis are excluded). 
2. Known history of HIV or active hepatitis B or active hepatitis C infection. 
3. Any of the following cardiac abnormalities: 
a. Myocardial infarction within six months prior to registration, 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
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28 October 2021 
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b. New York Heart Association Class III or IV (APPENDIX V) heart failure 
or known left ventricular ejection fraction (LVEF) <40%, 
c. A history of familial long QT syndrome, 
d. Symptomatic atrial or ventricular arrhythmias not controlled by 
medications, 
e. QTcF ≥470 msec, unless due to underlying bundle branch block 
and/or pacemaker and with approval of the medical monitor. 
4. Concomitant malignancies for which patients are receiving active therapy at 
the time of signing consent. For example, patients with adequately resected 
basal or squamous cell carcinoma of the skin, adequately resected carcinoma 
in situ (e.g. cervix), or breast cancer receiving adjuvant endocrine therapy may 
enroll irrespective of the time of diagnosis with Medical Monitor approval. 
5. Prior 
exposure 
to 
anticancer 
therapies 
including 
chemotherapy, 
radiotherapy or other investigational therapy, including targeted small 
molecule agents within 14 days of the first day of study treatment or within 
5 half-lives prior to first dose of study treatment. 
6. Prior exposure to biologic agents (e.g. monoclonal antibodies) for 
anti-neoplastic intent within 14 days prior to first dose of study drug. 
7. Known active CNS involvement from AML. A diagnostic lumbar puncture is 
not required in the absence of suspicion for CNS disease. 
8. Malabsorption syndrome or other condition that precludes enteral route of 
administration. 
9. Pregnancy or lactation.  
10. Active uncontrolled systemic infection (viral, bacterial or fungal). 
Treatment 
Plan 
Treatment may be administered on an outpatient basis. No investigational or 
commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's disease. Hydroxyurea may be used 
for control of leukocytosis. 
The study includes a safety lead-in dose-finding portion followed by the expansion 
portion, as outlined in Table 1. During the safety lead-in portion of the study, two 
cohorts will independently enroll patients following a 3 + 3 design.  
• 
Safety lead-in cohort 1 will enroll patients with TP53-mutant AML, who have 
received at least one prior HMA regimen for MDS. These patients will receive 
APR-246 at 4.5 g/day on days 1–4 of each 28-day cycle administered 
concurrently with venetoclax given orally at the dose of 400 mg daily. 
• 
Safety lead-in cohort 2 will enroll patients with previously untreated 
TP53-mutant AML. These patients will receive APR-246 at 4.5 g/day on days 
1–4 administered concurrently with venetoclax given orally at the dose of 400 
mg daily and with azacitidine at the standard dose of 75 mg/m2 over 7 
consecutive days as a subcutaneous injection or IV infusion, on days 1–7 of 
each 28-day cycle. 
 
Each cohort will enroll up to 6 patients. For dose-finding strategy please consult Study 
Design section of the Clinical Study Synopsis. 
 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
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The expansion portion will begin once the RP2D of APR-246 in combination with 
venetoclax and/or azacitidine has been determined in order to assess the antitumor 
activity of these combinations. Approximately 70 patients with TP53-mutant myeloid 
malignancies will be enrolled in up to five cohorts, as outlined in Table 1. 
 
In each portion, patients may continue treatment as long as toxicity remains 
acceptable and the patient has not withdrawn consent. Response will be assessed 
based on the International Working Group (IWG) AML response criteria (APPENDIX I) 
after every treatment cycle the first year, then every two cycles. 
Duration of 
Follow-Up  
 
Patients will be followed as per the Study Calendar. After a patient is removed or 
withdrawn from study treatment, the patient will be followed until death or 
withdrawal of consent for study participation.  
Off-treatment data on overall survival will be updated every month (i.e. every 28 days 
±3 days) or until death or withdrawal of consent for study participation, whichever 
occurs first. If a patient is removed from the study due to unacceptable adverse 
events (AEs), the event(s) will be followed until resolution or stabilization of the 
adverse event. Patients who respond and discontinue study treatment for reasons 
other than PD should have response assessments and survival should be collected 
every month until relapse, death or withdrawal of consent for study participation, 
whichever occurs first. After relapse, data for survival should be collected every 
month (i.e. every 28 days ±3 days) until death or withdrawal of consent for study 
participation, whichever occurs first. 
Criteria for Removal from Study Treatment 
Study treatment can continue for patients receiving clinical benefit, unless one or 
more withdrawal criteria are met, or at the patient’s discretion, or if the study is 
terminated.  
1. Study Treatment Discontinuation 
Study treatment must be discontinued if: 
• 
Evidence of disease progression. Patients who have relapsed or progressive 
disease but who are continuing to derive clinical benefit in the opinion of the 
investigator may continue to receive study treatment. 
• 
A patient becomes pregnant. 
• 
A patient is significantly non-compliant with the requirements of the 
protocol.  
• 
A patient has an adverse experience that would, in the Investigator’s 
judgment, make continued participation in the study an unacceptable risk. 
• 
The patient starts new treatment for their underlying disease. 
2. Patient Withdrawal from Study Treatment 
If the patient is permanently withdrawn from study treatment, but does not 
withdraw consent from the Study, the Investigator must make every effort to have 
the patient complete all withdrawal assessments at the time of withdrawal and 
complete all scheduled follow-up visits. 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
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3. Study Completion 
Patient must be taken off the study if: 
• 
The patient dies during the study. 
• 
The patient is lost to follow-up. 
• 
The patient withdraws consent. 
4. Patient Withdrawal from Study 
A patient may voluntarily withdraw from study treatment or withdraw consent from 
the study at any time. The investigator may also, at his or her discretion, discontinue 
a patient from participating in the Study Treatment at any time. The Investigator 
and/or designated staff will record the date and the reason for patient withdrawal 
from the study treatment and/or study participation, as applicable. 
Statistics 
This is a Phase I, open-label, dose-finding and cohort expansion study to determine 
the safety and preliminary efficacy of APR-246 in combination with venetoclax and/or 
azacitidine in patients with AML. 
The RP2D of APR-246 will be defined as the dose at which <2 out of 6 patients 
experience DLT during the 4-week safety assessment period after administration of 
APR-246 in combination with venetoclax and/or azacitidine. 
Definition of Dose-Limiting Toxicity (DLT) 
An event will be considered a DLT per NCI CTCAE version 5.0 criteria if it occurs within 
the 4-week safety assessment period (Cycle 1 of study treatment) and is not 
attributable to the underlying disease. DLT is defined as: 
 
• 
Absolute neutrophil count (ANC) not recovering to >0.5 × 109/L and/or 
platelets not recovering to >25 × 109/L by day 42 of study treatment in the 
absence of active leukemia or myelodysplasia; 
• 
Grade ≥ 3 nausea/vomiting/diarrhea or CNS toxicity that does not resolve to 
Grade ≤ 1 within 7 days despite treatment interruption and/or maximal 
medical therapy; 
• 
Treatment-related non-hematological Grade ≥ 3 toxicity that does not 
resolve to Grade ≤ 1.  
 
A DLT will be considered related to the study treatment unless there is a clear, 
alternative explanation for the AE. A ≥ Grade 3 metabolic or electrolyte abnormalities 
that is not clinically significant and is adequately controlled within 72 hours is not to 
be considered DLT. Tumor lysis syndrome (TLS) that responds to therapy and 
resolves within 72 hours is not considered DLT. 
 
Additionally, AEs that meet the above criteria, but occur after the DLT evaluation 
period will not be defined as DLTs, but will be reported as AEs/Serious Adverse Events 
(SAEs) and will be reviewed across all cohorts during the study to help determine the 
AE profile. A patient that discontinues therapy during Cycle 1 without DLT is 
considered evaluable for the purpose of safety only if at least 80% of scheduled Cycle 
1 dose of APR-246 in combination with venetoclax and/or azacitidine were 
administered in the first cycle. 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
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Confidential - Entire Page 
 
DRT consisting of the Medical Monitor, Site Principal Investigators, and other clinical 
research personnel that the Sponsor may deem appropriate, will hold DRM on an 
interim basis at a frequency dependent on study accrual. At these meetings, the DRT 
will review AEs and DLT and make recommendations regarding the RP2D. In the 
expansion portion of the study, the DRT will evaluate safety and tolerability after 5 
patients have completed 1 cycle of treatment in each cohort. All accumulated safety 
data will be discussed during DRMs. 
 
Determination of Sample Size 
This trial assumes a sample size of 12 – 36 patients (6 – 18 patients for each cohort) 
in the safety lead-in portion of the study and approximately 70 patients in the 
expansion portion of the study. 
Analysis Populations 
 
Safety population: Patients will be evaluable for safety if they receive at least one 
dose of APR-246 with venetoclax and/or azacitidine. The safety population will be 
used to summarize exposure and safety parameters. 
DLT-evaluable population: All patients who either experienced a DLT during first the 
4 weeks (Cycle 1) of the study treatment or received ≥80% of scheduled Cycle 1 dose 
of APR-246 in combination with venetoclax and/or azacitidine and did not experience 
a DLT. Any individual patient who is not evaluable for DLT will be replaced by a new 
patient through additional patient enrollment. 
Efficacy evaluable (EE) population: All patients who complete at least one treatment 
cycle of APR-246 in combination with venetoclax and/or azacitidine and who have at 
least one post-treatment clinical response assessment. Patients who fail to complete 
one treatment cycle will also be considered EE if they show clear evidence of clinically 
significant disease progression. The EE population will be the secondary analysis 
population for efficacy. 
Pharmacokinetics (PK) population: Patients will be evaluable for pharmacokinetics if 
at least one post-dose sample for PK evaluation has been obtained. 
Efficacy Analyses 
CR will be summarized for all enrolled patients as the proportion (%) of patients with 
CR. In addition to presenting the CR rate, its associated exact 95% confidence 
intervals (CI) for each treatment arm will also be presented. CR rate will not be 
formally compared between treatment arms. 
CR + CRh rate will be summarized as the proportion of patients who achieve CR or 
CRh. CRh is defined as bone marrow blasts <5%, ANC >0.5 × 109/L and platelets >50 
× 109/L. CR + CRi rate will be summarized as the proportion of patients who achieve 
CR or CRi. The rate of TI will be summarized as the proportion of patients with RBC 
and/or platelet TI for at least 56 days. 
Duration of response (DoR) is defined as the time from the date when criteria for 
response are met to the date of relapse or progressive disease (PD) or death due to 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
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any cause, whichever occurs first. Patients alive with no progressive disease will have 
their DOR censored at the date of the last clinical assessment. The duration of CR will 
be summarized in each treatment arm by providing duration of complete response 
(DOCR) and duration of overall response (DOR), using Kaplan-Meier methodology. 
DoR endpoints will not be formally compared between treatment arms.  
Overall response will be summarized in number (%) of patients in each category of 
responses and ORR will be analyzed by using the similar method as CR rate.  
Survival data are collected at treatment and follow-up periods. Patients will be 
followed until death or withdrawal of consent for study participation. Overall survival 
(OS) is defined as the number of days from the first day of treatment to the date of 
death. Kaplan-Meier methodology will be utilized. 
Progression-free survival (PFS) is defined as the time from the first day of treatment 
to disease progression or death from AML, whichever occurs first. If neither event 
occurs, PFS will be censored at the date of the last clinical assessment. Kaplan-Meier 
methodology will be utilized. 
Safety Analyses 
Safety data including AEs, vital signs, laboratory data, electrocardiogram (ECG), 
physical exam will be tabulated for the safety population. AEs will be tabulated by 
System Organ Class (SOC), preferred term, severity, and relationship to treatments. 
The tabulation of laboratory parameters will include the normal ranges for each 
parameter. Each value will be classified as falling above, below, or within the normal 
range. Laboratory parameters will also be tabulated by maximum NCI CTCAE v5.0 
severity grade. 
Pharmacokinetic Analysis 
PK sampling for APR-246 are performed in Cycle 1, on Days 1, 2 and 4, and on Day 4 
of every subsequent cycle.  
PK sampling for venetoclax is performed on Days 1, 2, 22 and 23 of Cycle 1 and on 
Day 4 of Cycles 2 – 5. 
Non-compartmental or population pharmacokinetic methods will be used to derive 
APR-246 and venetoclax PK parameters (Cmax, Tmax, AUC, Vd and CL). 
The pharmacokinetics of APR-246 and venetoclax will be summarized using 
descriptive statistics (mean, standard deviation, CV% mean, geometric mean, CV% 
geometric mean) and compared with historical control data. 
APR-246 AUC and Cmax will then be tested for association with signs of efficacy and 
safety. If an observable trend exists, a PK/PD model will be developed to evaluate the 
exposure-response relationship between APR-246 plasma exposure and outcome 
measures in the presence of venetoclax. Demographic and clinical data (ethnicity, 
current age, body weight, sex, disease status, etc.) will be utilized to assess 
interpatient variability in the PK and PK/PD relationships. 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
 
 
AE 
Adverse Event 
 
 
ALT 
Alanine Aminotransferase 
 
 
AML 
Acute Myeloid Leukemia 
 
 
ANC 
Absolute Neutrophil Count 
 
 
AST 
Aspartate Aminotransferase 
 
 
AUC 
Area Under Curve 
 
 
BUN 
Blood Urea Nitrogen 
 
 
CHF 
Congestive Heart Failure 
 
 
CI 
Confidence Interval 
 
 
Cmax 
Maximum Concentration 
 
 
CR  
Complete Remission 
 
 
CRF 
Case Report Form 
 
CRh 
 
Complete Remission with Partial Hematologic Recovery 
CRO 
Contract Research Organization 
 
 
CRp  
Complete Remission with Incomplete Platelet Recovery 
 
 
DLT 
Dose-Limiting Toxicity 
 
 
DOCR 
Duration of Complete Response 
 
 
DOR 
Duration of Overall Response 
 
 
DoR 
Duration of Response 
 
 
DRM 
Data Review Meeting 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
20 of 103 
28 October 2021 
Confidential - Entire Page 
 
 
DRT 
Data Review Team 
 
 
EC 
European Commission 
 
 
ECG 
Electrocardiogram 
 
 
ECOG 
Eastern Cooperative Oncology Group 
 
 
EDTA 
Ethylenediaminetetraacetic Acid 
 
 
EMD 
Extramedullary Disease 
 
 
EOI 
End of Infusion 
 
 
FDA 
Food and Drug Administration 
 
 
GCP 
Good Clinical Practice Guidelines 
 
 
HIV 
Human Immunodeficiency Virus 
 
 
HSCT 
Hematopoietic Stem Cell Transplantation 
 
 
HMA 
Hypomethylating Agent 
 
 
ICF 
Informed Consent Form 
 
 
ICH 
International Council for Harmonisation 
 
 
IEC 
Institutional Ethics Committee 
 
 
IHC 
Immunohistochemistry 
 
 
IMP 
Investigational Medicinal Product 
 
 
IPCW 
Inverse Probability of Censoring Weights 
 
 
IRB 
Institutional Review Board 
 
 
IV 
Intravenous 
 
 
IWG 
International Working Group 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
21 of 103 
28 October 2021 
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LBM 
Lean Body Mass 
 
 
LVEF 
Left Ventricular Ejection Fraction 
 
 
µg 
 
MDS 
Microgram 
 
Myelodysplastic Syndrome 
 
 
MLFS 
Morphologic Leukemia-Free State 
 
 
MTD 
Maximum Tolerated Dose 
 
 
NCI CTCAE 
National Cancer Institute – Common Terminology Criteria for 
Adverse Events 
 
 
NGS 
Next-Generation Sequencing 
 
 
OS 
Overall Survival 
 
 
ORR 
Overall Response Rate 
 
 
PFS 
Progression-Free Survival 
 
 
PK 
Pharmacokinetic(s) 
 
 
PLD 
Pegylated Liposomal Doxorubicin 
 
 
PR 
Partial Remission 
 
 
QTcF 
Corrected QT Interval by Fridericia’s formula 
 
 
RA 
Refractory Anemia 
 
 
RAEB 
Refractory Anemia with Excess Blasts 
 
 
RAEB-T 
Refractory Anemia with Excess Blasts in Transformation 
 
 
RP2D 
Recommended Phase II Dose 
 
 
SAE 
Serious Adverse Event 
 
 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
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SAR 
Suspected Adverse Reaction 
 
 
SCT 
Stem Cell Transplantation 
 
 
SOC 
System Organ Class 
 
 
TEAE 
Treatment-Emergent Adverse Event 
 
 
TI 
Transfusion Independence 
 
 
tid 
Three Times Daily (Ter in Die) 
 
 
TLS 
Tumor Lysis Syndrome 
 
 
TrxR1 
Thioredoxin Reductase 1 
 
 
ULN 
Upper Limit of Normal 
 
 
USPI 
US Prescribing Information 
 
 
VAF 
Variant Allele Frequency 
 
 
Vd 
Volume of Distribution 
 
 
WHO 
World Health Organization 
 
 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
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1.0 GENERAL INFORMATION 
1.1 
Protocol Number and Title of the Study 
Protocol No. A19-11184  
Protocol Title: A Phase I Study to Evaluate Safety and Tolerability of APR-246 in Combination 
with Venetoclax and Azacitidine in Patients with Myeloid Malignancies 
 
1.2 
Sponsor 
Aprea Therapeutics, Inc. 
 
 
 
1.3 
Monitor 
  
 
 
 
 
 
1.4 
Signature Authorization 
The protocol will be signed by Aprea Therapeutics, Inc. 
 
 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
24 of 103 
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2.0 BACKGROUND INFORMATION 
2.1 
Introduction 
2.1.1 Acute Myeloid Leukemia 
AML is a group of hematopoietic neoplasms characterized by a clonal proliferation of 
myeloid precursors with a reduced capacity to differentiate into mature cells. AML is the 
most common type of acute leukemia in adults, with an incidence of over 20,000 cases per 
year in the United States1–4.  
 
Cytogenetic and mutation testing remain critical prognostic tools to assess prognosis and 
plan induction and post-remission treatment strategies5. Testing peripheral blood and bone 
marrow samples using next generation sequencing (NGS) has developed into a standard of 
care for determining molecular mutations. Mutations in the tumor suppressor gene TP53 are 
found in approximately 20% of patients with AML and are associated with an adverse 
prognosis. In addition, approximately 80% of patients with TP53-mutant AML have a complex 
karyotype, which also confers an adverse prognosis6. 
 
Despite increased understanding of the biology and development of new therapeutic 
targets, AML treatment remains relatively unchanged, with therapies limited to intensive 
chemotherapy comprised of cytarabine and anthracycline and non-intensive therapies 
consisting of a HMA, sometimes incorporating the BCL-2 inhibitor venetoclax. Allogeneic 
stem cell transplantation is recommended for patients with high risk and relapsed or 
refractory (R/R) AML who achieve a suitable response and are eligible for SCT. 
 
Non-intensive therapies are utilized to treat patients who are considered ineligible for 
intensive chemotherapy on the basis of advanced age, comorbidities, and low likelihood of 
achieving a response based on adverse cytogenetic/molecular features and/or a history of 
an antecedent hematologic disorder. Non-intensive therapies consist of the HMAs decitabine 
and azacitidine and low-dose cytarabine (LDAC)7–10. Both agents have activity in AML as initial 
induction therapy and in the relapsed setting8,9,11. Recently, HMAs12 and LDAC13 have been 
combined with venetoclax in the initial treatment of AML. In addition, HMAs have been 
combined with venetoclax to treat patients with R/R AML14.  
 
2.1.2 TP53 Mutations in Myeloid Malignancies 
TP53 is a tumor suppressor protein that plays a pivotal role in maintaining genomic stability 
in response to DNA damage. It is mutated in over half of human cancers15,16, and such 
mutations represent an important mechanism of resistance to DNA-damaging 
chemotherapeutic agents17,18. A significant proportion of mutations recurrently target 
‘hot-spot’ codons. They either directly disrupt the DNA-binding domain of TP53 or cause 
conformational changes of the TP53 protein, thus leading to severely impaired TP53 function. 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
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28 October 2021 
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Mutated TP53 is predominantly observed in therapy-related AML19,20 and/or in patients with 
complex karyotype (70-80%)21. The reported frequency of TP53 mutations is 5-10% in de-novo 
AML22–24. It has been demonstrated that gain of function mutations in hot spot regions can 
promote a more aggressive AML25–28. In multivariate analysis, the presence of TP53 mutations 
predicted for poor overall survival and inferior response to treatment27,29–32. 
 
In a retrospective analysis of 55 patients who received azacitidine therapy for first line 
treatment of TP53-mutant AML, the CR + CRi rate was 21.8%33. Though the remission rate 
was not significantly different from patients with wild type TP53, the median survival was 
significantly shorter (7.9 vs 12.6 months, p<.001) for patients with TP53 mutations. A similar 
median OS of 7.9 months was observed in patients with TP53-mutant AML who received 
initial therapy with azacitidine34. Regarding patients with TP53 mutations who received 
venetoclax with HMAs, the CR/CRi rate was 47%12. In 10 patients who received venetoclax 
with LDAC, there were no CRs and 3 patients achieved CRi13. Responses in later lines are even 
poorer14. 
 
Together, these data highlight the poor outcomes of TP53-mutant patients, even with 
recently approved venetoclax-containing therapies, and the important need for the 
development of novel therapeutic strategies, particularly in this patient population. 
 
2.2 
APR-246 
 
 
 
 
 
 
  
 
 
2.3 
Venetoclax 
Venetoclax is a BCL-2 inhibitor that approved by the U.S. FDA for use in combination with 
HMAs for the treatment of patients with newly diagnosed AML who are 75 years or older or 
who have comorbidities that preclude use of intensive induction chemotherapy. Accelerated 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
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approval was granted based on the results of the Phase Ib study with HMAs for patients 65 
years or older with treatment-naïve AML, ineligible for intensive chemotherapy by age or 
comorbidities35. Sixty-seven percent of patients in the study achieved CR or CR with 
incomplete count recovery (CRi). The median DoR was 11.3 months, and median overall 
survival was 17.5 months in all patients. It was shown that treatment with venetoclax in 
combination with an HMA leads to a decrease in oxidative phosphorylation via disruption of 
electron transport chain in a glutathione-dependent fashion and selective targeting of the 
leukemia stem cell population36.  
 
Per venetoclax US Prescribing Information (USPI)37 dated May 2020, the most common 
adverse reactions (≥30%) of any grade in AML patients receiving venetoclax in combination 
with azacitidine are nausea, diarrhea, constipation, neutropenia, thrombocytopenia, 
hemorrhage, peripheral edema, vomiting, fatigue, febrile neutropenia, rash, and anemia. 
Serious adverse reactions were reported in 75% of AML patients receiving venetoclax in 
combination with azacitidine, with the most frequent serious adverse reactions in ≥5% of 
patients being febrile neutropenia, pneumonia (excluding fungal), sepsis (excluding fungal), 
respiratory failure, and multiple organ dysfunction syndrome. 
 
Following multiple doses under fed conditions, maximum plasma concentration of 
venetoclax are reached 5–8 hours after dose. It is recommended that venetoclax be 
administered with a meal as food increases the absorption after oral administration. 
Venetoclax is cleared from systemic circulation via hepatic elimination. The terminal 
elimination half-life is approximately 26 hours. The pharmacokinetics of venetoclax do not 
change over time. Venetoclax is predominantly metabolized by CYP3A4/5. CYP3A4 inhibitors 
and inducers as well as P-gp inhibitors cause clinically relevant drug-drug interactions with 
venetoclax. For the same reason certain food must be avoided: grapefruit, grapefruit juice, 
Seville oranges (often used in marmalades), starfruit (CYP3A inhibiting), and St John’s wort 
(CYP3A inducing). Based on their metabolic profiles, a pharmacokinetic drug-drug interaction 
of venetoclax with APR-246 is considered unlikely. 
 
2.4 
Azacitidine 
Azacitidine is a nucleoside metabolic inhibitor indicated by the U.S. FDA for the treatment of 
patients with the following French-American-British (FAB) MDS subtypes: refractory anemia 
(RA) or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or 
thrombocytopenia or requiring transfusions), refractory anemia with excess blasts (RAEB), 
refractory anemia with excess blasts in transformation (RAEB-T), and chronic 
myelomonocytic leukemia (CMML).  
 
In 2008, azacitidine was approved by the European Medicines Agency (EMA) for the 
treatment of AML patients with 20–30% bone marrow blasts, older than 64 years and who 
are ineligible for HSCT. EMA approval of azacitidine was expanded on 30 October 2015 to 
include AML patients with >30% bone marrow blasts. 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
27 of 103 
28 October 2021 
Confidential - Entire Page 
 
The recommended starting dose for the first treatment cycle, for all patients regardless of 
baseline hematology laboratory values, is 75 mg/m2 subcutaneously or intravenously, daily 
for 7 days. Cycles should be repeated every 28 days. Treatment may be continued as long as 
the patient derives clinical benefit.   
 
Azacitidine is rapidly absorbed after subcutaneous or IV administration with a Vd of 76 ± 26 
L and a half-life of 41 ± 8 minutes. Cmax is reached after about 30 minutes. Azacitidine and its 
metabolites are known to be substantially excreted by the kidney, and the risk of adverse 
reactions to this drug may be greater in patients with impaired renal function. Urinary 
excretion is the primary route of elimination; the cumulated urinary excretion is 85% of 
radioactive dose with less than 1% recovered in feces over 3 days. 
 
Azacitidine undergoes spontaneous hydrolysis in aqueous solution and is deaminated by 
cytidine deamidases, whereas APR-246 is glucuronidated. Drug-drug interaction is not likely 
although both compounds and their degradation products and metabolites are primarily 
eliminated by urinary excretion. The pharmacokinetic interaction between APR-246 and 
azacitidine will be investigated in an ongoing parallel trial.  
2.5 
Combination of Venetoclax with Azacitidine 
Venetoclax has demonstrated synergistic activity in combination with azacitidine in 
preclinical models38. This relationship was supported by clinical data from a large, 
multicenter, Phase Ib study (NCT02203773) in elderly patients with treatment-naive AML, 
ineligible for intensive chemotherapy12. Promising efficacy and a tolerable safety profile of 
this novel combination, with a high CR + CRi rate of 73% in the 400-mg venetoclax in 
combination with HMA (azacitidine or decitabine) cohort (P=0.35), low early mortality rates, 
and OS extending beyond 17 months. The median duration of CR + CRi for the venetoclax 
400 mg in combination with HMA was 12.5 months (95% CI). Patients with TP53 mutations 
achieved a CR/CRi rate of 47%22,39. Importantly, the best response of CR + CRi has been 
attained at median of 1.8 months compared with 3.5 months with azacitidine alone40. 
Response rates were similar between the azacitidine and decitabine cohorts (76% vs 71%, 
respectively). A Phase III, randomized, double-blind, placebo-controlled study of venetoclax 
400 mg combined with azacitidine in treatment-naïve elderly and adult patients with AML 
ineligible for standard induction therapy is currently underway (NCT02993523) and aims to 
evaluate the potential impact of venetoclax with azacitidine compared to azacitidine alone 
 
 
2.6 
APR-246 Preclinical Studies 
2.6.1 Pharmacology and Mode of Action 
 
 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
28 of 103 
28 October 2021 
Confidential - Entire Page 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
2.6.3 Pharmacokinetics and Metabolism in Animals 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
31 of 103 
28 October 2021 
Confidential - Entire Page 
 
2.7 
APR-246 Clinical Studies 
 
 
  
 
2.7.1 Phase I/II Study in Solid and Hematological Malignancies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
  
 
2.7.2 Phase I/II Study in TP53-Mutant Advanced Ovarian Cancer 
 
 
 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
32 of 103 
28 October 2021 
Confidential - Entire Page 
 
 
 
 
 
 
2.7.3 Phase I/Ib Study in Refractory Hematologic Malignancies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
33 of 103 
28 October 2021 
Confidential - Entire Page 
 
 
 
 
 
  
 
 
 
2.7.5 Phase III Multicenter, Randomized, Open Label Study of APR-246 in Combination 
with Azacitidine 
 
 
 
 
 
 
 
   
 
 
 
 
 
2.7.6 APR-246 CNS Safety Overview 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
  
 
 
 
 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
34 of 103 
28 October 2021 
Confidential - Entire Page 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
35 of 103 
28 October 2021 
Confidential - Entire Page 
2.8 
Dose Rationale for APR-246 in Combination with Venetoclax and/or Azacitidine  
 
 
 
 
 
 
 
 
 
2.8.1 APR-246 and Azacitidine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.8.2 Venetoclax and Azacitidine 
The doses of venetoclax and azacitidine for patients receiving doublet therapy (APR-246 and 
venetoclax) or triplet therapy (APR-246, venetoclax and azacitidine) are consistent with the 
doses recommended in the venetoclax USPI48 for patients with AML. 
 
2.8.3 Venetoclax and APR-246 
 
 
 
 
 
 
 
 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
36 of 103 
28 October 2021 
Confidential - Entire Page 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.8.4 Expansion Cohorts in Front Line AML 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
38 of 103 
28 October 2021 
Confidential - Entire Page 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.9.2 Potential Benefits 
Patients with TP53-mutant myeloid malignancies, including AML, have a poor prognosis and 
unmet medical need. Azacitidine and venetoclax represent standard of care agents for 
TP53-mutant AML. APR-246 in combination with azacitidine has demonstrated compelling 
clinical efficacy and a manageable safety profile in patients with TP53-mutant MDS/AML, and 
APR-246 has demonstrated in vitro synergy with azacitidine and venetoclax. The purpose of 
this clinical trial is to define the safety and tolerability of APR-246 in combination with 
venetoclax and/or azacitidine in patients with TP53-mutant AML and to determine 
preliminary efficacy. Given that TP53-mutant MDS and AML patients have a limited life 
expectancy and lack of effective treatments, the benefit/risk assessment supports the use of 
APR-246 in this trial. 
 
2.10 Characteristics of a Well-Conducted Trial 
The following characteristics of an adequate and well-conducted trial will be implemented: 
 
1. The Investigators will be well qualified by scientific training and experience. 
2. Detailed CRFs will be completed for every patient.  
3. Requirements for institutional ethics review as set forth by the appropriate 
Institutional Review Board/Independent Ethics Committee (IRB/IEC), Title 21 Code of 
Federal Regulations (CFR) Part 56, the European Union Directive 2001/20/EC and its 
associated Detailed Guidances, European Union GCP Directive 2005/28/EC, the ICH 
Guideline for GCP, Sections 3 and 4, and the terms of the Declaration of Helsinki 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
39 of 103 
28 October 2021 
Confidential - Entire Page 
(2013), will be followed.  
4. Requirements for informed consent in accordance with institutional guidelines, FDA 
requirements as specified in Title 21 CFR, Part 50, the European Union Directive 
2001/20/EC and its associated Detailed Guidances, European Union GCP Directive 
2005/28/EC, the ICH Guideline for GCP, Section 4.8, and the terms of the Declaration 
of Helsinki (2013), will be followed.  
5. Safety data will be recorded and evaluated.  
6. Routine monitoring visits will be conducted by the Sponsor’s representative to ensure 
data accuracy.  
7. Drug accountability will be strictly maintained.  
8. This trial will be conducted according to GCP, the protocol and applicable regulatory 
requirements. 
 
2.11 Patient Population 
This study will enroll adult male and female patients of age ≥ 18 years with documented 
diagnosis of AML, according to WHO classification, and documented TP53 mutation, which is 
not benign or likely benign, who also meet the eligibility requirements of this protocol. 
 
 
3.0 TRIAL OBJECTIVES AND PURPOSE 
Primary objective: 
To evaluate the safety and tolerability of administration of APR-246 in combination with 
venetoclax and/or azacitidine in patients with TP53-mutant myeloid malignancies. 
 
Secondary objectives: 
1. To assess the clinical activity of APR-246 in combination with venetoclax and/or 
azacitidine in patients with myeloid malignancies by determination of CR rate. 
2. To assess the clinical activity of APR-246 in combination with venetoclax and/or 
azacitidine in patients with myeloid malignancies by determination of CR plus CRi 
rate. 
3. To assess the clinical activity of APR-246 in combination with venetoclax and/or 
azacitidine in patients with myeloid malignancies by determination of CR plus CRh 
rate. 
4. To assess the clinical activity of APR-246 in combination with venetoclax and/or 
azacitidine in patients with myeloid malignancies by determination of ORR. 
5. To assess the clinical activity of APR-246 in combination with venetoclax and/or 
azacitidine in patients with AML by determination of PFS. 
6. To assess the clinical activity of APR-246 in combination with venetoclax and/or 
azacitidine in patients with AML by determination of transition rate to HSCT. 
7. To assess the clinical activity of APR-246 in combination with venetoclax and/or 
azacitidine in patients with AML by determination of OS. 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
40 of 103 
28 October 2021 
Confidential - Entire Page 
8. To assess clinical activity of APR-246 in combination with venetoclax and/or 
azacitidine in patients with AML by determining the rate of RBC and/or platelet TI for 
at least 56 days. 
9. To determine the pharmacokinetic profile of APR-246 and venetoclax. 
 
Exploratory objectives: 
1. To investigate molecular biomarkers for response prediction and disease monitoring 
in baseline and serial bone marrow or blood samples. 
 
 
4.0 TRIAL DESIGN 
4.1 
Overview of Trial Design 
Study treatment may be administered on an outpatient basis. No investigational or 
commercial agents or therapies other than those described below may be administered with 
the intent to treat the patient's disease. Hydroxyurea may be used for control of leukocytosis. 
The study includes a safety lead-in dose-finding portion followed by expansion portion. 
During the safety lead-in portion of the study, two cohorts will independently enroll patients 
following a 3 + 3 design.  
Safety lead-in cohort 1 will enroll patients with AML or MDS who have received at least one 
prior HMA regimen for MDS. These patients will receive APR-246 at 4.5 g/day on days 1 – 4 
of each 28-day cycle administered concurrently with venetoclax that is given orally at the 
dose of 400 mg daily once the ramp-up phase is completed. If a prophylactic antifungal agent 
is administered concurrently, the daily dose of venetoclax should be determined based on 
institutional practice and current prescribing information for venetoclax. Safety lead-in 
cohort 2 will enroll patients with previously untreated TP53-mutant AML (prior MDS is 
allowed, but not treatment with HMA), who will receive APR-246 at 4.5 g/day on days 1 – 4 
administered concurrently with venetoclax given orally at the dose of 400 mg daily and with 
azacitidine at the standard dose of 75 mg/m2 over 7 consecutive days as a subcutaneous 
injection or IV infusion on days 1 – 7 of each 28-day cycle.  
Each cohort will enroll up to 6 patients. DLT will be assessed after three patients have been 
enrolled in respective cohort and the last enrolled patient has completed the 4-week safety 
assessment period (i.e., one cycle of combination regimen). A patient that discontinues 
therapy during Cycle 1 without DLT is considered evaluable for the purpose of safety only if 
at least 80% of scheduled doses of APR-246 in combination with venetoclax and/or 
azacitidine were administered in the first cycle. At the first dose level of 4.5 g/day of APR-246, 
if ≤1 patient out of 3 experiences a DLT, 3 additional patients will be enrolled. If ≤1 patient 
out of 6 experiences DLT, the dose level (4.5 g/day of APR-246) will be deemed the RP2D for 
that cohort. If ≥2 patients out of the total 3–6 patients in the cohort experience DLT, the study 
will continue enrollment at Dose Level -1 (4.0 g/day of APR-246). If ≤1 patient out of 6 
experiences DLT at this dose level, the dose level (4.0 g/day of APR-246) will be deemed the 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
41 of 103 
28 October 2021 
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RP2D for that cohort. If ≥2 patients out of the total 3 – 6 patients at that dose level experience 
DLT, the study will continue enrollment at Dose Level -2 (3.5 g/day of APR-246). If ≤1 patient 
out of 6 experiences DLT at this dose level, the dose level (3.5 g/day of APR-246) will be 
deemed the RP2D for that cohort. If ≥2 patients out of the total 3–6 patients at this dose level 
experience DLT, no additional patients will be enrolled at this dose. The trial will be halted, 
and the DRT will consider potential future dosing modifications. 
 
Table 2. APR-246 Dose Levels 
 
Dose Modification 
APR-246 Dose 
Starting Dose Level 
(DL) 
APR-246 4.5 g/day 
1.5 g (for first 45 minutes) + 3.0 g (for 5 hours 15 minutes) 
Dose Level 
Reduction  
-1 (DL-1) 
APR-246 4.0 g/day  
1.33 g (for first 45 minutes) + 2.67 g (for 5 hours 15 minutes) 
Dose Level 
Reduction  
-2 (DL-2) 
APR-246 3.5 g/day  
1.17 g (for first 45 minutes) + 2.33 g (for 5 hours 15 minutes) 
 
The expansion portion will begin once the RP2D of APR-246 in combination with venetoclax 
and/or azacitidine have been determined in order to assess the antitumor activity of these 
combinations. Approximately 70 patients will be enrolled in up to five cohorts, as outlined in 
Table 3:  
Table 3. Study Treatment and Prior Therapy by Cohort 
Cohort 
Disease 
Study 
Treatment 
Prior Therapy Permitted 
 
 
 
VEN 
HMA 
LDAC 
APR-
246 
SCT 
IC 
Safety Lead-In Cohorts 
Cohort 1 
F/L AML 
APR-246 + 
VEN 
no 
≥ 1 prior 
for MDS 
required 
no 
no 
yes for 
MDS 
no 
Cohort 2 
F/L AML 
APR-246 + 
VEN + AZA 
no 
no 
no 
no 
no 
no 
Expansion Cohorts 
Cohort 1 
F/L AML 
APR-246 + 
VEN 
no 
yes for 
MDS 
no 
no 
yes for 
MDS 
no 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
42 of 103 
28 October 2021 
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Cohort 2 
F/L AML 
APR-246 + 
VEN + AZA 
no 
no 
no 
no 
no 
no 
Cohort 3 
R/R 
AML 
APR-246 + 
VEN 
yes 
yes 
Ye s 
yes for 
MDS 
yes 
yes 
Cohort 4 
R/R 
AML 
APR-246 + 
VEN + AZA 
yes 
no 
no 
yes for 
MDS 
yes 
≤ 1 prior 
Cohort 5 
F/L AML 
APR-246 + 
AZA 
no 
no 
no 
no 
no 
no 
Abbreviations: AZA = azacitidine; F/L = front line; HMA = hypomethylating agent; IC = intensive 
chemotherapy; LDAC = low-dose cytarabine; MDS = myelodysplastic syndrome; R/R = refractory or 
relapsed; SCT = stem cell transplant; VEN = venetoclax  
Cytopenia and related adverse events (thrombocytopenia, anemia, neutropenia, and febrile 
neutropenia) are common in patients with AML, particularly in patients with baseline 
neutropenia or those with secondary AML.  
 
For patients receiving venetoclax in combination with azacitidine, in a case of CRi or a 
morphologic leukemia-free bone marrow (MLFS) after completion of Cycle 1, administration 
of venetoclax and APR-246 may be interrupted to allow for ANC recovery from Day 29 until 
ANC ≥0.5 × 109/L. Blood counts can be assessed within 4 weeks of bone marrow biopsy for 
response assessments. Cycle 2 administration of azacitidine will also be delayed until ANC 
≥0.5 × 109/L. Both venetoclax, azacitidine, and APR-246 will resume on the same day after 
the interruption. If a patient 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, 
venetoclax dosing may be interrupted until ANC is ≥0.5 × 109/L. For subjects in CR/CRi who 
required interruption or delay of study drug administration for cytopenia (neutropenia or 
thrombocytopenia) venetoclax may be administered for 14-21 days out of 28 days during 
each of the subsequent cycles. 
 
If hematologic recovery is achieved within 14 days after completion of the cycle, the duration 
of venetoclax is reduced to 21 days of the cycle. If a 25% increase has not been achieved 
within 14 days after the completion of a cycle, azacitidine dose adjustment can be made 
based on bone marrow cellularity. In the setting of bone marrow hypocellularity, the dose of 
azacitidine in the next treatment cycle should be reduced to 50% for 15-50% hypocellularity 
and to 33% for <15% hypocellularity. 
 
In each portion of the study, patients may continue treatment as long as toxicity remains 
acceptable and the patient has not withdrawn consent. Response and progressive disease 
will be assessed based on the IWG AML response criteria (APPENDIX I) after every treatment 
cycle the first year, then every two cycles thereafter. 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
43 of 103 
28 October 2021 
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4.2 
End of Study 
The end of the study is defined as the date of the last visit of the last patient undergoing the 
trial. 
 
4.3 
Drug Products 
4.3.1 APR-246 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Administration: Venetoclax should be taken orally, with food, at a dose of 400 mg 
daily once the ramp-up phase is completed. If no prophylactic antifungal agent is 
administered concurrently, the ramp-up phase should consist of 100, 200, and 400 mg of 
venetoclax once daily given on days 1, 2, and 3 of Cycle 1, respectively. For day 4 of Cycle 1 
and beyond, the venetoclax dose is 400 mg once daily given in combination with APR-246 
with and without azacitidine. If a prophylactic antifungal agent is administered concurrently, 
the ramp-up phase and maintenance dose of venetoclax should be determined based on 
institutional practice and current prescribing information for venetoclax (see APPENDIX VIII). 
The dose of venetoclax should be modified accordingly to account for changes in a patient’s 
antifungal medication use. 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
44 of 103 
28 October 2021 
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4.3.3 Azacitidine 
Chemical Name: 4-amino-1--D-ribofuranosyl-s-triazin-2(1H)-one 
 
Formulation, preparation, storage and stability: Please see commercial package insert 
approved by regulatory agencies56. 
 
Route of Administration: Subcutaneous injection, or IV infusion for 7 consecutive days (Days 
1-7). Subcutaneous route is preferred but IV administration is acceptable at the Investigator’s 
discretion. The same route should be maintained over the 7-day treatment period. 
 
4.4 
Duration of Therapy 
Patients may remain on study treatment to the end of the trial while deriving clinical benefit, 
unless unacceptable toxicity, progression, death or patient withdrawal requires 
discontinuation. For patients without disease progression or unacceptable toxicity, study 
treatment should proceed for a minimum of 6 months to allow time for clinical response. 
Patients may remain on protocol therapy after relapse or progression if they are continuing 
to derive clinical benefit in the opinion of the Investigator.  


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
45 of 103 
28 October 2021 
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4.5 
Trial Discontinuation  
For reasonable cause, either the Investigator or the Sponsor may terminate this study 
prematurely. Written notification of the termination is required. Conditions that may warrant 
termination include, but are not limited to: 
 
• 
The discovery of an unexpected, significant, or unacceptable risk to the patients enrolled 
in the study. 
• 
Failure of the Investigator to enter patients at an acceptable rate. 
• 
Insufficient adherence to protocol requirements (non-compliance). 
• 
Lack of evaluable and/or complete data. 
• 
Decision to modify the developmental plan of the drug. 
• 
A decision on the part of the Sponsor to suspend or discontinue development of the drug. 
 
4.6 
Drug Accountability/Disposition of Clinical Trial Supplies 
Drug accountability records will be maintained for all clinical trial supplies. 
 
All unused clinical trial supplies will be destroyed per the institution’s standard operating 
procedure. Destruction of drug and trial supplies must be documented, and the 
documentation will be reviewed by/sent to the Sponsor or their Designee.  
 
4.7 
Registration 
Prior to registration and any study-specific evaluations being performed, all patients must 
have given written informed consent for the study and must have completed the pre-study 
evaluations (see Section 7.1). Patients must meet all of the eligibility requirements listed in 
Section 5.0. Patients will be registered on the study by using the 
 
Interactive Web Response System (IWRS) automated patient registration system. 
 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
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5.0 SELECTION AND WITHDRAWAL OF PATIENTS 
5.1 
Inclusion Criteria for Patients in Safety Lead-In Cohorts 
1. Signed ICF and ability to comply with protocol requirements. 
2. Documented diagnosis of initial or relapsed AML according to World Health Organization 
(WHO) classification.  
3. Adequate organ function as defined by the following laboratory values: 
a. Creatinine clearance >30 mL/min (by Cockcroft-Gault method; APPENDIX II), 
b. Total serum bilirubin <1.5 × ULN unless due to Gilbert’s syndrome, leukemic organ 
involvement, hemolysis or considered an effect of regular blood transfusions, 
c. ALT and AST <3 × ULN, unless due to leukemic organ involvement. 
4. Age ≥18 years at the time of signing the ICF. 
5. At least one TP53 mutation which is not benign or likely benign. 
6. ECOG performance status of 0, 1 or 2 (APPENDIX III). 
7. Projected life expectancy of ≥12 weeks. 
8. Negative serum or urine pregnancy test prior to study treatment initiation in female 
patients of childbearing potential. 
9. Females of childbearing potential and males with female partners of childbearing 
potential must be willing to use an effective form of contraception such as latex condom, 
hormonal birth control, intrauterine device or double barrier method (APPENDIX IV) 
during chemotherapy treatment and for at least six months thereafter. 
 
5.2 
Exclusion Criteria for Patients in Safety Lead-In Cohorts 
1. Prior treatment for TP53-mutant AML not permitted per Table 3. 
2. Known history of HIV or active hepatitis B or active hepatitis C infection. 
3. Any of the following cardiac abnormalities: 
a. Myocardial infarction within six months prior to registration, 
b. New York Heart Association Class III or IV (APPENDIX V) heart failure or known LVEF 
<40%; 
c. A history of familial long QT syndrome, 
d. Symptomatic atrial or ventricular arrhythmias not controlled by medications, 
e. QTcF ≥470 msec, unless due to underlying bundle branch block and/or pacemaker 
and with approval of the Medical Monitor. 
4. Concomitant malignancies for which patients are receiving active therapy at the time of 
signing consent. For example, patients with adequately treated basal or squamous cell 
carcinoma of the skin, adequately treated carcinoma in situ (e.g. cervix), or breast cancer 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
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receiving adjuvant endocrine therapy may enroll irrespective of the time of diagnosis 
with Medical Monitor approval. 
5. Known active CNS involvement from AML. A diagnostic lumbar puncture is not required 
in the absence of suspicion for CNS disease. 
6. Malabsorption syndrome or other condition that precludes enteral route of 
administration. 
7. Pregnancy or lactation. 
8. Active uncontrolled systemic infection (viral, bacterial or fungal). 
 
5.3 
Inclusion Criteria for Patients in Expansion Cohorts 
1. Signed ICF and ability to comply with protocol requirements. 
2. Newly diagnosed or R/R AML according to WHO classification with permitted prior 
therapy, as per Table 3. For patients with newly diagnosed AML bone marrow and/or 
blood evidence of AML with ≥20% blasts is required. For patients with newly diagnosed 
AML, prior therapy with HMA and/or any chemotherapeutic agent for MDS is excluded. 
3. Adequate organ function as defined by the following laboratory values: 
a. Creatinine clearance >30 mL/min (by Cockcroft-Gault method; APPENDIX II), 
b. Total serum bilirubin <1.5 × ULN unless due to Gilbert’s syndrome, leukemic organ 
involvement, hemolysis or considered an effect of regular blood transfusions, 
c. ALT and AST <3 × ULN, unless due to leukemic organ involvement. 
4. Age ≥18 years at the time of signing the ICF. 
5. At least one TP53 mutation which is not benign or likely benign, based on central TP53 
testing results. If local TP53 mutation and/or p53 IHC results become available before 
central TP53 mutation results, enrollment may be made based on local results with 
Medical Monitor approval.  
6. ECOG performance status of 0, 1 or 2 (APPENDIX III). 
7. Projected life expectancy of ≥12 weeks. 
8. Negative serum or urine pregnancy test prior to study treatment initiation in female 
patients of childbearing potential. 
9. Females of childbearing potential and males with female partners of childbearing 
potential must be willing to use an effective form of contraception such as latex condom, 
hormonal birth control, intrauterine device or double barrier method (APPENDIX IV) 
during chemotherapy treatment and for at least six months thereafter. 
 
5.4 
Exclusion Criteria for Patients in Expansion Cohorts 
1. Known history of MPN (i.e., polycythemia vera, essential thrombocythemia and primary 
myelofibrosis are excluded). 
2. Known history of HIV or active hepatitis B or active hepatitis C infection. 
3. Any of the following cardiac abnormalities: 
a. Myocardial infarction within six months prior to registration, 


Aprea Therapeutics  
Protocol Number A19-11184  
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b. New York Heart Association Class III or IV (APPENDIX V) heart failure or known LVEF 
<40%, 
c. A history of familial long QT syndrome, 
d. Symptomatic atrial or ventricular arrhythmias not controlled by medications, 
e. QTc ≥470 msec calculated from a mean of 3 ECG readings using Fridericia’s correction 
(QTcF = QT/RR0.33).  
4. Concomitant malignancies for which patients are receiving active therapy at the time of 
signing consent. For example, patients with adequately resected basal or squamous cell 
carcinoma of the skin, adequately resected carcinoma in situ (e.g. cervix), or breast cancer 
receiving adjuvant endocrine therapy may enroll irrespective of the time of diagnosis 
with Medical Monitor approval. 
5. Prior exposure to anticancer therapies including chemotherapy, radiotherapy or other 
investigational therapy, including targeted small molecule agents within 14 days of the 
first day of study drug treatment or within 5 half-lives prior to first dose of study drug. 
6. Prior exposure to biologic agents (e.g. monoclonal antibodies) for anti-neoplastic intent 
within 14 days prior to first dose of study drug. 
7. Known active CNS involvement from AML. A diagnostic lumbar puncture is not required 
in the absence of suspicion for CNS disease. 
8. Malabsorption syndrome or other condition that precludes enteral route of 
administration. 
9. Pregnancy or lactation.  
10. Active uncontrolled systemic infection (viral, bacterial or fungal). 
 
5.5 
Inclusion of Women, Minorities and Children 
Both men and women and members of all races and ethnic groups are eligible for this study. 
Children are not eligible for this study because the safety and tolerability of the proposed 
dosing schedule has not been determined in adults. 
 
5.6 
Withdrawal Criteria 
Protocol therapy can continue for patients receiving clinical benefit, unless one or more 
study treatment discontinuation criteria are met, or at the patient’s discretion, or if the study 
is terminated.  
 
5.6.1 Study Treatment Discontinuation 
Study treatment must be discontinued if: 
• 
Evidence of disease progression. Patients who have relapsed or progressive disease 
but who are continuing to derive clinical benefit in the opinion of the investigator may 
continue to receive study treatment. 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
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• 
A patient becomes pregnant. 
• 
A patient is significantly non-compliant with the requirements of the protocol.  
• 
A patient has an adverse experience that would, in the Investigator’s judgment, make 
continued participation in the study an unacceptable risk. 
• 
The patient starts new treatment for their underlying disease. 
 
5.6.2 Study Completion 
Patient must be taken off the study if: 
• 
The patient dies during the study. 
• 
The patient is lost to follow-up. 
• 
The patient withdraws consent. 
 
5.6.3 Withdrawn Patients  
When a patient is removed from the study treatment, the Investigator will clearly document 
the reason in the medical record and complete the appropriate CRF page describing the 
reason for discontinuation. In addition, every effort should be made to complete the 
appropriate assessments listed in Section 7.3. 
 
5.7 
Noncompliance 
All instances of protocol deviations will be recorded according to guidelines per Sponsor’s 
Representative.  
 
6.0 TREATMENT OF PATIENTS 
6.1 
Drug Preparation and Administration  
Study treatment may be administered on an outpatient basis. No investigational or 
commercial agents or therapies other than those described below may be administered with 
the intent to treat the patient's disease.  
 
6.1.1 APR-246 
APR-246 is administered as a 6-hour IV infusion daily on Days 1–4 of each 28-day cycle. 
APR-246 fixed dose is 4.5 g. APR-246 is administered in a 2-step infusion: 
 
Step 1: Loading dose of 1.5 g for the first 45 minutes (± 2 min) 
Step 2: Maintenance dose of 3 g over 5 hours 15 minutes (± 30 min) 
 


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In each portion of the study, if patients develop intolerable toxicity(ies) to APR-246 in 
combination with venetoclax and azacitidine, the dose of APR-246 may be reduced (please 
consult Section 4.1 and Table 2). 
APR-246 vials are to be stored at 2-8C (35.6-46.4F). At the pharmacies and at the study 
centers, the prepared APR-246 study product (diluted in sodium chloride solution) is to be 
stored at not more than 25C. The infusion should be completed within 24 hours from the 
time of preparation.  
 
Detailed instructions on vial concentration, preparation and dispensing can be found in the 
Pharmacy Binder. The infusion timing, including start/stop times and the time of rate change, 
must be recorded. 
 
6.1.2 Venetoclax 
After ramp-up (see below), venetoclax tablets at the dose 400 mg (4 tablets) should be taken 
orally once daily with a meal and water, at approximately the same time every day. On days 
1–4 of Cycle 1 it is recommended that venetoclax is taken approximately one hour after start 
of APR-246 infusion. On these days’ patients will consume a low-fat meal prior to venetoclax 
consumption. Starting at cycle 2 venetoclax can be taken before or after start of APR-246 
infusion (± 2 hours). 
 
During Cycle 1, treatment with venetoclax should start with a ramp-up phase. If no 
prophylactic antifungal agent is administered concurrently, the ramp-up phase should 
consist of 100, 200, and 400 mg of venetoclax once daily given on days 1, 2, and 3 of Cycle 1, 
respectively. For day 4 of Cycle 1 and beyond, the venetoclax dose is 400 mg once daily given 
in combination with APR-246 with and without azacitidine. If a prophylactic antifungal agent 
is administered concurrently, the ramp-up and maintenance dose of venetoclax should be 
determined based on institutional practice and current prescribing information for 
venetoclax (please see APPENDIX VIII). 
 
If required, any dosage modifications of venetoclax should be done based on clinical 
judgement and institutional practice. 
 
Detailed instructions on preparation and administration can be found in the Pharmacy 
Binder and current package insert. 
 
6.1.3 Azacitidine 
Azacitidine is given at the standard dose of 75 mg/m2 subcutaneously or intravenously over 
7 consecutive days, Days 1–7. On Days 1–4 azacitidine is administered immediately after the 
APR-246 infusion. SC method is preferred but IV is allowed at the Investigator’s discretion. 
The same route should be maintained over the 7-day treatment period (whichever route is 
used on Day 1, the other days should follow the same route of administration). Detailed 


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instructions on preparation and administration can be found in the Pharmacy Binder, 
current package insert, and in Section 6.2, below. The administration of azacitidine may be 
interrupted by up to 3 days to account for institutional administration practices and policies 
in addition to holidays. 
 
6.1.3.1 Administration on the Days of PK Blood Sampling 
On Cycle 1 Day 1, in subjects receiving APR-246 in combination with venetoclax and 
azacitidine, APR-246 is the first agent to be administered after the baseline blood sample for 
PK analysis is collected. Fifteen (15) minutes after the start of the infusion, the subject is 
asked to have breakfast. One (1) hour after the start of APR-246, the subject is to take 
venetoclax. Azacitidine is to be administered after the infusion of APR-246. 
 
After C1, venetoclax can be taken before or after start of APR-246 (2 hrs) and after the 
baseline PK sample is obtained, as indicated in the Schedule of Study Evaluations. 
 
On Day 1 of Cycle 1 patients will come to the clinic for PK blood sampling without taking the 
venetoclax in the morning. Patients will receive a low-fat meal and take the venetoclax within 
30 min after the meal is finished and a baseline blood sample is taken. 
 
6.1.4 Dose-Limiting Toxicity 
An event will be considered a DLT per NCI CTCAE version 5.0 criteria if it occurs within 4-week 
safety assessment period (Cycle 1 of study treatment) and meets at least one of the criteria 
below: 
 
• 
Absolute neutrophil count (ANC) not recovering to >0.5 × 109/L and/or platelets not 
recovering to >25 × 109/L by day 42 of study treatment in the absence of active 
leukemia/myelodysplasia; 
• 
Grade ≥ 3 nausea/vomiting/diarrhea or CNS toxicity that does not resolve to Grade ≤ 
1 within 7 days despite treatment interruption and maximum medical therapy; 
• 
Treatment-related non-hematological Grade ≥ 3 toxicity that does not resolve to 
Grade ≤ 1.  
 
A DLT will be considered related to the study treatment unless there is a clear, alternative 
explanation for the AE. A ≥ Grade 3 metabolic or electrolyte abnormalities that is not clinically 
significant and is adequately controlled within 72 hours is not to be considered DLT. A tumor 
lysis syndrome that responds to therapy and resolves within 72 hours is not to be considered 
DLT. 
 
Additionally, AEs that meet the above criteria, but occur after the DLT evaluation period will 
not be defined as DLTs, but will be reported as AEs/Serious Adverse Events (SAEs) and will 
be reviewed across all cohorts during the study to help determine the AE profile. A patient 


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that discontinues therapy during Cycle 1 without DLT is considered evaluable for the purpose 
of safety only if at least 80% of doses of APR-246 in combination with venetoclax with and 
without azacitidine were administered in the first cycle. 
 
Patients who are tolerating APR-246 in combination with venetoclax and/or azacitidine, will 
not have to discontinue dosing prematurely due to the occurrence of DLTs in another patient 
in the same cohort, unless decided by the DRT. If requested by the Investigator, depending 
on the nature of the DLT and patient status, the DRT and the Sponsor may allow a patient to 
continue with study treatment at a reduced dose. 
 
6.1.5 Recommended Phase II Dose (RP2D)  
The RP2D of APR-246 will be defined as the dose at which <2 out of 6 patients experience 
DLT during the 4-week safety assessment period after administration of APR-246 in 
combination with venetoclax and/or azacitidine. 
 
DRT consisting of the Medical Monitor, Site Principal Investigators, and other clinical research 
personnel that the Sponsor may deem appropriate, will hold DRM on an interim basis at a 
frequency dependent on study accrual. At these meetings, the DRT will review AEs and DLTs 
and make recommendations regarding the RP2D. In the expansion portion of the study, the 
DRT will evaluate safety and tolerability after 5 patients have completed 1 cycle of treatment 
in each cohort. All accumulated safety data will be discussed during DRMs. 
 
6.2 
Dose Interruptions/Withholding  
Study treatment may be withheld from a patient based on the Investigator‘s decision in the 
event of intercurrent illness, AE, administrative reasons, or other reasons. If the patient‘s 
condition subsequently improves, or the situation that resulted in withholding study drug 
rectifies itself, the Investigator may resume dosing as soon as possible, unless the delay is 
more than 4 weeks. 
 
Dosing should be delayed for any DLT-equivalent toxicity and possible NCI CTCAE > Grade 2 
AEs considered related to study medication. At the Investigator’s discretion, dosing may 
recommence when the toxicity has resolved to Grade 2 or less. Immune-related reactions or 
allergy should resolve to ≤ Grade 1. 
 
Treatment will be discontinued if a TEAE has not resolved (to acceptable grade) after ≤4 
weeks. 
 


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6.3 
Supportive Management 
6.3.1 APR-246 
This section outlines the requirements for proceeding with treatment with APR-246, and the 
protocol rules for APR-246 dose modification due to toxicity.  
 
At screening, 12-lead ECGs should be collected in triplicate to confirm QT interval does not 
exceed 470 msec in patients without pre-existing bundle branch block (BBB) and/or 
pacemaker.  For patients with pre-existing BBB and/or pacemaker, QTcF at screening should 
not exceed baseline reading known per medical history. QT interval must be calculated from 
a mean of all three ECG readings using Fridericia’s correction (QTcF = QT/RR0.33). 
 
During Cycle 1 ECG should be collected in triplicate prior to infusion of APR-246 and at the 
end of infusion (EOI) of APR-246 (6 hours after start of infusion, ±30 min) on Days 1–4. QTcF 
must be calculated from a mean of all three ECG readings to confirm it does not exceed 470 
msec in patients without pre-existing BBB and/or pacemaker. For patients with pre-existing 
BBB and/or pacemaker, QTcF measurements in Cycle 1 should be at or below values 
recorded during screening period.  
 
If a pre-dose ECG shows QTcF ≥470 msec, the QTc reading should be confirmed by manual 
assessment using Fridericia’s correction (QTcF = QT/RR0.33). Serum concentrations of 
electrolytes should be monitored and corrected, if necessary. Additionally, concomitant 
medication should be reviewed and adjusted, if necessary. ECG may be repeated at any time, 
including the same day. APR-246 may only be administered when QTcF has returned to <470 
msec. If APR-246 is given on the same day, procedures outlined in the Schedule of Study 
Evaluations (Table 8) must be followed. If APR-246 cannot be administered on the same day, 
that dose must be omitted from the cycle. 
 
If there is a significant change in QTcF, defined as either: a) increase >60 msec from baseline 
(or pre-dose), or b) increase to an absolute value ≥501 msec, i.e. consistent with NCI CTCAE 
Grade 3 QTc prolongation, QTc prolongation must be confirmed by a manual assessment of 
the ECG, and using Fridericia’s correction (QTcF = QT/RR0.33). If confirmed, the APR-246 
therapy should be interrupted until a cause (electrolyte disorders or an effect of a 
concomitant medication) has been identified and addressed, and QTcF has returned to <470 
msec. If all other causes for clinically significant QT interval prolongation are excluded, APR-
246 must be permanently discontinued. 
 
During subsequent cycles ECG should be collected in triplicate prior to infusion of APR-246 
on Day 1 of each cycle. QTcF must be calculated from a mean of all three ECG readings to 
confirm it does not exceed 449 msec in patients without pre-existing BBB and/or pacemaker. 
For patients with pre-existing BBB and/or pacemaker, QTcF measurements in subsequent 
cycles should be at or below values recorded during the screening period.  


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If pre-dose QTcF is 450-469 msec in patients with and without pre-existing BBB and/or 
pacemaker, APR-246 may be administered, and additional triplicate ECG should be 
performed at the EOI (6 hours after start of infusion, ±30 min).  
 
If post-dose ECG shows a significant change in QTcF, defined as either: a) increase >60 msec 
from baseline (or pre-dose), or b) increase to an absolute value ≥501 msec, i.e. consistent 
with NCI CTCAE Grade 3 QTc prolongation, QTc prolongation must be confirmed by a manual 
assessment of the ECG, and using Fridericia’s correction (QTcF = QT/RR0.33). If confirmed, the 
therapy should be interrupted until a cause (electrolyte disorders or an effect of a 
concomitant medication) has been identified and addressed, and QTcF has returned to <470 
msec. If all other causes for clinically significant QT interval prolongation are excluded, APR-
246 must be permanently discontinued. If QTcF is unchanged or there is no significant 
change, additional ECG is not required during that cycle. 
 
If repeated QTcF measurements show a stable QTcF <450 msec, or if QTcF remains stable 
within the interval of 450–469 msec with no significant change at the EOI during several 
cycles of treatment, reducing the number of ECGs performed in the study may be discussed 
with the Medical Monitor. 
 
If a patient starts treatment with another medication known to prolong QT interval at any 
time during the study therapy, an additional pre- and post-dose (6 hours after start of 
infusion, ±30 min) ECG should be performed on the next treatment day.  
 
6.3.2 Management of CNS Adverse Events  
If a patient reports any clinical AE of any grade during the administration period of APR-246 
that could be considered to originate from the CNS (e.g. dizziness, vertigo, nausea) then the 
patient will be given a rescue medication as per the institutional standard of care. 
 
Dose modifications of APR-246 have been successfully used to manage potential CNS effects 
occurring during the infusion (Table 4). For any clinical AE Grade ≥ 3, the infusion of APR-246 
should immediately be stopped, and if all symptoms resolve to CTCAE ≤ Grade 1 within 2 
hours, the infusion of APR-246 may be resumed at the same infusion rate. If the same 
symptoms do occur or increase in severity during re-challenge the infusion of APR-246 
should be stopped. 
 
If the event lasts longer than 2 hours, then the APR-246 infusion should be discontinued for 
that day, the remaining drug should be discarded. 
 


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Table 4. Management of CNS Adverse Events (Dizziness, Dyskinesia and Ataxia) 
Worst toxicity  
Dose Modifications for APR-246 
Grade 1 
Maintain dose level 
Grade 2 
If resolved to ≤ Grade 1 with medical therapy, continue same dose level 
If not resolved despite treatment interruption and maximal medical therapy, 
stop infusion and  1 dose level for subsequent dose 
Grade ≥ 3 
Stop infusion and give medical therapy. If resolved (to ≤ Grade 1) with medical 
therapy, infusion may continue at the Investigator’s discretion. 
  1 dose level for subsequent dose  
Grade 4 
Permanently discontinue patient from APR-246. 
 
In prior studies, prochlorperazine 10 mg orally tid (three times daily) has been reported to 
be an effective treatment that may also be used prophylactically. When prochlorperazine is 
used prophylactically, start the day prior to the Day 1 and continue 10 mg tid to day 4 (as 
needed). The US label for prochlorperazine does not list QT interval prolongation as a known 
risk associated with use of this drug.  
 
6.3.3 Management of Nausea and Vomiting  
Patients who experience nausea and vomiting in association with APR-246 infusion will be 
prescribed appropriate rescue treatment and prophylaxis (e.g., anti-nausea or anti-emetics 
medication) as per institutional guidelines. Patients who receive additional drugs that are 
known to cause QT interval prolongation must be monitored for any signs of QT interval 
prolongation via an ECG before and after the APR-246 infusion. 
 
• 
If QTc >501 msec is observed in a patient concomitantly treated with another QT 
interval prolonging drug, this drug should be stopped and treatment with APR-246 
may be restarted when QTc <470 msec or baseline measurement in patients with pre-
existing BBB and/or pacemaker (refer to Section 6.3.1). 
 
A list of suggested rescue medications is provided below in Table 5. 
Table 5. Medications for Managements of Nausea and Vomiting 
Drug 
Dosage 
QT Interval 
Prolongationa 
Ondansetron 
8 mg PO administered 30 minutes before the start 
of infusion or per label 
Yes 
Dolasetron 
100 mg PO administered within one 
hour before start of infusion or per label 
Yes 
Palonosetron 
0.25 mg IV administered over 30 seconds 
beginning approximately 30 min prior to the start 
of infusion on Day 1 only 
No 


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Prochlorperazine 
10 mg PO three times daily. Continue until the end 
of Day 4 of the cycle. When used prophylactically 
in subsequent cycles, start the day prior to Day 1 
administration of APR-246 
No 
a Please refer to Section 6.3.1 for details on concurrent administration of medications known to cause QTc 
interval prolongation. 
 
6.3.4 Management of Infusion Reactions 
If a patient experiences an infusion reaction during the study, the infusion will be stopped 
and appropriate medical care (e.g., epinephrine, oxygen, H1 and H2 antagonists, and/or 
corticosteroids) will be administered57. 
 
 
 
 
 
 
 
 
 
  
The following recommendations were taken from National Comprehensive Cancer Network 
Guidelines for Prevention and Treatment of Cancer-Related Infections (Version 1.2021). 
 
Table 6. Recommendations for prevention and treatment of cancer-related infections 
Organism 
Recommendations 
Bacterial 
Consider fluoroquinolone or other suitable anti-bacterial prophylaxis during 
neutropenia 
Fungal 
Consider prophylaxis during neutropenia and for anticipated mucositis. Assess risk for 
Pneumocystis jirovecii pneumonia (PJP) and select agent(s) as clinically indicated.   
Viral 
Start treatment with anti-viral medication in the setting of neutropenia and continually 
assess the risk for viral infection during treatment with anti-cancer therapy.  
 
Please refer to Section 6.2 Dose Interruptions/Withholding,for guidance on APR-246 dose 
modification in the setting severe infection and/or infestation event(s).    
 
Refer to Section 6.4 Concomitant Treatment, for a description of drugs that are not allowed 
to be used while a patient is on study treatment.  
 


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6.3.6 Management of Neutropenia with or without Fever 
Monitor complete blood counts at the time of study enrollment and throughout the course 
of study treatment. Supportive measures such as antimicrobials for prophylaxis or in the 
setting of prolonged myelosuppression, and/or at the first signs of infection are 
recommended to reduce the risk of a serious or severe infection that may lead to a fatal 
outcome in the setting of neutropenia with or without fever (see Section 6.3.5).   
 
Myeloid growth factors may be used in the setting of severe or prolonged neutropenia. Refer 
to Section 6.4 Concomitant Treatment, for a description of drugs that are not allowed to be 
used while a patient is on study treatment. 
 
Please refer to Section 6.2 Dose Interruption/Withholding for guidance on APR-246 dose 
modification in the setting neutropenia with or without fever.    
 
6.3.7 APR-246 Dose Modification in the Setting of Moderate Renal Impairment 
APR-246 is partially eliminated via the kidney and moderate renal impairment, defined by a 
creatinine clearance, or estimated glomerular filtration rate value of >30 to <60 mL/min, can 
lead to increases in plasma levels of approximately 30%. Therefore, for patients with 
moderate renal impairment, the dose of APR-246 should be reduced by 33% from the 
current dose (Table 7). 
 
Table 7: APR-246 Dose Modification in the Setting of Moderate Renal Impairment 
APR-246 Dose 
33% Reduced Dose 
Loading Dose (over 
45 min) 
Maintenance 
Dose 
(over 5 hr and 15 min) 
4.5 g 
3.0 g 
1.0 g 
2.0 g 
4.0 g 
2.7 g 
0.9 g 
1.8 g 
3.5 g 
2.3 g 
0.8 g 
1.5 g 
3.0 g 
2.0 g 
0.7 g 
1.3 g 
<3.0 g 
Please consult with Medical Monitor 
 
Monitoring renal function by assessment of serum creatinine prior to infusion of APR-246 is 
recommended in all patients. 
 
6.3.8 Venetoclax Dose Adjustments 
Please refer to venetoclax USPI 37 for recommended dose modifications. 
 


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6.3.9 Azacitidine Dose Adjustments 
Missed doses (for any reason but toxicity) may, at the Investigator’s decision, be 
compensated by adding an additional dosing day for azacitidine (e.g. Day 8) so that the 
patient receives the total 7 days of treatment per cycle. 
 
If unexplained reductions in serum bicarbonate levels to less than 20 mEq/L occur during 
treatment with azacitidine, contact the study medical monitor to discuss if a reduction in 
azacitidine dose by 50% should occur with the next scheduled cycle.  Similarly, if unexplained 
elevations in BUN or serum creatinine occur, contact the study medical monitor to discuss if 
a delay in the next cycle of azacitidine is warranted and/or a reduction in azacitidine dose by 
50% should occur with the next scheduled cycle.   
 
Please refer to azacitidine USPI58 for recommended dose modifications.  
 
6.3.10 Antifungal Prophylaxis 
Antifungal agents may be used at the investigator’s discretion and with appropriate 
monitoring of the QTc and adjustment of the venetoclax dose.  
 
6.4 
Concomitant Treatment  
Patients must not receive any other concurrent anti-cancer therapy, including investigational 
agents while on study treatment. Please also see Section 2.3, regarding known drug-drug 
interactions for venetoclax, and the importance of avoiding certain food such as grapefruits. 
This is important both for patient safety and for enabling a correct assessment of an unlikely 
drug-drug interaction between the study drug APR-246 and venetoclax. For patients 
concomitantly treated with strong or moderate CYP3A inhibitors, or P-gp inhibitors, the dose 
of venetoclax should be determined based on institutional practice and current prescribing 
information. Strong or moderate CYP3A inducers should be avoided (see APPENDIX VIII). 
 
Patients may continue their baseline medication(s) as long as they are not prohibited. 
Palliative and supportive care (e.g., anti-emetics, bisphosphonates) for disease-related 
symptoms will be offered to all patients in the study per institutional practices. AEs will be 
treated as clinically indicated. All concomitant medications that are currently in use or that 
become necessary during the study should be recorded. 
 
If the patient develops an acute infusion reaction ( Grade 2), the infusion must be stopped 
until the reaction is resolved to ≤ Grade 1. Premedication (e.g., systemic corticosteroids) may 
be used after the first cycle. 
 


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Use of myeloid growth factors is allowed at the discretion of the investigator per institutional 
practices. If patients experience prolonged myelosuppression, they should be placed on 
infection prophylaxis per standard of care. 
 
Hydroxyurea may be used for control of leukocytosis. 
 
6.5 
Monitoring Patient Compliance 
This study will be monitored by Aprea Therapeutics, Inc. or its CRO according to ICH E6 
guidelines of GCP. The study site monitor will regularly visit the study sites to ensure that the 
study is conducted according to the protocol and GCP principles. All instances of protocol 
deviations will be entered and reviewed by the Investigator, Sponsor and appropriate 
 designee.  
 
 
7.0 STUDY EVALUATIONS 
 
7.1 
Schedule of Study Evaluations 
Study evaluations are summarized in Table 8 and described in Sections 7.2 through 7.4. 


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Table 8: Study Calendar 
Study Calendar 
Evaluation a 
 
 
Screeninga 
 
Cycle 1  
Cycle 2 and Subsequent Cycles 
End of 
Odd 
Cycles 
End of 
Even 
Cycles 
End of 
Treat-
ment 
r 
Long-
Term 
Follow
-Up s 
D1 
D2 
D3 
D4 
D 
5-7 
D8 
b 
D 
15b 
D 
22b 
D 23 
D1
c 
D
2 
D3 
D4 
D 
5-7 
D8 
b 
D15
b 
D22
b 
D23
b 
Informed consent 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TP53 mutation by central lab d 
×  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history e 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination f 
× 
× 
 
 
 
 
 
 
 
 
× 
 
 
 
 
 
 
 
 
 
 
× 
 
Height 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
× 
× 
 
 
 
 
 
 
 
 
× 
 
 
 
 
 
 
 
 
 
 
× 
 
Vital signs f 
× 
× 
× 
× 
× 
 
 
 
 
 
× 
× 
× 
× 
 
 
 
 
 
 
 
× 
 
ECOG PS 
× 
× 
 
 
 
 
 
 
 
 
× 
 
 
 
 
 
 
 
 
 
 
× 
 
APR-246 g 
 
× 
× 
× 
× 
 
 
 
 
 
× 
× 
× 
× 
 
 
 
 
 
 
 
 
 
Venetoclax h 
 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
 
 
 
 
Azacitidine i 
 
× 
× 
× 
× 
× 
 
 
 
 
× 
× 
× 
× 
× 
 
 
 
 
 
 
 
 
Bone marrow/peripheral blood 
collection j 
× 
 
 
 
 
 
 
 
× 
 
 
 
 
 
 
 
 
 
 
 
× 
× 
× 
Response assessment k 
 
 
 
 
 
 
 
 
× 
 
 
 
 
 
 
 
 
 
 
× 
× 
 
 
Hematology l 
× 
× 
 
 
 
 
× 
× 
× 
 
×j 
 
 
 
 
× 
× 
× 
 
 
 
× 
× 
Blood chemistry m 
× 
× 
 
 
 
 
× 
× 
× 
 
× 
 
 
 
 
× 
× 
× 
 
 
 
× 
 
Pregnancy test n 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG o  
× 
×o 
×o 
×o 
×o 
 
 
 
 
 
× 
 
 
 
 
 
 
 
 
 
 
 
 
TLS lab monitoring p 
 
× 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APR-246 PK sample q 
 
× 
× 
 
× 
 
 
 
 
 
 
 
 
× 
 
 
 
 
 
 
 
 
 
Venetoclax PK sample q 
 
× 
× 
 
 
 
 
 
× 
× 
 
 
 
× 
 
 
 
 
 
 
 
 
 
Survival 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
× 
× 
Clinical toxicity assessment 
 
Starting at the time of study treatment initiation through 30 days after last dose t 
 


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Study Calendar 
Evaluation a 
 
 
Screeninga 
 
Cycle 1  
Cycle 2 and Subsequent Cycles 
End of 
Odd 
Cycles 
End of 
Even 
Cycles 
End of 
Treat-
ment 
r 
Long-
Term 
Follow
-Up s 
D1 
D2 
D3 
D4 
D 
5-7 
D8 
b 
D 
15b 
D 
22b 
D 23 
D1
c 
D
2 
D3 
D4 
D 
5-7 
D8 
b 
D15
b 
D22
b 
D23
b 
Concomitant medications 
× 
Reviewed throughout study 
 


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Footnotes to Study Calendar 
 
a. All screening/baseline evaluations are performed within 28 days prior to the start of study 
treatment. In the event that a visit or test cannot be scheduled on the exact visit day, a window of 
±3 days is allowable. 
b. A window of ±3 days applies to this study visit. 
c. After the first cycle, Day 1 evaluations of subsequent cycles are to be done within 3 days prior to 
next cycle drug administration. 
d. A bone marrow aspirate in ethylenediaminetetraacetic acid (EDTA) and peripheral blood sample 
in EDTA is required at the time of consent and screening for central lab TP53 mutation 
determination. If the bone marrow aspirate cannot be obtained due to a dry tap, peripheral blood 
alone can be used for TP53 mutation status for enrollment. If local TP53 mutation and/or p53 IHC 
results become available before central TP53 mutation results, enrollment may be made based on 
local results with Medical Monitor approval. 
e. Full medical history is obtained at screening for safety and eligibility purposes; this will include any 
clinically significant findings from 28 days prior to screening date. 
f. 
Physical exam and vital signs (including blood pressure, heart rate, respiration rate and 
temperature) are completed for safety purposes and clinically significant items are recorded as 
AEs where appropriate. Vital signs are collected prior to APR-246 infusion, 2 hours into infusion 
and at EOI (±30 minutes at all time points). 
g. APR-246 is administered IV on days 1–4 of each 28-day cycle. 
h. Only in cohorts with venetoclax: Venetoclax is given orally at the dose of 400 mg (4 tablets) once 
daily at approximately the same time every day, with a meal and water. On days 1 – 4 of Cycles 1 
and 2 it is recommended that venetoclax is taken approximately one hour after start of APR-246 
infusion. If a prophylactic antifungal agent is administered concurrently, the daily dose of 
venetoclax should be determined based on institutional practice and current prescribing 
information for venetoclax. 
i. 
Only in cohorts with azacitidine. Azacitidine is administered subcutaneously over 7 consecutive 
days, on Days 1-7 of each 28-day cycle. On Days 1–4 azacitidine is administered immediately after 
the APR-246 infusion. Subcutaneous route is preferred but azacitidine may be administered 
intravenously at the Investigator’s discretion. The same route should be maintained over the 7-day 
treatment period.  
j. 
Bone marrow aspirate sample is collected at baseline and when bone marrow is sampled for 
disease assessment. If no aspirate is available due to a dry tap, then peripheral blood is 
acceptable.. 
k. Initial response assessment (blasts percentage) is performed on Day 22 (±3 days). In patients with 
bone marrow hypocellularity, venetoclax may need to be held and restarted after recovery of 
blood counts (ANC ≥0.5 × 109/L, and platelets ≥25 × 109/L), confirmed by repeat bone marrow 
biopsy on approximately Day 35 and following discussion with Medical Monitor. For subjects who 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
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require a delay in study treatment for peripheral blood count recovery after a bone marrow 
evaluation, hematology values for up to 4 weeks from the bone marrow analysis can be used to 
determine the IWG response. Ongoing response assessments should be performed at the end of 
each cycle (every 4 weeks) starting at Cycle 2, based on peripheral blood and bone marrow sample 
(at the end of even cycles), and peripheral blood sample alone (at the end of odd cycles). After the 
first year of the study treatment response assessment will be performed every two months. 
Following a documented CR, a bone marrow aspirate/biopsy is not required if the response 
assessment can be made based on the peripheral blood, except at the time of suspected relapse 
at which time a bone marrow aspirate/biopsy is required.  
l. 
Hematology, including complete blood count with white blood cell differential, weekly. Additional 
peripheral blood sample should be collected on Day 1 of each cycle starting at Cycle 2 for disease 
assessment, if bone marrow aspirate is not available. 
m. Serum chemistry, including sodium, potassium, chloride, magnesium, CO2, blood urea nitrogen 
(BUN), creatinine, glucose, calcium, albumin, total protein, total bilirubin, AST, ALT, alkaline 
phosphatase weekly. At screening, the creatinine clearance may be calculated from the serum 
creatinine. A 24-hour urine for creatinine clearance may be performed at Investigator’s discretion. 
n. Serum or urine βhCG must be performed within 7 days prior to study treatment initiation in 
female patients of childbearing potential. 
o. Standard 12-lead ECGs in triplicate at screening, on Days 1–4 of Cycle 1 and on Days 1 of each 
subsequent cycle with patient in a semi-recumbent position. Please consult Table 12 for ECG 
collection schedule.  
p. Only in cohorts with venetoclax: Potassium, phosphorus, calcium and uric acid should be evaluated 
approximately 6-8 hr and 24 hr (± 4 hr) after the initial administration of venetoclax in order to 
monitor for potential development of TLS. 
q. Please consult Section 8.4 for PK collection schedule. 
r. 
Patients discontinuing treatment should complete their end of treatment visit within 
approximately 28 days of their last dose of APR-246. Physical exam, vital signs, clinical toxicity 
assessment, hematology, serum chemistry and bone marrow aspirate and biopsy with NGS 
analysis should be performed, if feasible.  
s. Long-term follow up can be done remotely (e.g. via telephone, via local practitioner or via review 
of medical records). Assuming there is no withdrawal of consent, patients who stop study 
treatment for any reason (e.g. toxicity, transition to SCT, PD) will continue long-term follow-up (see 
Section 7.4). If a patient is removed from the study due to unacceptable AEs, the event(s) will be 
followed until resolution or stabilization of the AE. Off-treatment data on overall survival will be 
updated every month (i.e. every 28 days ±3 days) or until death or withdrawal of consent for study 
participation, whichever occurs first. If a patient is removed from the study due to unacceptable 
adverse events (AEs), the event(s) will be followed until resolution or stabilization of the adverse 
event. Patients who respond and discontinue study treatment for reasons other than PD should 
have response assessments and survival should be collected every month until relapse, death or 
withdrawal of consent for study participation, whichever occurs first. After relapse, data for 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
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survival should be collected every month (i.e. every 28 days ±3 days) until death or withdrawal of 
consent for study participation, whichever occurs first. 
t. 
AE description, grade and start date and resolution date should be documented. 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
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7.2 
Pre-Study Assessments 
Prior to performing any procedures or assessments, the nature of the study and the 
potential risks associated with the trial will be explained to all patient candidates and written 
informed consent will be obtained. Patients who choose to participate will have to consent 
to the biobanking program and will be asked to sign the mandatory section in the main study 
consent form related to biobank samples. Evaluations obtained as part of routine medical 
care and performed during the screening period may be used in place of the study specific 
evaluations. Patients will acknowledge and agree to the possible use of this information for 
the study by giving informed consent.  
 
7.2.1 Screening 
All screening evaluations are to be performed within approximately 28 days of study 
treatment initiation, unless otherwise noted. 
• 
Signed written informed consent  
• 
TP53 mutation determination by central lab. Bone marrow aspirate in EDTA and 
peripheral blood samples in EDTA submitted to central lab. The peripheral blood 
sample may be submitted alone in cases where the aspirate is not obtainable due to 
a dry tap. If local TP53 mutation and/or p53 IHC results become available before 
central TP53 mutation results, enrollment may be made based on local results with 
Medical Monitor approval. 
• 
Medical history  
• 
Physical examination 
• 
Height 
• 
Weight  
• 
ECOG performance status (APPENDIX III) 
• 
Vital signs, including blood pressure, heart rate, respiration rate and temperature 
• 
Hematology, including complete blood count with white blood cell differential.  
• 
Serum chemistry, including sodium, potassium, chloride, magnesium, CO2, BUN, 
creatinine, glucose, calcium, albumin, total protein, total bilirubin, AST, ALT, alkaline 
phosphatase.  
• 
Creatinine clearance (Cockcroft-Gault method; APPENDIX II) 
• 
Serum or urine βhCG must be performed within 7 days prior to study treatment 
initiation for female patients of childbearing potential. 
• 
ECG: standard 12-lead ECGs with patient in a semi-recumbent position in triplicate. 
• 
Concomitant medication review 
• 
Baseline bone marrow aspirate for exploratory objectives. If no aspirate is available, 
then peripheral blood is acceptable. 
 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
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7.2.2 Cycle 1 
7.2.2.1 Cycle 1 Days 1-7  
Day 1 examinations marked * do not need to be repeated if already performed within 3 days 
prior to day 1 cycle 1.   
• 
Clinical toxicity assessment 
• 
Concomitant medications review 
• 
Physical examination: Day 1*  
• 
Weight: Day 1* 
• 
ECOG performance status (Day 1*; APPENDIX III) 
• 
Vital signs, including blood pressure, heart rate, respiration rate and temperature, 
collected 2 hours into APR-246 infusion (± 30 min) and at EOI (± 30 min) 
• 
Hematology (Day 1*), including complete blood count with white blood cell 
differential 
• 
Serum chemistry (Day 1*), including sodium, potassium, chloride, magnesium, CO2, 
BUN, creatinine, glucose, calcium, albumin, total protein, total bilirubin, AST, ALT, 
alkaline phosphatase 
• 
ECG: standard 12-lead ECG with patient in a semi-recumbent position; pre-dose (prior 
to the APR-246 PK blood draw before the infusion) and at the EOI, per Table 12 
• 
APR-246 administration: Days 1 – 4 
• 
Blood sample for APR-246 pharmacokinetics: on Days 1, 2 and 4, per Table 9 
• 
Only in cohorts with venetoclax. Venetoclax administration: once daily, at 
approximately the same time every day. On days 1 – 4 it is recommended that 
venetoclax is taken with a meal and water approximately one hour after start of 
APR-246 infusion. If no prophylactic antifungal agent is administered concurrently, 
the ramp-up phase should consist of 100, 200, and 400 mg of venetoclax once daily 
given on days 1, 2, and 3 of Cycle 1, respectively. If a prophylactic antifungal agent is 
administered concurrently, the ramp-up and maintenance dose of venetoclax should 
be determined based on institutional practice and current prescribing information for 
venetoclax 
• 
Only in cohorts with venetoclax. Blood sample for venetoclax pharmacokinetics in the 
presence of APR-246 (Table 10) 
• 
Only in cohorts with venetoclax. TLS lab monitoring: potassium, phosphorus, calcium 
and uric acid should be evaluated 6 – 8 hr and 24 hr (± 4 hr) after the initial 
administration of venetoclax in order to monitor for potential development of TLS 
• 
Azacitidine administration, only in cohorts with azacitidine. Administered daily for 7 
consecutive days starting on Day 1 (Days 1 to 7 inclusive). The same route should be 
maintained over the 7-day treatment period. On Days 1-4 azacitidine is given 
immediately after APR-246 infusion 
 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
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7.2.2.2 Cycle 1 Day 8 (±3 Days)  
• 
Clinical toxicity assessment 
• 
Concomitant medications review 
• 
Hematology, including complete blood count with white blood cell differential  
• 
Serum chemistry, including sodium, potassium, chloride, magnesium, CO2, BUN, 
creatinine, glucose, calcium, albumin, total protein, total bilirubin, AST, ALT, alkaline 
phosphatase 
• 
Only in cohorts with venetoclax. Venetoclax administration: 400 mg (4 tablets) once 
daily, at approximately the same time every day, with a meal and water. If a 
prophylactic antifungal agent is administered concurrently, the daily dose of 
venetoclax should be determined based on institutional practice and current 
prescribing information for venetoclax 
 
7.2.2.3 Cycle 1 Day 15 (±3 Days)  
• 
Clinical toxicity assessment 
• 
Concomitant medications review 
• 
Hematology, including complete blood count with white blood cell differential  
• 
Serum chemistry, including sodium, potassium, chloride, magnesium, CO2, BUN, 
creatinine, glucose, calcium, albumin, total protein, total bilirubin, AST, ALT, alkaline 
phosphatase 
• 
Only in cohorts with venetoclax. Venetoclax administration: 400 mg (4 tablets) once 
daily, at approximately the same time every day, with a meal and water. If a 
prophylactic antifungal agent is administered concurrently, the daily dose of 
venetoclax should be determined based on institutional practice and current 
prescribing information for venetoclax 
 
7.2.2.4 Cycle 1 Day 22 (±3 Days)  
• 
Clinical toxicity assessment 
• 
Concomitant medications review 
• 
Hematology, including complete blood count with white blood cell differential  
• 
Serum chemistry, including sodium, potassium, chloride, magnesium, CO2, BUN, 
creatinine, glucose, calcium, albumin, total protein, total bilirubin, AST, ALT, alkaline 
phosphatase 
• 
Only in cohorts with venetoclax. Blood sample for venetoclax pharmacokinetics in the 
presence of APR-246 (Table 10) 
• 
Bone marrow sample for response assessment (blasts percentage). In patients with 
bone marrow hypocellularity, venetoclax may need to be held and restarted after 
recovery of blood counts (ANC ≥0.5 × 109/L, and platelets ≥25 × 109/L), confirmed by 
repeat bone marrow biopsy on Day 35 and following discussion with Medical Monitor. 
 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
68 of 103 
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7.2.2.5 Weekly Assessments 
• 
Clinical toxicity assessment 
• 
Concomitant medications review 
• 
Hematology, including complete blood count with white blood cell differential 
• 
Serum chemistry, including sodium, potassium, chloride, magnesium, CO2, BUN, 
creatinine, glucose, calcium, albumin, total protein, total bilirubin, AST, ALT, alkaline 
phosphatase 
 
7.2.3 Cycle 2 Day 1 ±3 Day and Onwards (Cycle 3+) 
These tests should be performed prior to first dose 
• 
Clinical toxicity assessment 
• 
Concomitant medications review 
• 
Physical examination: Day 1*  
• 
Weight  
• 
ECOG performance status (Day 1; APPENDIX III) 
• 
Vital signs 
• 
Hematology (Day 1*), including complete blood count with white blood cell differential 
• 
Serum chemistry (Day 1*), including sodium, potassium, chloride, magnesium, CO2, 
BUN, creatinine, glucose, calcium, albumin, total protein, total bilirubin, AST, ALT, 
alkaline phosphatase 
• 
ECGs: see Table 12 
 
7.2.3.1 Cycle 2 Days 1-7  
• 
Clinical toxicity assessment 
• 
Concomitant medications review 
• 
Vital signs, including blood pressure, heart rate, respiration rate and temperature, 
collected 2 hours into APR-246 infusion (± 30 min) and at EOI (± 30 min) 
• 
Only in cohorts with venetoclax. Venetoclax administration: 400 mg (4 tablets) once 
daily, at approximately the same time every day, with a meal and water. If a 
prophylactic antifungal agent is administered concurrently, the daily dose of 
venetoclax should be determined based on institutional practice and current 
prescribing information for venetoclax. Note: Day 4 of Cycles 2–5 only: Blood sample 
for venetoclax pharmacokinetics in the presence of APR-246 (Table 10) 
• 
APR-246 administration: Days 1 – 4 
• 
Azacitidine administration, only in cohorts with azacitidine. Administered daily for 7 
consecutive days starting on Day 1 (Days 1 to 7 inclusive). The same route should be 
maintained over the 7-day treatment period. On Days 1-4 azacitidine is given 
immediately after APR-246 infusion 
• 
Blood sample for APR-246 pharmacokinetics: on Day 4, per Table 9. Samples for APR-
246 to be taken 1-3 hours after completion of APR-246 administration. 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
69 of 103 
28 October 2021 
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• 
ECG: standard 12-lead ECGs with patient in semi-recumbent position prior to the PK 
blood draw before APR-246 infusion on Day 1, per Table 12 
 
7.2.3.2 Cycle 2 Day 8 (±3 Days) 
• 
Clinical toxicity assessment 
• 
Concomitant medications review 
• 
Hematology, including complete blood count with white blood cell differential, weekly 
• 
Serum chemistry, including sodium, potassium, chloride, magnesium, CO2, BUN, 
creatinine, glucose, calcium, albumin, total protein, total bilirubin, AST, ALT, alkaline 
phosphatase, weekly 
• 
Only in cohorts with venetoclax. Venetoclax administration: 400 mg (4 tablets) once 
daily, at approximately the same time every day, with a meal and water. If a 
prophylactic antifungal agent is administered concurrently, the daily dose of 
venetoclax should be determined based on institutional practice and current 
prescribing information for venetoclax 
 
7.2.3.3 Cycle 2 Day 15 (±3 Days) 
• 
Clinical toxicity assessment 
• 
Concomitant medications review 
• 
Hematology, including complete blood count with white blood cell differential, weekly 
• 
Serum chemistry, including sodium, potassium, chloride, magnesium, CO2, BUN, 
creatinine, glucose, calcium, albumin, total protein, total bilirubin, AST, ALT, alkaline 
phosphatase, weekly 
• 
Only in cohorts with venetoclax. Venetoclax administration: 400 mg (4 tablets) once 
daily, at approximately the same time every day, with a meal and water. If a 
prophylactic antifungal agent is administered concurrently, the daily dose of 
venetoclax should be determined based on institutional practice and current 
prescribing information for venetoclax 
 
7.2.3.4 Cycle 2 Day 22 (±3 Days) 
• 
Clinical toxicity assessment 
• 
Concomitant medications review 
• 
Hematology, including complete blood count with white blood cell differential, weekly 
• 
Serum chemistry, including sodium, potassium, chloride, magnesium, CO2, BUN, 
creatinine, glucose, calcium, albumin, total protein, total bilirubin, AST, ALT, alkaline 
phosphatase, weekly 
• 
Only in cohorts with venetoclax. Venetoclax administration: 400 mg (4 tablets) once 
daily, at approximately the same time every day, with a meal and water. If a 
prophylactic antifungal agent is administered concurrently, the daily dose of 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
70 of 103 
28 October 2021 
Confidential - Entire Page 
venetoclax should be determined based on institutional practice and current 
prescribing information for venetoclax 
 
7.2.4 End of Odd Numbered Cycles 
• 
Response assessment, based on peripheral blood (blasts percentage) 
 
7.2.5 End of Even Numbered Cycles 
• 
Bone marrow sample for response assessment (blasts percentage) 
• 
Bone marrow aspirate for exploratory objectives (if no aspirate is available, then 
peripheral blood is acceptable) 
 
7.3 
End of Treatment Visit 
This visit should take place within 28 days of the last dose of study treatment, if treatment is 
stopped early for any reasons.   
 
• 
Physical examination 
• 
Weight  
• 
Vital signs 
• 
Disease assessment 
• 
Bone marrow aspirate for exploratory objectives. If no aspirate is available, then 
peripheral blood is acceptable 
• 
ECOG performance status (APPENDIX III) 
• 
Hematology, including complete blood count with white blood cell differential 
• 
Serum chemistry, including sodium, potassium, chloride, magnesium, CO2, BUN, 
creatinine, glucose, calcium, albumin, total protein, total bilirubin, AST, ALT, alkaline 
phosphatase 
• 
Clinical toxicity assessment up to 30 days after the last dose 
 
7.4 
Long-Term Follow-Up 
Long-term follow-up can be done remotely (e.g. via telephone, via local practitioner or via 
review of medical records). After a patient is removed or withdrawn from the study, the 
patient will be followed until death or withdrawal of consent for study participation. Off-
treatment data on overall survival will be updated every month (i.e. every 28 days ±3 days) 
or until death, whichever occurs first. If a patient is removed from the study due to 
unacceptable AEs, the event(s) will be followed until resolution or stabilization of the AE. 
Patients who respond and discontinue study treatment for reasons other than PD should 
have response assessments and survival should be collected every month until relapse or 
death, whichever occurs first. After relapse, data for survival should be collected every month 
until death or withdrawal of consent for study participation, whichever occurs first. 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
71 of 103 
28 October 2021 
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8.0 STUDY ASSESSMENTS 
8.1 
Safety Assessments 
8.1.1 Safety Analysis 
Safety data will be tabulated for all patients and include vital signs, laboratory parameters, 
and AEs. 
 
8.1.2 Reporting of Adverse Events 
8.1.2.1 Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product that does not necessarily have a causal relationship 
with the treatment. An AE can be any unfavorable and unintended sign (including a 
laboratory finding), symptom or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product.  
 
The treatment-emergent AE reporting period starts at study treatment initiation. All 
treatment-emergent AEs will be collected for up to 30 days after the last dose of study 
treatment. At each evaluation, patients should be interviewed in a non-directed manner to 
elicit potential adverse reactions from the patient. The occurrence of an AE will be based on 
changes in the patient’s physical examination, laboratory results, and/or signs and 
symptoms. 
 
On Cycle 1, Day 1, any events observed from the time of signing informed consent but prior 
to initial study drug administration will be recorded as a serious or non-serious adverse 
event, if considered by the Investigator to be causally related to a study-required procedure 
or activity that was conducted prior to Cycle 1, Day 1 (i.e., screening period). Events observed 
from the time of signing informed consent, but prior to initial study drug administration that 
are not considered to be causally related to a study-required procedure or activity should be 
recorded on the medical history CRF page.  
 
All AEs (except Grade 1 and 2 laboratory abnormalities that do not require an intervention), 
regardless of causal relationship, are to be recorded in the CRF and source documentation. 
The Investigator must determine the intensity of any AEs according to the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 and their causal relationship. 
Those AEs not covered by these criteria will be graded as follows:  
 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
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1. 
Mild: Discomfort noticed, but no disruption of normal daily activity. Prescription drug 
not ordinarily needed for relief of symptom but may be given because of personality 
of patient. 
2. 
Moderate: Discomfort sufficient to reduce or affect normal daily activity. Patient is 
able to continue in study; treatment for symptom may be needed. 
3. 
Severe: Incapacitating, severe discomfort with inability to work or to perform normal 
daily activity. Severity may cause cessation of treatment with test drug; treatment for 
symptom may be given and/or patient hospitalized. 
4. 
Life-Threatening: Symptom(s) place the patient at immediate risk of death from the 
reaction as it occurred; it does not include a reaction that, had it occurred in a more 
serious from, might have caused death. 
5.  
Fatal: Event caused the death of the patient.  
 
AEs will be followed until resolution or stabilization while the patient remains on-study. Once 
the patient is removed from study, events thought to be related to the study medication will 
be followed until resolution or stabilization, unless, in the Investigator’s opinion the event is 
unlikely to resolve due to the patient’s underlying disease, or until the patient starts a new 
treatment regimen or the patient is lost to follow-up. 
 
8.1.2.2 Attribution Definitions 
An AE is considered to be associated with the use of the study treatment if the attribution is 
determined as possible, probable or definite. Attribution of AEs will be recorded in the CRF 
as: 
 
• 
Unrelated: The AE is clearly not related to the study treatment. 
• 
Unlikely: The AE is doubtfully related to the study treatment. 
• 
Possible: The AE may be related to the study treatment. 
• 
Probable: The AE is likely related to the study treatment. 
• 
Definite: The AE is clearly related to the study treatment. 
 
8.1.2.3 Definition of an Unexpected Adverse Event 
An unexpected AE is defined as any adverse drug experience, the specificity or severity of 
which is not consistent with the current Investigator Brochure; or, if an Investigator Brochure 
is not available, the specificity or severity of which is not consistent with the risk information 
described in this protocol or in the regulatory agency study authorization application.   
 
For study treatments used in this protocol that have been approved for use in the US by the 
FDA (i.e., venetoclax, and azacitidine), the reference safety information that will be used for 
making expectedness decisions is the most current version of the product USPI that can be 
found on the FDA website.   
 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
73 of 103 
28 October 2021 
Confidential - Entire Page 
Unexpected, as used in this definition, refers to an adverse drug experience that has not 
been previously observed (e.g., included in the Investigator’s Brochure or USPI, as applicable) 
rather than from the perspective of such experience not being anticipated from the 
pharmacological properties of the pharmaceutical product. 
 
8.1.2.4 Serious Adverse Event (SAE) 
A serious adverse event is defined as any untoward medical occurrence that at any dose: 
 
1. 
Results in death, 
2. 
Is life-threatening (i.e., the patient was at risk of death at the time of the event. It does 
not refer to an event which hypothetically might have caused death if it was more 
severe), 
3. 
Requires in-patient hospitalization or prolongation of existing hospitalization 
excluding that for pain management, disease staging/re-staging procedures, or 
catheter placement unless associated with other serious events, 
4. 
Results in persistent or significant disability/incapacity, or 
5. 
Is a congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse drug events when, based on appropriate 
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
 
8.1.2.5 Pregnancy 
Any pregnancy detected during the study, or that occurs within 30 days after stopping study 
medication, must be reported immediately to the Investigator. Pregnancy, in and of itself, is 
not regarded as an AE, unless there is suspicion that study medication may have interfered 
with the effectiveness of a contraceptive medication. If the patient becomes pregnant while 
on-study, the study drug should be immediately discontinued. Pregnancy information about 
a female patient or a female partner of a male patient should be reported immediately from 
the time the Investigator first becomes aware of a pregnancy or its outcome. This will be 
performed by the Investigator per instructions from the Sponsor’s monitoring CRO.  
 
Any pregnancy complication, spontaneous abortion, elective termination of a pregnancy for 
medical reasons, outcome of stillbirth, congenital anomaly/birth defect, or serious adverse 
event in the mother will be recorded as an SAE and will be reported as described in Section 
8.1.2.6.  
 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
74 of 103 
28 October 2021 
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8.1.2.6 Reporting of Serious Adverse Events 
AEs classified as serious require expeditious handling and reporting to Sponsor’s monitoring 
CRO to comply with regulatory requirements. 
 
For any serious adverse event (SAE) that occurs while a patient is on-study; within 30 days of 
the last study treatment administration, regardless of any opinion as to the relationship of 
the SAE to the study treatment; or if any SAE that the Investigator feels is related to the study 
treatment occurs later than 30 days after the last study treatment administration, the 
Sponsor’s monitoring CRO must be notified immediately (within 24 hours of becoming aware 
of the event) by electronic data capture (EDC) system, email, fax or telephone. Notification 
by email is preferred. The primary mechanism for reporting an SAE to the sponsor will be 
the electronic data collection tool. An SAE eCRF should be completed in the electronic data 
capture (EDC) system within 24 hours of site becoming aware of the event. EDC Alerts will be 
sent to Safety desk for all SAEs. 
 
If the EDC system is inaccessible/unavailable, then the site will use the paper SAE form in 
order to report the SAE within 24 hours. Emailing the paper SAE forms is the preferred 
method of notification. 
 
SAEs will be reported to: Email:
 
 
8.1.2.7 Safety Monitoring Plan  
The medical monitor is responsible for ongoing safety monitoring for the study per the 
detailed safety plan. This monitoring will include a review of all serious AEs as they are 
reported by the study site. The medical monitor will also be in contact with site monitors and 
will be available to discuss any issues concerning safety with site staff. Safety data will be 
reviewed periodically by 
 and the Sponsor Medical Officer. 
 
DRT consisting of the Medical Monitor, Site Principal Investigators, and other clinical research 
personnel that the Sponsor may deem appropriate, will hold DRM on an interim basis at a 
frequency dependent on study accrual. At these meetings, the DRT will review AEs and DLTs 
and make recommendations regarding the RP2D. In the expansion portion of the study, the 
DRT will evaluate safety and tolerability after 5 patients have completed 1 cycle of treatment 
in each cohort. All accumulated safety data will be discussed during DRMs. 
 
The DRT will produce summaries or minutes of these meetings. These summaries will be 
available for inspection when requested by any of the regulatory bodies charged with the 
safety of human subjects and the integrity of data. 
 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
75 of 103 
28 October 2021 
Confidential - Entire Page 
8.2 
Efficacy Assessments 
8.2.1 Complete Remission Rate  
CR rate will be defined as the proportion of patients who achieve CR. 
 
8.2.2 Duration of Response 
DoR will be measured from the time of initial response to disease relapse/progression or 
death. 
 
8.2.3 Overall Response Rate 
Overall response rate (ORR) will be defined as the proportion of patients achieving CR, CRi, 
complete remission with CRp, partial remission (PR) and MLFS by the IWG 2003 AML criteria 
(APPENDIX I). 
 
8.2.4 Overall Survival 
Overall survival (OS) is defined for all enrolled patients, as measured from the date of 
enrollment until the date of death. 
 
8.2.5 Stem Cell Transplant  
Patients may go on to receive SCT and this is likely to be a reflection of a positive outcome to 
treatment. The primary approach will be to use a treatment policy strategy (ICH E9 (R1) 
addendum) where patients who receive SCT will continue to be followed for OS and relapse 
from any response with their date of death/relapse used in the analysis. If for any reason a 
patient receives SCT prior to a documented CR they will not be counted as a response. 
Sensitivity analyses may be performed as counting post-SCT CR/PR as a response.   
 
8.3 
Progression-Free Survival (PFS) 
Progression-free survival (PFS) is defined for each patient as the time from start of treatment 
to the date of the first documented progression or death due to any cause. Patients who die 
without a reported prior progression will be considered to have progressed on the date of 
their death. Patients who did not progress or die will be censored on the date of their last 
evaluable tumor assessment. Patients who started any subsequent therapy without a prior 
reported progression will be censored at the last evaluable tumor assessment prior to the 
initiation of the subsequent anticancer therapy. 
 
8.4 
Pharmacokinetics  


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
76 of 103 
28 October 2021 
Confidential - Entire Page 
Plasma concentrations of APR-246 will be measured in Cycle 1, at the timepoints provided in 
Table 9. Please refer to sections 2.3 and 6.4, regarding the risk of certain drugs and foods 
influencing the PK of venetoclax such as grapefruits (see APPENDIX VII). This is important 
both for patient safety and for enabling a correct assessment of an unlikely drug-drug 
interaction between the study drug APR-246 and venetoclax from PK samples.   
Table 9. PK Blood Sampling Timepoints for APR-246 
APR-246 plasma collection timepoints a 
Cycle 1 
 
Subsequent 
Cycles 
D1 
D2 
D4 
D4 
Prior to APR-246 infusion 
× 
× 
× 
× 
At the end of APR-246 infusion 
× 
 
× 
× 
1 hour after the end of APR-246 infusion 
× 
 
× 
× c 
3 hours after the end of APR-246 infusion 
b 
× 
 
 
 
a A window of ±15 min applies to each time point. 
b Samples are collected as part of the venetoclax PK sampling scheme below (Table 10). A single PK sample 
should be drawn and split into 2 samples for analysis of both drugs at these timepoints. 
c Sample collected between 1 and 3 hours after the end of infusion. 
 
Only in cohorts with venetoclax, plasma concentrations of venetoclax will be measured in 
Cycle 1, at the timepoints provided in Table 10, and then prior to venetoclax administration 
on Day 4 of Cycles 2 – 5 (Table 11). 
 
Table 10. PK Blood Sampling Timepoints for Venetoclax in Cycle 1 
Venetoclax plasma collection timepoints 
D1 
D2 
D22 
D23 
Prior to venetoclax administration a 
× 
× 
× 
× 
2 hours following venetoclax administration 
b 
x 
 
x 
 
3 hours following venetoclax administration 
c 
× 
 
× 
 
4 hours following venetoclax administration 
d 
× 
 
× 
 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
77 of 103 
28 October 2021 
Confidential - Entire Page 
6 hours following venetoclax administration 
e 
× 
 
× 
 
8 hours following venetoclax administration f 
× 
 
× 
 
 
a Baseline sample collected prior to venetoclax administration. On Day 1, it is recommended that 
venetoclax is given 1 hour after the start of APR-246 infusion (±10 min), following a meal that will start 
approximately 15 minutes after initiation of APR-246 infusion. On Day 1, the baseline sample prior to 
APR-246 infusion can be split into two samples and used as pre-dose sample for venetoclax as well. 
b 3 hours following initiation of APR-246 infusion on Day 1 (±15 min) 
c 4 hours following initiation of APR-246 infusion on Day 1 (±15 min) 
d 5 hours following initiation of APR-246 infusion on Day 1 (±15 min) 
e 7 hours following initiation of APR-246 infusion on Day 1 (±15 min). This blood draw is also used for 
the 3rd sample for APR-246 measurements (Table 10; 1 hour after EOI). 
f 9 hours following initiation of APR-246 infusion on Day 1 (±30 min). This blood draw is also used for 
the 4th sample for APR-246 measurements (Table 10; 3 hours after EOI) 
 
Table 11. PK Blood Sampling Timepoints for Venetoclax in Cycles 2-5 
Venetoclax plasma collection timepoints 
Day 4 
Prior to venetoclax administration a 
× 
 
8.5 
Electrocardiographic Assessment 
Table 12 describes the routine ECG requirements from screening through Cycle 4: 
Table 12. ECG Assessment Requirements 
Time Point 
ECG, number 
Timing 
Baseline/Screening Triplicate 
Must be within 28 days of C1D1 
Cycle 1, Days 1-4 
Triplicate 
Pre-dose; Post dose (6 hrs. after start of infusion; ± 
30 min) 
Cycles 2+, Day 1 
Triplicate 
Pre-dose 
 
If repeated QTcF measurements show a stable QTcF < 450 msec, or if QTcF remains stable 
within the interval of 450–469 msec with no significant change at the EOI during several 
cycles of treatment, reducing the number of ECGs performed in the study may be discussed 
with the Medical Monitor. 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
78 of 103 
28 October 2021 
Confidential - Entire Page 
If a patient starts treatment with another medication known to prolong QT interval at any 
time during the study therapy, an additional pre- and post-dose (6 hours after start of 
infusion, ±30 min) ECG should be performed on the next treatment day. 
Please consult Section 6.3.1 for additional requirements for proceeding with treatment with 
APR-246. 
 
8.6 
TP53 Testing 
Patients are enrolled based on the central lab result confirming at least one TP53 mutation 
not defined as benign or likely benign (see Laboratory Manual for mutation algorithm) in the 
bone marrow aspirate sample. The central peripheral blood sample may be used for 
enrollment in the event a TP53 mutation is not detected in the bone marrow aspirate sample 
or if the bone marrow aspirate cannot be obtained due to a dry tap.  
If local TP53 mutation and/or p53 IHC results become available before central TP53 mutation 
results, enrollment may be made based on local results with Medical Monitor approval.  
 
9.0 STATISTICS 
Demographic data and disease-related characteristics will be summarized using descriptive 
statistics (count and percent, mean, median, standard deviation, minimum, maximum). 
Continuous variables will be presented by n, mean, median, standard deviation and range 
(minimum and maximum), and categorical variables will be presented by count and 
percentage of patients as appropriate. Data will be presented by each dose cohort in safety 
lead-in dose-finding portion and by each treatment arm and dose cohort in the expansion 
portion. All patient data, efficacy and safety data will be summarized.   
 
9.1 
Sample Size 
This trial assumes a sample size of 12–36 patients (6–18 patients for each cohort) in the safety 
lead-in portion of the study and approximately 70 patients in the expansion portion of the 
study. 
In expansion cohorts 2 and 5, Simon’s two-stage “minimax” design will be used with alpha 
level of 0.05 and power of 80%. The null response rate will be set to 20% and the target 
response rate will be 40%. At the first stage if more than 4 responders in 18 patients 
observed, then the cohort will be continued to enroll another 15 patients in the second stage. 
A total of 11 responders or more in 33 patients will indicate the response rate is higher than 
the null response rate. 
 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
79 of 103 
28 October 2021 
Confidential - Entire Page 
9.2 
Analysis Populations 
Safety population: Patients will be evaluable for safety if they receive at least one dose of 
APR-246 with venetoclax and/or azacitidine. The safety population will be used to summarize 
exposure and safety parameters. 
 
DLT-evaluable population: All patients who either experienced a DLT during first 4 weeks 
(Cycle 1) of the study treatment or received ≥80% of scheduled Cycle 1 dose of APR-246 in 
combination with venetoclax and/or azacitidine and did not experience a DLT. Any individual 
patient who is not evaluable for DLT will be replaced by a new patient through additional 
patient enrollment. 
 
Efficacy evaluable (EE) population: All patients who complete at least one treatment cycle of 
APR-246 in combination with venetoclax and/or azacitidine and who have at least one post-
treatment clinical response assessment. Patients who fail to complete one treatment cycle 
will also be considered EE if they show clear evidence of clinically significant disease 
progression. The EE population will be the secondary analysis population for efficacy. 
 
Pharmacokinetics (PK) population: Patients will be evaluable for pharmacokinetics if at least 
one post-dose sample for PK evaluation has been obtained. 
 
9.3 
Endpoints 
9.3.1 Primary 
• 
DLTs, classified and graded according to the NCI CTCAE, version 5.0. 
• 
Frequency of treatment-emergent adverse events (TEAEs), and serious adverse events 
(SAEs) related to APR-246 in combination with venetoclax and/or azacitidine during 
the trial. 
• 
The RP2D of APR-246 (the dose at which <2 out of 6 patients experience dose-limiting 
toxicity during the safety assessment period). 
 
9.3.2 Secondary  
1. CR rate, defined as the proportion of patients who achieve CR. 
2. CR + CRi rate, defined as the proportion of patients who achieve CR or CRi.  
3. CR + CRh rate, defined as the proportion of patients who achieve CR or CRh. 
4. ORR, defined as the proportion of patients achieving CR, CRi, CRp, PR and MLFS by the 
IWG 2003 AML criteria (APPENDIX I). The CRh rate will also be determined and is 
defined as bone marrow blasts <5%, ANC >0.5 × 109/L and platelets >50 × 109/L. 
5. OS, measured from the date of initiating study treatment to the date of death. Patients 
who have not died by the analysis data cut-off date will be censored at their last date 
of contact. 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
80 of 103 
28 October 2021 
Confidential - Entire Page 
6. Rate of RBC and/or platelet TI for at least 56 days 
7. PFS, defined from the date of initiating study treatment to the date of disease 
progression per IWG 2003 AML criteria (APPENDIX I) or death as a result of any cause. 
8. Proportion of patients who transition to HSCT. 
9. Pharmacokinetic parameters: Cmax, AUC, Vd and CL of APR-246 and Tmax, Cmax and AUC 
of venetoclax. 
 
9.3.3 Exploratory 
• 
Exploratory molecular analyses may include, but are not limited to: TP53 VAF by NGS, 
p53 IHC, mutations in other genes by NGS, RNA expression. 
 
9.4 
Safety 
Safety data will be summarized for the safety population. These data will include AEs, ECGs 
and laboratory parameters. AE terms will be coded using the Medical Dictionary for Drug 
Regulatory Activities (MedDRA)®, version 22 or higher. AEs will be summarized by System 
Organ Class (SOC), preferred term, severity, and relationship to treatment. Serious adverse 
events, deaths, and AEs leading to dose modifications including early discontinuation of 
study treatment will be summarized. Laboratory parameters will be summarized by 
maximum NCI CTCAE version 5.0 severity grade and also by change from pre-treatment to 
scheduled time points using descriptive statistics. Laboratory parameter listings will include 
the normal ranges for each parameter. Each value will be classified as falling above, below, 
or within the normal range.  
 
Only AEs related to study screening procedures are to be collected prior to the initiation of 
study treatment. Data summaries will include only treatment-emergent adverse events 
(TEAEs), defined as events occurring at the start of infusion on Day 1, Cycle 1 up to and 
including 30 days after last dose. 
 
9.5 
Efficacy 
CR will be summarized for all enrolled patients as the proportion of patients (%) with CR. In 
addition to presenting the CR rate, its associated exact 95% CI for each treatment arm will 
also be presented. CR rate will not be formally compared between treatment arms. 
DoR will be defined as the time from the date when criteria for response are met to the date 
of PD or death due to any cause, whichever occurs first. Patients that are alive without 
relapse or progression will have their DOR censored at the date of the last clinical 
assessment. The duration of CR will be summarized in each treatment arm by providing 
DOCR and DOR, using Kaplan-Meier methodology. DoR endpoints will not be formally 
compared between treatment arms. 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
81 of 103 
28 October 2021 
Confidential - Entire Page 
Overall response will be summarized in number (%) of patients in each category of responses 
and ORR will be analyzed by using the similar method as CR rate.  
Survival data will be collected at treatment and follow-up periods. Patients will be followed 
until death, or withdrawal of consent for study participation. OS is defined as the number of 
days from the date of enrollment to the date of death. Kaplan-Meier methodology will be 
utilized. 
PFS will be defined as the time from the date of enrollment to disease progression or death 
from AML whichever occurs first. If neither event occurs, PFS will be censored at the date of 
the last assessment. Kaplan-Meier methodology will be utilized. 
Transition rate to SCT will be analyzed using the similar methods as CR. 
 
9.6 
Pharmacokinetic Analysis 
The pharmacokinetics of APR-246 and venetoclax will be summarized using descriptive 
statistics (mean, standard deviation, CV% mean, geometric mean, CV% geometric mean) and 
compared with historical control data. 
APR-246 and venetoclax concentrations will be determined, and PK parameters (Cmax, Tmax, 
AUC, Vd and CL) will be derived using population pharmacokinetic or non-compartmental 
methods. 
 
APR-246 concentrations will be determined by a validated high-performance liquid 
chromatography (HPLC) tandem mass spectrometry (LC/MS/MS) method. A population PK 
model will be used to estimate PK parameters Cmax, AUC and CL for each individual patient. 
APR-246 AUC and Cmax will then be tested for association with signs of efficacy and safety in 
the presence of venetoclax. If an observable trend exists, a PK/PD model will be developed 
to evaluate the exposure-response relationship between APR-246 plasma exposure and 
outcome measures. Demographic and clinical data (ethnicity, current age, body weight, sex, 
disease status, etc.) will be utilized to assess interpatient variability in the PK and PK/PD 
relationships. 
 
APR-246 PK parameters will be compared to historical controls for the assessment of drug-
drug interactions. 
 
9.7 
Exploratory analyses 
Descriptive statistics/results from exploratory molecular analyses will be written and may 
include, but are not limited to: TP53 VAF by NGS, p53 IHC, mutations in other genes by NGS, 
RNA expression. Please consult Laboratory Manual regarding details on the exploratory 
biomarker sample processing. 
 
 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
82 of 103 
28 October 2021 
Confidential - Entire Page 
10.0 QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES 
10.1 Monitoring of the Study and Regulatory Compliance 
The project manager, or designee, will make an initiation site visit to each institution to 
review the protocol and its requirements with the Investigator(s), inspect the drug storage 
area, fully inform the Investigator of his/her responsibilities and the procedures for assuring 
adequate and correct documentation. During the initiation site visit the CRFs will be 
reviewed. Other pertinent study materials will also be reviewed with the Investigator’s 
research staff. During the course of the study, the monitor will make regular site visits in 
order to review protocol compliance, examine CRFs and individual patient’s medical records 
and assure that the study is being conducted according to pertinent regulatory 
requirements. All CRF entries will be verified with source documentation. The review of 
medical records will be done in a manner to assure that patient confidentiality is maintained.  
 
10.2 Curricula Vitae and Financial Disclosure of Investigators  
All Principal Investigators will be required to provide a current signed and dated curriculum 
vitae, a completed FDA Form 1572 and a financial disclosure statement to Sponsor’s 
monitoring CRO. All Sub-Investigators will be required to provide a current curriculum vitae 
and a financial disclosure statement to Sponsor’s monitoring CRO. 
 
10.3 Protocol Modifications 
No modification of the protocol should be implemented without the prior written approval 
of the Sponsor or the Sponsor’s representative. Any such changes which may affect a 
patient’s treatment or informed consent, especially those increasing potential risks, must 
receive prior approval by the IRB/IEC. The exception to this is where modifications are 
necessary to eliminate an immediate hazard to trial patients, or when the change involves 
only logistical or administrative aspects of the trial (e.g., change in monitor, change in 
telephone number). Other administrative revisions which may impact the clinical portion of 
a study will be duly reported to the IRB/IEC by the Principal Investigator. 
 
10.4 Publication Policy 
The publication of the results of the study will be subject to the terms and conditions of the 
clinical trial agreement between the Sponsor and Investigators. Sponsor approval is required 
for publication of any data from this trial.  
 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
83 of 103 
28 October 2021 
Confidential - Entire Page 
11.0 ETHICAL CONSIDERATIONS 
11.1 Informed Consent 
The Investigator will obtain written informed consent from each patient, or their authorized 
representative, participating in the study. The form must be signed, witnessed and dated. 
The informed consent form will contain all the Essential Elements of Informed Consent set 
forth in 21 CFR, Part 50, the European Union Directive 2001/20/EC and its associated Detailed 
Guidances, European Union GCP Directive 2005/28/EC, the ICH Guideline for GCP, 
Section 4.8, and the terms of the Declaration of Helsinki (2013). Copies of the signed 
document should be given to the patient and filed in the Investigator’s study file, as well as 
the patient’s medical record if in conformance with the institution’s Standard Operating 
Procedures.  
 
11.2 Institutional Review Board/Independent Ethics Committee 
The study will not be initiated without approval of the appropriate IRB/IEC and compliance 
with all administrative requirements of the governing body of the institution. This protocol, 
consent procedures, and any amendments must be approved by the IRB/IEC in compliance 
with current regulations of the FDA and the European Union as applicable and in accordance 
with ICH/GCPs. A letter of approval will be sent to the Sponsor prior to initiation of the study 
and when any subsequent modifications are made. The IRB/IEC will be kept informed by the 
Investigator, Sponsor’s monitoring CRO or the Sponsor, as required by national regulations, 
as to the progress of the study as well as to any serious and unexpected AEs.  
 
11.3 Patient Privacy  
In order to maintain patient confidentiality, all CRFs, study reports and communications 
relating to the study will identify patients by initials and assigned patient numbers; patients 
should not be identified by name. In accordance with local, national or federal regulations, 
the Investigator will allow the Sponsor or designee personnel access to all pertinent medical 
records in order to verify the data gathered on the CRFs and to audit the data collection 
process. Regulatory agencies such as the U.S. FDA may also request access to all study 
records, including source documentation for inspection. Clinical information will not be 
released without the written permission of the patient as outlined in the patient consent 
form. 
 
12.0 DATA HANDLING AND RECORD KEEPING 
12.1 Data to be Entered Directly in the Case Report Form 
The CRF will be the source record. 
 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
84 of 103 
28 October 2021 
Confidential - Entire Page 
12.2 Recording of Data 
Data collected during the study will be entered in the patient’s CRF by the investigational site 
staff. The staff will keep records of the patient’s visit in the files considered as source 
documents for the site, e.g., hospital chart, research chart. The Investigator will be 
responsible for the recording of all data on the CRF and for submitting the data to the 
Sponsor or their designee in a timely manner. Should any value be significantly different 
from normal, the Investigator will comment in the appropriate sections provided in the CRF.  
 
The Investigator will provide access to his/her original records to permit a representative 
from the Sponsor to verify the proper transcription of data. To facilitate photocopying, 
entries must be recorded legibly in black ink only. Erroneous entries will be crossed out with 
a single line, so as to remain legible. The correct value will be entered above the error and 
then initialed and dated by the person authorized to make the correction. 
 
12.3 Study Records 
U.S. Federal laws require that an Investigator maintain all study records for the indication 
under investigation for two years following the date a Product Licensing Application is 
approved or, if no application is to be filed or if the application is not approved for such 
indication, until two years after the investigation is discontinued and the FDA is notified. 
 
 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
85 of 103 
28 October 2021 
Confidential - Entire Page 
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DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or 


Aprea Therapeutics  
Protocol Number A19-11184  
A Phase I Study of APR-246 in Combination 
with Venetoclax and/or Azacitidine in AML 
 
1184_CSP 5.0 
86 of 103 
28 October 2021 
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Rucker FG, Schlenk RF, Bullinger L, et al. TP53 alterations in acute myeloid leukemia 
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karyotype, and dismal outcome. Blood. 2012;119(9):2114-2121. doi:10.1182/blood-
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Sigal A, Rotter V. Oncogenic mutations of the p53 tumor suppressor: the demons of 
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Bowen D, Groves MJ, Burnett AK, et al. TP53 gene mutation is frequent in patients 
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poor prognosis. Leukemia. 2009;23(1):203-206. doi:10.1038/leu.2008.173 
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Wong TN, Ramsingh G, Young AL, et al. Role of TP53 mutations in the origin and 
evolution of therapy-related acute myeloid leukaemia. Nature. 2015;518(7540):552-
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Yanada M, Yamamoto Y, Iba S, et al. TP53 mutations in older adults with acute 
myeloid leukemia. Int J Hematol. 2016;103(4):429-435. doi:10.1007/s12185-016-1942-
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Seifert H, Mohr B, Thiede C, et al. The prognostic impact of 17p (p53) deletion in 2272 
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Parkin B, Erba H, Ouillette P, et al. Acquired genomic copy number aberrations and 
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Nakano Y, Naoe T, Kiyoi H, et al. Prognostic value of p53 gene mutations and the 
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Bories C. A Multidisciplinary Approach to Testing and Diagnosis, Evaluation of Risk, 
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Meeting 2018. ; 2018. 
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in older patients with acute myeloid leukemia treated with azacitidine or 
conventional care. Leukemia. 2018;32(12):2546-2557. doi:10.1038/s41375-018-0257-z 
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DiNardo CD, Rausch CR, Benton C, et al. Clinical experience with the BCL2-inhibitor 
venetoclax in combination therapy for relapsed and refractory acute myeloid 
leukemia and related myeloid malignancies. Am J Hematol. 2018;93(3):401-407. 
doi:10.1002/ajh.25000 
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Pollyea DA, Stevens BM, Jones CL, et al. Venetoclax with azacitidine disrupts energy 
metabolism and targets leukemia stem cells in patients with acute myeloid leukemia. 
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Al-Ali HK, Jaekel N, Junghanss C, et al. Azacitidine in patients with acute myeloid 
leukemia medically unfit for or resistant to chemotherapy: a multicenter phase I/II 
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Lehmann S, Bykov VJN, Ali D, et al. Targeting p53 in Vivo: A First-in-Human Study With 
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Deneberg S, Cherif H, Lazarevic V, et al. An open-label phase I dose-finding study of 
APR-246 in hematological malignancies. Blood Cancer J. 2016;6(7):e447. 
doi:10.1038/bcj.2016.60 
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Sallman DA, DeZern A, Sweet K, et al. Abstract CT068: Phase Ib/II combination study 
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Sallman D, DeZern A, Garcia‐Manero G, Steensma DP, Roboz GJ. Phase 2 Results of 
APR-246 and Azacitidine (AZA) in Patients with TP53 mutant Myelodysplastic 
Syndromes (MDS) and Oligoblastic Acute Myeloid Leukemia (AML). In: ; 2019. 
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Fenaux P, Steensma DP, Van Eygen K. Treatment with Imetelstat Provides Durable 
Transfusion Independence in Heavily Transfused Non-Del(5q) Lower Risk MDS 
Relapsed/Refractory to Erythropoiesis-Stimulating Agents. In: ; 2019. 
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VIDAZA (azacitidine for injection), Highlights of Prescribing Information. 2018. 
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FDA, CDER. Venetoclax Prescribing Information. www.fda.gov/medwatch. Accessed 
June 24, 2019. 
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Aprea Therapeutics. APR-246 Investigator’s Brochure v10.1. 2019:168. 
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NCCN. NCCN Clinical Practice Guidelines in Oncology for Chronic Myeloid Leukemia. 
Version 3.; 2020. 
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Lancet JE, Uy GL, Cortes JE, et al. Cpx-351 (cytarabine and daunorubicin) liposome for 
injection versus conventional cytarabine plus daunorubicin in older patients with 
newly diagnosed secondary acute myeloid leukemia. In: Journal of Clinical Oncology. 
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doi:10.1200/JCO.2017.77.6112 
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Lindsley RC. Genetic characteristics and outcomes by mutation status in a phase 3 
study of CPX-351 versus 7+3 in older adults with newly diagnosed, high-
risk/secondary acute myeloid leukemia. 2019 ASH Annual Meeting & Exposition. 
Abstract 15. In: ; 2019. 
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DiNardo CD. European Hematology Association Annual Congress. In: ; 2020. 
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Cluzeau T. European Hematology Association Annual Congress. In: ; 2020. 
55.  
FDA. Venetoclax Prescribing Information.; 2016. 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208573s000lbl.pdf. 
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FDA. Azacitidine Prescribing Information.; 2018. 
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Roselló S, Blasco I, García Fabregat L, Cervantes A, Jordan K, ESMO Guidelines 
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Clinical Practice Guidelines†. Ann Oncol. 2017;28(suppl_4):iv100-iv118. 
doi:10.1093/annonc/mdx216 


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58.  
Azacitidine. Highlights of Prescribing Information.; 2020. www.fda.gov/medwatch. 
Accessed September 23, 2020. 
59.  
Cheson BD, Bennett JM, Kopecky KJ, et al. Revised Recommendations of the 
International Working Group for Diagnosis, Standardization of Response Criteria, 
Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute 
Myeloid Leukemia. J Clin Oncol. 2003;21(24):4642-4649. doi:10.1200/JCO.2003.04.036 
 


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APPENDIX I – Response Criteria Based on Modified Recommendations of the 
International Working Group for Diagnosis, Standardization of Response 
Criteria, Treatment Outcomes, and Reporting Standards in Acute Myeloid 
Leukemia59 
 
Response Criterion 
Neutrophils, 
×109/L 
Platelets, 
×109/L 
Bone Marrow Aspirate Blasts (%) (by 
biopsy acceptable if aspirate not 
available) 
CR  
>1.0 
>100 
<5 
CRi 
ANC ≥1,000 OR platelets 
≥100,000 
<5 
MLFS 
NA 
NA 
<5 
PR 
>1.0 
>100 
>50% decrease from baseline to level 
of 5-25% 
SD (for patients 
without a prior best 
response of CR, CRi, 
MLFS, or PR) 
Absence of CR, CRi, PR, MLFS; and criteria for PD not met 
Hematologic 
relapse (for patients 
with a prior best 
response of CR, CRi, 
MLFS) 
Bone marrow blasts ≥5%, or reappearance of blasts in the 
blood, on two consecutive assessments separated by ≥28 days. 
Development of new extramedullary disease. 
PD (for patients 
with a prior best 
response of SD or 
PR) 
Evidence for an increase in bone marrow blast percentage and/or increase 
of absolute blast counts in the blood, on two consecutive assessments at 
least 28 days apart: 
 
>50% increase in marrow blasts over baseline (a minimum 15% point 
increase is required in cases with <30% blasts at baseline; or persistent 
marrow blast percentage of >70% over at least 3 months; without at least a 
100% improvement in 
ANC to an absolute level (>0.5 × 109/L [500/mL], and/or platelet count to 
>50 × 109/L [50,000/mL] non-transfused); or 
 
>50% increase in peripheral blasts (WBC × % blasts) to >25 × 109/L 
(>25,000/mL) (in the absence of differentiation syndrome); or 
 
New extramedullary disease 
 
Additional Responses to be Assessed in Addition to Above Responses 
These responses in addition to other responses and do not have specific hematologic criteria. 
 
Cytogenetic CR 
Normal karyotype in a patient with abnormal cytogenetics at baseline.  


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TP53 Molecular CR  
TP53 mutation not detected by NGS based on local testing in a patient with 
detectible TP53 VAF by NGS at baseline. 
 
Additional Responses to be Assessed in Addition to Above Responses 
These responses in addition to other responses and do not have specific hematologic criteria. 
 
Cytogenetic CR 
Cytogenetic CR 
TP53 Molecular CR  
TP53 Molecular CR  


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APPENDIX II - Cockcroft-Gault Equation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Males: 
 
 
Creatinine CL 
(mL/min) 
= 
  Weight (kg) × (140 – Age) 
72 × serum creatinine (mg/dL) 
Females: 
 
 
Creatinine CL 
(mL/min) 
= 
   Weight (kg) × (140 – Age)  × 0.85 
72 × serum creatinine (mg/dL) 


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APPENDIX III - ECOG Performance Status 
 
 
 
       Grade 
 
 
0 
 
Fully active, able to carry on all pre-disease performance without 
restriction. 
 
 
1 
 
Restricted in physically strenuous activity but ambulatory and 
able to carry out work of a light or sedentary nature, e.g., light 
housework, office work. 
 
 
2 
 
Ambulatory and capable of all self-care but unable to carry out 
any work activities. Up and about more than 50% of waking 
hours. 
 
 
3 
 
Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours. 
 
 
4 
 
Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair. 
 
 
5 
 
Dead. 
 
 
 
 


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APPENDIX IV - Acceptable Contraceptive Methods 
● Male or female condom with or without spermicide 
● Cervical cap, diaphragm or sponge with spermicide 
Highly Effective Contraceptive Methods That Are User Dependent a  
Failure rate of <1% per year when used consistently and correctly. 
● Combined (estrogen- and progesterone-containing) hormonal contraception b 
○ Oral  
○ Intravaginal  
○ Transdermal  
○ Injectable 
● Progestogen-only hormonal contraception b 
○ Oral  
○ Injectable  
Highly Effective Methods That Have Low User Dependency  
Failure rate of <1% per year when used consistently and correctly. 
● Progesterone-only contraceptive implant b, c  
● Intrauterine hormone-releasing system (IUS) b  
● Intrauterine device (IUD) 
● Bilateral tubal occlusion 
● Vasectomy  
Vasectomy is a highly effective contraception method provided that the partner is the 
sole male sexual partner of the female of childbearing potential and the absence of 
sperm has been confirmed. If not, an additional highly effective method of contraception 
should be used.  
● Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
treatment. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant.)  
Notes:  
Use should be consistent with local regulations regarding the use of contraceptive 
methods for participants of clinical studies. 
a) Typical use failure rates are lower than perfect-use failure rates (i.e., when used 
consistently and correctly).  
b) If hormonal contraception efficacy is potentially decreased due to interaction with 
study treatment, condoms must be used in addition to the hormonal contraception 
during the treatment period and for at least 120 days, (corresponding to time needed to 


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eliminate study treatment plus 30 days for study treatments with genotoxic potential) 
after the last dose of the study treatment. 
c) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable hormonal contraceptives are limited to those which inhibit ovulation.  
 
 
 


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APPENDIX V - New York Heart Association (NYHA) Classification 
 
NYHA Grading 
MET* 
Class I 
No limitations. Ordinary physical activity does not 
cause undue fatigue, dyspnea or palpitations 
(asymptomatic LV dysfunction) 
>7 
Class II 
Slight limitation of physical activity. Ordinary physical 
activity results in fatigue, palpitation, dyspnea or 
angina pectoris (mild Congestive Heart Failure (CHF)). 
5 
Class III 
Marked limitation of physical activity. Less than 
ordinary physical activity leads to symptoms 
(moderate CHF) 
2 – 3 
Class IV 
Unable to carry on any physical activity without 
discomfort. Symptoms of CHF present at rest (severe 
CHF). 
1.6 
 
*MET (metabolic equivalent) is defined as the resting VO2 for a 40-year-old 70kg man.  
1 MET = 3.5 mL O2/min/kg body weight. 
 
 


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APPENDIX VI - Study Drug Diaries 
 
VENETOCLAX DRUG DIARY 
 
Instructions:  
You will use this diary to record each dose of venetoclax that you take. You should also use 
this diary to record any side effects that you experience and medications that you take other 
than the venetoclax. Please be sure to bring this diary with you to your next clinic visit. 
 
Venetoclax:  
• 
Venetoclax is taken once a day every day, approximately 24 hours apart. 
• 
Venetoclax should be taken with food. On days 1 – 4 of cycle 1 it is recommended that 
venetoclax is taken approximately one hour after start of APR-246 infusion. Starting 
at cycle 2 venetoclax can be taken before or after start of APR-246 infusion (± 2 hours). 
• 
If you forget to take a dose of venetoclax and it is within 12 hours of when it should 
have been taken, you should take the dose. If it has been more than 12 hours, you 
should skip that dose and take the next dose at the next regular time.  
• 
If you vomit after taking a dose of venetoclax, you should not make up the dose or 
take additional pills, you should take the next dose at the next regular time.  
• 
Always bring your pill bottles (including those that are empty) and your diary with you 
to each clinic visit.   
 
If you have any questions, please ask a study team member or your doctor. 
 
 
 
 Patient Number:   __________ 
 
Patient Initials:   __________ 
 
Cycle Number:  _______ 
Start Date: _______________ 
 
Venetoclax tablets to take at each dose:  100 mg = _____ 
 
 
 
 
 
 
 
 
Other information/Comments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY STAFF USE ONLY 
 
Staff member reviewing diary at end of study 
cycle: 
 
 


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VENETOCLAX DRUG DIARY (continued)  
 
Patient Number/Initials:  ____________________ 
 
Cycle:  _____ 
 
Cycle 
Day 
Date Taken 
Time 
Taken 
Number of 
100mg 
venetoclax 
tablets 
taken 
Comments 
(Side effects, complaints, other 
medications) 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
22 
 
 
 
 
23 
 
 
 
 
24 
 
 
 
 
25 
 
 
 
 
26 
 
 
 
 
27 
 
 
 
 
28 
 
 
 
 
 
* NOTE: Add additional days in case needed due to scheduling delay or dose modifications. 


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APPENDIX VII - Patient Handout: Prohibited Medications (For Patients Enrolled 
in Cohorts with Venetoclax) 
PROHIBITED MEDICATIONS  
 
One of the medications you are receiving during this clinical trial, venetoclax, interacts with 
some drugs that are processed by your liver. Because of this, it is very important to tell your 
study doctors about all of your medicine before you start this study. It is also very important 
to tell them if you stop taking any regular medicine, or if you start taking a new medicine 
while you take part in this study. When you talk about your medicine with your study doctor, 
include medicine you buy without a prescription at the drug store (over-the counter remedy), 
or anything that you buy from the health food store or grocery store (herbal supplement). 
Many health care prescribers can write prescriptions. You must also tell your other 
prescribers (doctors, physicians’ assistants or nurse practitioners) that you are taking part in 
a clinical trial.  
 
Bring this paper with you.  
 
• 
Venetoclax is processed by a certain enzyme in the liver called CYP3A4. Drugs that 
increase the activity of this enzyme are called “inducers”, and drugs that decrease 
the activity of this enzyme are called “inhibitors”. Venetoclax must be used very 
carefully with other medicines that are inducers or inhibitors of CYP3A4. Venetoclax 
may also interact with other drugs that are processed by the liver. 
• 
You and healthcare providers who prescribe drugs for you must be careful about 
adding or removing any drug in this category. 
Before you start the study, your study doctor will work with your regular prescriber to switch 
the following medications if you are taking them:  
 
Avoid strong CYP3A inhibitors, i.e. clarithromycin, indinavir, itraconazole, ketoconazole, 
lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, 
telithromycin, and voriconazole. Avoid grapefruits and grapefruit juice. If a strong CYP3A 
inhibitor must be coadministered, the dose of venetoclax should be reduced. If the strong 
inhibitor is discontinued, the dose of venetoclax should be increased (after 3 to 5 half-lives 
of the inhibitor) to the dose used prior to initiation of the strong inhibitor. 
 
Avoid strong CYP3A inducers, i.e. phenytoin, rifampin, enzalutamide, and St John’s wort. 
 
Avoid P-gp inhibitors, i.e. amiodarone, carvedilol, clarithromycin, dronedarone, itraconazole, 
lapatinib, lopinavir and ritonavir, propafenone, quinidine, ranolazine, ritonavir, saquinavir 
and ritonavir, telaprevir, tipranavir and ritonavir, verapamil. 
 


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Avoid P-gp substrates with narrow therapeutic index, i.e. amitriptyline, carbamazepine, 
clonidine, ciclosporin, digitoxin, digoxin, imipramine, phenobarbital, phenytoin, quinidine. 
 
Your regular prescribers should look at these websites: https://www.crediblemeds.org 
http://medicine.iupui.edu/clinpharm/ddis/table.asp to see if any medicine they want to 
prescribe is on a list of drugs to avoid. Your study doctor may also have a list of medications 
for you to show your regular prescribers instead of, or in addition to, this website.   
 
Eating grapefruit, grapefruit containing products, Seville oranges (including marmalade 
made with Seville oranges), and starfruit is prohibited while you are taking venetoclax as 
these may increase the amount of venetoclax in your blood.  Please discuss any questions 
about prohibited foods with your study doctor.  
 
Other medicines can be a problem with your study drugs. 
o You should check with your doctor or pharmacist whenever you need to use an over-the-
counter medicine or herbal supplement. 
o Your regular prescriber should check a medical reference or call your study doctor before 
prescribing any new medicine for you. Your study doctor’s name is _______________ and he 
or she can be contacted at _______________________. 
 
 
 
 


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APPENDIX VIII - Dose Modifications for Use with CYP3A and P-gp Inhibitors 
Concomitant use of venetoclax with strong CYP3A inhibitors at initiation and during ramp-
up phase is contraindicated. Concomitant use of venetoclax with strong CYP3A inhibitors 
increases venetoclax exposure (i.e., Cmax and AUC) and may increase the risk for TLS at 
initiation and during ramp-up phase. For patients who have completed the ramp-up 
phase and are on a steady daily dose of venetoclax, reduce the venetoclax dose by at least 
75% when strong CYP3A inhibitors must be used concomitantly.  
 
Avoid concomitant use of venetoclax with moderate CYP3A inhibitors or P-gp inhibitors. 
Consider alternative treatments. If a moderate CYP3A inhibitor or a P-gp inhibitor must 
be used, reduce the venetoclax dose by at least 50%. Monitor these patients more closely 
for signs of toxicities.  
 
Resume the venetoclax dose that was used prior to initiating the CYP3A inhibitor or P-gp 
inhibitor 2 to 3 days after discontinuation of the inhibitor.  
 
The recommendations for managing drug-drug interactions are summarized in the table 
below. 
 
Co-administered drug 
Initiation and Ramp-Up 
Phase 
Steady Daily Dose (After 
Ramp-Up Phase) 
Posaconazole 
Day 1 – 10 mg 
Day 2 – 20 mg 
Day 3 – 50 mg 
Day 4 – 70 mg 
Reduce venetoclax dose to 
70 mg. 
Other 
strong 
CYP3A 
inhibitor 
Day 1 – 10 mg 
Day 2 – 20 mg 
Day 3 – 50 mg 
Day 4 – 100 mg 
Reduce venetoclax dose to 
100 mg. 
Moderate CYP3A inhibitor 
Reduce the venetoclax dose by at least 50% 
P-gp inhibitor 
 
Warfarin 
Concomitant use of venetoclax increases warfarin Cmax and AUCinf, which may increase the 
risk of bleeding. Closely monitor international normalized ratio (INR) in patients using 
warfarin concomitantly with venetoclax. 
 
P-gp Substrates 
Concomitant use of venetoclax increases Cmax and AUCinf of P-gp substrates, which may 
increase toxicities of these substrates. Avoid concomitant use of venetoclax with a P-gp 


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substrate. If a concomitant use is unavoidable, separate dosing of the P-gp substrate at 
least 6 hours before venetoclax. 
 
Please refer to the venetoclax USPI37 for additional details on drug-drug interactions. 
 
Below (Table 13) are examples of CYP3A inhibitors and inducers (strong and moderate); 
however, this is not an exhaustive list.   
 
 
Table 13. CYP3A Inhibitors and Inducers 1 
CYP3A Inhibitors 
Strong CYP3A Inhibitors 
Moderate CYP3A Inhibitors 
boceprevir, cobicistat, danoprevir and 
ritonavir, elvitegravir and ritonavir, 
indinavir and ritonavir, itraconazole, 
ketoconazole, lopinavir and ritonavir, 
paritaprevir and ritonavir and (ombitasvir 
and/or dasabuvir), posaconazole, 
ritonavir, saquinavir and ritonavir, 
telaprevir, tipranavir and ritonavir, 
telithromycin, troleandomycin, 
voriconazole 
aprepitant, ciprofloxacin, conivaptan, 
crizotinib, cyclosporine, diltiazem, 
dronedarone, erythromycin, fluconazole, 
fluvoxamine, imatinib, tofisopam, 
verapamil 
 
CYP3A Inducers 
Strong CYP3A Inducers 
Moderate CYP3A Inducers 
apalutamide, carbamazepine, 
enzalutamide, mitotane, phenytoin, 
rifampin, St. John’s wort 
 
bosentan, efavirenz, etravirine, 
phenobarbital, primidone 
Note: In addition to the medications listed above, patients taking venetoclax should not 
consume grapefruit, grapefruit products, Seville oranges, (including marmalade containing 
Seville oranges), or star fruit.