Conditions: Acute Myeloid Leukemia or Myelodysplastic Syndromes
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 33
Healthy volunteers: no

Brief summary:
A multi-center, open label, Phase II clinical trial to assess the safety and efficacy of APR-246 in combination with azacitidine as maintenance therapy after allogeneic HSCT (hematopoietic stem cell transplant) for patients with TP53 mutant AML or MDS.

Detailed description:
A multi-center, open label, Phase II clinical trial to assess the safety and efficacy of APR-246 in combination with azacitidine as maintenance therapy after allogeneic HSCT for patients with TP53 mutant AML or MDS.

Patients will be prescreened for TP53 mutant AML or MDS before they have a HSCT. In order to proceed with APR-246 and azacitidine treatment, engraftment must be confirmed between Day 30 to Day 100 post-HSCT.

APR-246 will be administered on Days 1-4, with azacitidine on Days 1-5, of every 28 day cycle. Patients may receive a maximum of 12 cycles.

Arms:
arm 1: APR-246 and azacitidine maintenance therapy will continue for a maximum of 12 cycles

Interventions: intervention 1: APR-246
Intervention descriptions: intervention 1: APR-246 will be administered on Days 1-4, with azacitidine on Days 1-5, of every 28 day cycle. Patients may receive a maximum of 12 cycles.

Protocol document:
Prot_SAP_000.pdf: 
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Phase II trial of APR-246 in combination with azacitidine as maintenance 
therapy for TP53 mutated AML or MDS following allogeneic stem cell transplant 
 
Protocol No.: 
A19-11172 
IND No.: 
139738 
 
 
Principal Investigator: 
Asmita Mishra, MD 
  
 
 
 
 
 
Sponsor: 
Aprea Therapeutics AB 
 
 
 
  
 
 
Medical Monitor: 
 
 
 
 
 
 
Protocol Version: 
3.0 
 
 
Replaces: 
2.0 / 22 May 2019 
 
 
Date: 
28 October 2021 
 
CONFIDENTIAL 
 
This document contains strictly confidential information and cannot be disclosed or 
used, unless authorized in writing by 
 and Aprea Therapeutics. 


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INVESTIGATOR’S STATEMENT 
1. 
I have carefully read this protocol entitled "Phase II trial of APR-246 in combination 
with azacitidine as maintenance therapy for TP53 mutated AML or MDS following 
allogeneic stem cell transplant" 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 participating patients 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 Good 
Clinical Practice, Section 4.8, and the terms of the Declaration of Helsinki (2013). 
 
4. 
I will enroll patients 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, a Competent Authority of the European Union or 
another Regulatory Authority. 
Investigator: 
 
 
 
Name:        
 
Telephone: 
 
 
 
 
 
Address: 
 
 
 
 
 
 
 
Signature: 
 
Date: 
 
 
 
 
 
Sponsor 
Representative: 
 
 
 
Signature: 
 
Date: 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
        Page No. 
 
INVESTIGATOR’S STATEMENT ................................................................................ 2 
TABLE OF CONTENTS ............................................................................................. 3 
CLINICAL STUDY SYNOPSIS ................................................................................... 8 
LIST OF ABBREVIATIONS ...................................................................................... 18 
1.0 
GENERAL INFORMATION ........................................................................ 21 
1.1 Protocol Number and Title of the Study ..................................................... 21 
1.2 Sponsor ........................................................................................................... 21 
1.3 Monitor ............................................................................................................ 21 
1.4 Signature Authorization ................................................................................ 21 
1.5 Principal Investigator ..................................................................................... 21 
2.0 
BACKGROUND INFORMATION ............................................................... 22 
2.1 Introduction .................................................................................................... 22 
2.2 TP53 Mutations in MDS and AML ................................................................. 22 
2.3 TP53 Mutations in HCT .................................................................................. 22 
2.4 Azacitidine After Allogeneic HCT .................................................................. 23 
2.5 APR-246 ........................................................................................................... 23 
2.6 Rationale for Current Study .......................................................................... 24 
2.7 Number of Patients ....................................................................................... 25 
2.8 Potential Risks ................................................................................................ 25 
2.9 Characteristics of a Well-Conducted Trial ................................................... 26 
3.0 
TRIAL OBJECTIVES AND PURPOSE ........................................................... 28 
3.1 Primary Objectives ......................................................................................... 28 
3.2 Secondary Objectives .................................................................................... 28 
3.3 Exploratory Objectives .................................................................................. 28 
3.4 Endpoints ........................................................................................................ 29 
3.4.1 Primary Endpoints .............................................................................. 29 
3.4.2 Secondary Endpoints ......................................................................... 29 
3.4.3 Exploratory Endpoints ....................................................................... 29 
4.0 
TRIAL DESIGN ........................................................................................... 30 
4.1 Overview of Trial Design ............................................................................... 30 
4.2 Safety Evaluation-First 6 Patients ................................................................. 31 
4.3 Study Stopping Criteria ................................................................................. 32 
4.4 End of Study .................................................................................................... 32 


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4.5 Duration of Therapy ...................................................................................... 32 
4.6 Trial Discontinuation ..................................................................................... 33 
4.7 Drug Accountability/Disposition of Clinical Trial Supplies ........................ 33 
4.8 Registration ..................................................................................................... 33 
5.0 
SELECTION AND WITHDRAWAL OF SUBJECTS ....................................... 34 
5.1 Pre-Screening ................................................................................................. 34 
5.1.1 Inclusion Criteria ................................................................................. 34 
5.1.2 Exclusion Criteria ................................................................................ 35 
5.2 Post-transplant Criteria for APR-246 and Azacitidine Treatment ............ 35 
5.2.1 Inclusion Criteria ................................................................................. 35 
5.2.2 Exclusion Criteria ................................................................................ 37 
5.3 Withdrawal Criteria ........................................................................................ 38 
5.3.1 Withdrawn Subjects ........................................................................... 38 
5.4 Noncompliance .............................................................................................. 38 
6.0 
TREATMENT OF SUBJECTS ....................................................................... 39 
6.1 Drug Preparation and Administration ........................................................ 39 
6.1.1 APR-246 ................................................................................................ 39 
6.1.2 Azacitidine ........................................................................................... 39 
6.2 Criteria for Retreatment and Dose Modifications ..................................... 40 
6.2.1 Dose Modifications ............................................................................. 42 
6.3 Concomitant Treatment ................................................................................ 46 
6.3.1 GVHD During Therapy ........................................................................ 46 
6.3.2 CNS Toxicity Management ................................................................ 47 
6.3.3 Management of Infection and/or Infestation Event(s) .................. 47 
6.3.4 Management of Neutropenia with or without Fever ..................... 48 
6.3.5 General Concomitant Medications and Supportive Care 
Guidelines ....................................................................................................... 48 
6.3.6 Prohibited Therapy ............................................................................. 49 
6.3.7 Other Concomitant Treatment (Medication and Non-
medication Therapy) ..................................................................................... 49 
6.3.8 Permitted Medications ....................................................................... 50 
6.4 Monitoring Subject Compliance ................................................................... 50 
7.0 
STUDY EVALUATIONS .............................................................................. 51 
7.1 Pre-Screening ................................................................................................. 51 
7.1.1 Pre-Screening (Day -28 to -1 prior to HSCT) .................................... 51 
7.1.2 Day 0 .................................................................................................... 51 
7.1.3 Post-Transplant, APR-246 Screening Period (Day 1 to 100) .......... 51 
7.1.4 Confirmation to Proceed to APR-246 and Azacitidine Treatment 


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(Day 30 to 100) ............................................................................................... 52 
7.2 APR-246 and Azacitidine Treatment ............................................................ 52 
7.2.1 Cycle 1, Day 1 ...................................................................................... 52 
7.2.2 Cycle 1, Days 2, 3, 4, 5 ........................................................................ 53 
7.2.3 Cycle 1, Days 7, 14, 21 ........................................................................ 53 
7.2.4 Cycle 1, Day 28 .................................................................................... 53 
7.2.5 Cycles 2-4, Day 1 (Day 29 of prior cycle) .......................................... 53 
7.2.6 Cycles 2-4, Days 2, 3, 4, 5 ................................................................... 54 
7.2.7 Cycles 2-4, Day 14 ............................................................................... 54 
7.2.8 Cycles 2-4, Day 28 ............................................................................... 54 
7.2.9 Cycles 5-12, Day 1 (Day 29 of prior cycle) ........................................ 54 
7.2.10 Cycles 5-12, Days 2, 3, 4, 5 ................................................................. 55 
7.2.11 Cycles 5-12, Day 14 ............................................................................. 55 
7.2.12 Cycles 5-12, Day 28 ............................................................................. 55 
7.3 End of Treatment Visit ................................................................................... 56 
7.4 30 Day Safety Follow-up Visit ........................................................................ 56 
7.5 Long-Term Follow-up..................................................................................... 56 
8.0 
STUDY ASSESSMENTS............................................................................... 57 
8.1 Safety Assessments ....................................................................................... 57 
8.1.1 Safety Analysis .................................................................................... 57 
8.1.2 Safety Evaluation ................................................................................ 57 
8.1.3 Reporting of Adverse Events ............................................................. 57 
8.1.4 GVHD Adverse Event Reporting ........................................................ 59 
8.2 Efficacy Assessments ..................................................................................... 61 
8.3 ECGs ................................................................................................................. 62 
8.4 Pharmacokinetics ........................................................................................... 62 
8.5 Correlatives/Exploratory Studies ................................................................. 63 
8.5.1 Donor/Recipient Chimerism .............................................................. 63 
8.5.2 Immune System Reconstitution ....................................................... 63 
8.5.3 MRD by NGS ........................................................................................ 64 
8.5.4 p53 IHC ................................................................................................. 64 
8.5.5 Post-Transplant Engraftment ............................................................ 64 
9.0 
STATISTICS ................................................................................................ 65 
9.1 Safety ............................................................................................................... 65 
9.2 Sample Size ..................................................................................................... 65 
9.3 Efficacy Endpoint and Analyses .................................................................... 66 
9.3.1 Relapse-Free Survival ......................................................................... 66 
9.3.2 Overall Survival ................................................................................... 66 


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9.3.3 Non-Relapse Mortality ....................................................................... 66 
9.3.4 Time to Progression (TTP).................................................................. 67 
9.3.5 Event-Free Survival (EFS) .................................................................... 67 
10.0 
QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES ........... 68 
10.1 Monitoring of the Study and Regulatory Compliance ............................... 68 
10.2 Curricula Vitae and Financial Disclosure of Investigators ......................... 68 
10.3 Protocol Modifications .................................................................................. 68 
10.4 Publication Policy ........................................................................................... 68 
11.0 
ETHICAL CONSIDERATIONS ..................................................................... 70 
11.1 Informed Consent .......................................................................................... 70 
11.2 Institutional Review Board/Independent Ethics Committee .................... 70 
11.3 Patient Privacy ................................................................................................ 70 
12.0 
DATA HANDLING AND RECORD KEEPING .............................................. 72 
12.1 Recording of Data .......................................................................................... 72 
12.2 Study Records ................................................................................................. 72 
13.0 
REFERENCES .............................................................................................. 73 
APPENDIX A- KARNOFSKY PERFORMANCE SCALE ............................................. 75 
APPENDIX B- SCHEDULE OF EVENTS ................................................................... 76 
APPENDIX C- ACUTE GVHD GRADING SCALE ..................................................... 80 
APPENDIX D- CHRONIC GVHD GRADING SCALE ................................................ 81 
 
 
 


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List of Tables and Figures 
 
Table 1: Dose Modifications for APR-246 ........................................................................ 42 
Table 2: APR-246 Dose Modification in the Setting of Moderate Renal Impairment 42 
Table 3: APR-246-Recommended Dose Modifications and Criteria for Treatment 
Interruption and Re-Initiation for Hepatorenal Toxicities ............................................ 44 
Table 4: APR-246 Dose Modifications for Neutropenia with or without Fever .......... 45 
Table 5: APR-246-Recommended Dose Modifications and Criteria for Treatment 
Interruption and Re-Initiation for Non-Hematological Toxicities ................................ 45 
Table 6. Recommendations for prevention and treatment of cancer-related 
infections ............................................................................................................................. 47 
Table 7: ECG Timepoints ................................................................................................... 62 
Table 8: PK Timepoints ...................................................................................................... 62 
Table 9: Biosampling Timepoints ..................................................................................... 63 
Table 10: Pre-Screen, APR-246/azacitidine Screening, Cycles 1-4 (Treatment Period)
 .............................................................................................................................................. 76 
Table 11: Cycle 5-12 (Treatment Period), EOT, 30 day Safety FUV, LTFU .................... 78 
 
Figure 1: Trial Overview ..................................................................................................... 31 
Figure 2: Overview of APR-246 and Azacitidine Treatment Per Cycle ......................... 39 
 
 
 


Aprea Therapeutics, Inc. 
Protocol Number A19-11172 
APR-246 and azacitidine post-transplant 
 maintenance in AML/MDS 
 
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CLINICAL STUDY SYNOPSIS 
Name of Sponsor:  
 
Aprea Therapeutics AB 
Name of Monitor:  
 
 
Title of the Study:   
Phase II trial of APR-246 in combination with azacitidine as maintenance therapy 
for TP53 mutated AML or MDS following allogeneic stem cell transplant 
 
Protocol Number: A19-11172 
 
Principal Investigator: 
Asmita Mishra (Moffitt Cancer Center, Tampa FL) 
 
Study Drugs:  APR-246 and azacitidine 
 
Clinical Phase:  II 
 
Objectives:   
Primary Objectives:  
1. To assess relapse-free survival (RFS) in patients with TP53 mutated AML or 
MDS who receive combination maintenance treatment with APR-246 with 
azacitidine after undergoing allogeneic hematopoietic stem cell transplant 
(HSCT). 
2. To evaluate the safety and tolerability of APR-246 in combination with 
azacitidine as maintenance treatment post-HSCT. 
 
Secondary Objectives: 
1. To assess the overall survival (OS). 
2. To assess non-relapse mortality (NRM). 
3. To assess time to progression (TTP). 
4. To evaluate cumulative incidence of Grades II-IV and III-IV acute graft versus 
host disease (GVHD). 
5. To evaluate 12-month cumulative incidence of mild, moderate, and severe 
GVHD. 
6. To describe event-free survival (EFS) 
 
Exploratory Objectives: 
1. To examine the effect of pre- and post-transplant minimal residual disease 
(MRD) (TP53 variant allele frequency, VAF) on RFS and overall survival (OS). 


Aprea Therapeutics, Inc. 
Protocol Number A19-11172 
APR-246 and azacitidine post-transplant 
 maintenance in AML/MDS 
 
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2. To determine if p53 protein expression and other potential genomic 
biomarkers at baseline before and after HSCT predicts potential effect on 
RFS and OS. 
3. To determine if TP53 clonal suppression (serial VAF in bone marrow) after 
HSCT correlates with outcomes. 
4. To evaluate APR-246 plasma pharmacokinetics (PK) when administered 
with azacitidine after transplantation. 
5. To evaluate post-transplant donor engraftment via chimerism studies in 
blood and bone marrow. 
Endpoints:   
Primary Endpoints:  
1. RFS 
2. Incidence, severity, relatedness of adverse events (AEs) and/or laboratory 
abnormalities 
 
Secondary Endpoints: 
1. OS 
2. NRM 
3. Time to progression or relapse 
4. Incidence and grade of acute and chronic GVHD (cumulative) 
5. Incidence and grade of acute and chronic GVHD (1-year) 
6. EFS 
 
Exploratory Endpoints: 
1. MRD defined by TP53 VAF 
2. RFS and OS in relation to baseline p53 protein expression (IHC) and other 
potential genomic biomarkers 
3. RFS and OS in relation to clonal suppression, i.e., depth and duration of TP53 
VAF reduction in bone marrow samples repeated every 3 months 
4. PK parameters: Cmax, AUC0-inf, T1/2 
5. Post-transplant donor engraftment via chimerism studies in blood and 
bone marrow (whole marrow and CD3/CD33 fractions) 
 
Study Design:   
This is a multi-center, open label, Phase II clinical trial to assess the safety and 
efficacy of APR-246 in combination with azacitidine as maintenance therapy after 
allogeneic HSCT for patients with TP53 mutant AML or MDS. 
 


Aprea Therapeutics, Inc. 
Protocol Number A19-11172 
APR-246 and azacitidine post-transplant 
 maintenance in AML/MDS 
 
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To be eligible to participate in this study, all patients must have either: 1) pre-
screening next generation sequencing (NGS) on peripheral blood (PB) or bone 
marrow (BM) samples at time of HSCT work up to determine presence of TP53 
mutation status or, 2) previously documented evidence of TP53 mutation by NGS 
on PB or BM samples.   
 
Patients will sign consent and be prescreened for TP53 mutant AML or MDS before 
they have a HSCT (Day 0). During the post-HSCT period (Day 1 to 100 post-HSCT), 
patients are screened for eligibility to receive APR-246 and azacitidine 
maintenance treatment. In order to proceed with APR-246 and azacitidine 
treatment, neutrophil and platelet engraftment (recovery) must be confirmed 
between Day 30 to Day 100 post-HSCT. APR-246 and azacitidine must be initiated 
no more than 28 days after confirmation. 
 
APR-246 will be administered on Days 1-4, with azacitidine on Days 1-5, of every 
28-day cycle. Patients may receive a maximum of 12 cycles of treatment. Patients 
may continue to receive study treatment in the setting of relapse or progression, 
up to a maximum of 12 cycles, provided they are continuing to derive benefit in 
the opinion of the Investigator. 
 
A safety evaluation will be performed by the Safety Monitoring Committee after 
the first 6 patients have completed 1 cycle of APR-246 and azacitidine combination 
therapy. The Committee will decide if it is appropriate to continue at the current 
dose; or, in the event the combination is not tolerated the dose of APR-246 will be 
reduced for subsequent patients. 
Trial Overview: 
 
Prescreening (prior to APR-246 and azacitidine) 
 
 
 
 


Aprea Therapeutics, Inc. 
Protocol Number A19-11172 
APR-246 and azacitidine post-transplant 
 maintenance in AML/MDS 
 
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APR-246 and Azacitidine Treatment Period, EOT and LTFU 
Dose Modification: 
 
 
APR-246 
Azacitidine 
Starting dose level 
3.7g 4h infusion days 1-4 
q28d cycle 
36 
mg/m2 
sc 
or 
iv, 
days 1-5 q28d cycle 
-1 dose level reduction 
3.3g 4h infusion days 1-4 
q28d cycle 
36 
mg/m2 
sc 
or 
iv, 
days 1-5 q28d cycle 
-2 dose level reduction 
3.0g 4h infusion days 1-4 
q28d cycle 
36 
mg/m2 
sc 
or 
iv, 
days 1-5 q28d cycle 
 
Number of patients:  At least 31 patients 
Inclusion Criteria: 
 
Pre-Screening:   
These observations will be done ≤ 28 days prior to beginning conditioning 
chemotherapy in anticipation for allograft infusion. 
1. Documentation of a TP53 gene mutation (which is not benign or likely 
benign) by NGS based on local evaluation with study eligibility confirmed 
centrally. 
2. Must provide a pre-HSCT bone marrow biopsy. 
3. Age ≥18 years at the time of signing the informed consent form 
4. Institutional Review Board/Independent Ethics Committee (IRB/IEC) 
approved written informed consent and privacy language as per national 
regulations (e.g., Health Insurance Portability and Accountability Act 
Authorization (HIPAA) for US sites) obtained from the participant or legally 
authorized representative prior to any study-related procedures (including 
withdrawal of prohibited medication, if applicable).   
5. Patient has confirmed, morphologically documented MDS or AML by WHO 
criteria.   
6. Patient is considered a suitable candidate for HSCT and has an acceptable 
source of allogeneic donor hematopoietic stem cells, as defined per 


Aprea Therapeutics, Inc. 
Protocol Number A19-11172 
APR-246 and azacitidine post-transplant 
 maintenance in AML/MDS 
 
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institutional practice (allogeneic HSCT for any donor source [matched 
sibling, unrelated donor (URD), mismatched URD, related haploidentical,] 
and any graft source [BM, PB], and any non-study conditioning 
[myeloablative conditioning (MAC), reduced intensity conditioning (RIC), or 
non-myeloablative conditioning (NMA)] will be permitted).  Additionally, 
any standard (non-study) GVHD prophylaxis regimen will be permitted. 
7. Females must either:  
a. Be of non-childbearing potential 
i. postmenopausal (defined as at least 1 year without menses) 
prior to screening, or  
ii. documented as surgically sterilized at least 1 month prior to 
the screening visit 
b. Or, if of childbearing potential,  
i. Agree not to try to become pregnant during the study and for 
6 months after the final study drug administration 
ii. And have a negative serum pregnancy test at screening 
iii. And, if heterosexually active, agree to consistently use highly 
effective contraception per locally accepted standards in 
addition to a barrier method starting at screening and 
throughout the study period and for 6 months after final study 
drug administration. 
8. Females must agree not to breastfeed or donate ova throughout the study 
drug treatment period and for 6 months after the final study drug 
administration.   
9. Males (even if surgically sterilized), and their partners who are women of 
childbearing potential must be using highly effective contraception in 
addition to a barrier method throughout the study drug treatment period 
and for 127 days after the final study drug administration.  
10. Males must not donate sperm throughout the study drug treatment period 
and for 127 days after the final study drug administration. 
Exclusion Criteria Pre-Transplant: 
1. Patient has had a prior allogeneic transplant. 
2. Patient has any of the following cardiac abnormalities (as determined by 
treating physician): 
a. Myocardial infarct within six months prior to registration 
b. New York Heart Association Class III or IV heart failure or known left 
ventricular ejection fraction (LVEF) < 40% 
c. A history of familial long QT syndrome 


Aprea Therapeutics, Inc. 
Protocol Number A19-11172 
APR-246 and azacitidine post-transplant 
 maintenance in AML/MDS 
 
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d. Symptomatic atrial or ventricular arrhythmias not controlled by 
medications 
e. QTc ≥ 470 ms calculated from a mean of 3 ECG readings using Fridericia’s 
correction (QTcF = QT/RR0.33). Patients with QTc ≥ 470 ms and bundle 
branch block and/or pacemaker rhythm may be enrolled following 
approval by the Medical Monitor.  
Post-transplant Inclusion Criteria for APR-246 and azacitidine treatment: 
1. Patient has received one allogeneic transplant for AML or MDS.  At time of 
treatment, patient must in morphologic remission for AML or MDS as defined 
as < 5% blasts for AML and ≤ 5% blasts for MDS, and in cytogenetic remission 
with no morphologic characteristics of acute leukemia (e.g., Auer Rods) in the 
BM with no evidence of extramedullary disease such as central nervous system 
involvement or granulocytic sarcoma. Patients with CR with incomplete count 
recovery (CRp or CRi) are allowed. Incomplete platelet recovery (CRp) is defined 
as CR with platelet count < 100 x 109/L. Incomplete blood count recovery (CRi) 
is defined as CR with neutropenia < 1 x 109/L with or without complete platelet 
recovery. Red blood cell count (RBC) and platelet transfusion independence is 
not required. 
2. Any standard (non-study) conditioning [MAC, RIC, or NMA] will be permitted. 
Acceptable source of allogeneic donor hematopoietic stem cells, as defined per 
institutional practice (allogeneic HCT for any donor source [matched sibling, 
URD, mismatched URD, or related haploidentical] and any PB or BM graft 
source. 
3. Patient is ≥ 30 days and ≤ 100 days from hematopoietic cell infusion. 
4. Patient is in complete remission after the transplant and has achieved 
engraftment. Engraftment is defined as ANC≥500/μL and platelets ≥ 20000/μL 
on 3 consecutive measurements (each occurring at least 1 day apart). The 
patient must not have had a platelet transfusion within 7 days prior to the first 
measurement. 
5. Patients who have developed grades II-IV acute GVHD will be allowed to initiate 
maintenance therapy based on the following criteria: 
• Does not require high dose steroids as defined as dosage of > 0.5 mg/kg of 
prednisone (or equivalent) daily dose within 1 week of post-HSCT screening 
• No escalation of systemic immunosuppression in terms of increase of 
corticosteroids or addition of new agent/modality within 2 weeks of post-
HSCT screening.  Dose adjustments (both increase and decrease) of GVHD 
preventative medications such as calcineurin inhibitors or sirolimus to 
achieve therapeutic trough levels, is allowed. Topical skin and topical 
gastrointestinal steroids are allowed.   


Aprea Therapeutics, Inc. 
Protocol Number A19-11172 
APR-246 and azacitidine post-transplant 
 maintenance in AML/MDS 
 
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6. Females must either:  
• Be of non-childbearing potential 
o postmenopausal (defined as at least 1 year without menses) prior 
to screening, or  
o documented as surgically sterilized (e.g., hysterectomy or tubal 
ligation) at least 1 month prior to the screening visit 
• Or, if of childbearing potential,  
o Agree not to try to become pregnant during the study and for 6 
months after the final study drug administration 
o And have a negative serum pregnancy test at screening 
o And, if heterosexually active, agree to consistently use highly 
effective contraception per locally accepted standards in addition 
to a barrier method starting at screening and throughout the 
study period and for 6 months after final study drug 
administration. 
7. Females must agree not to breastfeed or donate ova throughout the study 
drug treatment period and for 6 months after the final study drug 
administration.  
8. Males (even if surgically sterilized), and their partners who are women of 
childbearing potential must be using highly effective contraception in 
addition to a barrier method throughout the study drug treatment period.  
9. Males must not donate sperm throughout the study drug treatment period. 
10. Agrees not to participate in another interventional study while on 
treatment. 
11. Karnofsky Performance Status 70 or greater is required.  
12. Patient has adequate organ function as defined by the following laboratory 
values: 
a. Creatinine clearance > 30 mL/min by Cockcroft-Gault formula; 
b. Total serum bilirubin < 1.5 x ULN unless due to Gilbert's Syndrome, 
underlying disease of MDS, hemolysis or considered an effect of 
regular blood transfusions; 
c. ALT/AST < 2.5 x ULN, unless due to underlying disease of MDS. 
Post-transplant Exclusion Criteria for APR-246 and azacitidine treatment: 
1. Use of umbilical cord blood donor and stem cell source. 
2. Patient has uncontrolled infection. Definitive therapy for infection is 
required and must have no signs of progression within 7 days of first day of 
study drug treatment. 
3. Use of investigational agent within 14 days of pre-HSCT screening or 


Aprea Therapeutics, Inc. 
Protocol Number A19-11172 
APR-246 and azacitidine post-transplant 
 maintenance in AML/MDS 
 
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anytime thereafter.  
4. Use of hypomethylating agent, cytotoxic chemotherapeutic agents, or 
experimental agents (agents that are not commercially available) for the 
treatment of MDS or AML within 14 days of the first day of pre-HSCT 
screening or anytime thereafter.  
5. Patient has used experimental therapy for acute GVHD at any time post-
transplant. If unsure of the definition of “experimental”, discussion with the 
Medical Monitor is recommended. 
6. Patient requires treatment with supplemental oxygen not including usage 
of non-invasive CPAP at night. 
7. Patient has any of the following cardiac abnormalities (as determined by 
treating physician): 
a. Myocardial infarct within six months prior to registration 
b. New York Heart Association Class III or IV 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 ms calculated from a mean of 3 ECG readings using Fridericia’s 
correction (QTcF = QT/RR0.33). Patients with QTc ≥ 470 ms and bundle 
branch block and/or pacemaker rhythm may be enrolled after approval 
by the Medical Monitor. 
 
Duration of treatment:   
APR-246 and azacitidine maintenance therapy will continue for a maximum of 12 
cycles or until one of the following criteria applies: 
• Evidence of disease relapse defined as ≥5% blasts for AML patients or >5% 
blasts for MDS patients. Patients who are continuing to derive clinical 
benefit in the opinion of the investigator may remain on study treatment 
following relapse. 
• Inter-current illness that prevents further administration of treatment. 
• Unacceptable adverse event (AE)(s). 
• Patient decides to withdraw from treatment. 
• General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
• Patient begins other treatment for underlying disease (i.e., MDS or AML). 
• Grade 3-4 acute GVHD or Severe chronic GVHD. 


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If the patient discontinues treatment early, then the reason for treatment 
discontinuation and the date the patient was removed will be documented.  
Patients removed from treatment for unacceptable AEs will be followed until 
resolution or stabilization of the AE.   
 
Patients may continue to receive study treatment in the setting of relapse or 
progression, up to a maximum of 12 cycles, provided they are continuing to derive 
benefit in the opinion of the Investigator. 
Criteria for evaluation:   
Efficacy:  Bone marrow aspirate and biopsy following cycle 3, cycle 6, cycle 9, and 
cycle 12, or when clinically indicated, and monthly CBC. 
 
Safety:  CTCAE v5.0. Weekly history and physical for AE assessment (CTCAE v5.0), 
including CBC with diff, CMP and LDH for the first month on treatment, then 
monthly. 
 
GVHD assessment (Harris, 2016; Jagasia, 2015) will be performed weekly for the 
first month on treatment, then monthly. 
 
PK: Cycle 1 only. Pre-dose, 45 min (+/- 5min) after SOI, at EOI (4 hr +/- 30 min after 
SOI), 5-6 hr after SOI, 24 hr after SOI/Day 2 (before Day 2 dose). 
 
Statistical Methods:   
Demographic and clinical variables for the study patients will be summarized 
using descriptive statistics (mean, standard deviation, median, inter-quartile 
range, range, frequency counts and percentages). Safety and efficacy data will be 
analyzed overall as well as separately for each dose cohort when appropriate. 
 
Analysis Populations: 
 
Safety Evaluable Population: 
All subjects who are registered on the study and received any dose of APR-246 or 
azacitidine. 
 
Efficacy Evaluable Population: 
All subjects who are registered on the study and received at least one dose of 
APR-246 or azacitidine, and have at least one efficacy assessment, or had 


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relapse/progression.  
 
Sample Size: 
The primary endpoint of the study is the relapse-free survival (RFS) at 12 months. 
The primary analysis will be done using Kaplan-Meier methodology. Based upon 
the published data, the risk of relapse and non-relapse mortality in TP53 mutated 
MDS is assumed to be ~40% and ~30% at 1 year, respectively. Thus, the 
assumptions used for the sample size determination are:  
• 
the null hypothesis: the RFS at 1 year is 30%, 
• 
the alternative hypothesis: the RFS at 1 year is 50% or higher, 
• 
accrual time: 24 months, 
• 
follow-up time: 12 months, 
• 
the RFS follows the exponential distribution. 
 
With a one-sided significance level of 10%, 31 subjects will provide 90.1% power to 
test the null hypothesis against the alternative. The expected number of events 
during the study is 23 and the power was computed by a one-sided one-sample 
logrank test. The final analysis will be conducted when the follow-up time for all 
censored patients exceed 12 months. The null hypothesis will be rejected if a one-
sided p-value by the log-rank test is less than or equal to 0.1.  
 
Efficacy Analyses: 
All efficacy analyses will be provided by using Efficacy Evaluable population. 
 
Relapse-Free Survival 
The primary endpoint, RFS, is defined as the time from the date of registration to 
disease relapse after SCT, or death, whichever occurs earlier. If patients 
discontinued treatment due to toxicity, and withdrew consent without relapse 
disease (RD) or death at the time of data cut off, RFS will be censored at the date 
of the last assessment. 
 
RFS will be analyzed using Kaplan-Meier methodology. Kaplan-Meier curves will be 
plotted. Median relapse-free survival will be estimated and their 95% confidence 
intervals based on Brookmeyer-Crowley methodology will be calculated. 
 
Event-Free Survival (EFS) 
EFS is defined as from registration to the first of: morphologic disease relapse, 
death from any cause, reappearance of a pre-transplant cytogenetic alteration, 
donor lymphocyte infusion (DLI) for the purpose of treating MDS/AML, or 


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institution of anti-MDS/AML therapy. 
  
Overall Survival 
Overall survival (OS) is defined as the number of days from the date of registration 
to the date of death, irrespective of the cause. In the event of no death, overall 
survival will be censored at the last known alive date. 
 
OS will be analyzed using the similar methods as RFS. 
 
Non-Relapse Mortality (NRM) 
NRM is defined as time to deaths without relapse/recurrence. Deaths from any 
cause without prior progression are events. Events related to the disease such as 
relapse and progression are competing events. Patients lost to follow‐up are 
censored.  
 
NRM will be analyzed using the similar methods as RFS. 
 
Time to Progression (TTP) 
Time to progression or relapse is time to first event related to the disease, such as 
disease progression, disease relapse/recurrence, death from disease progression, 
and/or initiation of any therapy given to prevent relapse. Deaths without prior 
relapse/recurrence (i.e., NRM) are competing events. 
 
TTP will be analyzed using the similar methods as RFS. 
 
Safety Analyses:  
Safety data including adverse events, vital signs, laboratory data, ECG, physical 
exam will be tabulated for the Safety Evaluable population.  Adverse events will be 
tabulated by body system, preferred term, severity, and relationship. 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 severity grade. Incidence and grade of acute and chronic GVHD at 1-year 
and cumulative will be summarized by number (%) of subjects for each dose level 
and overall. 
 
LIST OF ABBREVIATIONS 
AE 
adverse events 


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ALT 
alanine aminotransferase  
AML 
acute myeloid leukemia 
AST 
aspartate aminotransferase  
AUC 0-inf 
area under curve, time 0 to infinity 
BM 
bone marrow 
CFR 
Code of Federal Regulations 
Cmax 
maximum concentration 
CBC 
complete blood count 
CIBMTR 
Center for International Blood and Marrow Transplant Research Repository 
CMP 
complete metabolic panel 
CNS 
central nervous system 
CPAP 
continuous positive airways pressure 
CR 
complete remission 
CRi 
complete remission with incomplete blood recovery 
CRp 
complete remission with incomplete platelet recovery 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLI 
donor lymphocyte infusions 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
EFS 
event-free survival 
ECOG 
Eastern Cooperative Oncology Group (performance status) 
EOI 
end of infusion 
EOT 
end of treatment 
ESA 
erythropoiesis-stimulating agents 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
GVHD 
graft versus host disease 
HCT 
hematopoietic cell transplant 
HIPAA 
Health Insurance Portability and Accountability Act Authorization 
HSCT 
hematopoietic stem cell transplant 
IB 
Investigator's Brochure 
ICH 
International Council for Harmonisation 
IHC 
 
immunohistochemistry 
IMP 
investigational medicinal product 
iv 
intravenous 
IPSS 
International Prognosis Scoring System 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
LDH 
lactate dehydrogenase 
LLN 
lower limit normal 
LTFU 
long term follow-up 
LVEF 
left ventricular ejection fraction 
MAC 
myeloablative conditioning 
MDS 
myelodysplastic syndromes 
MRD 
minimal residual disease 


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ms 
millisecond 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NGS 
next generation sequencing 
NMA 
non-myeloablative conditioning 
NMT 
no more than 
NRM 
non-relapse mortality 
OS 
overall survival 
PB 
peripheral blood 
PK 
pharmacokinetics 
PLD 
pegylated liposomal doxorubicin 
PRBC 
packed red blood cells 
QTc and QTcF 
corrected QT interval, by Fredericia 
RBC 
red blood cells 
RD 
relapse disease 
RFS 
relapse-free survival 
RIC 
reduced intensity conditioning 
RP2D 
recommended phase II dose 
sc 
subcutaneous 
SOI 
start of infusion 
T1/2 
half-life 
TBL 
total bilirubin 
TTP 
time to progression 
ULN 
upper limit normal 
URD 
unrelated donor 
VAF 
variant allele frequency 
WHO 
World Health Organization 
 
 
 
 


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1.0 GENERAL INFORMATION 
1.1 Protocol Number and Title of the Study 
A19-11172: Phase II trial of APR-246 in combination with azacitidine as maintenance 
therapy for TP53 mutated AML or MDS following allogeneic stem cell transplant 
 
1.2 Sponsor 
Aprea Therapeutics AB 
Nobels väg 3 
SE-171 65 Solna 
Sweden 
 
1.3 Monitor 
 
 
 
 
 
 
1.4 Signature Authorization 
The protocol will be signed by Aprea Therapeutics. 
 
1.5 Principal Investigator 
 
  
 
 
 
 
 


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2.0 BACKGROUND INFORMATION 
2.1 Introduction 
Transplantation of healthy hematopoietic stem cells from an allogeneic donor (HSCT) 
is the only curable treatment option to improve outcomes for otherwise incurable 
myeloid diseases such as acute myeloid leukemias (AML) and myelodysplastic 
syndromes (MDS). With the development of safer transplant conditioning regimens 
and supportive care measures, transplant can now be offered as a potential curative 
option to a wider population.  However, the potential benefits can be offset by 
potential resurgence of the disease after HSCT.  Disease recurrence is a major cause 
of treatment failure in patients with AML or MDS who undergo allogeneic HSCT to 
treat high risk disease, with limited treatment options in the post-HSCT relapsed 
setting.  Thus maintenance strategies need to be explored after transplantation to 
prevent disease recurrence and improve upon survival. 
 
2.2 TP53 Mutations in MDS and AML 
Next generation sequencing (NGS) is becoming more commonly employed as a 
means to provide detailed and rapid assessment of genome studies that continues 
to enhance the diagnostic, prognostic, and therapeutic capabilities within myeloid 
malignancies.1 Most commonly utilized NGS myeloid panels incorporate 20-50 genes 
and can identify mutations in the vast majority of patients,2,3 several of which that 
have been independently associated with decreased survival.4 More recent 
investigations have uncovered the most negative prognostic factor in MDS patients 
noting the impact of the mutation status of TP53. Not only are (non-benign) TP53 
mutations associated with decreased OS in mutated patients,4 but also predicts poor 
response and resistance in patients treated with the only currently available FDA-
approved disease modifying agents in MDS, lenalidomide and azacitidine (AZA).4,5,6,7,8 
Similarly, patients with AML with evidence of TP53 mutation are associated with 
NCCN poor risk AML, complex karyotype, and monosomal karyotype and 
demonstrate poor overall survival and relapse-free survival similar to what has been 
reported in MDS.9,10   
 
2.3 TP53 Mutations in HCT 
Genetic profiling of patients at time of undergoing HSCT continues to inform 
clinicians regarding risk stratification of allogeneic transplant recipients. Mutations 
of TP53 strongly predict for lack of benefit to HCT, and additionally demonstrate the 
prognostic significance of TP53 mutation as patients with complex karyotype without 


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mutant TP53 had similar survival to patients with normal karyotype.11,12  Using the 
Center for International Blood and Marrow Transplant Research Repository 
(CIBMTR), Lindsley and colleagues furthermore reported the largest data analysis to 
date on the prognostic impact genomic mutations in HSCT recipients for MDS.  At 
least 1 genomic abnormality was detected in nearly 80% of patients who underwent 
HSCT.  TP53 mutations were represented in 19% of all patients and at a higher 
frequency (34%) in patients with Intermediate-2 or High Risk stratification by the 
International Prognosis Scoring System (IPSS).  In multivariate analysis, TP53 was 
independently associated with shorter survival and shorter time to relapse in 
comparison to no evidence of TP53 mutation. Three-year overall survival for TP53 
mutated patients was 20% with median overall survival of approximately 8 months, 
in comparison to those that did not have TP53 mutation having a median OS of 
approximately 2 years.12  This study underscores the importance of alternative 
strategies for TP53 mutated patients particularly those eligible curable intent therapy 
utilizing HSCT. 
 
2.4 Azacitidine After Allogeneic HCT 
Azacitidine (AZA) is a DNA methyltransferase inhibitor that shows significant clinical 
activity in both MDS and AML.13,14   Additionally, AZA has been shown to an effective 
salvage therapy in patients who relapse after HCT.15  Given the efficacy of AZA in 
these settings, maintenance strategies have been evaluated post-allogeneic 
transplant to prevent disease recurrence. The efficacy of low-dose AZA after 
allogeneic transplantation was originally reported in AML 16 and subsequently in a 
larger phase I dose finding study including AML and MDS patients.17  In a cohort of 
forty-five patients who receive 4 cycles of post-HCT AZA, one year event-free survival 
and overall survival were reported as 58% and 77%, respectively, with reversible 
thrombocytopenia noted to be the dose-limiting toxicity.  Tolerability and efficacy of 
AZA for one year after HCT has been reported by Craddox et al.18  Thirty seven 
patients were treated in AZA in the peri-transplant period with the day 100 and 1 year 
NRM was 0% and 8%, respectively, with no patients having any evidence of chronic 
graft versus host disease, underscoring the tolerability of the treatment. The 1-year 
and 2-year RFS were 57% and 49%, respectively, with patients demonstrating CD8+ T 
cell response demonstrating reduced relapse rate.  Thus AZA dosing of 36 mg/m2 
subcutaneously for five consecutive days is effective and tolerable, and will be 
utilized at this dose for this study. 
 
 
2.5 APR-246 


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.   
 
2.6 Rationale for Current Study 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
  
 


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2.7 Number of Patients 
Approximately 31 patients.  
 
2.8 Potential Risks 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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c
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
2.9 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 Case Report Forms (CRFs) will be completed for every patient. 
 


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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 Good Clinical Practice, Sections 3 
and 4, and the terms of the Declaration of Helsinki (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 Good Clinical 
Practice, 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 Good Clinical Practice (GCP), the 
protocol and applicable regulatory requirements. 
 
 
 
 


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3.0 TRIAL OBJECTIVES AND PURPOSE 
3.1 Primary Objectives 
1. To assess relapse-free survival (RFS) in patients with TP53 mutated AML or 
MDS who receive combination maintenance treatment with APR-246 with 
azacitidine after undergoing allogeneic hematopoietic stem cell transplant 
(HSCT). 
2. To evaluate the safety and tolerability of APR-246 in combination with 
azacitidine as maintenance treatment post-HSCT. 
 
3.2 Secondary Objectives 
1. To assess the overall survival (OS). 
2. To assess non-relapse mortality (NRM). 
3. To assess time to progression (TTP). 
4. To evaluate cumulative incidence of Grades II-IV and III-IV acute graft versus 
host disease (GVHD). 
5. To evaluate 12-month cumulative incidence of mild, moderate, and severe 
GVHD. 
6. To describe event-free survival (EFS). 
 
3.3 Exploratory Objectives 
1. To examine the effect of pre- and post-transplant MRD (TP53 variant allele 
frequency, VAF) on RFS and OS. 
2. To determine if p53 protein expression and other potential genomic 
biomarkers at baseline before and after HSCT predicts potential effect on RFS 
and OS. 
3. To determine if TP53 clonal suppression (serial VAF in bone marrow) after 
HSCT correlates with outcomes. 
4. To evaluate APR-246 plasma pharmacokinetics (PK) when administered with 
azacitidine after transplantation. 
5. To evaluate post-transplant donor engraftment via chimerism studies in blood 
and bone marrow. 
 
 
 


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3.4 Endpoints 
3.4.1 Primary Endpoints 
1. RFS 
2. Incidence, severity, relatedness of adverse events (AEs) and/or laboratory 
abnormalities 
 
3.4.2 Secondary Endpoints 
1. OS 
2. NRM 
3. Time to progression or relapse 
4. Incidence and grade of acute and chronic GVHD (cumulative) 
5. Incidence and grade of acute and chronic GVHD (1-year) 
6. EFS 
 
3.4.3 Exploratory Endpoints 
1. MRD defined by TP53 VAF 
2. RFS and OS in relation to baseline p53 protein expression (IHC) and other 
potential genomic biomarkers 
3. RFS and OS in relation to clonal suppression, i.e., depth and duration of TP53 
VAF reduction in BM samples repeated every 3 months 
4. PK parameters: Cmax, AUC0-inf, T1/2 
5. Post-transplant donor engraftment via chimerism studies in blood and bone 
marrow (whole marrow and CD3/CD33 fractions) 
 
 
 
 


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4.0 TRIAL DESIGN 
4.1 Overview of Trial Design 
This is a multi-center, open label, Phase II clinical trial to assess the safety and efficacy 
of APR-246 in combination with azacitidine as maintenance therapy after allogeneic 
HSCT for patients with TP53 mutant AML or MDS. 
 
To be eligible to participate in this study, all patients must have either: 1) pre-
screening NGS on peripheral blood (PB) or bone marrow (BM) samples at time of 
HSCT work up to determine presence of TP53 mutation status or, 2) previously 
documented evidence of TP53 mutation by NGS on PB or BM samples.   
 
Patients will sign consent and be prescreened for TP53 mutant AML or MDS before 
they have a HSCT (Day 0). During the post-HSCT period (Day 1 to 100 post-HSCT), 
patients are screened for eligibility to receive APR-246 and azacitidine maintenance 
treatment. In order to proceed with APR-246 and azacitidine treatment, neutrophil 
and platelet engraftment (recovery) must be confirmed between Day 30 to Day 100 
post-HSCT. APR-246 and azacitidine must be initiated no more than 28 days after 
confirmation. 
 
APR-246 will be administered on Days 1-4, with azacitidine on Days 1-5, of every 28 
day cycle. Patients may receive a maximum of 12 cycles of treatment. Patients may 
continue to receive study treatment in the setting of relapse or progression, up to a 
maximum of 12 cycles, provided they are continuing to derive benefit in the opinion 
of the Investigator. 
 
A safety evaluation will be performed by the Safety Monitoring Committee after the 
first 6 patients have completed 1 cycle of APR-246 and azacitidine combination 
therapy. The Committee will decide if it is appropriate to continue at the current 
dose; or, in the event the combination is not tolerated (e.g. patients experience dose 
limiting toxicity) the dose of APR-246 will be reduced for subsequent patients. 
 
 
 


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Figure 1: Trial Overview 
 
Enrollment, Pre-screening, Pre-/Post-HSCT APR-246 Screening 
 
 
 
APR-246 and Azacitidine Treatment Period, EOT and LTFU 
 
 
 
 
 
4.2 Safety Evaluation-First 6 Patients 
A safety evaluation will be performed by the Safety Monitoring Committee after the 
first 6 patients have completed 1 cycle of APR-246 and azacitidine combination 
therapy. If >1 of 6 patients experience any of the following toxicities, then the 
APR-246 dose will be reduced for subsequently enrolled patients.  
 
• Treatment related non-hematological CTCAE grade 3-4 toxicity that lead to 
dose modification or withdrawal. 
• Absolute neutrophil count (ANC) not recovering to >500/μL by day 56 of a cycle 
in the absence of active leukemia/myelodysplasia.  
• Grade 3 metabolic/electrolyte abnormalities that are clinically significant, and 
not adequately controlled within 72 hours. 
6 patient safety 
evaluation 


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• Grade 3 nausea/vomiting/diarrhea or CNS toxicity that does not resolve within 
28 days despite treatment interruption and maximum medical therapy. 
 
4.3 Study Stopping Criteria 
If any of the following occur, the study will be temporarily paused until a full review 
by the safety monitoring committee is completed: 
• Any death (other than death related to progressive disease) that occurs within 
30 days of study drug administration. 
 
4.4 End of Study 
The end of the study is defined as the date of the last visit of the last patient 
undergoing the trial. 
 
4.5 Duration of Therapy 
Maintenance therapy will continue for a maximum of 12 cycles (28 days/cycle) from 
first dose of APR-246, or until one of the following criteria applies: 
• Evidence of disease relapse defined as ≥5% blasts for AML patients or >5% 
blasts for MDS patients. Patients who are continuing to derive clinical benefit 
in the opinion of the investigator may remain on study treatment following 
relapse. 
• Inter-current illness that prevents further administration of treatment. 
• Unacceptable AEs. 
• Participant decides to withdraw from treatment. 
• General or specific changes in the patient's condition render the patient. 
unacceptable for further treatment in the judgment of the investigator. 
• Participant begins other treatment for underlying disease (MDS or AML). 
• Grade 3-4 acute GVHD or Severe chronic GVHD. 
 
If the participant discontinues treatment early, then the reason for treatment 
discontinuation and the date the participant was removed will be documented.  
Participants removed from treatment for unacceptable AEs will be followed until 
resolution or stabilization of the AE.  Participants that discontinue treatment early 
will continue to be followed for relapse, if not yet documented, and survival. 
 


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Patients may continue to receive study treatment in the setting of relapse or 
progression, up to a maximum of 12 cycles, provided they are continuing to derive 
benefit in the opinion of the Investigator. 
 
4.6 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. 
 
4.7 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 returned to the Sponsor, or at the Sponsor's 
directive, destroyed by the site following site standard practices for disposal. 
 
4.8 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. Patients must meet all 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 (see 
the Study Operations Manual for specific instructions). 
 
 
 


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5.0 SELECTION AND WITHDRAWAL OF SUBJECTS 
To participate in this study, patients must meet: 
• Transplant and enrollment criteria in Sections 5.1.1-5.1.2; and, 
• APR-246 and azacitidine treatment criteria in Sections 5.2.1-5.2.2. 
 
5.1 Pre-Screening 
5.1.1 Inclusion Criteria 
These observations will be done ≤ 28 days prior to beginning conditioning 
chemotherapy in anticipation for allograft infusion. 
 
1. Documentation of a TP53 gene mutation (which is not benign or likely benign) 
by NGS based on local evaluation with study eligibility confirmed centrally. 
2. Must provide a pre-HSCT bone marrow biopsy. 
3. Age ≥18 years at the time of signing the informed consent form 
4. Institutional Review Board/Independent Ethics Committee (IRB/IEC) approved 
written informed consent and privacy language as per national regulations 
(e.g., Health Insurance Portability and Accountability Act Authorization (HIPAA) 
for US sites) obtained from the participant or legally authorized representative 
prior to any study-related procedures (including withdrawal of prohibited 
medication, if applicable).   
5. Patient has confirmed, morphologically documented MDS or AML by WHO 
criteria.     
6. Patient is considered a suitable candidate for HSCT and has an acceptable 
source of allogeneic donor hematopoietic stem cells, as defined per 
institutional practice (allogeneic HSCT for any donor source [matched sibling, 
unrelated donor (URD), mismatched URD, related haploidentical] and any graft 
source [BM, PB], and any non-study conditioning [myeloablative conditioning 
(MAC), reduced intensity conditioning (RIC), or non-myeloablative conditioning 
(NMA)] will be permitted).  Additionally, any standard (non-study) GVHD 
prophylaxis regimen will be permitted. 
7. Females must either:  
a. Be of non-childbearing potential 
i. postmenopausal (defined as at least 1 year without menses) prior 
to screening, or  
ii. documented as surgically sterilized at least 1 month prior to the 
screening visit 


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b. Or, if of childbearing potential,  
i. Agree not to try to become pregnant during the study and for 6 
months after the final study drug administration 
ii. And have a negative serum pregnancy test at screening 
iii. And, if heterosexually active, agree to consistently use highly 
effective contraception per locally accepted standards in addition 
to a barrier method starting at screening and throughout the 
study period and for 6 months after final study drug 
administration. 
8. Females must agree not to breastfeed or donate ova throughout the study 
drug treatment period and for 6 months after the final study drug 
administration.   
9. Males (even if surgically sterilized), and their partners who are women of 
childbearing potential must be using highly effective contraception in addition 
to a barrier method throughout the study drug treatment period and for 127 
days after the final study drug administration.  
10. Males must not donate sperm throughout the study drug treatment period 
and for 127 days after the final study drug administration. 
 
5.1.2 Exclusion Criteria 
1. Patient has had a prior allogeneic transplant. 
2. Patient has any of the following cardiac abnormalities (as determined by 
treating physician): 
a. Myocardial infarct within six months prior to registration 
b. New York Heart Association Class III or IV 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. QTc ≥ 470 ms calculated from a mean of 3 ECG readings using Fridericia’s 
correction (QTcF = QT/RR0.33). Patients with QTc ≥ 470 ms and bundle 
branch block and/or pacemaker rhythm may be enrolled after approval by 
Medical Monitor. 
5.2 Post-transplant Criteria for APR-246 and Azacitidine Treatment 
5.2.1 Inclusion Criteria 
1. Patient has received one allogeneic transplant for AML or MDS.  At time of 


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treatment, patient must in morphologic remission for AML or MDS as defined as 
< 5% blasts for AML and ≤ 5% blasts for MDS, and in cytogenetic remission with 
no morphologic characteristics of acute leukemia (e.g., Auer Rods) in the BM with 
no evidence of extramedullary disease such as central nervous system 
involvement or granulocytic sarcoma. Patients with CR with incomplete count 
recovery (CRp or CRi) are allowed. Incomplete platelet recovery (CRp) is defined 
as CR with platelet count < 100 x 109/L. Incomplete blood count recovery (CRi) is 
defined as CR with neutropenia < 1 x 109/L with or without complete platelet 
recovery. Red blood cell count (RBC) and platelet transfusion independence is not 
required. 
2. Any standard (non-study) conditioning [MAC, RIC, or NMA] will be permitted. 
Acceptable source of allogeneic donor hematopoietic stem cells, as defined per 
institutional practice (allogeneic HCT for any donor source [matched sibling, URD, 
mismatched URD, related haploidentical] and any graft source [BM, PB].  
3. Patient is ≥ 30 days and ≤ 100 days from hematopoietic cell infusion. 
4. Patient is in complete remission after the transplant and has achieved 
engraftment. Engraftment is defined as ANC≥500/μL and platelets ≥ 20000/μL on 
3 consecutive measurements (each occurring at least 1 day apart). The patient 
must not have had a platelet transfusion within 7 days prior to the first 
measurement. 
5. Patients who have developed grades II-IV acute GVHD will be allowed to initiate 
maintenance therapy based on the following criteria: 
• Does not require high dose steroids as defined as dosage of > 0.5 mg/kg of 
prednisone (or equivalent) daily dose within 1 week of post-HSCT screening 
• No escalation of systemic immunosuppression in terms of increase of 
corticosteroids or addition of new agent/modality within 2 weeks of post-HSCT 
screening.  Dose adjustments (both increase and decrease) of GVHD 
preventative medications such as calcineurin inhibitors or sirolimus to achieve 
therapeutic trough levels, is allowed. Topical skin and topical gastrointestinal 
steroids are allowed.   
6. Females must either:  
• Be of non-childbearing potential 
o postmenopausal (defined as at least 1 year without menses) prior to 
screening, or  
o documented as surgically sterilized (e.g., hysterectomy or tubal 
ligation) at least 1 month prior to the screening visit 
• Or, if of childbearing potential,  
o Agree not to try to become pregnant during the study and for 6 
months after the final study drug administration 


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o And have a negative serum pregnancy test at screening 
o And, if heterosexually active, agree to consistently use highly 
effective contraception per locally accepted standards in addition to 
a barrier method starting at screening and throughout the study 
period and for 6 months after final study drug administration. 
7. Females must agree not to breastfeed or donate ova throughout the study drug 
treatment period and for 6 months after the final study drug administration.  
8. Males (even if surgically sterilized), and their partners who are women of 
childbearing potential must be using highly effective contraception in addition to 
a barrier method throughout the study drug treatment period.  
9. Males must not donate sperm throughout the study drug treatment period. 
10. Agrees not to participate in another interventional study while on treatment. 
11. Karnofsky Performance Status 70 or greater is required. (APPENDIX A)  
12. Patient has adequate organ function as defined by the following laboratory 
values: 
a. Creatinine clearance > 30 mL/min by Cockcroft-Gault formula; 
b. Total serum bilirubin < 1.5 x ULN unless due to Gilbert's Syndrome, 
underlying disease of MDS, hemolysis or considered an effect of regular 
blood transfusions; 
c. ALT/AST < 2.5 x ULN, unless due to underlying disease of MDS. 
 
5.2.2 Exclusion Criteria 
1. Use of umbilical cord blood donor and stem cell source. 
2. Patient has uncontrolled infection. Definitive therapy for infection is required 
and must have no signs of progression within 7 days of first day of study drug 
treatment. 
3. Use of investigational agent within 14 days of pre-HSCT screening or anytime 
thereafter.  
4. Use of hypomethylating agent, cytotoxic chemotherapeutic agents, or 
experimental agents (agents that are not commercially available) for the 
treatment of MDS or AML within 14 days of the first day of pre-HSCT screening 
or anytime thereafter.  
5. Patient has used experimental therapy for acute GVHD at any time post-
transplant. If unsure of the definition of “experimental”, discussion with the 
Medical Monitor is recommended. 
6. Patient requires treatment with supplemental oxygen not including usage of 
non-invasive CPAP at night. 
7. Patient has any of the following cardiac abnormalities (as determined by 


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treating physician): 
a. Myocardial infarct within six months prior to registration 
b. New York Heart Association Class III or IV 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 ms calculated from a mean of 3 ECG readings using Fridericia’s 
correction (QTcF = QT/RR0.33). Patients with QTc ≥ 470 ms and bundle 
branch block and/or pacemaker rhythm may be enrolled after approval by 
Medical Monitor. 
5.3 Withdrawal Criteria 
Protocol therapy will be discontinued at any time if any of the following situations 
occur: 
 
1. Relapsed disease, unless Investigator believes patient is receiving clinical benefit.  
2. The development of toxicity which, in the Investigator’s judgment, precludes 
further therapy.  
3. Patient refusal. 
4. Lost to follow-up/noncompliance. 
5. Intercurrent illness. 
6. At the discretion of the Investigator. 
7. Pregnancy. 
8. Study termination. 
9. Initiation of anti-MDS/AML therapy or DLI for purpose of treating MDS/AML. 
 
5.3.1 Withdrawn Subjects  
When a patient is removed from the study, the Investigator will clearly document the 
reason in the medical record and complete the appropriate case report form page 
describing the reason for discontinuation.  In addition, every effort should be made 
to complete the appropriate assessments listed in Section 7.3. 
 
5.4 Noncompliance 
All instances of noncompliance and all resulting protocol deviations will be entered 
in the case report forms.  
 


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6.0 TREATMENT OF SUBJECTS 
6.1 Drug Preparation and Administration 
Patients will receive APR-246 and azacitidine on days 1-4 and 1-5, respectively, every 
28-day cycle. APR-246 and azacitidine are administered in the clinic. 
 
Figure 2: Overview of APR-246 and Azacitidine Treatment Per Cycle 
APR-246 
administration 
→ 
→ 
→ 
→ 
 
 
Next Cycle: 
Day 
1 
2 
3 
4 
5 
6-28 
D29 prior cycle/D1 
Azacitidine 
administration 
→ 
→ 
→ 
→ 
→ 
 
+4 wk window 
permitted 
 
6.1.1 APR-246 
At the pharmacies, the IMP vials are to be stored at 2-8ºC (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 25ºC. The infusion 
should be completed within 24 hours from the time of preparation (see Study 
Manual).  
 
A fixed dose of 3.7g APR-246 will be administered as an intravenous infusion daily on 
days 1-4 of each 28 day cycle. Total infusion time is 4 hours, administered in 2 
consecutive steps: 
1)  
1.6 g for the first 45 minutes (+/- 2 min) 
2) 
2.1 g over 3 hours 15 minutes (+/- 15 min) 
 
Detailed instructions on vial concentration, preparation and dispensing can be found 
in the Pharmacy Manual. The infusion timing, including start/stop times and the time 
of rate change, must be recorded. 
 
6.1.2 Azacitidine 
Azacitidine (36 mg/m2) is administered sc or iv for 5 consecutive days. The same route 
of administration should be used each day of a cycle. 
Azacitidine will be administered within 1 hour following the end of the APR-246 
infusion. 


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6.2 Criteria for Retreatment and Dose Modifications 
This section outlines the requirements for proceeding with treatment with APR-246, 
and the protocol rules for APR-246 dose modification due to toxicity.  
 
ECGs 
For all patients 
• Patients with screening QTcF ≥470 ms (average from triplicate ECG) are 
excluded from the study. Rescreening is allowed. 
• At a minimum, ECG should be performed pre-dose and end-of-infusion (EOI) 
on Day 1, Cycle 1-4. This ECG may be done as single or replicate (i.e. duplicate 
or triplicate, average QTcF should be used). Patients with screening or any pre-
dose 450 ≤ QTc < 470 ms should be subject to more intense ECG monitoring 
(see below). 
• If a pre-dose ECG shows QTcF ≥470 ms the QTc reading should be manually 
confirmed. Serum concentrations of electrolytes should be controlled and 
adjusted if necessary. Concomitant medication should be reviewed and 
adjusted if necessary. A new ECG may be done at any time, even the same day. 
The patient should not be treated unless QTc is <470. If the dose is given later 
on the same day, follow the planned cycle. If the dose cannot be given, omit 
that dose from the cycle. 
• If the patient at any time during the study starts with a concomitant 
medication known to prolong the QT interval, a pre-dose and EOI ECG should 
be performed for the next planned dose 
• If any ECG during the study shows a significant change (vs baseline or pre-
dose) in QTcF, defined as either i) increase >60 ms, ii) increase >25 %, or iii) 
increase to an absolute value ≥500 ms, the dose should be held/interrupted. 
If the QTc prolongation is confirmed by a manual read, the therapy should 
stop until the cause has been identified and eliminated (electrolyte 
disturbance or concomitant drug) and QTc is again <470ms. Discontinue APR-
246 permanently, if other causes for clinically significant QTcF increase are 
excluded. 
 
Additional monitoring for patients with 450 ≤ QTc < 470 ms at baseline or any 
pre-dose measurement 
• ECG should be performed pre-dose and end-of-infusion (EOI) for all doses (Day 
1-4, all cycles). This ECG may be done as single or replicate (i.e., duplicate or 
triplicate, average QTcF should be used).  
• Dose should be held for pre-dose QTcF ≥470 ms (see above). For a post-dose 


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(EOI) ECG showing >60 ms increase vs pre-dose or any QTcF >500 ms, see 
above. 
• Patients should avoid QTc prolonging drugs on infusion days, if possible, and 
have any electrolyte imbalance checked and corrected (CTCAE ≤Grade 1). 
• If repeated QTcF measurements show a stable QTcF <450, or if the patient is 
stable in the interval 450 to <470 ms with no significant change at EOI (several 
cycles of treatment) the investigator may discuss with the Medical Monitor to 
decrease the number of ECGs performed in the study. 
 
Other toxicity 
All dose modifications, interruptions or discontinuations must be based on the worst 
preceding toxicity as graded by the NCI Clinical Toxicity Criteria (NCI-CTCAE version 
5). Once a dose has been reduced during a treatment cycle, re-escalation will not be 
permitted during any subsequent cycle (with exception of CNS events). If the 
administration of APR-246 is interrupted for reasons other than toxicity, then 
treatment with APR-246 may be resumed at the same dose. The same provision 
applies if the patient experienced an unacceptable toxicity not specifically described 
in this section, provided that this toxicity resolved to ≤ CTCAE grade 1, unless 
otherwise specified. 
 
Day 1 of next cycle treatment with APR-246 and azacitidine can be delayed for up to 
4 weeks (28 days) to allow for count recovery at Investigator discretion pending 
discussion with the Sponsor and Medical Monitor. Non-hematologic grade 4 
treatment related adverse events will lead to permanent discontinuation, 
irrespective of recovery time, unless otherwise specified.  
 
Exceptions would include nausea/vomiting/diarrhea which can be controlled by 
medications and/or asymptomatic electrolyte imbalances which can be corrected. In 
addition, in most instances, patients that experience a prolonged treatment 
interruption because of an adverse event and/or a grade 3 adverse event will 
decrease the dose of study drug after their recovery (see tables in this section for 
dose adjustment guidelines).  
 
If any other drug-related grade 3 or 4 toxicity that is not clearly related to azacitidine 
is observed, APR-246 dose must be reduced for the next and subsequent cycles. 
 
 
 


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6.2.1 Dose Modifications 
Table 1: Dose Modifications for APR-246  
 
APR-246 
Azacitidine 
Starting dose level 
3.7g 4h infusion days 1-4 
q28d cycle 
36 
mg/m2 
sc 
or 
iv, 
days 1-5 q28d cycle 
-1 dose level reduction 
3.3g 4h infusion days 1-4 
q28d cycle 
36 
mg/m2 
sc 
or 
iv, 
days 1-5 q28d cycle 
-2 dose level reduction 
3.0g 4h infusion days 1-4 
q28d cycle 
36 
mg/m2 
sc 
or 
iv, 
days 1-5 q28d cycle 
 
 
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 2). 
 
Table 2: 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 3 hr and 15 
min) 
3.7 g 
2.5 g 
1.1 g 
1.4 g 
3.3 g 
2.2 g 
1.0 g 
1.2 g 
3.0 g 
2.0 g 
0.9 g 
1.1 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. 
 
Patients requiring >2 dose reductions for APR-246 will be permanently discontinued 
from study drug. Patients who permanently discontinue APR-246 or azacitidine 
should have follow-up within 30 days after discontinuation of all study treatment or 
resolution of the AE to ≤ grade 1, whichever occurs first, that includes all study 
assessments appropriate to monitor the event. 
 
Azacitidine dose modifications will be per the prescribing information and 
institutional guidelines. Patients may continue with APR-246 without azacitidine if ≥ 


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2 dose modifications have been due to cytopenias. APR-246 study drug may resume 
at last dosage received. 
 
Any changes in dose must be recorded on the Dosage Administration Record CRF. 
 
 


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Table 3: APR-246-Recommended Dose Modifications and Criteria for 
Treatment Interruption and Re-Initiation for Hepatorenal Toxicities 
Hepatorenal Toxicities 
Worst toxicity (CTCAE 5 Grade)† 
Dose Modifications for APR-246 
Serum Creatinine  
Grade 1 (< 1.5 × ULN)  
Maintain dose level  
Grade 2 (> 1.5 to 3.0 × ULN)  
Omit dose until resolved to ≤ Grade 1, then: 
If resolved in ≤ 7 days, then maintain dose level 
If resolved in > 7 days, then  1 dose level 
Grade 3 (> 3.0 – 6.0 × ULN)  
If resolved in ≤ 7 days, then  1 dose level 
If resolved in > 7 days, discontinue patient from APR-246  
Grade 4 (> 6.0 × ULN)  
Permanently discontinue patient from APR-246 
Bilirubin‡  
Grade 1 (> ULN - 1.5 × ULN) 
Maintain dose level with LFTs* monitored as per protocol 
Grade 2 (> 1.5 - 3.0 × ULN) with ALT or 
AST ≤ 3.0 × ULN 
Omit dose until resolved to ≤ Grade 1, then: 
If resolved in ≤ 7 days, then maintain dose level 
If resolved in > 7 days, then  1 dose level 
Grade 3 (> 3.0 - 10.0 × ULN) with ALT or 
AST ≤ 3.0 × ULN 
Omit dose until resolved to ≤ Grade 1, then: 
If resolved in ≤ 7 days,  1 dose level 
If resolved in  7 days, discontinue patient from APR-246 
Grade 4 (> 10.0 × ULN) 
Permanently discontinue patient from APR-246 
AST or ALT 
Grade 1 (> ULN - 3.0 × ULN if baseline 
was normal; 1.5 - 3.0 × baseline if 
baseline was abnormal) 
Maintain dose level with LFTs* monitored per protocol 
Grade 2 (> 3.0 - 5.0 × ULN if baseline 
was normal; >3.0 - 5.0 × baseline if 
baseline was abnormal) without total 
bilirubin elevation to > 2.0 × ULN 
Omit dose until resolved to ≤ Grade 1, then 
If resolved in ≤ 7 days, then maintain dose level 
If resolved in > 7 days, then  1 dose level 
Grade 3 (> 5.0 - 20.0 × ULN if baseline 
was normal; > 5.0 – 20.0 x baseline if 
baseline was abnormal) without total 
bilirubin elevation to > 2.0 × ULN 
Omit dose until resolved to ≤ Grade 1, then 
If resolved in ≤ 7 days, then maintain dose level 
If resolved in > 7 days, then  1 dose level 
Grade 4 (> 20.0 × ULN if baseline was 
normal; > 20.0 × baseline if baseline was 
abnormal) without bilirubin elevation to 
> 2.0 × ULN 
Permanently discontinue patient from APR-246 
*(LFTs include albumin, ALT, AST, total bilirubin (fractionated if total bilirubin > 2.0 × ULN), alkaline 
phosphatase. 
† Common Terminology Criteria for Adverse Events (CTCAE) version 5. 
‡ For patients with Gilbert’s syndrome, these dose modifications apply to changes in direct bilirubin only.  
* LFTs include albumin, ALT, AST, total bilirubin (fractionated if total bilirubin > 2.0 × ULN), alkaline phosphatase. 
 
 


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Table 4: APR-246 Dose Modifications for Neutropenia with or without Fever 
Parameter † 
Worst toxicity ‡ 
Dose modifications for APR-246 
Neutropenia 
with or without 
fever 
Grade 3 or 4 
neutropenic fever 
or worsening 
neutropenia from 
baseline to Grade 
4 without fever 
1st 
occurrence 
• 
Interrupt dosing and monitor patient; 
treat promptly.  
• 
Resume at current dose level if 
neutropenia and fever (if present) 
resolve to baseline within 7 days after 
onset. 
• 
If toxicity does not resolve to baseline 
despite maximal medical intervention(s) 
within 7 days of onset, then reduce APR-
246 by 1 dose level once the toxicity 
resolves to baseline.  
• 
Initiate or reassess prophylaxis 
measures. Refer to Sections 6.3.3 and 
6.3.4 for supportive management 
guidelines specific to infection 
prophylaxis and neutropenia, 
respectively.  
 
2nd occurrence 
• 
Hold all study treatments and monitor 
patient; treat promptly.  
• 
Assess current infection prophylaxis 
and adjust treatment plan as clinically 
indicated. Refer to Sections 6.3.3 and 
6.3.4 for supportive management 
guidelines specific to infection 
prophylaxis and neutropenia, 
respectively.  
• 
While APR-246 and azacitidine are 
interrupted, consult with study medical 
monitor to determine if a dose 
modification of APR-246 is warranted.   
Thrombocytope
nia 
Grade 4 (platelet 
count <25 x 
109/L) and major 
bleeding event 
Permanently discontinue patient from APR-246.  
† Only applicable for patients with normal baseline absolute neutrophil count (ANC) and platelets) 
‡ Common Terminology Criteria for Adverse Events (CTCAE) version 5. 
 
 
Table 5: APR-246-Recommended Dose Modifications and Criteria for 
Treatment Interruption and Re-Initiation for Non-Hematological Toxicities 


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Other Non-Hematological Toxicities 
Worst toxicity 
(CTCAE 5 Grade)† 
Dose Modifications for APR-246 
CNS – dizziness, dyskinesia and ataxia 
Grade 1 
Maintain dose level 
Grade 2 
If resolved 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 
If resolved 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 4 
Permanently discontinue patient from APR-246. 
Infusion Related Reaction 
Grade 1 
Maintain dose level. 
Grade 2 
Maintain dose level; Symptomatic management (e.g., antihistamines, 
corticosteroids, narcotics, IV fluids) 
Grade 3 
If resolved in < 4 hours with treatment interruption and medical therapy (e.g., 
antihistamines, corticosteroids, narcotics, IV fluids), continue same dose level 
and rate. 
If not resolved in < 4 hours despite treatment interruption and maximal 
medical therapy, stop infusion and  1 dose level for subsequent dose 
Grade 4 
Permanently discontinue patient from APR-246. 
Nausea/Vomiting/Diarrhea  
Grade 1  
Maintain dose level  
Grade 2  
If resolved, then maintain dose level 
If not resolved despite maximal medical therapy, 
then  1 dose level 
Grade 3  
If resolved, then maintain dose level 
If not resolved despite maximal medical therapy, then  1 dose level 
Grade 4  
Permanently discontinue patient from APR-246 
Any Other Toxicity  
Grade 3 or 4 
Delay dose until resolution to ≤ Grade1, then  1 dose level 
† Common Terminology Criteria for Adverse Events (CTCAE) version 5. 
 
6.3 Concomitant Treatment  
6.3.1 GVHD During Therapy 
If a participant develops new onset GVHD, or experiences an increase in the severity 
of pre-existing GVHD requiring an escalation of immunosuppressive medication, 
every effort should be made to continue the study drug without any dose reduction. 
If the participant is unable to take study drug as a result of GVHD, the study drug can 
be withheld until the participant is able to resume treatment. 


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6.3.1.1 Management of Acute GVHD 
Acute GVHD should be managed per institutional guidelines. Therapies considered 
standard are allowed and use of investigational therapy while on study drug is not 
allowed. 
 
6.3.1.2 Management of Chronic GVHD 
Chronic GVHD should be managed per institutional guidelines. Therapies considered 
standard are allowed and use of investigational therapy while on treatment is not 
allowed. 
 
 
 
 
 
 
 
 
As
 
 
 
 
 
 
  
 
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 


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Fungal 
Consider prophylaxis during neutropenia and for anticipated mucositis. 
Assess risk for Pneumocystis jirovecii pneumonia 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.  
  
Refer to Section 6.2 for guidance on APR-246 dose modification in the setting severe 
infection and/or infestation event, using the parameter titled, “Any Other Toxicity” 
(Table 5). 
   
Refer to Section 6.3 for a description of drugs that are not allowed to be used while 
a patient is on study treatment. 
 
6.3.4 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 6.3.3). 
 
Myeloid growth factors may be used in the setting of severe or prolonged 
neutropenia. Refer to Section 6.3 for a description of drugs that are not allowed to 
be used while a patient is on study treatment.  
 
Refer to Section 6.2.1 for APR-246 dose modification in the setting of severe or life-
threatening neutropenia with or without fever. 
 
 
6.3.5 General Concomitant Medications and Supportive Care Guidelines 
6.3.5.1 Antimicrobials 
Antibacterial, antiviral and antifungal prophylaxis and treatment during and after 
allogeneic HSCT are recommended and can be administered based on local 
institutional guidelines. 
 


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6.3.5.2 Tapering of GVHD Prophylaxis 
Tapering of immunosuppression should be followed per institutional practice in the 
absence of GVHD. There are no formal recommendations given that participants 
receiving HCT from any type of donor, after any conditioning and receiving any GVHD 
prophylaxis regimen are eligible. 
 
6.3.5.3 Donor Lymphocyte Infusions 
Pre-emptive/prophylactic administration of donor lymphocytes for disease 
progression (morphological or molecular) is not permitted in this protocol. DLI for 
infectious complications or modulation of T cell donor chimerism after allograft 
administration per institutional guidelines is allowed. For any unresolved questions 
regarding DLI administration should be discussed with the Medical Monitor. 
 
6.3.6 Prohibited Therapy 
• Other anticancer therapy:  Anticancer therapy (chemotherapy, endocrine, 
biologic or radiation therapy, and surgery) other than the study treatments 
must not be given to patients while the patient is enrolled in the treatment 
portion of the trial. If such agents are required for a patient then, the patient 
must be permanently discontinued from the treatment portion of the study. 
Exception: for breast cancer or prostate patients on adjuvant hormonal 
therapy (e.g., anastrozole/tamoxifen or leuprolide) who have been disease 
free for at least 1 year. 
 
• Other investigational therapies: Other investigational therapies must not be 
used while the patient is on the study including those for disease or GVHD. 
 
6.3.7 Other 
Concomitant 
Treatment 
(Medication 
and 
Non-medication 
Therapy) 
In general, the use of any concomitant medications/therapies deemed necessary for 
the care of the patient are allowed, with specific exceptions below. Prophylactic anti-
emetic therapy is permitted where indicated.  Participating centers will adhere to 
institutional 
practice 
regarding 
the 
monitoring 
of 
serum 
levels 
of 
immunosuppressive agents such as tacrolimus or azoles.  
 
Any disease progression that requires other specific anti-tumor therapy will be cause 
for discontinuation from the trial. 


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6.3.8 Permitted Medications 
6.3.8.1 Growth Factors 
Erythropoiesis-stimulating agents (ESAs) are not allowed for anemia during the 
study. G-CSF is allowed for evidence of neutropenia. 
 
6.3.8.2 Anticoagulant Therapy 
Subjects who are taking warfarin (or equivalent) may participate in this study; 
however, it is recommended that prothrombin time (PT-INR) and PTT be monitored 
carefully at least once per week for the first month, then monthly if the INR is stable. 
Subcutaneous heparin, low molecular weight heparin and oral anticoagulants are 
permitted. 
 
6.3.8.3 Blood Products 
The use of blood products to include packed red blood cells (PRBCs) and platelet 
transfusions are permitted and to be given at the discretion of the treating physician. 
Recommended guidelines for transfusion include a platelet threshold of 10,000/L for 
platelet transfusion and a hemoglobin threshold of 8.0g/dL for PRBC transfusion or 
as clinically deemed by the discretion of treating physician. 
 
6.4 Monitoring Subject Compliance 
Study drug will be administered only to eligible patients by the appropriate study 
personnel. Drug dispensing and administration records will be maintained. 
 
 
 


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7.0 STUDY EVALUATIONS 
Unscheduled visits and laboratory monitoring may occur as needed. Window of 3 
days applies except where noted. 
 
7.1 Pre-Screening  
APPENDIX B lists visits and assessments prior to starting APR-246 and azacitidine. 
Unscheduled visits and laboratory monitoring may occur as needed.  
 
7.1.1 Pre-Screening (Day -28 to -1 prior to HSCT) 
• Sign informed consent 
• TP53 mutation confirmation 
• Disease assessment: BM aspirate and/or biopsy sample must be collected 
prior to the start of the pre-transplant conditioning regimen.  
• Pregnancy test (women of child-bearing potential only) 
• ECGs; see Table 7.  
 
7.1.2 Day 0 
• Transplant 
 
7.1.3 Post-Transplant, APR-246 Screening Period (Day 1 to 100) 
Post-HSCT evaluation will occur as per institutional standard practices.  
 
APR-246/azacitidine screening period occurs during Day 30 to 100 post-HSCT. The 
date will vary but should start (Day -28 relative to first dose) as soon as engraftment 
and the requirements in Section 7.1.4 are confirmed. The first dose must be 
administered no more than 28 days after confirmation. 
 
The procedures listed below should be performed within 28 days prior to the first 
dose, or as indicated. Starred (*) procedures should be done within 3 days prior to 
the first dose. 
 
• Sign informed consent 
• Disease assessment 
• Eligibility 
• Karnofsky performance status 


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• Medical history and Transplant Details 
• Physical exam with Weight* 
• Vital signs* 
• CBC* 
• CMP* 
• ECGs*; see Table 7.  
• Pregnancy test (women of child-bearing potential only)* 
• Pre-treatment/baseline Bone marrow (BM)/Aspirate (BMA) for 
correlatives/exploratory: see Table 9  
• GVHD monitoring 
• Chimerism, immune reconstitution 
• Monitor adverse events 
• Concomitant medications 
 
7.1.4 Confirmation to Proceed to APR-246 and Azacitidine Treatment (Day 30 
to 100) 
• Bone marrow exam, including cytomorphology, cytogenetic assessment, and 
flow cytometry analysis. 
• Engraftment is defined as ANC≥500/μL and platelets ≥ 20000/μL on 3 
consecutive measurements (each occurring at least 1 day apart). The patient 
must not have had a platelet transfusion within 7 days prior to the first 
measurement. 
• Once this BM biopsy confirms CR and all other eligibility is confirmed, the 
patient must start APR-246 and azacitidine treatment within 28 days of 
confirmation. 
 
7.2 APR-246 and Azacitidine Treatment  
APPENDIX B lists visits and assessments. Unscheduled visits and laboratory 
monitoring may occur as needed.  The first dose must be administered no more than 
28 days after confirmation. 
 
7.2.1 Cycle 1, Day 1  
• APR-246 (administered Days 1-4) 
• Azacitidine (administered Days 1-5) 
• PK sampling Day 1 pre- and post-dosing: see Section 8.4 
• ECGs; see Table 7. 


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• Adverse events 
• Concomitant medications 
 
7.2.2 Cycle 1, Days 2, 3, 4, 5 
• APR-246 (administered Days 1-4) 
• Azacitidine (administered Days 1-5) 
• Additional ECG monitoring in select patients; see Section 6.2 
• PK sampling predose Day 2: see Section 8.4 
• Adverse events 
• Concomitant medications 
 
7.2.3 Cycle 1, Days 7, 14, 21  
• Vital Signs 
• CBC 
• CMP 
• Adverse events 
• Concomitant medications 
 
7.2.4 Cycle 1, Day 28 
• Physical exam with Weight 
• Vital signs 
• CBC 
• CMP 
• GVHD monitoring 
• Adverse events 
• Concomitant medications 
• Disease assessment (blood) 
 
7.2.5 Cycles 2-4, Day 1 (Day 29 of prior cycle) 
First dose of next cycle may be delayed up to 4 weeks. 
• APR-246 (administered Days 1-4) 
• Azacitidine (administered Days 1-5) 
• Physical exam with Weight; Does not need to be repeated if done within 3 days 
prior 
• Vital signs; Does not need to be repeated if done within 3 days prior 
• CBC; Does not need to be repeated if done within 3 days prior 


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• CMP; Does not need to be repeated if done within 3 days prior 
• ECGs; see Table 7. 
• Adverse events 
• Concomitant medications 
 
7.2.6 Cycles 2-4, Days 2, 3, 4, 5 
• APR-246 (administered Days 1-4) 
• Azacitidine (administered Days 1-5) 
• Additional ECG monitoring in select patients; see Section 6.2 
• Adverse events 
• Concomitant medications 
 
7.2.7 Cycles 2-4, Day 14 
• CMP 
• Adverse events 
• Concomitant medications 
 
7.2.8 Cycles 2-4, Day 28 
• Physical exam with Weight 
• Vital signs 
• CBC 
• CMP 
• GVHD monitoring 
• Adverse events 
• Concomitant medications 
• Disease assessment, blood every cycle, bone marrow end of Cycle/Month 3 
• Chimerism, end of Cycle/Month 3 
 
7.2.9 Cycles 5-12, Day 1 (Day 29 of prior cycle) 
First dose of next cycle may be delayed up to 4 weeks. 
• APR-246 (administered Days 1-4) 
• Azacitidine (administered Days 1-5) 
• Physical exam with Weight; Does not need to be repeated if done within 3 days 
prior 
• Vital signs; Does not need to be repeated if done within 3 days prior 
• CBC; Does not need to be repeated if done within 3 days prior 


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• CMP; Does not need to be repeated if done within 3 days prior 
• Adverse events 
• Concomitant medications 
 
7.2.10 Cycles 5-12, Days 2, 3, 4, 5 
• APR-246 (administered Days 1-4) 
• Azacitidine (administered Days 1-5) 
• Additional ECG monitoring in select patients; see Section 6.2 
• Adverse events 
• Concomitant medications 
 
7.2.11 Cycles 5-12, Day 14 
• CMP 
• Adverse events 
• Concomitant medications 
 
7.2.12 Cycles 5-12, Day 28 
Every cycle: 
• Physical exam with Weight 
• Vital signs 
• CBC 
• CMP 
• GVHD evaluation 
• Adverse events 
• Concomitant medications 
• Disease assessment, blood 
 
Additionally, Every 3 cycles/months: 
• Disease assessment, bone marrow end of Cycle/Month 6, 9, 12 
o Bone marrow aspirate sample and biopsy core are collected for MRD 
assessment and correlatives/exploratory (per Section 8.5) when bone 
marrow is sampled for disease assessment. 
• Chimerism, end of Cycle/Month 6, 9, 12 
 
Additionally, Every 6 cycles/months: 
• Immune reconstitution, end of Cycle/Month 5, 11 


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7.3 End of Treatment Visit 
Patients discontinuing study early should complete their end of treatment (EOT) visit 
within 30 days after their last dose. For patients who complete treatment per 
protocol, EOT is the last day of APR-246 and azacitidine dosing in Cycle 12. 
  
If patients discontinue prior to receiving any APR-246 or azacitidine, the EOT is the 
date of relapse or Day 100 post-HSCT (the last day of post-transplant window 
eligibility requirement). 
 
The following should be performed at EOT: 
• Disease assessment (blood and bone marrow) 
• Vital signs 
• CBC 
• CMP 
• ECGs; see Table 7. 
• Pregnancy test (women of child-bearing potential only) 
• Adverse events 
• Concomitant medications 
 
7.4 30 Day Safety Follow-up Visit 
This visit applies only to patients who received any APR-246 or azacitidine. This visit 
should occur 30 days after the last dose. 
• Adverse events 
• Concomitant medications 
 
7.5 Long-Term Follow-up 
This applies to all patients. Long term follow-up via phone call for survival will occur 
every 6 months until death or study closure. If GVHD or response assessment is 
conducted by the site per institutional standard of care, the site should report results 
to the sponsor until relapse is documented. 
 
 
 


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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, ECGs and adverse events. 
 
8.1.2 Safety Evaluation 
A safety evaluation will be performed by the Safety Monitoring Committee after the 
first 6 patients have completed 1 cycle of APR-246 and azacitidine combination 
therapy. The Committee will decide if it is appropriate to continue at the current 
dose; or, in the event of the combination is not tolerated (e.g. patients experience 
dose limiting toxicity) the dose of APR-246 will be reduced for subsequent enrolled 
patients. 
 
Adverse events and lab values will be reviewed. No formal analysis is planned. 
 
8.1.3 Reporting of Adverse Events 
8.1.3.1 Adverse Events 
An adverse event (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 adverse event 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 AE reporting period starts from the day of signing consent. If an AE occurs before 
the first dose of study drug it will be considered a non-treatment emergent AE. All 
AEs will be collected for 30 days after the last dose of study drug; see Section 8.1.4 
for GVHD reporting. 
 
At each evaluation patients should be interviewed in a non-directed manner to elicit 
potential adverse reactions from the patient.  The occurrence of an adverse event 
will be based on changes in the patient’s physical examination, laboratory results, 
and/or signs and symptoms. 


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All adverse events (except grade 1 and 2 laboratory abnormalities that do not require 
an intervention), regardless of causal relationship, are to be recorded in the case 
report form and source documentation.  The Investigator must determine the 
intensity of any adverse events according to the NCI Common Terminology Criteria 
for 
Adverse 
Events 
(CTCAE) 
Version 
5.0 
(see 
https://ctep.cancer.gov/protocoldevelopment/ electronic_applications/ctc.htm#ctc_50) and 
their causal relationship. Those AEs not covered by these criteria will be graded as 
follows:  
 
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.  
 
Adverse events 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. 
 
8.1.3.2 Attribution Definitions 
An adverse event is considered to be associated with the use of the Investigational 
agent if the attribution is determined as possible, probable or definite. Attribution of 
AEs will be recorded in the CRF as: 


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• 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. 
 
8.1.3.3 Definition of an Unexpected Adverse Event 
An unexpected adverse event 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.   
 
Unexpected, as used in this definition, refers to an adverse drug experience that has 
not been previously observed (e.g., included in the Investigator Brochure) rather than 
from the perspective of such experience not being anticipated from the 
pharmacological properties of the pharmaceutical product. 
 
8.1.4 GVHD Adverse Event Reporting 
All occurrences of GVHD will be reported as Adverse Events (or SAEs), regardless of 
their start date in relation to study drug. Acute GVHD will be followed until resolution, 
or until further improvement is no longer expected. Chronic GVHD events will be 
collected for 30 days after the last dose of study drug.  
 
GVHD evaluation and grading will be performed per Harris 2016 (APPENDIX C) and 
Jagasia 2015 (APPENDIX D).25,26 
 
8.1.4.1 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), 


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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 or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed above. 
 
8.1.4.2 Pregnancy 
Any pregnancy diagnosed 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 adverse event, 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 completing a Pregnancy Form and emailing it or 
faxing it to the 
 
  
 
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 8.1.4.3.  
 
8.1.4.3 Reporting of Serious Adverse Events 
Adverse events classified as serious require expeditious handling and reporting to 
o comply with regulatory requirements. 
 


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For any serious adverse event (SAE) that occurs from APR-246 consent up to 30 days 
after the last study drug administration, regardless of any opinion as to the 
relationship of the SAE to the study drug; or if any SAE that the Investigator feels is 
related to the study drug occurs later than 30 days after the last study drug 
administration, the 
 
 
 
 
 
 
All SAEs require that a Serious Adverse Event Report Form be completed and sent as 
a PDF via email (preferred method) or faxed to 
 at the address below within 
24 hours of becoming aware of the event.  
In the USA, SAEs will be reported to: 
 
 
 
 
8.1.4.4 Safety Monitoring Committee 
The Safety Monitoring Committee, consisting of the Principal Investigator and 
Treating Investigator(s) (if different from the Principal Investigator), Sponsor and 
Medical Monitor, will perform a safety evaluation after the first 6 patients have 
completed 1 cycle of APR-246 and azacitidine combination therapy.  Afterwards, 
safety will continue to be monitored and discussed during the regular study status 
meetings per the scheduled plan.  
8.2 Efficacy Assessments 
Treatment response will be assessed by review of BM/BMA and flow cytometry at the 
protocol-specified timepoints. In the LTFU period, assessments may be performed 
per institutional standard frequency. 
CBC and differential will also be used to assess the presence of blasts in PB, as well 
as the extent of hematopoietic recovery. 


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Disease assessment, according to the Investigator, will be determined at each 
assessment according to the modified International Working Group (IWG) response 
criteria appropriate to the patient's underlying disease (Cheson 2003, 2006).27, 28 
 
8.3 ECGs 
For all patients, ECGs will be read at the timepoints listed in Table 7. Patients with 
screening or any pre-dose QTc of 450 ≤ QTc <470 ms should be subject to more 
intense ECG monitoring described in Section 6.2. 
 
Table 7: ECG Timepoints 
Schedule 
# of ECGs 
Timing 
Pre screening 
Triplicate 
N/A 
Post-transplant, pre-
screening (before APR-
246) 
Triplicate 
N/A 
Cycle 1, Day 1 
Single or 
replicate 
Pre-dose; EOI/Post dose (4 hrs. after SOI; +/- 30 min.) 
Cycle 2, Day 1 
Pre-dose; EOI/Post dose (4 hrs. after SOI; +/- 30 min.) 
Cycle 3, Day 1 
Pre-dose; EOI/Post dose (4 hrs. after SOI; +/- 30 min.) 
Cycle 4, Day 1 
Pre-dose; EOI/Post dose (4 hrs. after SOI; +/- 30 min.) 
EOT 
N/A 
EOT: end of treatment; SOI=start of infusion; EOI=end of infusion 
 
8.4 Pharmacokinetics 
PK blood samples will be collected per Table 8. 
 
Table 8: PK Timepoints  
 
Cycle 
Study 
Day 
Nominal time 
Time-point 
Cycle 1 
 
Day 1 
0 hours 
0-2 hrs prior to APR-246 infusion 
0.75 hours 
45 minutes after start of infusion 
4 hours 
+/-5 min relative to the end of infusion 
 
5-6 hours 
60-120 min AFTER end of infusion 
Day 2 
24 hours 
0-2 hrs prior to APR-246 infusion on Day 2
 
 


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8.5 Correlatives/Exploratory Studies 
Table 9: Biosampling Timepoints 
Cycle 
Timepoint(s) 
Window 
Blood and 
Bone 
Marrow 
for 
chimerism 
Blood for 
immune 
reconstitution 
BMA 
for 
MRD 
BM 
biopsy 
for IHC 
pre-
transplant 
Baseline 
-28 to -1 prior 
to HSCT 
 
 
X 
X 
post-
transplant, 
before APR-
246/ 
azacitidine 
per institutional 
standard of care  ◊ 
Day 1 to 100 
post-
transplant ◊ 
X 
X 
 
 
APR-246/ 
azacitidine 
treatment 
period 
Baseline ¥ 
-28 to -1 prior 
to starting 
APR-246 and 
azacitidine 
 
 
X 
X 
APR-246/ 
azacitidine 
treatment 
period 
end of C3, 6, 9, 12 
(or EOT) ¥ 
 
 
up to 14 days 
X 
 
X 
X 
APR-246/ 
azacitidine 
treatment 
period 
end of C5 and 11 
+/- 3 days 
 
X 
 
 
◊ A patient could proceed to APR-246/azacitidine treatment as early as Day 30 post-
transplant. Therefore sampling frequency will depend on institutional practices and 
patient status. 
¥ Bone marrow aspirate sample and biopsy core are collected when bone marrow is 
sampled for disease assessment. 
 
8.5.1 Donor/Recipient Chimerism 
Post-transplant donor/recipient chimerism will be monitored every 3 months by PCR 
on CD3/CD33 cells according to local practice. Refer to Table 9. 
 
8.5.2 Immune System Reconstitution 
Post-transplant immune system reconstitution will be monitored every 6 months by 
flow cytometry on blood samples according to local practice. Refer to Table 9. 


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8.5.3 MRD by NGS 
Minimal/measurable residual disease (MRD) is monitored by a high-sensitivity NGS 
panel, including TP53, at a central laboratory. The TP53 variant allele frequency (VAF) 
will be determined as a measure of MRD. Bone marrow aspirates will be obtained at 
pre-HSCT baseline, post-HSCT baseline, C3, C6, C9 and C12. Material for additional 
explorative biomarker research will be collected from the same samples. Refer to 
Table 9. 
 
8.5.4 p53 IHC 
p53 protein expression as marker for cells with TP53 mutation will be monitored by 
immunohistochemistry (IHC) at a central laboratory. Bone marrow biopsy cores will 
be obtained at pre-HSCT baseline, post-HSCT baseline, C3, C6, C9 and C12. Refer to 
Table 9. 
 
8.5.5 Post-Transplant Engraftment 
Post-transplant donor engraftment via chimerism studies in blood and bone marrow 
will be summarized as continuous data for each dose level and overall respectively. 
 
 
 


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9.0 STATISTICS 
Demographic and clinical variables for the study patients will be summarized using 
descriptive statistics (mean, standard deviation, median, inter-quartile range, range, 
frequency counts and percentages). Safety and efficacy data will be analyzed overall 
as well as separately for each dose cohort when appropriate. 
 
9.1 Safety 
Safety data including adverse events, vital signs, laboratory data, ECG, physical exam 
will be tabulated for the Safety Evaluable population which is all subjects who are 
registered on the study and received any dose of APR-246 or azacitidine. Adverse 
events will be tabulated by body system, preferred term, severity, and relationship 
to study drugs. 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 severity grade. Incidence and grade of acute and chronic GVHD at 1-
year and cumulative will be summarized by number (%) of subjects for each dose 
level and overall. 
 
9.2 Sample Size 
The primary endpoint of the study is the relapse-free survival (RFS) at 12 months. The 
primary analysis will be done using the Kaplan-Meier method. Based upon the 
published data, the risk of relapse and non-relapse mortality in TP53 mutated MDS 
is assumed to be ~40% and ~30% at 1 year, respectively. Thus the assumptions used 
for the sample size determination are:  
• 
the null hypothesis: the RFS at 1 year is 30%, 
• 
the alternative hypothesis: the RFS at 1 year is 50% or higher, 
• 
accrual time: 24 months, 
• 
follow-up time: 12 months, 
• 
the RFS follows the exponential distribution. 
 
With a one-sided significance level of 10%, 31 subjects will provide 90.1% power to 
test the null hypothesis against the alternative. The expected number of events 
during the study is 23 and the power was computed by a one-sided one-sample 
logrank test. The final analysis will be conducted when the follow-up time for all 


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censored patients exceed 12 months. The null hypothesis will be rejected if a one-
sided p-value by the log-rank test is less than or equal to 0.1. 
 
9.3 Efficacy Endpoint and Analyses 
All efficacy analyses will be provided by using Efficacy Evaluable population. All 
subjects who are registered on the study and received at least one dose of APR-246 
or azacitidine, and have at least one efficacy assessment, or had relapse/progression.  
 
9.3.1 Relapse-Free Survival 
The primary endpoint, RFS, is defined as the time from the date of registration to 
disease relapse after SCT, or death, whichever occurs earlier. If patients discontinued 
treatment due to toxicity, and withdrew consent without relapse disease (RD) or 
death at the time of data cut off, RFS will be censored at the date of the last 
assessment. 
 
RFS will be analyzed using Kaplan-Meier methodology. Kaplan-Meier curves will be 
plotted. Median relapse-free survival will be estimated and their 95% confidence 
intervals based on Brookmeyer-Crowley methodology will be calculated. 
 
9.3.2 Overall Survival 
Overall survival (OS) is defined as the number of days from the date of registration 
to the date of death, irrespective of the cause. In the event of no death, overall 
survival will be censored at the last known alive date. 
 
OS will be analyzed using the similar methods as RFS. 
 
9.3.3 Non-Relapse Mortality 
Non-relapse 
mortality 
(NRM) 
is 
defined 
as 
time 
to 
deaths 
without 
relapse/recurrence. Deaths from any cause without prior progression are events. 
Events related to the disease such as relapse and progression are competing events. 
Patients lost to follow‐up are censored. 
 
NRM will be analyzed using the similar methods as RFS. 
 


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9.3.4 Time to Progression (TTP) 
Time to progression or relapse is time to first event related to the disease, such as 
disease progression, disease relapse/recurrence, death from disease progression, 
and/or initiation of any therapy given to prevent relapse. Deaths without prior 
relapse/recurrence (i.e., NRM) are competing events. 
 
TTP will be analyzed using the similar methods as RFS. 
 
9.3.5 Event-Free Survival (EFS) 
EFS is defined as from registration to the first of: morphologic disease relapse, death 
from any cause, reappearance of a pre-transplant cytogenetic alteration, DLI for the 
purpose of treating MDS/AML, or institution of anti-MDS/AML therapy. 
 
 
 
 
 
 
 


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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 case report forms (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 subject’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
. All Sub-investigators will be required to provide a current curriculum 
vitae and a financial disclosure statement to
. 
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 
subjects, 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 Investigator agrees to inform the Sponsor of any publication or presentations on 
the study. All manuscripts, abstracts or presentations (in outline form with copies of 


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slides if available) will be submitted to the Sponsor and 
x at least 30 days 
prior to the submission of the data for publication in order for the Sponsor to protect 
proprietary information.  The Sponsor will review the submitted material within a 
reasonable period of time and will not unreasonably withhold publication 
permission. 
 
 
 


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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 Good Clinical Practice, 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.  
 
In cases where minors or incapacitated subjects are to be included, two sets of 
information sheets might be needed according to national regulations. In addition to 
the information given to the patient’s parent or legal representative, the patient 
should be given information according to his/her capacity to understand.  This 
information should include, where appropriate, a statement that the patient’s 
decision not to participate or to withdraw from a trial will be respected, even if 
consent is given by the parent/legal representative. 
 
11.2 Institutional Review Board/Independent Ethics Committee 
The study will not be initiated without approval of the appropriate Institutional 
Review Board/Independent Ethics Committee (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, 
 or the 
Sponsor, as required by national regulations, as to the progress of the study as well 
as to any serious and unexpected adverse events.  
 
11.3 Patient Privacy  
In order to maintain patient confidentiality, all case report forms, study reports and 
communications relating to the study will identify patients by initials and assigned 


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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 case report forms and to audit the data collection process.  
Regulatory agencies such as the US Food and Drug Administration (FDA) and the UK 
Medicine and Healthcare Products Regulatory Agency (MHRA) 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. 
 
 
 


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12.0 DATA HANDLING AND RECORD KEEPING 
12.1 Recording of Data 
Data collected during the study will be entered in the patient’s Case Report Form 
(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. 
 
12.2 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. 
 
Subject’s medical files should be retained in accordance with applicable legislation 
and in accordance with the maximum period of time permitted by the hospital, 
institution or private practice. 
 
 
 


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13.0 REFERENCES 
 
1 Margulies M, Egholm M, Altman WE, et al. Genome sequencing in microfabricated high-density 
picolitre reactors. Nature 2005;437:376-80. 
2 Malcovati L, Hellstrom-Lindberg E, Bowen D, et al. Diagnosis and treatment of primary 
myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. Blood 
2013;122:2943-64. 
3 Papaemmanuil E, Gerstung M, Malcovati L, et al. Clinical and biological implications of driver 
mutations in myelodysplastic syndromes. Blood 2013;122:3616-27; quiz 99. 
4 Bejar R, Stevenson K, Abdel-Wahab O, et al. Clinical Effect of Point Mutations in Myelodysplastic 
Syndromes. New England Journal of Medicine 2011;364:2496-506. 
5 Kulasekararaj AG, Smith AE, Mian SA, et al. TP53 mutations in myelodysplastic syndrome are 
strongly correlated with aberrations of chromosome 5, and correlate with adverse prognosis. British 
journal of haematology 2013;160:660-72. 
6 Bally C, Ades L, Renneville A, et al. Prognostic value of TP53 gene mutations in myelodysplastic 
syndromes and acute myeloid leukemia treated with azacitidine. Leukemia research 2014;38:751-5. 
7Mallo M, Del Rey M, Ibanez M, et al. Response to lenalidomide in myelodysplastic syndromes with 
del(5q): influence of cytogenetics and mutations. British journal of haematology 2013;162:74-86.  
8 Takahashi K, Patel K, Bueso-Ramos C, et al. Clinical implications of TP53 mutations in 
myelodysplastic syndromes treated with hypomethylating agents. Oncotarget 2016;7:14172-87. 
9 Ferrari A, Papayannidis C, Baldazzi C, et al. Leukemia Associated TP53 Mutations in AML Patients 
ARE Strongly Associated with Complex Karyotype and Poor Outcome. Blood 2014;124:2379. 
10 Getta BM, Ghosh A, Coombs CC, et al. TP53 Mutations in AML Predict Adverse Outcome in Patients 
Undergoing Allogeneic Hematopoietic Stem Cell Transplant. Blood 2016;128:3481. 
11 Bejar R, Stevenson KE, Caughey B, et al. Somatic mutations predict poor outcome in patients with 
myelodysplastic syndrome after hematopoietic stem-cell transplantation. Journal of clinical oncology 
: official journal of the American Society of Clinical Oncology 2014;32:2691-8. 
12 Lindsley RC, Saber W, Mar BG, et al. Prognostic Mutations in Myelodysplastic Syndrome after 
Stem-Cell Transplantation. New England Journal of Medicine 2017;376:536-47. 
13 Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of 
conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a 
randomised, open-label, phase III study. The Lancet Oncology 2009;10:223-32. 
14 Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Azacitidine prolongs overall survival compared with 
conventional care regimens in elderly patients with low bone marrow blast count acute myeloid 
leukemia. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 
2010;28:562-9. 
15 Czibere A, Bruns I, Kroger N, et al. 5-Azacytidine for the treatment of patients with acute myeloid 
leukemia or myelodysplastic syndrome who relapse after allo-SCT: a retrospective analysis. Bone 
marrow transplantation 2010;45:872-6. 
16 Jabbour E, Giralt S, Kantarjian H, et al. Low-dose azacitidine after allogeneic stem cell 
transplantation for acute leukemia. Cancer 2009;115:1899-905. 
17 de Lima M, Giralt S, Thall PF, et al. Maintenance therapy with low-dose azacitidine after allogeneic 
hematopoietic stem cell transplantation for recurrent acute myelogenous leukemia or 
myelodysplastic syndrome: a dose and schedule finding study. Cancer 2010;116:5420-31. 
 


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18 Craddock C, Jilani N, Siddique S, et al. Tolerability and Clinical Activity of Post-Transplantation 
Azacitidine in Patients Allografted for Acute Myeloid Leukemia Treated on the RICAZA Trial. Biology 
of Blood and Marrow Transplantation 2016;22:385-90. 
19 Bykov VJN, Issaeva N, Selivanova G, Wiman KG. Mutant p53-dependent growth suppression 
distinguishes PRIMA-1 from known anticancer drugs: a statistical analysis of information in the 
National Cancer Institute database. Carcinogenesis 2002;23:2011-8. 
20 Nahi H, Merup M, Lehmann S, et al. PRIMA-1 induces apoptosis in acute myeloid leukaemia cells 
with p53 gene deletion. British journal of haematology 2006;132:230-6. 
21 APREA THERAPEUTICS. INVESTIGATOR’S BROCHURE (IB) APR-246. 
22 Lambert JM, Gorzov P, Veprintsev DB, et al. PRIMA-1 reactivates mutant p53 by covalent binding to 
the core domain. Cancer cell 2009;15:376-88. 
23 Peng X, Zhang MQ, Conserva F, et al. APR-246/PRIMA-1MET inhibits thioredoxin reductase 1 and 
converts the enzyme to a dedicated NADPH oxidase. Cell death & disease 2013;4:e881. 
24 Lehmann S, Bykov VJ, Ali D, et al. Targeting p53 in vivo: a first-in-human study with p53-targeting 
compound APR-246 in refractory hematologic malignancies and prostate cancer. Journal of clinical 
oncology: official journal of the American Society of Clinical Oncology 2012;30:3633-9. 
25 Harris AC, et al. International, Multicenter Standardization of Acute Graft-Versus-Host Disease 
Clinical Data Collection: A report from the Mount Sinai Acute GVHD International Consortium. Biol 
Blood Marrow Transplant 2016 Jan;22(1):4-10. 
26 Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, Palmer J, Weisdorf D, Treister 
NS, Cheng GS, Kerr H. National Institutes of Health consensus development project on criteria for 
clinical trials in chronic graft-versus-host disease: I. The 2014 Diagnosis and Staging Working Group 
report. Biology of Blood and Marrow Transplantation. 2015 Mar 1;21(3):389-401. 
27 Cheson BD, et al. Clinical application and proposal for modification of the International Working 
Group (IWG) response criteria in myelodysplasia. Blood 2006:108.2:419-425. 
28 Cheson BD, 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. Journal of clinical oncology 2003;21(24):4642-49. 
 
 


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APPENDIX A- KARNOFSKY PERFORMANCE SCALE 
 
 
 
 


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APPENDIX B- SCHEDULE OF EVENTS 
Table 10: Pre-Screen, APR-246/azacitidine Screening, Cycles 1-4 (Treatment Period) 
 
Pre-
screen 
HSCT 
 
Post HSCT/ 
Screening 
Period APR-
246/AZA (3) 
APR-246/AZA Treatment 
Cycle 1 
APR-246/AZA Treatment 
Cycles 2, 3, 4 
(Cycles 5+; see Table 11) 
Day 
-28 to -1 
to HSCT 
0 
Max up to 
Day 100 post-
HSCT 
1 (first dose) 
2, 3, 
4 
5 
7, 
14, 
21 
28 
1 (D29 
prior 
cycle) 
2, 3, 
4 
5 
14 
28 
Window 
 
 
 
NMT 28 days after 
engraftment 
confirmation 
 
 
+/- 3 
+/-3 
* 
+28 
 
 
+/-3 
+/-3 * 
Informed Consent 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
HSCT-eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
 
TP53 mutation confirmation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Engraftment confirmation 
 
 
X (3) 
 
 
 
 
 
 
 
 
 
 
APR-246  
 
 
 
X 
X 
 
 
 
X 
X 
 
 
 
Azacitidine 
 
 
 
X 
X 
X 
X 
X 
X 
APR-246/AZA Eligibility 
 
 
X (4) 
 
 
 
 
 
 
 
 
 
 
Karnofsky Performance 
Status 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Medical History and 
Transplant Details 
 
 
X (4) 
 
 
 
 
 
 
 
 
 
 
Physical Exam with Weight 
 
 
X (5) 
 
 
 
 
X 
X (5) 
 
 
 
X 
Vital Signs 
 
 
X (5) 
 
 
 
X 
X 
X (5) 
 
 
 
X 
CBC 
 
 
X (5) 
 
 
 
X 
X 
X (5) 
 
 
 
X 
CMP 
 
 
X (5) 
 
 
 
X 
X 
X (5) 
 
 
X 
X 
Cardiac function (ECG) 
X 
 
X (5) (7) 
X (7) 
X (7) 
 
 
 
X (7) 
X (7) 
 
 
 
Pregnancy Test (1) 
X 
 
X (5) 
 
 
 
 
 
 
 
 
 
 
Disease Assessment (9) 
X 
 
X (4) 
 
 
 
 
X (9) 
 
 
 
 
X (9) 
BM/BMA for Correlatives/ 
exploratory (2) 
X (2) 
 
X (2) 
 
 
 
 
 
 
 
 
 
X (2) 
GVHD monitoring 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
Blood sample (chimerism) 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 3 
(8) 
Blood sample for flow 
(immune reconstitution) 
 
 
X (4) 
 
 
 
 
 
 
 
 
 
 
PK sampling (blood) 
 
 
 
X (6) 
X (6) 
 
 
 
 
 
 
 
 


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Pre-
screen 
HSCT 
 
Post HSCT/ 
Screening 
Period APR-
246/AZA (3) 
APR-246/AZA Treatment 
Cycle 1 
APR-246/AZA Treatment 
Cycles 2, 3, 4 
(Cycles 5+; see Table 11) 
Day 
-28 to -1 
to HSCT 
0 
Max up to 
Day 100 post-
HSCT 
1 (first dose) 
2, 3, 
4 
5 
7, 
14, 
21 
28 
1 (D29 
prior 
cycle) 
2, 3, 
4 
5 
14 
28 
Window 
 
 
 
NMT 28 days after 
engraftment 
confirmation 
 
 
+/- 3 
+/-3 
* 
+28 
 
 
+/-3 
+/-3 * 
Adverse Events  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
(1) Pregnancy test applies to women of child-bearing potential only.  
(2) Bone marrow aspirate sample and biopsy core are collected for correlatives/exploratory (per Section 8.5) when bone marrow is sampled 
for disease assessment. 
(3) APR-246/azacitidine Screening Period starts when engraftment is confirmed between Day 30 to 100 post-HSCT. The first dose must be 
administered no more than 28 days after engraftment is confirmed. 
(4) Perform within 28 days prior to first dose (Cycle 1 Day 1). 
(5) Perform within 3 days prior to first dose (Cycle 1 Day 1); for Cycle 2+, do not need to repeat if done within 3 days prior to dosing. 
(6) PK: see Section 8.4. 
(7) Day 1 ECGs for all patients; see Table 7.  Day 2, 3, 4 Additional ECG monitoring in select patients; see Section 6.2. 
(8) CD3/CD33 in the blood should be done every 3 months same time marrows for disease assessment are being done.  Additionally, whole 
bone marrow chimerism should be done from the marrow every 3 months collected at same time disease assessment labs are done 
(9) Disease assessment by blood test must be done after every cycle. Response assessment based on CBC may utilize the most recently 
available bone marrow results. Disease assessment by bone marrow is done C3. 
* Up to 14 day window is permitted for disease assessments. 
 
 
 
 


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Table 11: Cycle 5-12 (Treatment Period), EOT, 30 day Safety FUV, LTFU 
 
APR-246/AZA Treatment 
Cycles 5 - 12 
EOT 
(5) 
Follow-up 
safety visit 
Long Term 
Follow-up (6) 
Day 
1 (D29 
prior 
cycle) 
2, 3, 
4 
5 
14 
28 
 
30 +/- 3 after 
last dose 
 
Window 
+28 
 
 
+/- 3 
+/- 3 * 
 
 
 
 
 
 
 
 
 
 
 
 
APR-246  
X 
X 
 
 
 
 
 
 
Azacitidine 
X 
X 
X 
Physical Exam with Weight 
X (3) 
 
 
 
X 
 
 
 
Vital Signs 
X (3) 
 
 
 
X 
X 
 
 
CBC 
X (3) 
 
 
 
X 
X 
 
 
CMP 
X (3) 
 
 
X 
X 
X 
 
 
Cardiac function (ECG) 
X (4) 
X (4) 
 
 
 
X 
 
 
Pregnancy Test (1) 
 
 
 
 
 
X 
 
 
Disease Assessment 
 
 
 
 
X (8) 
X 
 
X (6) 
BM/BMA for Correlatives/exploratory (2) 
 
 
 
 
C 6, 9, 12 (2) 
 
 
 
GVHD monitoring 
 
 
 
 
X 
 
 
X (6) 
Blood sample (chimerism) (7) 
 
 
 
 
C 6, 9, 12 
 
 
 
Blood sample for flow (immune 
reconstitution) 
 
 
 
 
C 5, 11 
 
 
 
Adverse Events  
X 
X 
X 
X 
X 
X 
X 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
 
Survival 
 
 
 
 
 
 
 
every 6 months 
(1) Pregnancy test applies to women of child-bearing potential only.  
(2) Bone marrow aspirate sample and biopsy core are collected for correlatives/exploratory (per Section 8.5) when bone marrow is sampled 
for disease assessment. 
(3) Do not need to repeat if done within 3 days prior to dosing. 
(4) After Cycle 4, perform additional ECG monitoring in select patients; see Section 6.2. 
(5) EOT: see Section 7.3. 
(6) LTFU applies to all patients. LTFU via phone call for survival will occur every 6 months until death or study closure. If GVHD or response 
assessment is conducted by the site per institutional standard of care, the site should report results to the sponsor until relapse is 
documented. 
(7) CD3/CD33 in the blood should be done every 3 months same time marrows for disease assessment are being done.  Additionally, whole 
bone marrow chimerism should be done from the marrow every 3 months collected at same time disease assessment labs are done 
(8) Disease assessment by blood test must be done after every cycle. Response assessment based on CBC may utilize the most recently 


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available bone marrow results. Disease assessment by bone marrow is done C3. 
* Up to 14 day window is permitted for disease assessments. 
 


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APPENDIX C- ACUTE GVHD GRADING SCALE 
GVHD Target Organ Staging 
Stage 
Skin (Active Erythema 
Only) 
Liver (bilirubin) 
Upper GI 
Lower GI (stool 
output/day) 
0 
No active (erythematous) 
GVHD rash 
< 2 mg/dl 
No intermittent nausea, 
vomiting, or anorexia 
<500 mL/day or <3 
episodes/day 
1 
Maculopapular rash 
<25% BSA 
2-3 mg/dl 
Persistent nausea, vomiting or 
anorexia 
500-999 mL/day or 3-4 
episodes/day 
2 
Maculopapular rash 25%-
50% BSA 
3.1-6 mg/dl 
 
1000-1500 mL/day or 5-7 
episodes/day 
3 
Maculopapular rash 
>50% BSA 
6.1-15 mg/dl 
 
>1500 mL/day or >7 
episodes/day 
4 
Generalized 
erythroderma (>50% BSA) 
plus bullous formation 
and desquamation >5% 
BSA 
>15 mg/dl 
 
Severe abdominal pain 
with or without ileus or 
grossly bloody stool 
(regardless of stool 
volume) 
 
Overall clinical grade (based on most severe target organ involvement): 
Grade 0: 
No Stage 1-4 of any organ. 
Grade 1: 
Stage 1-2 skin without liver, upper GI, or lower GI involvement. 
Grade 2: 
Stage 3 rash and/or stage 1 liver and/or stage 1 upper GI and/or stage 1 lower GI. 
Grade 3: 
Stage 2-3 liver and/or stage 2-3 lower GI, with stage 0-3 skin and/or stage 0-1 upper GI. 
Grade 4: 
Stage 4 skin, liver, or lower GI involvement, with stage 0-1 upper GI. 
Reference:  Harris AC, et al. Biol Blood Marrow Transplant 2016; 22:4 
 
 
 


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APPENDIX D- CHRONIC GVHD GRADING SCALE 
Excerpted from Jagasia 2015: The following outlines the computation of the chronic GVHD global severity scoring, which is categorized as 
mild, moderate, or severe. 
 
NIH Global Severity of chronic GVHD 
 
Mild chronic GVHD: 
1 or 2 organs involved with no more than score 1 plus 
Lung score 0 
 
Moderate chronic GVHD: 
3 or more organs involved with no more than score 1 
OR, 
At least 1 organ (not lung) with a score of 2 
OR, 
Lung score 1 
 
Severe chronic GVHD: 
At least 1 organ with a score of 3 
OR 
Lung score of 2 or 3 
 
KEY POINTS: 
In skin: higher of the 2 scores to be used for calculating global severity. 
In lung: FEV1 is used instead of clinical score for calculating global severity. 
If the entire abnormality in an organ in noted to be unequivocally explained by a non-GVHD documented cause, that organ is not included 
for calculation of the global severity. 
If the abnormality in an organ is attributed to multifactorial causes (GVHD plus other causes) the second organ will be used for calculation 
of the global severity regardless of the contributing causes (no downgrading of organ severity score).