Clinical trial NCT04419389
Conditions: Non Hodgkin Lymphoma Chronic Lymphocytic Leukemia Mantle Cell Lymphoma
Keywords: APR-246 eprenetapopt
Sponsor: Aprea Therapeutics
Start date: 2021-03-02; Completion date: 2021-08-24
Enrollment: 1 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Study to determine the preliminary safety, tolerability, and pharmacokinetic (PK) profile of APR-246 in combination with either acalabrutinib or venetoclax + rituximab therapy in subjects with NHL, including relapsed and/or refractory (R/R) CLL and R/R MCL.

Detailed description:
Phase 1, open-label, dose-finding and cohort expansion study to determine the preliminary safety, tolerability, and pharmacokinetic (PK) profile of APR-246 (eprenetapopt) in combination with either acalabrutinib or venetoclax + rituximab therapy in subjects with NHL, including relapsed and/or refractory (R/R) CLL and R/R MCL.

The study includes a safety lead-in portion followed by an expansion portion in subjects with R/R CLL, Richter Transformation (RT), and R/R MCL.

Arms: arm 1: APR-246 4.5 g/d + Acalabrutinib in Subjects with R/R CLL (APR 246 Monotherapy Lead-in; 4.5 g/d x 2) arm 2: APR-246 4.5 g/d + Venetoclax + Rituximab in Subjects with R/R CLL (APR 246 Monotherapy Lead-in; 4.5 g/d x 2). arm 3: APR-246 4.5 g/d + (Acalabrutinib, OR, (Ven+R)) in Subjects with R/R TP53-mutant CLL, and/or MCL, and/or RT arm 4: APR-246 4.5 g/d + Venetoclax + Rituximab in Subjects with RT
Interventions: intervention 1: APR-246 (eprenetapopt) + Acalabrutinib in CLL intervention 2: APR-246 (eprenetapopt) 4.5 g/d + Venetoclax + Rituximab in CLL intervention 3: APR-246 (eprenetapopt) 4.5 g/d + (Acalabrutinib, OR, (Venetoclax +Rituximab)), in CLL and/or MCL and/or RT intervention 4: APR-246 (eprenetapopt) 4.5 g/d + Venetoclax + Rituximab in RT
Intervention descriptions: intervention 1: APR-246 D1, 8 and 15 of each cycle Acalabrutinib will be given at a standard dose and schedule (APR 246 Monotherapy Lead-in; 4.5 g/d x 2) intervention 2: APR-246 D1, 8 and 15 of each cycle Venetoclax + Rituximab will be given at a standard dose and schedule (APR 246 Monotherapy Lead-in; 4.5 g/d x 2) intervention 3: APR-246 D1, 8 and 15 of each cycle Acalabrutinib will be given at a standard dose and schedule Venetoclax and Rituxiab will be given at a standard dose and schedule intervention 4: APR-246 4.5 g/d D1, 8 and 15 of each cycle Venetoclax + Rituximab will be given at a standard dose and schedule

Protocol documents:
Prot_SAP_000.pdf: 
Aprea Therapeutics  
Protocol Number A20-11197  
Phase 1 Study of APR-246 with 
Venetoclax-Based Therapy in NHL 
 
1197_CSP_7.0 
 
1 of 104 
 31 January 2022 
Confidential - Entire Page 
Phase 1 Study of APR-246 in Combination with Venetoclax and Rituximab Therapy in 
Patients with Richter’s Transformed Non-Hodgkin’s Lymphomas 
 
 
Protocol No.: 
A20-11197 
 
IND No.: 
147956 
 
 
 
 
 
Sponsor: 
Aprea Therapeutics, Inc. 
 
 
 
 
 
 
 
Responsible Medical Officer: 
Eyal C. Attar, M.D. 
 
 
Medical Monitor: 
 
 
 
 
 
 
Protocol Version: 
7.0 
 
Replaces: 
 
6.0 
Date: 
31 January 2022 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
 
This document contains strictly confidential information and cannot be disclosed or used, 
unless authorized in writing by Aprea Therapeutics, Inc. 
 


Aprea Therapeutics  
Protocol Number A20-11197  
Phase 1 Study of APR-246 with 
Venetoclax-Based Therapy in NHL 
 
1197_CSP_7.0 
 
2 of 104 
 31 January 2022 
Confidential - Entire Page 
Name: 
 
 
 
Telephone: 
 
 
 
 
 
 
Address: 
 
 
 
 
 
 
 
 
 
Signature: 
 
 
Date: 
 
 
Sponsor/Representative: 
 
Date: 
 
INVESTIGATOR’S STATEMENT 
1. 
I have carefully read this protocol entitled “Phase 1 Study of APR-246 in Combination with 
Venetoclax and Rituximab Therapy in Patients with Richter’s Transformed Non-Hodgkin's 
Lymphomas” 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 Board/Independent Ethics Committee (IRB/IEC), and that all 
administrative requirements of the governing body of the Institution will be complied with 
fully. 
3. 
Informed written consent will be obtained from all participants in accordance with 
institutional guidelines, Food and Drug Administration (FDA) requirements as specified in 
Title 21 Code of Federal Regulations (CFR), Part 50, the European Union Directive 
2001/20/European Commission (EC) and its associated Detailed Guidances, European 
Union Good Clinical Practice (GCP) Directive 2005/28/EC, the International Council for 
Harmonization (ICH) Guideline for GCP, Section 4.8, and the terms of the Declaration of 
Helsinki (2013). 
4. 
I will only enroll participants who meet the protocol criteria for entry. 
5. 
I understand that my signature on each completed electronic Case Report Form (eCRF) 
indicates that I have carefully reviewed the complete set of eCRFs 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 FDA, 
a Competent Authority of the European Union or another Regulatory Authority. 
Protocol Version 7.0: 31 January 2022 


Aprea Therapeutics  
Protocol Number A20-11197  
Phase 1 Study of APR-246 with 
Venetoclax-Based Therapy in NHL 
 
1197_CSP_7.0 
 
3 of 104 
 31 January 2022 
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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 Medical Monitor ............................................................................................................. 21 
1.4 Signature Authorization ................................................................................................ 21 
2.0 
BACKGROUND INFORMATION ................................................................................ 21 
2.1 Disease Background ...................................................................................................... 21 
2.2 APR-246 ........................................................................................................................... 22 
2.3 APR-246 Preclinical Studies ........................................................................................... 23 
2.3.1 Pharmacology and Mode of Action ................................................................. 23 
2.3.2 Safety Pharmacology......................................................................................... 24 
2.3.3 Pharmacokinetics and Metabolism in Animals .............................................. 24 
2.3.4 Toxicology ........................................................................................................... 24 
2.4 APR-246 Clinical Studies ................................................................................................ 25 
2.4.1 Phase 1/2 Study in Solid and Hematological Malignancies .......................... 26 
2.4.2 Phase 1/1b Study in Refractory Hematologic Malignancies ......................... 26 
2.4.3 Phase 1/2 Study in TP53-Mutant Advanced Ovarian Cancer ........................ 27 
2.4.4 Phase 1b/2 Studies in TP53-Mutant Myeloid Neoplasms ............................. 27 
2.4.5 Phase 3 Study in TP53-Mutant MDS ................................................................ 27 
2.4.6 Phase 1 Study in Combination with Venetoclax and Azacitidine in TP53-
Mutant Myeloid Neoplasms ......................................................................................... 28 
2.4.7 APR-246 CNS Safety Overview ......................................................................... 29 
2.4.8 APR-246 Cardiac Safety Overview .................................................................... 29 
2.4.9 APR-246 Pharmacokinetics in Humans ........................................................... 29 
2.5 Venetoclax ....................................................................................................................... 30 
2.6 Rituximab ........................................................................................................................ 31 
2.7 Rationale for Combinations of APR-246 with Venetoclax + Rituximab .................... 32 
2.8 Rationale for Dose of APR-246 in Combination with Venetoclax and Rituximab ... 32 
2.9 Rationale for Oral Dose of APR-246 in the Monotherapy Cycle ............................... 33 
2.10 Potential Risks and Benefits .......................................................................................... 33 
2.10.1 Potential Risks .................................................................................................... 33 
2.10.2 Potential Benefits .............................................................................................. 35 
2.11 Characteristics of a Well-Conducted Trial ................................................................... 35 


Aprea Therapeutics  
Protocol Number A20-11197  
Phase 1 Study of APR-246 with 
Venetoclax-Based Therapy in NHL 
 
1197_CSP_7.0 
 
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 31 January 2022 
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2.12 Patient Population ......................................................................................................... 35 
3.0 
TRIAL OBJECTIVES AND PURPOSE ........................................................................... 35 
3.1 Primary Objective ........................................................................................................... 35 
3.2 Secondary Objectives .................................................................................................... 35 
3.3 Exploratory Objectives ................................................................................................... 36 
4.0 
TRIAL DESIGN ............................................................................................................ 36 
4.1 Overview of Trial Design ................................................................................................ 36 
4.2 End of Study .................................................................................................................... 38 
4.3 Drug Products ................................................................................................................. 38 
4.3.1 APR-246 ............................................................................................................... 38 
4.3.2 Venetoclax .......................................................................................................... 39 
4.3.3 Rituximab ........................................................................................................... 39 
4.4 Duration of Therapy....................................................................................................... 39 
4.5 Trial Discontinuation ...................................................................................................... 40 
4.6 Drug Accountability/Disposition of Experimental Drug Supplies ............................. 40 
4.7 Inclusion Criteria ............................................................................................................ 40 
4.8 Exclusion Criteria ............................................................................................................ 41 
4.9 Inclusion of Women, Minorities and Children ............................................................ 42 
4.10 Withdrawal Criteria ........................................................................................................ 42 
4.10.1 Study Treatment Discontinuation ................................................................... 43 
4.10.2 Study Completion .............................................................................................. 43 
4.10.3 Withdrawn Patients ........................................................................................... 43 
4.11 Noncompliance .............................................................................................................. 43 
5.0 
TREATMENT OF PATIENTS ........................................................................................ 43 
5.1 Drug Preparation and Administration ......................................................................... 43 
5.1.1 APR-246 ............................................................................................................... 44 
5.1.2 Venetoclax .......................................................................................................... 45 
5.1.3 Rituximab ........................................................................................................... 45 
5.1.4 Dose-Limiting Toxicity ....................................................................................... 45 
5.1.5 Recommended Dose of APR-246 ..................................................................... 46 
5.2 Dose Interruptions/Withholding .................................................................................. 47 
5.3 Supportive Management ............................................................................................... 51 
5.3.1 Neutropenia with or without Fever ................................................................. 51 
5.3.2 APR-246 ............................................................................................................... 51 
5.3.3 Venetoclax .......................................................................................................... 59 
5.3.4 Rituximab ........................................................................................................... 62 
5.4 Concomitant Treatment ................................................................................................ 64 
5.5 Monitoring Patient Compliance .................................................................................... 64 
6.0 
STUDY EVALUATIONS ............................................................................................... 64 
6.1 Schedule of Study Evaluations ...................................................................................... 64 
6.2 Pre-Study Assessments ................................................................................................. 68 


Aprea Therapeutics  
Protocol Number A20-11197  
Phase 1 Study of APR-246 with 
Venetoclax-Based Therapy in NHL 
 
1197_CSP_7.0 
 
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 31 January 2022 
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6.3 Screening ......................................................................................................................... 68 
6.4 APR-246 Monotherapy Lead-in ..................................................................................... 68 
6.4.1 Day 1 ................................................................................................................... 68 
6.4.2 Day 2 ................................................................................................................... 69 
6.4.3 Day 3 ................................................................................................................... 69 
6.5 Cycle 1 (Venetoclax Ramp-up, Weeks 1-5) ................................................................... 70 
6.5.1 Days 1 and 2 ....................................................................................................... 70 
6.5.2 Day 8 ................................................................................................................... 70 
6.5.3 Day 15 ................................................................................................................. 70 
6.6 Cycles 2-7 ........................................................................................................................ 71 
6.6.1 Day 1 ................................................................................................................... 71 
6.6.2 Day 2 ................................................................................................................... 71 
6.6.3 Day 8 (±3 Days) .................................................................................................. 71 
6.6.4 Day 15 (±3 Days) ................................................................................................ 72 
6.7 Tumor Assessment (Cycles 4, 7, 10, 13, 19, 22 and 25) .............................................. 72 
6.8 Cycle 8 and Beyond ........................................................................................................ 72 
6.8.1 Day 1 ................................................................................................................... 72 
6.8.2 Day 8 (±3 Days) .................................................................................................. 73 
6.8.3 Day 15 (±3 Days) ................................................................................................ 73 
6.9 End of Treatment Visit ................................................................................................... 73 
6.10 Long-Term Follow-Up .................................................................................................... 74 
7.0 
STUDY ASSESSMENTS ............................................................................................... 74 
7.1 Safety Assessments ....................................................................................................... 74 
7.1.1 Safety Analysis ................................................................................................... 74 
7.1.2 Reporting of Adverse Events ............................................................................ 74 
7.2 Efficacy Assessments ..................................................................................................... 78 
7.2.1 Complete Response Rate .................................................................................. 78 
7.2.2 Duration of Response ....................................................................................... 78 
7.2.3 Objective Response Rate .................................................................................. 78 
7.2.4 Overall Survival .................................................................................................. 78 
7.3 Progression-Free Survival ............................................................................................. 78 
7.4 Pharmacokinetic and Pharmacodynamic Evaluation ................................................ 78 
7.5 Electrocardiographic Assessment ................................................................................ 80 
8.0 
STATISTICS ................................................................................................................. 80 
8.1 Sample Size ..................................................................................................................... 80 
8.2 Analysis Populations ...................................................................................................... 81 
8.3 Endpoints ........................................................................................................................ 81 
8.3.1 Primary ............................................................................................................... 81 
8.3.2 Secondary ........................................................................................................... 81 
8.3.3 Exploratory ......................................................................................................... 81 
8.4 Safety Stopping Criteria ................................................................................................. 82 
8.5 Futility Criteria ................................................................................................................ 82 


Aprea Therapeutics  
Protocol Number A20-11197  
Phase 1 Study of APR-246 with 
Venetoclax-Based Therapy in NHL 
 
1197_CSP_7.0 
 
6 of 104 
 31 January 2022 
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8.6 Safety ............................................................................................................................... 82 
8.7 Efficacy ............................................................................................................................. 82 
8.8 Pharmacodynamic Analysis .......................................................................................... 83 
8.9 Pharmacokinetic Analysis.............................................................................................. 83 
9.0 
QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES ............................ 84 
9.1 Monitoring of the Study and Regulatory Compliance ................................................ 84 
9.2 Curricula Vitae and Financial Disclosure of Investigators ......................................... 84 
9.3 Protocol Modifications ................................................................................................... 84 
9.4 Publication Policy ........................................................................................................... 84 
10.0 
ETHICAL CONSIDERATIONS ..................................................................................... 84 
10.1 Informed Consent .......................................................................................................... 84 
10.2 Institutional Review Board/Independent Ethics Committee ..................................... 85 
10.3 Patient Privacy ................................................................................................................ 85 
11.0 
DATA HANDLING AND RECORD KEEPING .............................................................. 85 
11.1 Data to be Entered Directly in the Case Report Form................................................ 85 
11.2 Recording of Data .......................................................................................................... 85 
11.3 Study Records ................................................................................................................. 86 
12.0 
REFERENCES .............................................................................................................. 87 
APPENDIX I - Cockcroft-Gault Equation .............................................................................. 91 
APPENDIX II - ECOG Performance Status ............................................................................ 92 
APPENDIX III - Acceptable Contraceptive Methods ........................................................... 93 
APPENDIX IV - New York Heart Association (NYHA) Classification ................................. 94 
APPENDIX V - Lugano Criteria for RT Patients 55 ................................................................ 95 
APPENDIX VI - Dose Modifications of Venetoclax with Use of CYP3A or P-gp Inhibitors
 
98 
APPENDIX VII - Patient Handout: Prohibited Medications ............................................. 103 
 
 
 


Aprea Therapeutics  
Protocol Number A20-11197  
Phase 1 Study of APR-246 with 
Venetoclax-Based Therapy in NHL 
 
1197_CSP_7.0 
 
7 of 104 
 31 January 2022 
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List of In-text Tables  
Table 1. Average Exposure After Infusion of a Fixed Dose of 4.5 g of APR-246 for 6 hours in 
Males and Females ......................................................................................................................... 30 
Table 2. Predicted Exposures of APR-246 Oral Starting Dose (500 mg) ................................... 30 
Table 3. APR-246 Dose Levels ....................................................................................................... 37 
Table 4. Dosing Schedule for Ramp-Up Period in Cycle 1 ......................................................... 45 
Table 5. Dose management guidelines for new onset hematologic toxicities ........................ 48 
Table 6. Dose management guidelines for Grade 3 or 4 non-hematologic toxicities ............ 50 
Table 7. APR-246 Dose Modification in the Setting of Moderate Renal Impairment .............. 51 
Table 8. Recommendations for Prevention and Treatment of Cancer-Related Infections .... 52 
Table 9. Management Guidelines for QTc Prolongation ............................................................ 54 
Table 10. Recommendations for APR-246 Dose Modifications and Criteria for Treatment 
Interruption and Re-Initiation with Treatment-Related Adverse Events  ................................. 55 
Table 11. Management of CNS Adverse Events (e.g., Dizziness, Tremor, Confusion, and 
Ataxia) .............................................................................................................................................. 58 
Table 12. Medications for Management of Nausea and Vomiting ........................................... 59 
Table 13. Recommended Venetoclax Dose Modifications for Toxicities ................................. 60 
Table 14. Dose Reduction for Toxicity During Venetoclax Treatment ...................................... 61 
Table 15. Venetoclax Dose Modifications for Use with CYP3A Inhibitors ................................ 61 
Table 16. Recommended TLS Prophylaxis Based on Tumor Burden in Patients .................... 61 
Table 17: Schedule of Assessments ............................................................................................. 65 
Table 18: PK and PD Blood Sampling Timepoints for APR-246 ................................................. 79 
Table 19. ECG Assessment Requirements ................................................................................... 80 
Table 20. CYP3A Inhibitors and Inducers ..................................................................................... 99 
 
 
List of In-text Figures 
Figure 1: Clinical Trial Schema ........................................................................................................ 8 
Figure 2. Structure of APR-246 ...................................................................................................... 23 
 


Aprea Therapeutics  
Protocol Number A20-11197  
Phase 1 Study of APR-246 with 
Venetoclax-Based Therapy in NHL 
 
1197_CSP_7.0 
 
8 of 104 
 31 January 2022 
Confidential - Entire Page 
CLINICAL STUDY SYNOPSIS 
Title 
Phase 1 Study of APR-246 in Combination with Venetoclax and Rituximab Therapy in Patients 
with Richter’s Transformed Non-Hodgkin's Lymphomas (NHL) 
Sponsor 
Aprea Therapeutics, Inc. 
Monitor/ 
Contract 
Research 
Organization 
(CRO) 
Number of 
Study Centers 
Up to 10 
Clinical Phase 
1 
Investigational 
Agent 
APR-246 (eprenetapopt) 
Study Design 
This is a phase 1, open-label study to determine the pharmacologically active dose range of 
APR-246 in combination with venetoclax and rituximab in patients with Richter’s Transformed 
NHL (RT) and to select a recommended dose for further development. The study includes a 
dose escalation design (Figure 1). It is preceded by a brief APR-246 monotherapy lead-in to 
establish a baseline pharmacokinetic (PK) / pharmacodynamic (PD) profile after intravenous 
(IV) dosing in each patient and to obtain APR-246 PK after a single dose of APR-246 
administered orally (PO). The recommended dose will be based on the safety, tolerability, PK 
and PD profile of APR-246 in combination with venetoclax and rituximab therapy in patients 
with RT. Once the recommended dose of APR-246 in combination with venetoclax and 
rituximab is established, further explorations in expansion arms may be pursued following a 
protocol amendment. 
 
Patients with RT will receive APR-246 administered IV at the assigned cohort dose with 
standard doses of venetoclax and rituximab. Dose escalation will proceed in a standard 3 + 3 
dose escalation design. 
 
 
 
 
 
 
 
 
 
 
 
 
 
X = assigned cohort dose 
Figure 1: Clinical Trial Schema 
Cycle 1: D1-35 
APR-246 IV Dose X D1, 8, 15 
Venetoclax PO Ramp Up 
Cycle 2 and beyond: D1-28 
APR-246 IV Dose X D1, 8, 15 
Venetoclax PO 400 mg/day 
Rituximab 375 mg/m2 (Day 2 Cycle 2), 500 mg/m2 Day 2 Cycles 3-7 
Monotherapy Lead-In: D1-7 
APR-246 IV Dose X: D1 
APR-246 500 mg PO: D2 


Aprea Therapeutics  
Protocol Number A20-11197  
Phase 1 Study of APR-246 with 
Venetoclax-Based Therapy in NHL 
 
1197_CSP_7.0 
 
9 of 104 
 31 January 2022 
Confidential - Entire Page 
The intended three dose levels of APR-246 are: 1.5 g/day, 3.0 g/day, and 4.0 g/day 
administered as an IV infusion over 6 hours. The dose escalation will proceed until a 
pharmacologically active dose level is achieved. It will be stopped if maximum tolerated dose 
(MTD) is reached at a dose level below the maximum planned dose of 4.0 g/day. For the 
determination of MTD the following rules will be applied: 
 
• 
Three patients will be enrolled to Dose Level 1. 
• 
If 0 patients out of 3 experience a dose limiting toxicity (DLT) at Dose Level 1 (1.5 g/day 
of APR-246), the dose will advance to the next level (Dose Level 2, 3.0 g/day). 
• 
If 1 of the first 3 patients at Dose Level 1 experiences a DLT, 3 additional patients will be 
recruited and treated at the same dose level (1.5 g/day of APR-246).  
• 
If ≥2 patients out of 3-6 patients in a cohort experience a DLT at Dose Level 1 (1.5 g/day 
of APR-246), the study will temporarily discontinue enrollment and the Data Review Team 
(DRT) will consider further enrollment and possible dose/schedule adjustments. 
• 
If <2 patients out of 6 experiences a DLT at Dose Level 1 (1.5 g/day), dose escalation will 
proceed to the next cohort level (Dose Level 2, 3.0 g/day). 
• 
For each cohort, if there are 0 DLTs in the first 3 patients enrolled, the cohort will advance 
to the next level. If there is 1 DLT in the first 3 patients enrolled to a cohort, the cohort 
will enroll an additional 3 patients. If there are ≥2 DLTs in a cohort, the prior lower dose 
level will be declared the MTD. 
• 
If there are ≤1 DLT in the first 3 patients enrolled at Dose Level 3, 4.0 g/day APR-246, the 
study will enroll 3 additional patients at Dose Level 3. If there are ≤1 DLTs in 6 patients 
enrolled at Dose Level 3, 4.0 g/day APR-246 will be declared the MTD. 
 
Upon determination of the pharmacologically active dose or MTD, or when the maximally 
intended dose is reached, up to 10 additional patients may be enrolled at this dose level to 
confirm the assessment and to collect additional safety, PK and PD data to aid in determining 
the recommended dose of APR-246 in combination with venetoclax and rituximab. 
 
Prior to initiation of study treatment with APR-246 administered IV in combination with 
venetoclax and rituximab (during treatment cycles 2-7), patients will receive APR-246 alone on 
Day 1 and Day 2 of the 7-day monotherapy lead-in period, during which PK and PD of APR-246 
following IV and PO administration will be evaluated. On Day 1 of the monotherapy lead-in 
period, APR-246 will be administered IV at the assigned cohort dose. On Day 2, APR-246 will 
be administered PO at the dose of 500 mg. This dose may be increased based on emerging 
PK data to determine dose linearity after oral dosing. Patients will be required to fast for at 
least 10 hours prior to APR-246 PO administration. Furthermore, a sub-group of patients may 
receive an oral dose of APR-246 in combination with a standard high-fat meal to determine 
the effect of food on APR-246 absorption. 
 
Study Objectives 
Primary objective:   
To evaluate the PD, safety and tolerability of APR-246 administered IV in combination with 
venetoclax and rituximab in patients with RT to determine the recommended dose of 
APR-246. 
 
Secondary objectives: 
1. 
To investigate PD markers of APR-246 activity, including in peripheral blood malignant 
cells, using flow cytometry and other techniques. 
2. 
To investigate PD markers of APR-246 activity in monotherapy, including in peripheral 
blood malignant cells, using flow cytometry and other techniques (PK/PD Substudy of 
APR-246 Monotherapy). 
3. 
To determine the PK profile of APR-246. 


Aprea Therapeutics  
Protocol Number A20-11197  
Phase 1 Study of APR-246 with 
Venetoclax-Based Therapy in NHL 
 
1197_CSP_7.0 
 
10 of 104 
 31 January 2022 
Confidential - Entire Page 
4. 
To investigate the PK of APR-246 administered PO (PK/PD Substudy of APR-246 
Monotherapy). 
5. 
To assess preliminary clinical activity of APR-246 in combination with venetoclax and 
rituximab therapy. 
 
Exploratory objectives: 
To explore the exposure response relationship of APR-246 with safety and/or efficacy 
when combined with venetoclax and rituximab therapy. 
 
Study Endpoints 
Primary endpoints: 
1. 
PD analysis of circulating peripheral blood cells to determine effects of APR-246 on 
cellular viability and apoptosis. 
2. 
Frequency of treatment-emergent adverse events (TEAEs) and serious adverse events 
(SAEs) related to APR-246 in combination with venetoclax and rituximab therapy. 
3. 
The highest tested dose of APR-246 with acceptable toxicity (the dose producing <33% of 
DLT). 
 
Secondary endpoints: 
1. 
PK parameters: maximum concentration (Cmax), area under the curve (AUC), volume of 
distribution (Vd) and clearance (CL) of APR-246; and Cmax, time to maximum concentration 
(Tmax), and AUC of venetoclax. 
2. 
PD analysis of circulating peripheral blood cells to determine effects of APR-246 on 
cellular viability and apoptosis (PK/PD Substudy of APR-246 Monotherapy). 
3. 
PK parameters after oral dosing: Cmax, Tmax, AUC, relative bioavailability (F), apparent 
volume of distribution (Vd/F) and apparent clearance (CL/F) of APR-246, (PK/PD Substudy of 
APR-246 Monotherapy). 
4. 
Complete remission (CR) rate, defined as the proportion of patients who achieve CR as 
per response criteria. 
5. 
Objective response rate (ORR), defined as the proportion of patients achieving a response, 
as per response criteria. 
6. 
Duration of response (DOR), defined as the time from documentation of tumor response 
to disease progression or death as a result of any cause. 
7. 
Progression-free survival (PFS), defined as the time from the first study dose date to the 
date of first documentation of confirmed disease progression or death (whichever occurs 
first). 
 
Exploratory endpoints: 
The exposure response relationship for safety and efficacy of APR-246 when combined 
with venetoclax and rituximab therapy. 
 
Criteria for 
Inclusion 
Inclusion criteria: 
 
1. 
Patient is able to understand the study requirements and is willing and able to comply 
with them and provide written informed consent. 
2. 
Patients with documented histologic diagnosis of RT by World Health Organization 
criteria who have relapsed and/or refractory disease following at least one line of 
prior therapy for RT. 
3. 
Prothrombin time (or international normalized ratio) and partial thromboplastin time 
not to exceed 1.2 × the institution’s normal range (patients with an elevated 
prothrombin time and known lupus anticoagulant may be eligible for participation 
after consulting the Medical Monitor). 


Aprea Therapeutics  
Protocol Number A20-11197  
Phase 1 Study of APR-246 with 
Venetoclax-Based Therapy in NHL 
 
1197_CSP_7.0 
 
11 of 104 
 31 January 2022 
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4. 
Adequate bone marrow (BM) function independent of growth factor or transfusion 
support, per local laboratory reference range at screening as follows: 
a. 
Platelet count ≥75,000/mm3 
b. 
Absolute neutrophil count ≥1,000/mm3 unless cytopenia is clearly due to 
marrow involvement from NHL 
c. 
Total hemoglobin ≥9 g/dL (without transfusion support within 2 weeks of 
screening) 
If any of the above-mentioned cytopenia (a-c) are present due to BM involvement 
with disease (requiring transfusion or granulocyte colony-stimulating factor [G-CSF] 
support) NHL patients may proceed with enrollment after discussion with the 
Medical Monitor. Cytopenia may not be due to evidence of myelodysplastic 
syndrome (MDS) or hypoplastic BM. 
5. 
Adequate organ function as defined by the following laboratory values: 
a. 
Creatinine CL ≥60 mL/min (by Cockcroft-Gault method, Appendix I) 
b. 
Total serum bilirubin ≤1.5 × upper limit of normal (ULN) unless due to Gilbert’s 
syndrome, NHL organ involvement, controlled immune hemolysis or 
considered an effect of regular blood transfusions 
c. 
Alanine aminotransferase and aspartate aminotransferase ≤2.5 × ULN, unless 
due to NHL organ involvement 
6. 
Age ≥18 years at the time of signing the informed consent form. 
7. 
Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 
(APPENDIX II). 
8. 
Projected life expectancy of ≥12 weeks. 
9. 
Female patients must be surgically sterile, postmenopausal (for at least 1 year), or 
have negative results for a pregnancy test at screening, on a serum sample obtained 
within 7 days prior to initiation of study treatment. 
10. Women of childbearing potential and men with female partners of childbearing 
potential must be willing to use an effective form of contraception (Appendix III). 
11. Patients should use an effective form of contraception for up to 6 months after the 
last dose of APR-246 in combination with venetoclax or up to 12 months after the last 
dose of rituximab, whichever time period is longer. 
 
Exclusion criteria: 
1. 
Patients with known allergies to xanthine oxidase inhibitors or rasburicase. 
2. 
Prior allergy to rituximab, defined as a clinically significant infusion-related reaction 
(IRR) in the opinion of the Investigator. 
3. 
Other severe acute or chronic medical or psychiatric condition or laboratory 
abnormality that, in the opinion of the Investigator, may increase the risk associated 
with study participation or study treatment administration or may interfere with the 
interpretation of study results and/or would make the patient inappropriate for 
enrollment into this study. 
4. 
Concomitant anticancer therapies, immunotherapies, cellular, or radiotherapy; major 
surgery within 3 weeks prior to first dose of study treatment. Washout period for 
chemotherapy is 14 days. Washout period for targeted agents is 2 weeks or 5 half-
lives 
(T1/2) 
(whichever 
is 
shorter). 
Washout 
period 
for 
antibody-based 
immunotherapies or cellular therapies is 4 weeks. Washout period for radiotherapy 
is 7 days (limited field) and 28 days (extended field that includes BM). Washout period 
must be completed prior to any treatment administration.  
5. 
Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia. 
6. 
Consumption of grapefruit, grapefruit products, Seville oranges, or star fruit within 
7 days of starting study treatment. 


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7. 
Concomitant steroids for disease related pain control are allowed at any dose but 
must be discontinued prior to any study treatment initiation. Chronic use of 
corticosteroids is allowed up to ≤20 mg prednisone daily for non-cancer related 
conditions at the time of study start.  
8. 
History of allogeneic or autologous stem cell transplant or chimeric antigen receptor 
T-cell therapy (CAR-T) within the last 30 days or with any of the following:  
a. 
Active graft versus host disease 
b. 
Cytopenia from incomplete blood cell count recovery post-transplant 
c. 
Need for anti-cytokine therapy for residual symptoms of neurotoxicity grade >1 
from CAR-T  
d. 
Ongoing immunosuppressive therapy. 
9. 
Known history of human immunodeficiency virus (HIV) serum positivity.  
10. Active hepatitis B/C. Patients with prior exposure to hepatitis B (i.e., positive 
anti-hepatitis B core antibody) must demonstrate hepatitis B polymerase chain 
reaction to be negative during screening period and undergo prophylaxis and 
monitoring for hepatitis B according to institutional guidelines. 
11. Known central nervous system (CNS) involvement by lymphoma. Patients with 
previous treatment for CNS involvement who are neurologically stable and without 
evidence of disease may be eligible if a compelling clinical rationale is provided to 
sponsor.  
12. Known neurologic disorder or residual neurologic toxicities that may put patients at 
increased risk of neurologic toxicity in the opinion of the Investigator. 
13. Any of the following cardiac abnormalities: 
a. 
Myocardial infarction within six months prior to enrollment 
b. 
New York Heart Association Class III or IV heart failure (Appendix IV) or known 
left ventricular ejection fraction <40% 
c. 
A history of familial long QT syndrome 
d. 
Symptomatic atrial or ventricular arrhythmias not controlled by medications 
e. 
Corrected QT interval by Fridericia formula (QTcF) ≥470 msec, unless due to 
underlying bundle branch block and/or pacemaker and with the approval of the 
Medical Monitor.  
14. Concomitant malignancies or previous malignancies with less than a 1-year 
disease-free interval at the time of signing consent. Patients with adequately treated 
basal or squamous cell carcinoma of the skin, or adequately treated carcinoma in situ 
(e.g., cervix) may enroll irrespective of the time of diagnosis. Patients with controlled, 
advanced prostate cancer are permitted. 
15. Female patients who are pregnant or breast-feeding. 
16. Active uncontrolled systemic infection. 
17. Received an investigational agent within 30 days or within 5 T1/2, whichever is shorter 
prior to the first dose of study treatment. 
18. Clinically significant active malabsorption syndrome or other condition likely to affect 
gastrointestinal absorption.  
19. Current treatment with certain strong cytochrome P450 3A4 (CYP3A4) inhibitors or 
inducers and/or strong P-gp or breast cancer resistance protein inhibitors (see 
Appendix VI). 
Treatment Plan 
Treatment will be administered on an outpatient basis but may be administered in the 
inpatient setting for patients who are hospitalized and meet criteria for study enrollment. No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's disease under study. 
 
Monotherapy Cycle 
There is a 7-day monotherapy cycle where patients receive APR-246 IV on Day 1 and 


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APR-246 PO on Day 2. The primary purpose of the monotherapy cycle is to obtain peripheral 
blood for monotherapy PK and PD analyses following IV and PO administration of APR-246. 
 
Patients will start treatment with APR-246 IV as a single agent administered on Day 1 of a 
single 7-day monotherapy cycle at the assigned cohort dose level, prior to Cycle 1 Day 1 of 
combination therapy. On Day 2 of the 7-day monotherapy lead-in period, patients will receive 
a single dose of APR-246 administered PO at the dose of 500 mg. After review of oral PK data 
from at least 6 patients, a decision can be made whether to increase the PO dose of APR-246 
and/or administer APR-246 with a standard high-fat meal to investigate, respectively, dose 
linearity in PK and/or the effect of food on oral absorption of APR-246. Dose escalation of the 
oral dose or switching to administration with food will be determined by PK to ensure that the 
APR-246 exposure levels after oral dosing do not exceed the exposure levels after IV 
administration in terms of Cmax and AUC. 
 
Combination Treatment 
After the APR-246 monotherapy lead-in, study treatment will consist of APR-246 administered 
as an IV infusion, at the same assigned dose that was used during the monotherapy lead-in 
period,  once weekly, on Days 1, 8 and 15 of each cycle, concurrently with venetoclax for the 
5-week ramp-up at the dose of 20 mg during Week 1, 50 mg during Week 2, 100 mg during 
Week 3, 200 mg during Week 4, and 400 mg during Week 5. Beginning Cycle 2 Day 1, 
venetoclax will be administered at 400 mg (or tolerable dose following 5-week ramp up) PO 
daily. IV rituximab will be initiated at 375 mg/m2 on Cycle 2, Day 2 and then administered at 
500 mg/m2 on Day 2 of Cycles 3-7. After 6 cycles of treatment with APR-246 in combination 
with venetoclax + rituximab, APR-246 + venetoclax will continue to be administered starting at 
Cycle 8 for up to a total of 24 cycles. The safety assessment (DLT) period will occur in the 
monotherapy lead-in and throughout Cycles 1, 2, and 3 of combination treatment. 
 
Patients with RT will receive APR-246 administered IV as the assigned cohort dose with 
standard doses of venetoclax and rituximab. Dose escalation will proceed in a standard 3 + 3 
dose escalation design. 
 
Patients who miss >25% of APR-246 doses for a nonmedical reason (patient’s preference) or 
noncompliance will be replaced. 
 
Patients who receive at least 3 cycles of study treatment at the assigned dose of APR-246 may 
proceed to the next dose level of APR-246 that has been demonstrated as safe and tolerable 
by the DRT in at least 3 patients, provided the dose increase is considered to be in the patient’s 
best interest by the Investigator. 
 
Responses will be assessed according to response criteria for RT (Appendix V) via blood, BM, 
and imaging (positron emission tomography [PET]/computed tomography [CT]). Response 
assessments are to be performed every 3 cycles and PET-CT scanning is recommended. For 
patients who achieve CR, imaging may be omitted, and minimal residual disease (MRD) 
assessment will be completed using flow cytometry and/or molecular techniques from the BM 
and/or peripheral blood. 
 
Duration of 
Follow-Up  
 
Patients will be followed as per the Schedule of Study Assessments for up to 26 months 
through the end of trial visit and then will enter into long-term follow-up per Section 6.10. 
 
After a patient is removed or withdrawn from study treatment, the patient will be followed in 
the study until death or withdrawal of consent for study participation, whichever occurs first.  
 


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Off-treatment data on overall survival (OS) will be updated every 3 months or until death or 
withdrawal of consent for study participation, whichever occurs first. If a patient is removed 
from the study due to unacceptable adverse event(s) (AEs), the event(s) will be followed until 
resolution or stabilization. Patients who respond and discontinue study treatment for reasons 
other than disease progression should have response assessments, and survival should be 
collected every 2 months until disease progression, withdrawal of consent for study 
participation, or death, whichever occurs first. After disease progression, data for survival 
should be collected every 3 months until death or withdrawal of consent for study 
participation. 
 
Criteria for Removal from Study Treatment 
Study treatment can continue for patients deriving clinical benefit in the opinion of the 
Investigator, unless one or more withdrawal criteria are met, or at the patient’s discretion, or 
if the study is terminated. 
 
Study Treatment Discontinuation 
 
1. 
Study treatment must be discontinued if: 
• 
Evidence of disease progression is observed. Note that patients who have disease 
progression but are continuing to derive clinical benefit in the opinion of the 
Investigator may continue to receive study treatment. 
• 
A female patient becomes pregnant. 
• 
A patient is non-compliant with the requirements of the protocol.  
• 
A patient has an adverse experience that would, in the Investigator’s judgment, make 
continued participation in the study an unacceptable risk. 
• 
The patient starts new treatment for their disease under study. 
 
2. 
Patient Withdrawal from Study Treatment 
If the patient is permanently withdrawn from study treatment, but does not withdraw consent 
from the study, the Investigator should make every effort to have the patient complete all 
withdrawal assessments at the time of withdrawal and complete all scheduled follow-up visits. 
 
3. 
Study Completion 
A patient must be taken off the study if: 
• 
The patient dies during the study. 
• 
The patient is lost to follow-up. 
• 
The patient withdraws consent for study participation. 
 
4. 
Patient Withdrawal from Study 
A patient may voluntarily withdraw from study treatment or withdraw consent from study 
participation at any time. The Investigator may also, at his or her discretion, discontinue a 
patient from study treatment at any time. The Investigator and/or designated staff will record 
the date and the reason for patient withdrawal from the study. 
 
Statistics 
This is a phase 1, open-label study to determine the pharmacologically active dose range of 
APR-246 in combination with venetoclax and rituximab and to select a recommended dose 
for further development. 
 
The recommended dose of APR-246 in combination with venetoclax and rituximab will be 
defined as the dose determined to be producing the greatest level of cellular apoptosis in 
circulating peripheral blood malignant cells in the monotherapy portion. Dose escalation will 
be stopped when either the MTD or the intended maximum dose of the study is reached. 


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Phase 1 Study of APR-246 with 
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Definition of DLT 
All TEAEs are relevant to the determination of DLTs unless they are clearly and solely due to 
the disease under study. The DLT evaluation period will be up to 91 days (7 days of APR-246 
monotherapy plus 84 days for Cycle 1–3 with combination therapy) after the first dose of 
APR-246 is administered. A DLT is defined as any of the following TEAEs using the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), as follows: 
  
• 
Any neurologic toxicity of grade 4 
• 
Any grade ≥3 non-hematologic toxicity except for:  
• 
First occurrence of grade 3 electrolyte abnormalities and/or creatinine CL 
decrease resolving to grade 2 (or baseline if baseline is grade ≥2) within 48 
hours with supportive treatment.  
• 
Grade 3 fatigue, nausea, vomiting, diarrhea or other manageable 
constitutional symptom(s) that is/are responsive to supportive therapy.  
• 
Grade 3 infection responding to appropriate antimicrobial therapy.  
• 
Any neurologic toxicity of grade 3 that does not return to grade ≤1 or 
baseline within 7 days. 
• 
Any grade ≥3 hematologic toxicity will be considered a DLT except for:  
• 
Grade 3 neutropenia without fever  
• 
Grade 4 neutropenia without fever lasting 8 days or less 
• 
Grade 3 thrombocytopenia that does not result in bleeding or transfusion  
• 
Grade 3/4 lymphopenia/lymphocytosis 
• 
Grade 3/4 white blood cell (WBC) decreased  
• 
Grade 3/4 WBC increased  
 
Any toxicity, regardless of the NCI-CTCAE v5.0 grade, resulting in discontinuation, dose 
reduction or treatment with less than 75% of planned doses of APR-246 study drug, will be 
reviewed by the DRT, and will be considered a DLT unless clearly and solely related to the 
disease under study. The DRT will consist of the Medical Monitor, Site Principal Investigators, 
and other clinical research personnel that the Sponsor may deem appropriate. 
 
G-CSF support for the management of neutropenia and prophylactic antimicrobial therapy 
are allowed, including during the DLT period.  
 
TEAEs that meet the above criteria but that occur after the DLT evaluation period will not be 
defined as DLTs and will be reported as AEs/SAEs and will be reviewed across all cohorts 
during the study to help determine the AE profile for the respective treatment regimens under 
study. A patient that discontinues APR-246 therapy before completion of Cycle 3 without DLT 
is considered evaluable for the purpose of safety review by the DRT only if at least 75% of the 
scheduled doses of APR-246 were administered in Cycles 1 through 3. 
 
The study will implement the following stopping criteria: 
 
• 
Any death occurring between receipt of the first dose of APR-246 through 30 days of 
last dose of study treatment which is not clearly and solely due to underlying disease, 
• 
A medically equivalent SAE experienced by >1 patient, which is not clearly and solely 
due to underlying disease, 
• 
A severe AE (NCI-CTCAE toxicity grade >3) experienced by >2 patients that does not 
return to grade ≤1 or baseline within 7 days , 
• 
A grade ≥3 neurologic AE that does not return to grade ≤1 or baseline within 7 days. 
 


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Phase 1 Study of APR-246 with 
Venetoclax-Based Therapy in NHL 
 
1197_CSP_7.0 
 
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If a stopping criterion is met, enrollment will be temporarily suspended until the DRT has 
performed a prompt cumulative review of safety data and the circumstances of the event(s) 
in question, to determine whether dosing and/or the protocol should be modified. 
 
Determination of Sample Size 
This trial assumes a sample size of up to 48 patients in total, with up to 6 patients in each of 
the 3 cohorts and an additional 10 patients added at the MTD, or maximum tolerated dose, 
to gain further confidence in the recommended dose of APR-246. If Dose Level 3 is determined 
to be the MTD, up to 10 additional patients may be added and treated at both Dose Levels 1 
and 2 to obtain additional safety, PK, and/or PD information. No sample size and power 
calculations are performed for this phase 1 study. 
 
Patients who miss >25% of APR-246 doses for a nonmedical reason (patient’s preference) or 
noncompliance in the safety lead-in cohorts will be replaced. 
 
Recommended Dose 
The recommended dose of APR-246 in combination with venetoclax and rituximab represents 
the dose of APR-246 at or below the maximum tested dose, or the MTD, that results in the 
greatest apoptosis of circulating malignant cells in the monotherapy cycle. 
 
Analysis Populations 
 
Safety population: Patients will be evaluable for safety if they receive at least one dose of 
APR-246. The safety population will be the primary analysis population used for all analyses 
such as patient disposition, patient demographics, exposure, safety parameters and efficacy 
parameters. The safety population will be the primary analysis population for efficacy. 
 
Efficacy evaluable (EE) population: All patients who complete at least one treatment cycle of 
APR-246 and venetoclax and rituximab and who have at least one post-treatment clinical 
response assessment. The EE population will be the secondary analysis population for 
efficacy. 
 
PD population: Patients will be evaluable for PD if at least one sample for PD evaluation has 
been obtained after administration of APR-246. 
 
PK population: Patients will be evaluable for PK if at least one sample for PK evaluation has 
been obtained. 
 
Efficacy Analyses 
CR rate will be summarized for the safety and EE patients as the proportion (%) of patients 
with CR. In addition to presenting the CR rate, its associated exact 95% confidence intervals 
(CI) will also be presented. 
 
DOR is defined as the time from the date when criteria for response are met to the date of 
disease progression or death due to any cause, whichever occurs first. Patients alive with no 
disease progression will have their DOR censored at the date of the last clinical assessment. 
The duration of CR will be summarized by providing the median DOR together with associated 
95% CI, using Kaplan-Meier methodology.  
 
ORR will be summarized in number (%) of patients in each category of responses and ORR will 
be analyzed by using a similar method to the one used for the CR rate. ORR is defined as the 
number of patients who achieve CR and partial remission. 
 


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Phase 1 Study of APR-246 with 
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Survival data are collected at treatment and follow-up periods. Patients will be followed until 
death or withdrawal of consent from the study, whichever occurs first.  
 
OS is defined as the number of days from the first day of treatment to the date of death due 
to any cause. Kaplan-Meier methodology will be utilized. 
 
PFS is defined as the time from the first day of treatment to disease progression or death due 
to any cause, whichever occurs first. If neither event occurs, PFS will be censored at the date 
of the last clinical assessment. Kaplan-Meier methodology will be utilized. 
 
Safety Analyses 
Safety data including AEs, vital signs, laboratory data, electrocardiogram, and physical exam 
findings will be tabulated for the safety population. AEs will be tabulated by System Organ 
Class, preferred term, severity, and relationship to treatments. The tabulation of laboratory 
parameters will include the normal ranges for each parameter. Each value will be classified as 
falling above, below, or within the normal range. Laboratory parameters will also be tabulated 
by maximum NCI-CTCAE v5.0 severity grade. 
 
Pharmacodynamic Analysis 
PD analysis will be conducted using flow cytometry of circulating chronic lymphocytic 
leukemia (CLL)/RT cells before and after treatment with APR-246 during monotherapy and the 
first day of combination treatment ramp-up, to assess viability and apoptosis. Descriptive 
statistics (mean, standard deviation, coefficient of variation (CV%) mean, geometric mean, 
CV% geometric mean) will be utilized to compare the post- and pre-treatment samples and 
the differences at each dose cohort level will be tested for relationship to dose. 
 
Pharmacokinetic Analysis 
During the APR-246 monotherapy lead-in period, PK sampling for APR-246 will be performed 
on Days 1 - 3. Noncompartmental PK analysis will be used to determine Cmax, Tmax, AUC and 
bioavailability after oral dosing for decision making on dose escalation of the oral dose. 
 
PK sampling for APR-246 will be performed during Cycle 2, on Day 1, 8 and 15 and on Day 1 
from Cycle 3 onwards. 
 
PK sampling for venetoclax and rituximab will not be performed for this study. 
 
The PK of APR-246 will be summarized using descriptive statistics (mean, standard deviation, 
CV% mean, geometric mean, CV% geometric mean). The concentration data for APR-246 will 
be evaluated using population PK analysis in combination with data from other studies. 
 
APR-246 AUC and Cmax will then be tested for association with signs of efficacy and safety. If 
an observable trend exists, a PK/PD model will be developed to evaluate the exposure-
response relationship between APR-246 plasma exposure and outcome measures. 
Demographic and clinical data (ethnicity, current age, body weight, sex, disease status, etc.) 
will be utilized to assess interpatient variability in the PK and PK/PD relationships. 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event 
AIHA 
Autoimmune hemolytic anemia 
AML 
Acute myeloid leukemia 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BBB 
Bundle branch block 
Bcl-2 
B-cell lymphoma-2 
βhCG 
Beta-human chorionic gonadotrophin 
BM 
Bone marrow 
BUN 
Blood urea nitrogen 
CAR-T 
Chimeric antigen receptor T-cell therapy 
CFR 
Code of Federal Regulations 
CHF 
Congestive heart failure 
CI 
Confidence interval 
CIT 
Chemoimmunotherapy 
CL 
Clearance 
CLL 
Chronic lymphocytic leukemia 
Cmax 
Maximum concentration 
CNS 
Central nervous system 
CR  
Complete remission 
CRO 
Contract Research Organization 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV% 
Coefficient of variation 
CYP3A4 
Cytochrome P450 3A4 
DLT 
Dose limiting toxicity 
DOR 
Duration of response 
DRM 
Data review meeting 
DRT 
Data Review Team 
EC 
European Commission 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EE 
Efficacy evaluable 
EOI 
End of infusion 
ER 
Endoplasmic reticulum 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice  
G-CSF 
Granulocyte colony-stimulating factor 
GLP 
Good Laboratory Practice 
HBV 
Hepatitis B virus 
HBsAg 
Hepatitis B surface antigen 
HGSOC 
High-grade serous ovarian cancer 


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HIV 
Human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICH 
International Council for Harmonization 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
IRR 
Infusion-related reaction 
IV 
Intravenous(ly) 
LBM 
Lean body mass 
LDH 
Lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MDS 
Myelodysplastic syndrome 
MQ 
2-methylene-quinuclidin-3-one 
MRD 
Minimal residual disease 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
NGS 
Next-generation sequencing 
NHL 
Non-Hodgkin’s lymphoma 
OS 
Overall survival 
ORR 
Objective response rate 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamic(s) 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PK 
Pharmacokinetic(s) 
PLD 
Pegylated liposomal doxorubicin 
PML 
Progressive multifocal leukoencephalopathy 
PO 
Orally (per os) 
popPK 
Population pharmacokinetics 
PR 
Partial remission 
PRBC 
Packed red blood cells 
QTcF 
Corrected QT interval by Fridericia formula 
RT 
Richter’s transformed NHL 
SAE 
Serious adverse event 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
TLS 
Tumor lysis syndrome 
Tmax 
Time to maximum concentration 
TrxR1 
Thioredoxin reductase 1 
T1/2 
Half-life 
ULN 
Upper limit of normal 
US 
United States 
USPI 
United States Prescribing Information 
VAF 
Variant allele frequency 
Vd 
Volume of distribution 
WBC 
White blood cell 


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Protocol Number A20-11197  
Phase 1 Study of APR-246 with 
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1197_CSP_7.0 
 
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WHO 
World Health Organization 


Aprea Therapeutics  
Protocol Number A20-11197  
Phase 1 Study of APR-246 with 
Venetoclax-Based Therapy in NHL 
 
1197_CSP_7.0 
 
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1.0 GENERAL INFORMATION 
1.1 
Protocol Number and Title of the Study 
Protocol No. A20-11197 
 
Protocol Title: Phase 1 Study of APR-246 in Combination with Venetoclax and Rituximab Therapy in 
Patients with Richter’s Transformed Non-Hodgkin’s Lymphomas 
 
1.2 
Sponsor 
Aprea Therapeutics, Inc. 
 
 
 
1.3 
Medical Monitor 
 
 
 
 
 
1.4 
Signature Authorization 
The protocol will be signed by Aprea Therapeutics. 
 
 
2.0 BACKGROUND INFORMATION 
2.1 
Disease Background 
Non-Hodgkin’s lymphomas (NHL) are lymphoid malignant neoplasms with diverse biological and 
clinical behavior, variously derived from the clonal expansion of B cells, T cells, natural killer cells or 
precursors of these cells.  
 
Chronic lymphocytic leukemia (CLL) is one of the most common types of B-cell NHL, characterized by 
a progressive accumulation of functionally incompetent monoclonal lymphocytes1. The incidence 
rates among men and women in the United States (US) are approximately 6.75 and 3.65 cases per 
100,000 population per year, respectively2,3.  
 
CLL is associated with a highly heterogeneous disease course, with some patients surviving for more 
than 10 years without needing treatment, and others experiencing rapid disease progression and 
poor outcomes despite effective chemoimmunotherapy (CIT)4–8. This heterogeneity is partly explained 
by the diverse genetic aberrations identified in approximately 80% of CLL patients9–12, including a 
deletion in chromosome 13q14.3 (del(13q)), del(11q), del(17p) and trisomy 12, associated with an 
intermediate prognosis. Del(13q) is the most common chromosomal alteration, evident in >50% of 
patients, and is associated with favorable prognosis13. Del(17p) is found in 7% of patients and is 
associated with loss of the tumor suppressor gene TP5314, whereas del(11q) is found in 18% of patients 


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Phase 1 Study of APR-246 with 
Venetoclax-Based Therapy in NHL 
 
1197_CSP_7.0 
 
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and is often associated with alterations in ATM; each of these chromosomal alterations is associated 
with adverse clinical outcome9,15. Deletions in chromosome 17p [del(17p)] resulting in loss of the TP53 
gene, which encodes the tumor-suppressor protein p53, belong to the strongest prognostic and 
predictive markers guiding treatment decisions in CLL, and are associated with markedly decreased 
survival and impaired response to CIT16–20. CLL patients with alterations of TP53 have inferior 
outcomes with all CLL directed therapies, in particular CIT combinations, and these patients (if fit) 
were historically considered for referral for allogeneic hematopoietic stem cell transplantation in first 
remission21–25. New small-molecule inhibitors that are efficacious in patients harboring TP53 
mutations are now available, including the BTK inhibitors ibrutinib and acalabrutinib, the 
phosphatidylinositol 3-kinase inhibitors idelalisib and duvelisib, and the B cell lymphoma-2 (Bcl-2) 
inhibitor venetoclax26–34. 
  
Despite the introduction of targeted agents, 5-10% of previously treated CLL patients undergo 
transformation into high-grade lymphoma, a condition known as Richter’s transformed NHL (RT). 
These patients typically present with an aggressive disease course and have poor response to 
traditional chemotherapy used to treat de novo diffuse large B-cell lymphoma and similar or shorter 
overall survival (OS) (median 3-11 months)35,36. Based on clonal relationship of large cell component 
to CLL, 2 distinct subtypes could be identified: clonally-related RT which carries a worse outcome, and 
clonally-unrelated RT where the outcomes are similar to de novo diffuse large B-cell lymphoma37. 
Specific risk factors for the development of RT in a patient with CLL have yet to be identified; however, 
TP53 disruption, c-MYC abnormalities, unmutated immunoglobulin heavy chain <2%, non-del13q 
cytogenetics, CD38 gene polymorphisms, stereotypy, and VH4-39 gene usage may predispose to 
RT35,37,38. The CLL-International Prognostic Index aids in predicting time to first therapy among 
previously untreated patients38. The prognosis of patients with RT generally is poor, particularly for 
those who are heavily pretreated for CLL and/or who have transformation involving lymphocytes that 
are clonally related to the underlying CLL39. 
 
There is no standard of care for patients with RT, which represents a disease with unmet medical 
needs. Development of rituximab-containing intensive chemotherapy regimens and chemo-
immunotherapy regimens have improved response rates but have not clearly affected long-term 
outcomes35. CIT remains the treatment of choice, though the outcomes remain suboptimal, with the 
median survival of less than 1 year. 
   
2.2 
APR-246 
 
 
 
 
 
  


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Phase 1 Study of APR-246 with 
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1197_CSP_7.0 
 
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Figure
 
2.3 
APR-246 Preclinical Studies 
2.3.1 
Pharmacology and Mode of Action 
 
 
 
, 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1197_CSP_7.0 
 
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2.3.2 
Safety Pharmacology 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
2.3.3 
Pharmacokinetics and Metabolism in Animals 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
2.3.4 
Toxicology 
 
 
 
  


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In
 
 
 
 
  
 
 
246 Clinical Studies 
 
 
 


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2.4.1 
Phase 1/2 Study in Solid and Hematological Malignancies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
2.4.2 
Phase 1/1b Study in Refractory Hematologic Malignancies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol Number A20-11197  
Phase 1 Study of APR-246 with 
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2.4.6 
Phase 1 Study in Combination with Venetoclax and Azacitidine in TP53-Mutant Myeloid 
Neoplasms 
 
 
 
 
 
 
 
 
 
 
 
 


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2.4.7 
APR-246 CNS Safety Overview 
 
 
 
 
 
 
 
 
. 
 
2.4.8 
APR-246 Cardiac Safety Overview 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
246 Pharmacokinetics in Humans 
 
 
 
 
 


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Table 1. Average Exposure After Infusion of a Fixed Dose of 4.5 g of APR-246 for 6 hours in 
Males and Females 
 
 
Males 
Females 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
2.5 
Venetoclax 
Venetoclax is a Bcl-2 inhibitor that was approved by the U.S. FDA for the treatment of adult patients 
with CLL or small lymphocytic lymphoma in the front line and relapsed/refractory settings. 


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In the phase 3 study comparing venetoclax plus rituximab with bendamustine plus rituximab in 
relapsed and/or refractory CLL (MURANO), the 2-year rates of progression-free survival (PFS) were 
significantly higher in the venetoclax-rituximab group (84.9%) than in the bendamustine–rituximab 
group (36.3%)46. The benefit was maintained across all clinical and biologic sub-groups, including the 
sub-group of patients with chromosome 17p deletion, where the 2-year rate of PFS among patients 
with chromosome 17p deletion was 81.5% in the venetoclax–rituximab group versus 27.8% in the 
bendamustine–rituximab group (hazard ratio, 0.13; 95% CI, 0.05 to 0.29). 
 
The most common adverse reactions (≥20%) of any grade in patients receiving venetoclax 
monotherapy are neutropenia, diarrhea, nausea, anemia, upper respiratory tract infection, 
thrombocytopenia, and fatigue. Serious adverse reactions were reported in 43.8% of patients. The 
most frequent serious adverse reactions (≥2%) were pneumonia, febrile neutropenia, pyrexia, 
autoimmune hemolytic anemia (AIHA), anemia, and tumor lysis syndrome (TLS). More detailed 
information about the safety profile of venetoclax in combination with rituximab may be found in the 
United States prescribing information (USPI) for venetoclax47.  
 
Following multiple doses under fed conditions, Cmax of venetoclax is reached 5 – 8 hours after dose. It 
is recommended that venetoclax be administered with a meal as food increases the absorption after 
oral administration. Venetoclax is cleared from systemic circulation via hepatic elimination. The T1/2 is 
approximately 26 hours. The PK of venetoclax does not change over time. Venetoclax is 
predominantly metabolized by CYP3A4/5. CYP3A4 inhibitors and inducers as well as P-gp inhibitors 
cause clinically relevant drug-drug interactions with venetoclax. For the same reason certain food 
must be avoided: grapefruit, grapefruit juice, Seville oranges (often used in marmalades), starfruit 
(CYP3A inhibiting), and St John’s wort (CYP3A inducing). Based on their metabolic profiles, a PK drug-
drug interaction of venetoclax with APR-246 is considered unlikely. 
 
2.6 
Rituximab 
Rituximab is a monoclonal antibody that targets the CD20 antigen expressed on the surface of pre-B 
and mature B-lymphocytes. Upon binding to CD20, rituximab mediates B-cell lysis. Possible 
mechanisms of cell lysis include complement dependent cytotoxicity and antibody dependent cell 
mediated cytotoxicity. B cells are believed to play a role in the pathogenesis of rheumatoid arthritis 
and associated chronic synovitis. In this setting, B cells may be acting at multiple sites in the 
autoimmune/inflammatory process, including through production of rheumatoid factor and other 
autoantibodies, antigen presentation, T-cell activation, and/or proinflammatory cytokine production. 
 
In NHL patients, administration of rituximab resulted in depletion of circulating and tissue-based B 
cells. Among 166 patients in NHL Study 1 (NCT000168740), circulating CD19-positive B cells were 
depleted within the first three weeks with sustained depletion for up to 6 to 9 months post treatment 
in 83% of patients. B-cell recovery began at approximately 6 months and median B-cell levels returned 
to normal by 12 months following completion of treatment. There were sustained and statistically 
significant reductions in both IgM and IgG serum levels observed from 5 through 11 months following 
rituximab administration; 14% of patients had IgM and/or IgG serum levels below the normal range48. 
 
The PK was characterized in 203 NHL patients receiving 375 mg/m2 rituximab weekly by IV infusion 
for 4 doses. Rituximab was detectable in the serum of patients 3 to 6 months after completion of 


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treatment. Based on a population PK (popPK) analysis of data from 298 NHL patients who received 
rituximab once weekly or once every three weeks, the estimated median T1/2 was 22 days (range, 6.1 
to 52 days). Patients with higher CD19-positive cell counts or larger measurable tumor lesions at 
pretreatment had a higher CL. However, dose adjustment for pretreatment CD19 count or size of 
tumor lesion is not necessary. Age and gender had no effect on the PK of rituximab48.  
 
As rituximab is a monoclonal antibody, no PK drug-drug interaction is expected with APR-246. 
 
2.7 
Rationale for Combinations of APR-246 with Venetoclax + Rituximab 
 
 
 
 
 
 
 
 
 
 
 
2.8 
Rationale for Dose of APR-246 in Combination with Venetoclax and Rituximab 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


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venetoclax and rituximab. 
 
2.9 
Rationale for Oral Dose of APR-246 in the Monotherapy Cycle 
 
 
 
 
 
 
 
 
 
 
 
 
 
n
 
 
 
2.10 Potential Risks and Benefits 
2.10.1 Potential Risks 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 


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(
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2.10.2 Potential Benefits 
The purpose of this clinical trial is to define the PD, safety and tolerability of APR-246 in combination 
with venetoclax and rituximab in patients with RT and to determine preliminary efficacy. Considering 
the lack of effective treatment options in these patients, the benefit/risk assessment supports the use 
of APR-246 in this trial. 
 
2.11 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 electronic Case Report Forms (eCRFs) will be completed for every patient.  
3. Requirements for institutional ethics review as set forth by the appropriate Institutional 
Review Board/Independent Ethics Committee (IRB/IEC), Title 21 Code of Federal Regulations 
(CFR) Part 56, the European Union Directive 2001/20/European Commission (EC) and its 
associated Detailed Guidances, European Union Good Clinical Practice (GCP) Directive 
2005/28/EC, the International Council for Harmonization (ICH) Guideline for GCP, 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 GCP, Section 4.8, and the terms of the Declaration of Helsinki (2013), will be 
followed.  
5. Safety data will be recorded and evaluated.  
6. Routine monitoring visits will be conducted by the Sponsor’s representative to ensure data 
accuracy.  
7. Drug accountability will be strictly maintained.  
8. This trial will be conducted according to GCP, the protocol and applicable regulatory 
requirements. 
 
2.12 Patient Population 
This study will enroll adult male and female patients of ≥18 years of age with documented histologic 
diagnosis of RT by WHO criteria who have relapsed and/or refractory disease following at least 
one line of prior therapy for RT.  
 
3.0 TRIAL OBJECTIVES AND PURPOSE 
3.1 
Primary Objective 
To evaluate the PD, safety and tolerability of APR-246 administered IV in combination with 
venetoclax and rituximab in patients with RT to determine the recommended dose of APR-246. 
 
3.2 
Secondary Objectives 
1. To investigate a pharmacologically active dose of APR-246 by using PD markers of APR-246 activity, 


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including in peripheral blood malignant cells, using flow cytometry and other techniques. 
2. To investigate PD markers of APR-246 activity in monotherapy, including in peripheral blood 
malignant cells, using flow cytometry and other techniques (PK/PD Substudy of APR-246 
Monotherapy). 
3. To determine the PK profile of APR-246. 
4. To investigate the PK of APR-246 administered PO (PK/PD Substudy of APR-246 Monotherapy). 
5. To assess preliminary clinical activity of APR-246 in combination with venetoclax and rituximab 
therapy. 
 
3.3 
Exploratory Objectives 
To explore the exposure response relationship of APR-246 with safety and/or efficacy when 
combined with venetoclax and rituximab therapy. 
 
4.0 TRIAL DESIGN 
4.1 
Overview of Trial Design 
Treatment will be administered on an outpatient basis but may be administered in the inpatient 
setting for patients who are hospitalized and meet criteria for study enrollment. No investigational or 
commercial agents or therapies other than those described below may be administered with the 
intent to treat the patient's disease under study.  
 
Monotherapy Cycle 
There is a 7-day monotherapy cycle where patients receive APR-246 IV on Day 1 and APR-246 PO on 
Day 2. The primary purpose of the monotherapy cycle is to obtain peripheral blood for monotherapy 
PK and PD analyses following IV and PO administration of APR-246. 
 
Patients will start treatment with APR-246 IV as a single agent administered on Day 1 of a single 7-day 
monotherapy cycle at the assigned cohort dose level, prior to Cycle 1 Day 1 of combination therapy. 
On Day 2 of the 7-day monotherapy lead-in period, patients will receive a single dose of APR-246 
administered PO at the dose of 500 mg. After review of oral PK data from at least 6 patients, a decision 
can be made whether to increase the PO dose of APR-246 and/or administer APR-246 with a standard 
high-fat meal to investigate, respectively, dose linearity in PK and/or the effect of food on oral 
absorption of APR-246. Dose escalation of the oral dose or switching to administration with food will 
be determined by PK to ensure that the APR-246 exposure levels after oral dosing do not exceed the 
exposure levels after IV administration in terms of Cmax and AUC. 
 
Combination Treatment 
After the APR-246 monotherapy lead-in, study treatment will consist of APR-246 administered as an 
IV infusion at the same assigned dose that was used during the monotherapy lead-in period once 
weekly, on Days 1, 8 and 15 of each cycle, concurrently with venetoclax for the 5-week ramp-up at the 
dose of 20 mg during Week 1, 50 mg during Week 2, 100 mg during Week 3, 200 mg during Week 4, 
and 400 mg during Week 5. Beginning Cycle 2 Day 1, venetoclax will be administered at 400 mg (or 
tolerable dose following 5-week ramp up) PO daily. IV rituximab will be initiated at 375 mg/m2 on Cycle 
2, Day 2 and then administered at 500 mg/m2 on Day 2 of Cycles 3-7. After 6 cycles of treatment with 
APR-246 in combination with venetoclax + rituximab, APR-246 + venetoclax will continue to be 


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administered starting at Cycle 8 for up to a total of 24 cycles. Cycle 1 will consist of 35 days. Cycles 2 
and beyond will be 28 days. The safety assessment (DLT) period begins at the start of treatment and 
extends to the end of Cycle 3. 
 
Patients with RT will receive APR-246 administered IV at the assigned cohort dose with standard doses 
of venetoclax and rituximab. Dose escalation will proceed in a standard 3 + 3 dose escalation design. 
 
The intended three dose levels of APR-246 are: 1.5 g/day, 3.0 g/day, and 4.0 g/day administered as an 
IV infusion over 6 hours. The dose escalation will proceed until a pharmacologically active dose level 
is achieved. It will be stopped if the maximum tolerated dose (MTD) is reached at a dose level below 
the maximum planned dose of 4.0 g/day. For the determination of MTD the following rules will be 
applied: 
 
• 
Three patients will be enrolled to Dose Level 1.   
• 
If 0 patients out of 3 experience a DLT at Dose Level 1 (1.5 g/day of APR-246), the dose will advance 
to the next level (Dose Level 2, 3.0 g/day). 
• 
If 1 of the first 3 patients at Dose Level 1 experiences a DLT, 3 additional patients will be recruited 
and treated at the same dose level (1.5 g/day of APR 246).  
• 
If ≥2 patients out of 3-6 patients in a cohort experience a DLT at Dose Level 1 (1.5 g/day of 
APR-246), the study will temporarily discontinue enrollment and the Data Review Team (DRT) will 
consider further enrollment and possible dose/schedule adjustments. 
• 
If <2 patients out of 6 experiences a DLT at Dose Level 1 (1.5 g/day), dose escalation will proceed 
to the next cohort level (Dose Level 2, 3.0 g/day). 
• 
For each cohort, if there are 0 DLTs in the first 3 patients enrolled, the cohort will advance to the 
next level. If there is 1 DLT in the first 3 patients enrolled to a cohort, the cohort will enroll an 
additional 3 patients. If there are ≥2 DLTs in a cohort, the prior lower dose level will be declared 
the MTD. 
• 
If there are ≤1 DLT in the first 3 patients enrolled at Dose Level 3, 4.0 g/day APR-246, the study 
will enroll 3 additional patients at Dose Level 3. If there are ≤1 DLTs in 6 patients enrolled at Dose 
Level 3, 4.0 g/day APR-246 will be declared the MTD. 
 
Upon determination of the pharmacologically active dose or MTD, or when the maximally intended 
dose is reached, up to 10 additional patients may be enrolled at this dose level to confirm the 
assessment and to collect additional safety, PK and PD data to aid in determining the recommended 
dose of APR-246 in combination with venetoclax and rituximab. 
 
Table 3. APR-246 Dose Levels 
Dose Modification 
APR-246 Dose 
Dose Level 1 
APR-246 1.5 g/day 
0.5 g (for first 45 minutes) + 1.0 g (for 5 hours 15 minutes) 
Dose Level 2 
APR-246 3.0 g/day  
1.0 g (for first 45 minutes) + 2.0 g (for 5 hours 15 minutes) 
Dose Level 3 
APR-246 4.0 g/day  
1.33 g (for the first 45 minutes) + 2.66 g (for 5 hours 15 minutes) 
 


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Prior to initiation of study treatment with APR-246 administered IV in combination with venetoclax 
and rituximab (during treatment cycles 2-7), patients will receive APR-246 alone on Day 1 and Day 2 
of the 7-day monotherapy lead-in period, during which PK and PD of APR-246 following IV and PO 
administration will be evaluated. On Day 1 of the monotherapy lead-in period, APR-246 will be 
administered IV at the assigned cohort dose. On Day 2, APR-246 will be administered PO at the dose 
of 500 mg. This dose may be increased based on emerging PK data to determine dose linearity after 
oral dosing. Patients will be required to fast for at least 10 hours prior to APR-246 PO administration. 
Furthermore, a sub-group of patients may receive an oral dose of APR-246 in combination with a 
standard high-fat meal to determine the effect of food on APR-246 absorption. 
 
Additional dose levels may be explored if warranted based on emerging DLT, safety, PK, and/or PD 
data. In addition, patients who have received at least 3 cycles of therapy at the assigned dose cohort 
level may advance to the next higher dose level once the next higher dose level has been declared 
safe by the DRT.   
 
Responses will be assessed according to response criteria for RT (Appendix V) via blood, BM, and 
imaging (positron emission tomography [PET]/computed tomography [CT]). Response assessments 
are to be performed every 3 cycles and PET-CT scanning is recommended. For patients who achieve 
CR, imaging may be omitted, and minimal residual disease (MRD) assessment will be completed using 
flow cytometry and/or molecular techniques from the BM and/or peripheral blood. 
 
Patients may continue treatment as long as toxicity remains acceptable, the patient has not withdrawn 
consent and is deriving clinical benefit in the opinion of the Investigator while receiving study 
treatment according to the treatment durations specified for the agents in Section 4.4. Response and 
disease progression will be assessed based on the Revised Criteria for Response Assessment of 
Hodgkin’s and Non-Hodgkin’s Lymphoma (Lugano Criteria; see Appendix V), as outlined in the 
Schedule of Study Evaluations. 
 
4.2 
End of Study 
The end of the study is defined as the date of the last visit of the last patient undergoing the trial. 
 
4.3 
Drug Products 
4.3.1 
APR-246 
 
 
 
 
   
 
 
 
 
 
 


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4.3.2 
Venetoclax 
Chemical 
Name: 
4-{4-[(4'-chloro-5,5-dimethyl[3,4,5,6-tetrahydro[1,1'-biphenyl]]-2-yl)methyl] 
piperazin-1-yl}-N-(3-nitro-4-{[(oxan-4-yl)methyl]amino}benzene-1-sulfonyl)-2-[(1H-pyrrolo[2,3-b]pyrid
ine-5-yl)oxy]benzamide. 
 
Formulation, preparation, storage and stability: Please see venetoclax USPI52. 
 
Route of Administration: Venetoclax should be taken PO, with food, at a dose of 400 mg daily once the 
ramp-up phase is completed. During the 5-week ramp-up in Cycle 1, venetoclax is given PO at the 
dose of 20 mg during Week 1, 50 mg during Week 2, 100 mg during Week 3, 200 mg during Week 4, 
and 400 mg during Week 5. Use of posaconazole and strong CYP inhibitors is contraindicated in the 
ramp up phase. For patients receiving a steady daily dose of venetoclax, the dose of venetoclax should 
be modified accordingly to account for changes in concomitant use of posaconazole and CYP 
inhibitors in accordance with the venetoclax USPI52. 
 
4.3.3 
Rituximab 
Chemical Name: Immunoglobulin G1 (human-mouse monoclonal IDEC-C2B8 gamma 1-chain 
anti-human antigen CD 20), disulfide with human-mouse monoclonal IDEC-C2B8 kappa-chain, dimer 
 
Formulation, preparation, storage and stability: Rituximab injection is a sterile, preservative-free, clear, 
colorless solution for IV infusion. Store rituximab vials refrigerated at 2°C to 8°C (36°F to 46°F) and 
protect from direct sunlight. Do not freeze or shake. Please see Rituximab USPI48. 
 
Route of administration: Rituximab is administered as an IV infusion with starting dose of 375 mg/m2 
in Cycle 2 and then 500 mg/m2 in Cycles 3−7. 
 
4.4 
Duration of Therapy 
Patients may remain on study treatment to the end of the trial visit while deriving clinical benefit, 
unless unacceptable toxicity, progression, death or patient withdrawal occurs. Rituximab may be 
given for up to 6 cycles and venetoclax for up to 2 years. Patients may remain on study treatment 
after disease progression if they are continuing to derive clinical benefit in the opinion of the 
Investigator. 
 


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4.5 
Trial Discontinuation  
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. 
 
The Sponsor reserves the right to discontinue the study for clinical or administrative reasons at any 
time. If the site does not recruit at a reasonable rate, the study may be discontinued at that site. 
Should the study be terminated and/or the site closed for whatever reason, all documentation and 
study drug pertaining to the study must be returned to the Sponsor or its representative, and the 
Investigators, IRB/IEC and Regulatory Authorities will be promptly informed of the termination and 
the reason for the decision. The Investigator should promptly inform the patients and ensure 
appropriate therapy and follow-up. Patients should then be withdrawn from the study. 
 
4.6 
Drug Accountability/Disposition of Experimental Drug Supplies 
The Investigator or designee will maintain accurate records of receipt and the condition of the study 
drug supplied for this study, including dates of receipt. In addition, accurate records will be kept of 
when and how much study drug is dispensed and administered to each patient in the study. Any 
reasons for departure from the protocol dispensing regimen must also be recorded.  
 
At the completion of the study, there will be a final reconciliation of all study drugs.  
 
4.7 
Inclusion Criteria 
1. Patient is able to understand the study requirements and is willing and able to comply with 
them and provide written informed consent. 
2. Patients with documented histologic diagnosis of RTby WHO criteria who have relapsed 
and/or refractory disease following at least one line of prior therapy for RT. 
3. Prothrombin time (or international normalized ratio) and partial thromboplastin time not to 
exceed 1.2 × the institution’s normal range (patient with an elevated prothrombin time and 
known lupus anticoagulant may be eligible for participation after consulting the Medical 
Monitor). 
4. Adequate BM function independent of growth factor or transfusion support, per local 
laboratory reference range at screening as follows: 
a. Platelet count ≥75,000/mm3 
b. Absolute neutrophil count ≥1,000/mm3 unless cytopenia is clearly due to marrow 
involvement from NHL 
c. Total hemoglobin ≥9 g/dL (without transfusion support within 2 weeks of screening) 


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If any of the above-mentioned cytopenia (a-c) are present due to significant BM involvement 
with disease (requiring transfusion or granulocyte colony stimulating factor [G-CSF] support) 
NHL patients may proceed with enrollment after discussion with the Medical Monitor. 
Cytopenia may not be due to evidence of MDS or hypoplastic BM. 
5. Adequate organ function as defined by the following laboratory values: 
a. Creatinine CL ≥60 mL/min (by Cockcroft-Gault method, Appendix I) 
b. Total serum bilirubin ≤1.5 × upper limit of normal (ULN) unless due to Gilbert’s 
syndrome, NHL organ involvement, controlled immune hemolysis or considered an 
effect of regular blood transfusions 
c. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN, 
unless due to NHL organ involvement 
6. Age ≥18 years at the time of signing the informed consent form. 
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 (Appendix II). 
8. Projected life expectancy of ≥12 weeks. 
9. Female patient must be surgically sterile, postmenopausal (for at least 1 year), or have 
negative results for a pregnancy test performed at screening, on a serum sample obtained 
within 7 days prior to initiation of study treatment. 
10. Women of childbearing potential and men with female partners of childbearing potential must 
be willing to use an effective form of contraception (Appendix III). 
11. Patients should use an effective form of contraception for up to 6 months after the last dose 
of APR-246 in combination with venetoclax or up to 12 months after the last dose of rituximab, 
whichever time period is longer.  
 
4.8 
Exclusion Criteria 
1. Patients with known allergies to xanthine oxidase inhibitors or rasburicase. 
2. Prior allergy to rituximab, defined as a clinically significant infusion-related reaction (IRR) in 
the opinion of the Investigator. 
3. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that, 
in the opinion of the Investigator, may increase the risk associated with study participation or 
study treatment administration or may interfere with the interpretation of study results 
and/or would make the patient inappropriate for enrollment into this study. 
4. Concomitant anticancer therapies, immunotherapies, cellular, or radiotherapy; major surgery 
within 3 weeks prior to first dose of study treatment. Washout period for chemotherapy is 14 
days. Washout period for targeted agents is 2 weeks or 5 T1/2 (whichever is shorter). Washout 
period for antibody-based immunotherapies or cellular therapies is 4 weeks. Washout period 
for radiotherapy is 7 days (limited field) and 28 days (extended field that includes BM). 
Washout period must be completed prior to any treatment administration.  
5. Uncontrolled AIHA or immune thrombocytopenia. 
6. Consumption of grapefruit, grapefruit products, Seville oranges, or star fruit within 7 days of 
starting study treatment. 
7. Concomitant steroids for disease related pain control are allowed at any dose but must be 
discontinued prior to any study treatment initiation. Chronic use of corticosteroids is allowed 
up to ≤20 mg prednisone daily for non-cancer related conditions at the time of study start.  
8. History of allogeneic or autologous stem cell transplant (SCT) or chimeric antigen receptor 
T-cell therapy (CAR-T) within the last 30 days or with any of the following:  
a. Active graft versus host disease 


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b. Cytopenia from incomplete blood cell count recovery post-transplant 
c. Need for anti-cytokine therapy for residual symptoms of neurotoxicity grade >1 from 
CAR-T  
d. Ongoing immunosuppressive therapy. 
9. Known history of human immunodeficiency virus (HIV) serum positivity.  
10. Active hepatitis B/C. Patients with prior exposure to hepatitis B (i.e., positive anti-hepatitis B 
core antibody) must demonstrate hepatitis B polymerase chain reaction (PCR) to be negative 
during screening period and undergo prophylaxis and monitoring for hepatitis B according to 
institutional guidelines. 
11. Known CNS involvement by lymphoma. Patients with previous treatment for CNS involvement 
who are neurologically stable and without evidence of disease may be eligible if a compelling 
clinical rationale is provided to sponsor.  
12. Known neurologic disorder or residual neurologic toxicities that may put patients at increased 
risk of neurologic toxicity in the opinion of the Investigator. 
13. Any of the following cardiac abnormalities: 
a. Myocardial infarction within six months prior to enrollment 
b. New York Heart Association Class III or IV heart failure (Appendix IV) or known left 
ventricular ejection fraction <40% 
c. A history of familial long QT syndrome 
d. Symptomatic atrial or ventricular arrhythmias not controlled by medications 
e. QTcF ≥470 msec, unless due to underlying BBB and/or pacemaker and with the approval 
of the Medical Monitor.  
14. Concomitant malignancies or previous malignancies with less than a 1-year disease-free 
interval at the time of signing consent. Patients with adequately treated basal or squamous 
cell carcinoma of the skin, or adequately treated carcinoma in situ (e.g., cervix) may enroll 
irrespective of the time of diagnosis. Patients with controlled, advanced prostate cancer are 
permitted. 
15. Female patients who are pregnant or breast-feeding. 
16. Active uncontrolled systemic infection. 
17. Received an investigational agent within 30 days or within 5 T1/2, whichever is shorter prior to 
the first dose of study treatment. 
18. Clinically significant active malabsorption syndrome or other condition likely to affect 
gastrointestinal absorption of any of the study drugs.  
19. Current treatment with certain strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers 
and/or strong P-gp or breast cancer resistance protein inhibitors (see Appendix VI). 
4.9 
Inclusion of Women, Minorities and Children 
Both men and women ≥18 years of age and members of all races and ethnic groups are eligible for 
this study. Children are not eligible for this study because the safety and tolerability of the proposed 
dosing schedule have not been determined in adults. 
 
4.10 Withdrawal Criteria 
Protocol therapy can continue for patients receiving clinical benefit, unless one or more study 
treatment discontinuation criteria are met, or at the patient’s discretion, or if the study is terminated. 
Patients are free to discontinue treatment or withdraw from the study at any time and for any reason, 
without penalty to their continuing medical care. Any discontinuation of treatment or withdrawal from 


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the study must be fully documented in the eCRF and should be followed up by the Investigator. The 
Investigator may withdraw a patient at any time if this is considered to be in the patient’s best interest. 
4.10.1 Study Treatment Discontinuation 
Study treatment must be discontinued if: 
• 
Evidence of disease progression is observed. Note that patients who have disease progression 
but are continuing to derive clinical benefit in the opinion of the Investigator may continue to 
receive study treatment. 
• 
A female patient becomes pregnant. 
• 
A patient is non-compliant with the requirements of the protocol.  
• 
A patient has an adverse experience that would, in the Investigator’s judgment, make 
continued participation in the study an unacceptable risk. 
• 
The patient starts new treatment for their disease under study. 
 
4.10.2 Study Completion 
A patient must be taken off the study if: 
• 
The patient dies during the study. 
• 
The patient is lost to follow-up. 
• 
The patient withdraws consent. 
 
4.10.3 Withdrawn Patients  
When a patient is removed from the study treatment, the Investigator will clearly document the 
reason in the medical record and complete the appropriate eCRF page describing the reason for 
discontinuation. In addition, every effort should be made to complete the appropriate assessments 
listed in Section 6.9. 
 
Patients who miss >25% of APR-246 doses for a nonmedical reason (patient’s preference) or 
noncompliance will be replaced. 
 
4.11 Noncompliance 
All instances of protocol deviations will be recorded according to guidelines per Sponsor’s 
Representative.  
 
5.0 TREATMENT OF PATIENTS 
5.1 
Drug Preparation and Administration 
Study treatment may be administered on an outpatient basis or on an inpatient basis if the patient is 
hospitalized. No investigational or commercial agents or therapies other than those described below 
may be administered with the intent to treat the patient’s disease under study. 
 


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5.1.2 
Venetoclax 
In Cycle 1, treatment with venetoclax should be administered over a 5-week ramp up period per the 
USPI (refer to Table 4 below). The 5-week ramp-up dosing schedule is designed to gradually reduce 
tumor burden (debulk) and decrease the risk of TLS53. After the ramp-up phase is completed, 
venetoclax at a dose of 400 mg should be taken PO once daily with a meal and water, at approximately 
the same time every day. Note that on Day 1 of Cycle 1, venetoclax will be taken 1 hour prior to 
administration of the APR-246 infusion. 
Table 4. Dosing Schedule for Ramp-Up Period in Cycle 1 
Week Number 
Venetoclax Daily Dose 
Week 1 
20 mg 
Week 2 
50 mg 
Week 3 
100 mg 
Week 4 
200 mg 
Week 5 and beyond 
400 mg 
 
If required, any dosage modifications of venetoclax are presented in Section 5.3.3. 
 
Detailed instructions on administration of venetoclax can be found in the Pharmacy Binder and 
current USPI47. 
 
5.1.3 
Rituximab 
Rituximab will be given on Day 2 of each cycle for a maximum of 6 cycles starting in Cycle 2. Rituximab 
will be given at a dose of 375 mg/m2 in Cycle 2 and 500 mg/m2 for Cycles 3 through 7.  
 
The first infusion of rituximab should be initiated at a rate of 50 mg/hour. In the absence of infusion 
toxicity, increase infusion rate by 50 mg/hour increments every 30 minutes, to a maximum of 
400 mg/hour. 
 
For subsequent infusions, initiate infusion at a rate of 100 mg/hour. In the absence of infusion toxicity, 
increase rate by 100 mg/hour increments at 30-minute intervals, to a maximum of 400 mg/hour. 
 
Interrupt the infusion or slow the infusion rate for IRRs. Continue the infusion at one-half the previous 
rate upon improvement of symptoms. 
 
5.1.4 
Dose-Limiting Toxicity 
All TEAEs are relevant to the determination of DLTs unless they are clearly and solely due to the 
disease under study. The DLT evaluation period will be up to 91 days (7 days of APR-246 monotherapy 
plus 84 days for Cycle 1-3 with combination therapy) after the first dose of APR-246 is administered. 
A DLT is defined as any of the following TEAEs using the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE), as follows: 
 


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• 
Any neurologic toxicity of grade 4 
• 
Any grade ≥3 non-hematologic toxicity except for:  
• 
First occurrence of grade 3 electrolyte abnormalities and/or creatinine CL decrease 
resolving to grade 2 (or baseline if baseline is grade ≥2) within 48 hours with 
supportive treatment.  
• 
Grade 3 fatigue, nausea, vomiting, diarrhea or other manageable constitutional 
symptom(s) that is/are responsive to supportive therapy.  
• 
Grade 3 infection responding to appropriate antimicrobial therapy.  
• 
Any neurologic toxicity of grade 3 that does not return to grade ≤1 or baseline within 
7 days. 
• 
Any grade ≥3 hematologic toxicity will be considered a DLT except for:  
• 
Grade 3 neutropenia without fever  
• 
Grade 4 neutropenia without fever lasting 8 days or less 
• 
Grade 3 thrombocytopenia that does not result in bleeding or transfusion  
• 
Grade 3/4 lymphopenia/lymphocytosis 
• 
Grade 3/4 WBC decreased  
• 
Grade 3/4 WBC increased  
 
Any toxicity, regardless of the NCI-CTCAE v5.0 grade, resulting in discontinuation, dose reduction or 
treatment with less than 75% of planned doses of APR-246 study drug, will be reviewed by the DRT, 
and will be considered a DLT unless clearly and solely related to the disease under study. The DRT will 
consist of the Medical Monitor, Site Principal Investigators, and other clinical research personnel that 
the Sponsor may deem appropriate. 
 
G-CSF support for the management of neutropenia and prophylactic antimicrobial therapy are 
allowed, including during the DLT period.  
 
TEAEs that meet the above criteria but that occur after the DLT evaluation period will not be defined 
as DLTs and will be reported as AEs/SAEs and will be reviewed across all cohorts during the study to 
help determine the AE profile for the respective treatment regimens under study. A patient that 
discontinues APR-246 therapy before completion of Cycle 3 without DLT is considered evaluable for 
the purpose of safety review by the DRT only if at least 75% of the scheduled doses of APR-246 were 
administered in Cycles 1 through 3. 
 
5.1.5 
Recommended Dose of APR-246  
The recommended dose of APR-246 in combination with venetoclax and rituximab represents the 
dose of APR-246 at or below the maximum intended dose, or the MTD, that results in the greatest 
apoptosis of circulating malignant cells in the monotherapy cycle. 
 
The MTD of APR-246 will be defined as the dose at which <2 out of 6 patients experience DLT during 
the defined safety assessment period after administration of APR-246 in combination with venetoclax 
and rituximab. Up to 10 additional patients may be enrolled at the MTD, and at prior dose levels, to 
confirm the confidence at that dose level. 
 
A DRT consisting of the Medical Monitor, Site Principal Investigators, and other clinical research 
personnel that the Sponsor may deem appropriate, will hold Data Review Meetings (DRMs) on an 


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interim basis at a frequency dependent on study accrual. At these meetings, the DRT will review any 
AEs, DLTs, and any available PK and PD data and make recommendations regarding the optimal dose 
of APR-246. All accumulated safety data will be discussed during DRMs. The optimal dose of APR-246 
will be based upon the MTD and upon all accumulated safety data, PK/PD data, and preliminary 
efficacy data. 
 
5.2 
Dose Interruptions/Withholding  
Study treatment, including APR-246, venetoclax, and/or rituximab, may be withheld from a patient 
based on the Investigator’s decision in the event of intercurrent illness, AE, administrative reasons, or 
other reasons. If the patient’s condition subsequently improves, or the situation that resulted in 
withholding study drug rectifies itself, the Investigator may resume dosing as soon as possible, unless 
the delay is more than 4 weeks. For study treatments held longer than 4 weeks, the Investigator should 
consult with the Medical Monitor before study treatments are resumed. 
 
Dose management guidelines in Table 5 should be followed for each occurrence of a grade ≥3 
hematologic toxicity or those in Table 6 for non-hematologic toxicity. 
 


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Table 5. Dose management guidelines for new onset hematologic toxicities 
Toxicity 
Occurrence 
APR-246 
Venetoclax 
Rituximab 
Grade 3 
hematolog
ic toxicity 
with fever 
and/or 
infection; 
or grade 4 
hematolog
ic toxicity  
1st occurrence 
• 
Hold all study 
treatments 
until blood 
count(s) return 
to baseline or 
grade ≤1 and 
fever and/or 
infection 
resolve if 
present. Treat 
promptly. 
• 
Consider reducing APR-246 by one dose 
level from starting dose for all future 
cycles of treatment if toxicity does not 
resolve to grade ≤1 within 7 days from 
onset date despite maximal medical 
intervention(s). 
• 
If unable to reduce APR-246 dose, 
discuss with study Medical Monitor 
before resuming or discontinuing 
treatment. 
• 
Initiate or reassess prophylaxis 
measures. Refer to Section 5.3.2.2 for 
supportive management guidelines 
specific to infection prophylaxis and 
neutropenia. 
• 
Refer to 
Section 
5.3.3.1 for 
venetoclax 
dose 
modification 
guidelines. 
• 
Resume rituximab at same dose level 
once event resolves to baseline or 
grade ≤1, except in case of serious 
infection. For patients diagnosed with a 
serious grade ≥3 infection, rituximab 
should be permanently discontinued.  
2nd occurrence 
• 
Hold all study 
treatments 
until blood 
count(s) return 
to baseline or 
Grade ≤1 and 
fever and/or 
infection 
resolve if 
present. Treat 
promptly. 
• 
Consider reducing APR-246 by one dose 
level from current dose for all future 
cycles of treatment if the toxicity does 
not resolve to grade ≤1 within 7 days 
from onset despite maximal medical 
intervention(s). 
• 
If unable to reduce APR-246 dose, 
discuss with study Medical Monitor 
before resuming or discontinuing 
treatment. 
• 
Initiate or reassess prophylaxis 
measures. Refer to Section 5.3.2.2 for 
supportive management guidelines 
specific to infection prophylaxis and 
neutropenia. 
• 
Refer to 
Section 
5.3.3.1 for 
venetoclax 
dose 
modification 
guidelines. 
• 
Reduce rituximab dose from 500 mg/m2 
to 375 mg/m2. If unable to reduce dose 
of rituximab, discuss with study Medical 
Monitor before resuming treatment. For 
patients diagnosed with a serious 
grade ≥3 infection, rituximab should be 
permanently discontinued.  
3rd occurrence 
• 
Hold all study 
treatments 
until blood 
• 
Consult with study medical monitor to determine if further dose modifications of study treatment(s) are 
medically necessary or if study treatment(s) should be discontinued. 


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count(s) return 
to baseline or 
grade ≤1 and 
fever and/or 
infection 
resolve if 
present. Treat 
promptly. 
• 
Assess current prophylaxis measures being administered and adjust treatment plan as clinically indicated. 
Refer to Section 5.3.2.2 for supportive management guidelines specific to infection prophylaxis and 
neutropenia. 
Administration of supportive measures such as G-CSF, platelet or blood transfusions, and/or antimicrobial therapy should be considered as clinically indicated.  
 


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Actions noted in table above for rituximab are specific to toxicities occurring during Cycles 2 through 7. 
Rituximab may be reduced by one dose level, from 500 mg/m2 to 375 mg/m2, when clinically indicated. 
Please consult with study Medical Monitor to discuss dose modification(s) for rituximab.   
 
Patients experiencing 3 occurrences of the same toxicity should be discussed with the study Medical 
Monitor before study treatments are resumed. 
 
Dose management guidelines for non-hematologic toxicities are provided below in Table 6. 
 
Table 6. Dose management guidelines for Grade 3 or 4 non-hematologic toxicities 
Occurrence 
APR-246 
Venetoclax 
Rituximab 
1st occurrence 
• 
Hold all study 
treatments 
until toxicity 
returns to 
baseline or 
grade ≤1. Treat 
promptly.  
• 
Consider reducing APR-246 by 
one dose level from current 
dose for all future cycles of 
treatment if toxicity does not 
resolve to grade ≤1 within 7 
days from onset date despite 
maximal medical 
intervention(s).  
• 
If unable to reduce APR-246 
dose, discuss with study 
Medical Monitor before 
resuming or discontinuing 
treatment.  
Refer to 
Section 
5.3.3.1 for 
venetoclax 
dose 
modification 
guidelines. 
Resume rituximab at same 
dose level once event 
resolves to baseline or 
grade ≤1, except in case of 
serious infection. For 
patients diagnosed with a 
serious grade ≥3 infection, 
rituximab should be 
permanently 
discontinued. 
2nd occurrence 
• 
Hold all study 
treatments 
until toxicity 
returns to 
baseline or 
grade ≤1 
• 
Consider reducing APR-246 by 
one dose level from starting 
dose for all future cycles of 
treatment. 
Refer to 
Section 
5.3.3.1 for 
venetoclax 
dose 
modification 
guidelines. 
Reduce rituximab dose 
from 500 mg/m2 to 375 
mg/m2. If unable to reduce 
rituximab, discuss with 
study Medical Monitor 
before resuming or 
discontinuing rituximab. 
For patients diagnosed 
with serious grade ≥3 
infection, rituximab should 
be permanently 
discontinued. 
3rd occurrence 
• 
Hold all study 
treatments 
until toxicity 
returns to 
baseline or 
grade ≤1. Treat 
promptly. 
• 
Consult with study medical monitor to determine if further dose modifications 
of study treatment(s) are medically necessary or if study treatment(s) should 
be discontinued.  
 
 


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Actions noted in table above for rituximab are specific to toxicities occurring during Cycles 2 through 7. 
Rituximab may be reduced by one dose level, from 500 mg/m2 to 375 mg/m2, when clinically indicated. 
Please consult with study Medical Monitor to discuss dose modification(s) for rituximab.   
 
Treatment may be discontinued if a TEAE has not improved (to an acceptable grade) or resolved after 
≥4 weeks, at the discretion of the Investigator. Please consult study Medical Monitor if this situation 
occurs. 
  
Patients experiencing 3 occurrences of the same toxicity should be discussed with the study Medical 
Monitor before study treatments are resumed. 
 
5.3 
Supportive Management 
5.3.1 
Neutropenia with or without Fever  
Monitor complete blood counts throughout the treatment period. Consider supportive measures 
including antimicrobials for prophylaxis, in the setting of prolonged myelosuppression, and/or at the 
first signs of infection and use of growth factors (e.g., G-CSF). Myeloid growth factors may be used in 
the setting of neutropenia with or without fever as clinically indicated. Refer to Section 5.2 for 
guidelines on dose modifications.  
 
5.3.2 
APR-246 
This section outlines the requirements for proceeding with treatment with APR-246, and the protocol 
rules for APR-246 dose modification due to management of QTc prolongation, CNS related AEs, 
nausea and vomiting, and infections. 
 
5.3.2.1 
APR-246 Dose Modification in the Setting of Moderate Renal Impairment 
APR-246 is partially eliminated via the kidney and moderate renal impairment, defined by a creatinine 
CL or estimated glomerular filtration rate value of >30 to <60 mL/min, can lead to increases in plasma 
levels of approximately 30%. Therefore, for patients with moderate renal impairment, the dose of 
APR-246 should be reduced by 33% from the current dose (Table 7). 
Table 7. APR-246 Dose Modification in the Setting of Moderate Renal Impairment 
APR-246 Dose 
33% Reduced Dose 
Reduced Loading Dose 
(45mins) 
Reduced Maintenance 
Dose (5h 15mins) 
1.5 g 
1.0 g 
0.33 g 
0.67 g 
3.0 g 
2.0 g 
0.66 g 
1.33 g 
4.0 g 
2.7 g 
0.9 g 
1.8 g 
 
Monitoring renal function by assessment of serum creatinine prior to infusion of APR-246 is 
recommended in all patients. 
 
5.3.2.2 
Bone Marrow Suppression Management Guidelines  
Complete blood counts should be monitored throughout the course of treatment with APR-246. 
Supportive measures such as antimicrobials administered for prophylaxis or in the setting of 


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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. Antimicrobial prophylaxis should be implemented, including appropriate 
prophylaxis for bacterial, viral, fungal or other types of infections or infestations (Table 8). Treatment 
should be individualized based on level of myelosuppression at the time of study enrollment and 
throughout the course of study treatment, with consideration for the patient’s medical history, 
inclusive of prior infections. 
 
The following recommendations were taken from National Comprehensive Cancer Network 
Guidelines for Prevention and Treatment of Cancer-Related Infections (Version 1.2021). 
 
Table 8. Recommendations for Prevention and Treatment of Cancer-Related Infections 
Organism 
Recommendations 
Bacterial 
Consider fluoroquinolone or other suitable anti-bacterial prophylaxis during neutropenia 
Fungal 
Consider prophylaxis during neutropenia and for anticipated mucositis. Assess risk for 
Pneumocystis jirovecii pneumonia 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.  
 
Myeloid growth factor may be used in the setting of severe or prolonged neutropenia. The use of 
blood products, including 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 10×109/L for platelet transfusion and a hemoglobin threshold of 
8.0 g/dL for PRBC transfusion or as clinically indicated at the discretion of the treating physician. 
 
5.3.2.3 
Management Guidelines for QTc Prolongation 
At screening, 12-lead ECGs should be collected in triplicate to confirm QTcF interval does not exceed 
470 msec. The mean QT interval must be calculated from three ECG readings using Fridericia’s 
correction (QTcF = QT/RR0.33). 
 
During APR-246 monotherapy lead-in period, and first cycle of combination therapy (venetoclax ramp-
up), ECG should be collected in triplicate within 30 minutes prior to the infusion of APR-246 and within 
±30 min of end of the 6-hour infusion on all days APR-246 is administered (Days 1 and 2 of the APR-246 
monotherapy lead-in, and Day 1, 8, 15 of Cycle 1). QTcF must be calculated from a mean of all three 
ECG readings.  
 
On Day 2 of the APR-246 monotherapy lead-in period, ECG will be obtained prior to PO administration 
of APR-246, and then 6 hours after APR-246 administration. 
 
If a pre-dose ECG shows QTcF ≥470 msec, the QTc reading should be confirmed by manual assessment 
using Fridericia’s correction (QTcF=QT/RR0.33), unless due to BBB and/or pacemaker. Serum 
concentrations of electrolytes should be monitored and corrected, if necessary. Additionally, 
concomitant medication should be reviewed and adjusted, if necessary. ECG may be repeated at any 
time, including the same day. APR-246 may only be administered when QTcF has returned to 
<470 msec, unless due to BBB and/or pacemaker. If APR-246 is given on the same day, procedures 


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outlined in the Schedule of Study Evaluations must be followed. If APR-246 cannot be administered 
on the same day, that dose must be omitted from the cycle. 
 
If there is a significant change in QTcF, defined as either: a) increase >60 msec from baseline (or 
pre-dose), or b) increase to an absolute value ≥501 msec, i.e., consistent with NCI-CTCAE grade 3 QTc 
prolongation, QTc prolongation must be confirmed by a manual assessment of the ECG, and using 
Fridericia’s correction (QTcF = QT/RR0.33). If confirmed, APR-246 should be interrupted until a cause 
(electrolyte disorders or an effect of a concomitant medication) has been identified and addressed, 
and QTcF has returned to <470 msec, or baseline in patients with BBB and/or pacemaker. If all other 
causes for clinically significant QT interval prolongation are excluded, APR-246 may be permanently 
discontinued. Please consult with study Medical Monitor for discussion when clinically significant QT 
interval prolongation is identified in a patient receiving APR-246. 
 
During subsequent cycles, ECG should be collected in triplicate prior to infusion of APR-246 and at end 
of infusion (EOI) on Day 1 of each cycle. QTcF must be calculated from the mean of all three ECG 
readings to confirm it does not exceed 469 msec for the cycle to be initiated. If post-dose ECG shows 
a significant change in QTcF, defined as either: a) increase >60 msec from baseline (or pre-dose), or b) 
increase to an absolute value ≥501 msec, i.e., consistent with NCI-CTCAE grade 3 QTc prolongation, 
QTc prolongation must be confirmed by a manual assessment of the ECG, and using Fridericia’s 
correction (QTcF = QT/RR0.33). If confirmed, the therapy should be interrupted until a cause (electrolyte 
disorders or an effect of a concomitant medication) has been identified and addressed, and QTcF has 
returned to <470 msec, unless due to BBB and/or pacemaker. If all other causes for clinically 
significant QT interval prolongation are excluded, APR-246 may be permanently discontinued. Please 
consult with study Medical Monitor for discussion when clinically significant QT interval prolongation 
is identified in a patient receiving APR-246. If QTcF is unchanged or there is no significant change, 
additional ECG is not required during that cycle. 
 


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Table 9. Management Guidelines for QTc Prolongation 
 
ECG 
QTcF <450 
msec 
QTcF = 450-469 
msec 
QTcF = 470-500 msec 
QTcF ≥501 or absolute 
increase >60 msec 
Pre-
dose a 
No action 
required. APR-
246 may be 
administered. 
APR-246 
may 
be 
administered, 
and 
additional triplicate 
ECG 
should 
be 
collected at the EOI 
(6 hours after start of 
infusion, ±30 min) 
QTc 
reading 
should 
be 
confirmed 
by 
manual 
assessment, unless due to BBB and/or pacemaker. 
Review serum concentrations of electrolytes and 
concomitant medications and adjust if necessary. ECG 
may be repeated at any time, including the same day. 
APR-246 may be administered when QTcF has returned 
to <470 msec, unless due to BBB and/or pacemaker. If 
APR-246 cannot be administered on the same day, that 
dose should be omitted from the cycle. 
Post-
dose 
No action required 
If QT prolongation 
confirmed by manual 
assessment, APR-246 
should be interrupted until 
a cause has been identified 
and addressed, and QTcF 
has returned to <470 msec 
or baseline value for patient 
with BBB or pacemaker. 
If all other causes for 
clinically significant QT 
interval prolongation are 
excluded, APR-246 may be 
permanently discontinued. 
Please consult study 
Medical Monitor to discuss 
patient's condition.  
a During APR-246 monotherapy lead-in, ECG should be collected in triplicate within 30 minutes prior to the infusion of 
APR-246 and within ±30 min of end of the 6-hour infusion (EOI) of APR-246 on Days 1 – 2. QTcF must be calculated 
from a mean of all three ECG readings. 
 
If a patient starts treatment with a medication associated with QT interval prolongation, such as 
triazole antifungals, fluoroquinolones, and anti-emetics, while receiving study treatment, an 
additional pre- and post-dose (within 30 minutes prior to the infusion of APR-246 and within ±30 min 
of 6 hours after start of infusion) ECG should be performed on the next APR-246 treatment day.  
 
 
 
 
 
 
 
 
 
 
 


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5.3.2.4 
Management Guidelines for APR-246 Dose Modifications and Criteria for Treatment 
Interruption and Re-Initiation with Treatment-Related Adverse Events 
Table 10. Recommendations for APR-246 Dose Modifications and Criteria for Treatment 
Interruption and Re-Initiation with Treatment-Related Adverse Events  
 
Renal Toxicities 
 
Parameter 
Worst toxicity 1   
Dose Modifications for APR-246 
Serum 
Creatinine 
Grade 1 (<1.5 × baseline) 
Maintain dose level  
Grade 2  
(>1.5–3.0 × baseline)  
Omit dose until resolved to grade ≤1, then: 
If first occurrence, then maintain dose level 
If second or more consecutive occurrence, then  1 dose 
level 
Grade 3  
(>3.0–6.0 × baseline)  
Omit dose until resolved to grade ≤1, then:  1 dose level 
If not resolved or resolved in >7 days, evaluate if other 
contributing factors are present. If none, or after 
consideration of best interest of the patient, discontinue 
patient from APR-246.  
If other factors present, consider continuing after  1 dose 
level 
Grade 4 (>6.0 × baseline)  
Permanently discontinue patient from APR-246 
1 Common Terminology Criteria for Adverse Events (CTCAE) version 5.  
 
Hepatic Toxicities 1 
 
Parameter 
Worst toxicity 2   
Dose Modifications for APR-246 
Bilirubin 
3 
Grade 1 (>ULN-1.5×ULN) 
Maintain dose level with LFTs 4 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, if first occurrence, then 
maintain dose level 
If second or more consecutive occurrence or 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 no 
subsequent event, consider re-escalation to original 
dose level. 
Omit dose until resolved to grade ≤1, then:  1 dose 
level. 
If second or more consecutive occurrence or if not 
resolved or resolved in >7 days, evaluate if other 
contributing factors are present. If none, or after 
consideration of best interest of the patient, 
discontinue patient from APR-246.  
If other factors present, consider continuing after  1 
dose level. 
Grade 4 (>10.0×ULN) 
Permanently discontinue patient from APR-246 


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Parameter 
Worst toxicity 2   
Dose Modifications for 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 4 monitored per 
protocol 
Grade 2 (>3.0-5.0×ULN if baseline 
was normal; >3.0-5.0 × baseline if 
baseline was abnormal) in the 
absence of total bilirubin elevation to 
> 2.0×ULN 
Omit dose until resolved to grade ≤1, then 
If resolved in ≤7 days, if first consecutive occurrence, 
then maintain dose level 
If second or more consecutive occurrence or 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) in the 
absence of total bilirubin elevation to 
>2.0×ULN 
Omit dose until resolved to grade ≤1, then 
If resolved in ≤7 days, if first consecutive occurrence, 
then maintain dose level. 
If second or more consecutive occurrence or if not 
resolved or resolved in >7 days, evaluate if other 
contributing factors are present. If none, or after 
consideration of best interest of the patient, 
discontinue patient from APR-246. If other factors 
present, consider continuing after  1 dose level 
Grade 4 (>20.0×ULN if baseline was 
normal; >20.0 × baseline if baseline 
was abnormal) 
Permanently discontinue patient from APR-246 
1 Please note that the Investigator is responsible for determining whether a patient meets potential Hy’s Law (PHL) 
criteria at any point during the study. Hy’s law identifies patients at risk for severe drug-induced liver injury and is defined 
as AST or ALT ≥3× ULN together with Total Bilirubin Level ≥2×ULN, where no other reason, other than the suspected drug, 
can be found to explain the combination of increases, e.g., elevated ALP indicating cholestasis, viral hepatitis, or another 
drug. 
2 Common Terminology Criteria for Adverse Events (CTCAE) version 5.  
3 For patients with Gilbert’s syndrome, these dose modifications apply to changes in direct bilirubin only.   
4 LFTs include albumin, ALT, AST, total bilirubin (fractionated if total bilirubin >2.0×ULN), alkaline phosphatase. 
 
 
Other Non-Hematological Toxicities 
 
Toxicity 
Worst 
toxicity 1 
Dose Modifications for 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 (to grade ≤1) 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, and/or 
Diarrhea 
Grade 1  
Maintain dose level. Monitor subject and provide supportive care 
measures as clinically indicated.  
Grade 2  
Interrupt APR-246 dosing and monitor subject; treat promptly.   
Resume at current dose level if toxicity resolves to grade ≤1 or baseline, 
with or without use of supportive care measures, within 72 hours of onset. 
If toxicity does not resolve to grade ≤1 within 72 hours despite maximal 
medical intervention(s), then reduce APR-246 by 1 dose level once the 


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Toxicity 
Worst 
toxicity 1 
Dose Modifications for APR-246 
toxicity resolves to grade ≤1 or baseline. If unable to reduce APR-246 dose, 
discuss with study Medical Monitor before resuming or discontinuing 
treatment. For subsequent doses of APR-246, premedication with 
prophylactic supportive therapy should be given if clinically indicated. 
Grade 3  
1st occurrence: Interrupt APR-246 dosing and monitor subject; treat 
promptly.  
Resume at current dose level if toxicity resolves to grade ≤1 or baseline, 
with supportive care measures, within 72 hours of onset.  
If toxicity does not resolve to grade ≤1 within 72 hours despite maximal 
medical intervention(s), then reduce APR-246 by 1 dose level once the 
toxicity resolves to grade ≤1 or baseline.  
If unable to reduce APR-246 dose, discuss with study Medical Monitor 
before resuming or discontinuing APR-246. 
For subsequent doses of APR-246, pre-medication with prophylactic 
supportive therapy should be given. 
2nd occurrence: Interrupt APR-246 dosing and monitor subject; treat 
promptly.  
Reduce APR-246 by 1 dose level if the toxicity resolves to grade ≤1 or 
baseline within 72 hours of onset.  
If toxicity does not resolve to grade ≤1 despite maximal medical 
intervention(s) within 72 hours of onset, then consult with study Medical 
Monitor before resuming or discontinuing APR-246.  
If unable to reduce APR-246 dose, discuss with study Medical Monitor 
before resuming or discontinuing treatment.  
Prior to subsequent doses of APR-246, reassess prophylactic supportive 
therapy regimen and adjust as clinically indicated.  
3rd occurrence: Interrupt APR-246 dosing and monitor subject; treat 
promptly. Consult with study Medical Monitor before resuming or 
discontinuing APR-246.  
Grade 4  
Interrupt APR-246 dosing and monitor subject; treat promptly. Consult 
with study Medical Monitor to discuss dose modification or permanent 
discontinuation of APR-246.  
Any Other 
Toxicity 
Grade 3 or 
4 
Delay dose until resolution to grade ≤1 or baseline, then  1 dose level.  
If unable to reduce APR-246 dose, discuss with study Medical Monitor 
before resuming or discontinuing APR-246. 
1 Common Terminology Criteria for Adverse Events (CTCAE) version 5. 
 
Treating physicians should use clinical judgment and may consult the Medical Monitor for additional 
guidance with APR-246 dose modifications.  
 
5.3.2.5 
Management of CNS Adverse Events  
If a patient reports any clinical AE of any grade during the administration period of APR-246 that could 
be considered to originate from the CNS (e.g., dizziness, tremor, vertigo, nausea), then the patient will 
be given a rescue medication as per the institutional standard of care. 
 
Dose modifications have been successfully used to manage potential CNS effects occurring during the 
infusion (Table 11). For any clinical AE grade ≥3, the infusion should be interrupted and if the AE 
resolves to CTCAE grade ≤1 within 2 hours, the infusion may be resumed at the same infusion rate. If 


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the same symptoms recur or increase in severity during re-challenge, the infusion should be 
interrupted. 
 
If the event lasts longer than 2 hours, then the APR-246 infusion should be discontinued for that day 
and the remaining drug should be discarded. 
 
Table 11. Management of CNS Adverse Events (e.g., Dizziness, Tremor, Confusion, and Ataxia) 
Worst 
toxicity  
Dose Modifications for APR-246 
Grade 1 
Maintain dose level 
Grade 2 
If resolved to grade ≤1 with medical therapy, continue same dose level 
If not resolved despite treatment interruption and maximal medical therapy, stop infusion and  
1 dose level for subsequent dose. If unable to reduce APR-246, discuss with study Medical Monitor 
before resuming or discontinuing APR-246. 
Grade ≥3 
Stop infusion and give medical therapy. If resolved (to grade ≤1) with medical therapy in ≤2 hours 
from onset, infusion may resume at the Investigator’s discretion. If not resolved despite treatment 
interruption and maximal medical therapy, infusion should be discontinued for that day.  
  1 dose level for subsequent dose. If unable to reduce APR-246 dose, discuss with study Medical 
Monitor before resuming or discontinuing APR-246.   
Grade 4 
Permanently discontinue patient from APR-246. 
 
In prior APR-246 studies, prochlorperazine 10 mg PO three times daily, anti-emetics (e.g., 
ondansetron), or medication(s) to treat motion sickness (e.g., meclizine) have been used for 
prophylaxis and/or to treat CNS-related AEs that have occurred during treatment with APR-246. 
Prochlorperazine, anti-emetic, or motion sickness medication(s) should be administered as clinically 
indicated to prevent or treat CNS-related AEs while subjects are receiving treatment with APR-246. 
When prophylaxis is clinically indicated, it is recommended to start prochlorperazine, anti-emetic, or 
motion sickness medication(s) at least one day prior to the scheduled dose of APR-246. Please follow 
dose administration guidelines in the current USPI for prochlorperazine, anti-emetic, or motion 
sickness medication(s). The US label for prochlorperazine does not list QT interval prolongation as a 
known risk associated with use of this drug.  
 
5.3.2.6 
Management of Nausea, Vomiting, and Diarrhea 
Prior to starting study treatment, patients should be evaluated to determine risk for nausea, vomiting, 
and/or diarrhea based on medical history and concomitant medications. Anti-nausea, anti-emetic, 
and/or anti-diarrheal medications should be initiated in patients with intermediate or high risk for 
nausea, vomiting, or diarrhea. Patients who experience nausea, vomiting, and/or diarrhea in 
association with APR-246 administration should be prescribed appropriate rescue treatment and 
prophylaxis (e.g., anti-nausea, anti-emetics, or anti-diarrheal medication).  
 
A list of suggested rescue medications for nausea and vomiting is provided below in Table 12. 
 
 


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Table 12. Medications for Management of Nausea and Vomiting 
Drug 
Dosage 
QT Interval 
Prolongation a 
Ondansetron 
8 mg PO administered 30 minutes before the start of infusion 
or per label 
Yes 
Dolasetron 
100 mg PO administered within one 
hour before start of infusion or per label 
Yes 
Palonosetron 
0.5 mg PO administered approximately one hour prior to the 
start of infusion or per label 
No 
Prochlorperazine 
10 mg PO three times daily. Continue until the end of Day 4 of 
the cycle. When used prophylactically in subsequent cycles, 
start the day prior to Day 1 administration of APR-246 
No 
a Please refer to Section 5.3.2.3 for details on concurrent administration of medications known to cause QTc interval 
prolongation. 
 
Monitor electrolyte levels and renal function during the course of study treatment and institute 
appropriate supportive care measures, such as electrolyte and/or fluid repletion, in the setting of 
vomiting and/or diarrhea. 
 
5.3.2.7 
Management of Infusion Reactions Associated with APR-246 Administration  
If a patient experiences an infusion reaction during the study, the infusion may be stopped and 
appropriate medical care (e.g., epinephrine, oxygen, H1 and H2 antagonists, and/or corticosteroids) 
administered54. Consultation with the Medical Monitor before additional administration of APR-246 is 
encouraged. 
 
If the patient develops an acute infusion reaction (grade 2), the infusion should be interrupted until 
the reaction has resolved to grade ≤1. Premedication (e.g., systemic corticosteroids) may be used as 
required. 
 
5.3.3 
Venetoclax 
5.3.3.1 
Dosage Modifications Based on Toxicities 
Interrupt dosing or reduce dose for toxicities. See tables below for recommended dose modifications 
for toxicities related to venetoclax. For patients who have had a dosing interruption greater than 
1 week during the first 5 weeks of ramp-up phase or greater than 2 weeks after completing the 
ramp-up phase, reassess for risk of TLS to determine if re-initiation with a reduced dose is necessary. 
Please consult full prescribing information in USPI47, as clinically warranted, and Section 5.2 for 
management of overlapping toxicities. 
 
 
 


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Table 13. Recommended Venetoclax Dose Modifications for Toxicities  
Event 
Occurrence 
Action 
Tumor Lysis Syndrome 
Blood chemistry 
changes or symptoms 
suggestive of TLS 
Any 
Withhold the next day’s dose. If resolved within 24 to 
48 hours of last dose, resume at the same dose. 
For any blood chemistry changes requiring more 
than 48 hours to resolve, resume at a reduced dose. 
For any events of clinical TLS resume at a reduced 
dose following resolution. 
Non-Hematologic Toxicities 
Grade 3 or 4 
nonhematologic 
toxicities 
 
1st occurrence 
Interrupt venetoclax. 
 
Once the toxicity has resolved to grade 1 or 
baseline level, venetoclax therapy may be resumed 
at the same dose. No dose 
modification is required. 
 
2nd and subsequent 
occurrences 
 
Interrupt venetoclax. 
 
Follow dose reduction guidelines in the table below 
when resuming treatment with venetoclax 
after resolution. A larger dose reduction may occur 
at the discretion of the physician. 
 
Hematologic Toxicities 
Grade 3 neutropenia 
with infection or fever, 
or grade 4 hematologic 
toxicities (except 
lymphopenia) 
1st occurrence 
Interrupt venetoclax. 
 
To reduce the infection risks associated with 
neutropenia, granulocyte-colony stimulating factor 
(G-CSF) may be administered with venetoclax if 
clinically indicated. Once the toxicity has resolved to 
grade 1 or baseline level, venetoclax therapy may be 
resumed 
at the same dose. 
2nd and subsequent 
occurrences 
Interrupt venetoclax. 
 
Consider using G-CSF as clinically indicated. Follow 
dose reduction guidelines in the table below when 
resuming treatment with venetoclax after resolution. 
A larger dose reduction may 
occur at the discretion of the physician. 
Consider discontinuing venetoclax for patients who require dose reductions to less than 100 mg for more than 2 weeks. 


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Table 14. Dose Reduction for Toxicity During Venetoclax Treatment  
Dose Interruption, mg 
Restart Dose, mg a 
400 
300 
300 
200 
200 
100 
100 
50 
50 
20 
20 
10 
a During the ramp-up phase, continue the reduced dose for 1 week before increasing the dose. 
 
5.3.3.2 
Management of Potential Venetoclax Interactions with CYP3A and P-gp Inhibitors 
Table 15. Venetoclax Dose Modifications for Use with CYP3A Inhibitors 
Co-administered Drug 
Initiation and Ramp-Up Phase 
Steady Daily Dose (After Ramp-Up 
Phase) a 
Posaconazole 
 Contraindicated 
Reduce venetoclax dose to 70 mg 
Other strong CYP3A inhibitor 
 Contraindicated 
Reduce venetoclax dose to 100 mg 
Moderate CYP3A inhibitor 
Reduce venetoclax dose by at least 50% 
P-gp inhibitor 
a Consider alternative medications or reduce the venetoclax dose as described in table. 
 
 
5.3.3.3 
Tumor Lysis Syndrome 
TLS, including fatal events and renal failure requiring dialysis, has occurred in patients with high tumor 
burden when treated with venetoclax. 
 
Venetoclax can cause rapid reduction in tumor and thus poses a risk for TLS at initiation and during 
the ramp-up phase. Changes in blood chemistries consistent with TLS that require prompt 
management can occur as early as 6 to 8 hours following the first dose of venetoclax and at each dose 
increase. 
 
The risk of TLS is a continuum based on multiple factors, including tumor burden and comorbidities. 
Reduced renal function further increases the risk. Patients should be assessed for risk and should 
receive appropriate prophylaxis for TLS, including hydration and antihyperuricemics. Monitor blood 
chemistries and manage abnormalities promptly. Interrupt dosing if needed. Employ more intensive 
measures (IV hydration, frequent monitoring, hospitalization) as overall risk increases. 
 
Concomitant use of venetoclax with P-gp inhibitors or strong or moderate CYP3A inhibitors increases 
venetoclax exposure, may increase the risk of TLS at initiation and during ramp-up phase and requires 
venetoclax dose adjustment. 
 
 
Table 16. Recommended TLS Prophylaxis Based on Tumor Burden in Patients  
Tumor Burden 
Prophylaxis 
Blood Chemistry Monitoring c,d 
Hydration a 
Anti-
hyperuricemics 
Setting and 
Frequency of 


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Assessments 
 
Low 
All LN <5 cm 
AND ALC 
<25×109/L 
Oral 
(1.5-2 L) 
Allopurinol b 
Outpatient 
• 
For first dose of 20 mg and 50 mg: 
Pre-dose, 6 to 8 hours, 24 hours 
• 
For subsequent ramp-up doses: 
Pre-dose 
Medium 
Any LN 5 cm 
to <10 cm OR 
ALC 
≥25×109/L 
 
Oral (1.5-2 L) 
and consider 
additional 
IV 
Allopurinol 
Outpatient: 
• 
For first dose of 20 mg and 50 mg: 
Predose, 6 to 8 hours, 24 hours 
• 
For subsequent ramp-up doses: 
Predose 
• 
For first dose of 20 mg and 50 mg: 
Consider hospitalization for 
patients with creatinine CL <80 
mL/min; see below for monitoring 
in hospital 
High 
Any LN ≥10 
cm OR ALC 
≥25 x109/L 
AND any LN 
≥5 cm 
Oral (1.5-2L) 
and IV 
(150-200 mL/h 
as tolerated) 
Allopurinol; 
consider 
rasburicase if 
baseline uric 
acid is elevated 
In hospital 
• 
For first dose of 20 mg and 50 mg: 
Pre-dose, 4, 8, 12 and 24 hours 
 
Outpatient 
• 
For subsequent ramp-up doses: 
Pre-dose, 6 to 8 hours, 24 hours 
ALC = absolute lymphocyte count; LN = lymph node. 
a Administer IV hydration for any patient who cannot tolerate oral hydration. 
b Start allopurinol or xanthine oxidase inhibitor 2 to 3 days prior to initiation of Venetoclax. 
c Evaluate blood chemistries (potassium, uric acid, phosphorus, calcium, and creatinine); review in real time. 
d For patients at risk of TLS, monitor blood chemistries at 6 to 8 hours and at 24 hours at each subsequent ramp-up dose. 
 
5.3.3.4 
Missed Dose  
If the patient misses a dose of venetoclax within 8 hours of the time it is usually taken, the patient 
should take the missed dose as soon as possible and resume the normal daily dosing schedule. If a 
patient misses a dose by more than 8 hours, the patient should not take the missed dose and should 
resume the usual dosing schedule the next day. 
 
If the patient vomits following dosing, no additional dose should be taken that day. The next 
prescribed dose should be taken at the usual time. 
 
5.3.4 
Rituximab 
5.3.4.1 
Infusion-Related Reactions 
Rituximab can cause severe, including fatal, IRRs. Severe reactions typically occurred during the first 
infusion with time to onset of 30−120 minutes. Rituximab induced IRRs and sequelae include urticaria, 
hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress 
syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, anaphylactoid events, or 
death. Please consult full prescribing information in USPI48, as clinically warranted. 
 


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Premedicate patients with an antihistamine and acetaminophen prior to dosing. Institute medical 
management (e.g., glucocorticoids, epinephrine, bronchodilators, or oxygen) for IRRs as needed. 
Depending on the severity of the IRR and the required interventions, temporarily or permanently 
discontinue rituximab. Resume infusion at a minimum 50% reduction in rate after symptoms have 
resolved. Closely monitor the following patients: those with pre-existing cardiac or pulmonary 
conditions, those who experienced prior cardiopulmonary adverse reactions, and those with high 
numbers of circulating malignant cells (≥25,000/mm3).  
 
5.3.4.2 
Severe Mucocutaneous Reactions 
Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with rituximab. 
These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, 
vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of these reactions has been 
variable and includes reports with onset on the first day of rituximab exposure. Discontinue rituximab 
in patients who experience a severe mucocutaneous reaction. The safety of re-administration of 
rituximab to patients with severe mucocutaneous reactions has not been determined. 
 
5.3.4.3 
Hepatitis B Virus Reactivation 
Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and 
death, can occur in patients treated with drugs classified as CD20-directed cytolytic antibodies, 
including rituximab. 
 
HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase 
in serum HBV DNA levels or detection of hepatitis B surface antigen (HBsAg) in a person who was 
previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by 
hepatitis, i.e., increase in transaminase levels. In severe cases increase in bilirubin levels, liver failure, 
and death can occur. 
 
Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of 
hepatitis or HBV reactivation during and for several months following rituximab therapy. HBV 
reactivation has been reported up to 24 months following completion of rituximab therapy. 
 
In patients who develop reactivation of HBV while on rituximab, immediately discontinue rituximab 
and any concomitant chemotherapy, and institute appropriate treatment. Insufficient data exist 
regarding the safety of resuming rituximab treatment in patients who develop HBV reactivation. 
 
5.3.4.4 
Progressive Multifocal Leukoencephalopathy  
John Cunningham virus infection resulting in progressive multifocal leukoencephalopathy (PML) and 
death can occur in rituximab-treated patients with hematologic malignancies or with autoimmune 
diseases. 
 
Consider the diagnosis of PML in any patient presenting with new-onset neurologic manifestations. 
Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain magnetic 
resonance imaging (MRI), and lumbar puncture. 
 


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Discontinue rituximab and consider discontinuation or reduction of any concomitant chemotherapy 
or immunosuppressive therapy in patients who develop PML. 
 
5.3.4.5 
Cardiovascular Adverse Reactions 
Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring 
during and after all infusions of rituximab for patients who develop clinically significant arrhythmias, 
or who have a history of arrhythmia or angina. 
 
5.4 
Concomitant Treatment  
Patients must not receive any other concurrent anti-cancer therapy, including investigational agents 
while on study treatment. Please also see Section 2.5, regarding known drug-drug interactions for 
venetoclax, and the importance of avoiding certain food such as grapefruits and Seville oranges. This 
is important both for patient safety and for enabling a correct assessment of an unlikely drug-drug 
interaction between the study drug APR-246 and the combination treatments.  
 
For patients taking blood thinners, such as warfarin, and anti-platelet agents, international 
normalization ratio should be monitored closely due to increased risk of bleeding. 
 
As the mechanism of action for APR-246 is associated with enhanced oxidative stress in tumor cells, 
use of the following medications that may antagonize therapeutic effects of APR-246 is discouraged, 
but not prohibited during study treatment administration:  
 
• 
Antioxidants (including but not limited to coenzyme Q10) 
• 
Supplementation with vitamin C, vitamin E, zinc and/or selenium outside of a daily multi-vitamin 
• 
Iron chelators (e.g., deferoxamine or deferasirox) 
• 
Melatonin 
 
Patients may continue their baseline medication(s) as long as they are not prohibited. Palliative and 
supportive care (e.g., anti-emetics, bisphosphonates) for disease-related symptoms may be utilized 
according to institutional practices. AEs will be treated as clinically indicated. All concomitant 
medications should be recorded in the eCRF. 
 
5.5 
Monitoring Patient Compliance 
This study will be monitored by Aprea Therapeutics, Inc. or its Contract Research Organization (CRO) 
according to ICH E6 guidelines of GCP. The study site monitor will regularly visit the study sites to 
ensure that the study is conducted according to the protocol and GCP principles. All instances of 
protocol deviations will be entered and reviewed by the Investigator, Sponsor and appropriate 
 designee.  
 
6.0 STUDY EVALUATIONS 
6.1 
Schedule of Study Evaluations 
Study evaluations are summarized in Table 17 and described in Sections 6.2 through 6.10.


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Table 17: Schedule of Assessments 
 
 
Protocol activities 
Screening a 
APR-246  
Lead-In  b 
Cycle 1 
Cycles 2 -7 
Cycles 8 and Beyond 
Cycles 4, 7, 
10, 13, 16, 
19, 22 and 
25i 
End of 
Treat
ment p 
Follow-up 
(28 Days 
after End of 
Treatment) q 
D1 
D2 
D3 
D1 
D2 
D8 b 
D15b 
D1c 
D2 
D8 b 
D15b 
D1c 
 D8 b 
D15b 
D1 
Informed consent 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history d 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination e 
× 
× 
 
 
× 
 
 
 
× 
 
 
 
× 
 
 
 
× 
 
Height s 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
× 
× 
 
 
× 
 
 
 
× 
 
 
 
× 
 
 
 
× 
 
Vital signs e 
× 
× 
× 
 
× 
 
× 
× 
× 
× 
× 
× 
× 
× 
× 
 
× 
 
ECOG PS 
× 
× 
 
 
× 
 
 
 
× 
 
 
 
× 
 
 
 
× 
 
APR-246 (IV) f 
 
× 
 
 
× 
 
× 
× 
× 
 
× 
× 
× 
× 
× 
 
 
 
APR-246 (PO) f 
 
 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Venetoclax g 
 
 
 
 
Ramp-up Week 1-5 
Given PO at a dose of 400 mg daily through Cycle 24 
 
 
Rituximab h 
 
 
 
 
 
 
 
 
 
× 
 
 
 
  
 
 
 
 
Disease assessment i 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
× 
× 
 
Hematology j 
× 
×j 
×j 
×j 
× 
 
 
× 
× 
 
× 
× 
× 
× 
× 
 
× 
 
Serum chemistry k 
× 
× 
 
 
× 
 
 
× 
× 
 
× 
× 
× 
× 
× 
 
× 
 
Creatinine CL l 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD assessments u 
 
× 
× 
× 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for GSH assay (Local 
Lab) v 
 
× 
× 
× 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
HCV/HBV test t 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test m 
× 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG n 
× 
× 
× 
 
× 
 
× 
× 
× 
 
 
 
× 
 
 
 
× 
 
APR-246 PK sample o 
 
× 
× 
× 
 
 
 
 
× 
 
× o 
× o 
× 
 
 
 
 
 
Clinical toxicity assessment 
 
Starting at the time of informed consent through 30 days after last dose r 
 
Concomitant medications 
Reviewed throughout study 
 
Survival 
 
 
× 


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Footnotes to Schedule of Assessments 
 
a. 
All screening/baseline evaluations are performed within 28 days prior to the start of study treatment. In the 
event that a visit or test cannot be scheduled on the exact visit day, a window of ±3 days is allowable. Cycle 1 
is 5 weeks (35 days) in duration. Subsequent cycles are 28 days in duration. 
b. 
A window of ±3 days applies to this study visit. 
c. 
After the first cycle, Day 1 evaluations of subsequent cycles are to be done within 3 days prior to next cycle 
drug administration. 
d. 
Full medical history is obtained at screening for safety and eligibility purposes; this will include any clinically 
significant findings from 28 days prior to screening date. 
e. 
Physical exam and vital signs (including blood pressure, heart rate, respiration rate and temperature) are 
completed for safety purposes and clinically significant items are recorded as AEs where appropriate. Vital 
signs are collected prior to APR-246 infusion, 2 hours into infusion and at EOI (±30 minutes at all time points). 
On Day 2 of the APR-246 monotherapy lead-in period, vital signs are collected prior to PO administration of 
APR-246, and then 2 hours and 6 hours after APR-246 administration. For patients with palpable 
lymphadenopathy and/or organomegaly, 2 dimensional measurements of lymph nodes and measurements 
of liver/spleen size (below costal margin) may be included as part of each physical examination as clinically 
indicated.     
f. 
Study treatment will consist of APR-246 at assigned dose level administered once weekly, on Days 1, 8 and 
15 of each 28-day cycle. On Day 2 of the monotherapy lead-in period, a single dose of APR-246 will be 
administered PO. 
g. 
Venetoclax is given PO at the dose of 20 mg during Week 1, 50 mg during Week 2, 100 mg during Week 3, 
200 mg during Week 4, and 400 mg during Week 5 and thereafter. Each dose should be given once daily at 
approximately the same time every day, with a meal and water. At the discretion of the treating Investigator, 
patient may be hospitalized prior to administration of the first dose of venetoclax (20 and 50 mg) and 
continuing for 24 hours after. 
h. 
Rituximab will be initiated IV, following the 5-week venetoclax dose ramp-up, at 375 mg/m2 on Cycle 2, Day 2 
(+3 days) and 500 mg/m2 on Day 2 (+3 days) of Cycles 3-7. After 6 cycles of treatment with APR-246 + 
venetoclax + rituximab, APR-246 and venetoclax will continue to be administered in Cycle 8 and beyond for 
up to 24 cycles. 
i. 
Responses will be assessed every 3 cycles starting at Cycle 4 on Day 1 (±7 days) according to Lugano response 
criteria via PET/CT imaging, blood, and BM. For patients who achieve CR, imaging may be omitted, and MRD 
assessment will be completed using flow cytometry and/or molecular techniques. 
j. 
Hematology must include complete blood count with differential. Hematology test should be completed 
before and after APR-246 administration on Days 1and 2 of the APR-246 monotherapy lead-in period, Day 3 
of the lead-in period, and on Day 1 of Cycle 1 before and approximately 4 hours after APR-246 administration.  
k. 
Serum chemistry must include sodium, potassium, magnesium, phosphorus, chloride, CO2, blood urea 
nitrogen (BUN), creatinine, glucose, calcium, albumin, total protein, total bilirubin, AST, ALT, alkaline 
phosphatase, uric acid, and lactate dehydrogenase (LDH). 
l. 
Cockcroft-Gault method (see Appendix I). 


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m. Serum or urine beta-human chorionic gonadotrophin (βhCG) must be performed within 7 days prior to study 
treatment initiation in female patients of childbearing potential. 
n. 
Standard 12-lead ECGs in triplicate at screening, Days 1-2 of APR-246 Lead-In, Days 1, 8 and 15 of Cycle 1 and 
on Days 1 of each subsequent cycle with patient in a semi-recumbent position prior to APR-246 
administration. Please consult Table 19 for ECG collection schedule.  
o. 
Please consult Section 7.4 for PK sample collection schedule. 
p. 
Patients discontinuing treatment should complete their end of treatment visit within approximately 28 days 
of their last dose of APR-246. Physical exam, weight, vital signs, ECOG PS, clinical toxicity assessment, 
concomitant medications, hematology, serum chemistry, ECG and disease assessment should be performed, 
if feasible.  
q. 
Long-term follow up can be done remotely (e.g., via telephone, via local practitioner or via review of medical 
records). Assuming there is no withdrawal of consent, patients who stop study treatment for any reason (e.g., 
toxicity, transition to stem cell transplant, disease progression) will continue long term follow-up (see 
Section 6.9). If a patient is removed from the study due to unacceptable AEs, the event(s) will be followed 
until resolution or stabilization. 
r. 
AE description, grade and start date and resolution date should be documented. 
s. 
Historical record can be used from up to 1 year in the past. 
t. 
Testing mandatory. Patients with prior exposure to hepatitis B (i.e., positive anti-hepatitis B core antibody) 
must demonstrate hepatitis B PCR to be negative during screening period and undergo prophylaxis and 
monitoring for hepatitis B according to institutional guidelines. Reflex PCR testing is required if serology is 
positive.  
u. 
PD analyses as described in Table 18 and Section 8.8.  
v. 
Blood sample collected for glutathione assay to measure reduced glutathione (GSH) levels in blood during 
APR-246 monotherapy lead-in period (prior to and approximately 4 hours after APR-246  IV infusion on Day 
1, prior to and approximately 10 hours after APR-246 administration PO on Day 2, and approximately 24 
hours after Day 2 APR-246 PO administration on Day 3) and during Cycle 1 (prior to and approximately 4 
hours after APR-246  IV infusion on Day 1). *GSH sample is collected and sent to LabCorp following sites 
standard practice.  


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6.2 
Pre-Study Assessments 
Prior to performing any procedures or assessments, the nature of the study and the potential risks 
associated with the trial will be explained to all patient candidates and written informed consent will 
be obtained. Patients who choose to participate will have to consent to collection and storage of blood 
for correlative studies. Evaluations obtained as part of routine medical care and performed during the 
screening period may be used in place of the study specific evaluations. Patients will acknowledge and 
agree to the possible use of this information for the study by giving informed consent. 
 
6.3 
Screening 
All screening evaluations are to be performed within approximately 28 days of study treatment 
initiation, unless otherwise noted. 
• 
Signed written informed consent  
• 
Medical history  
• 
Physical examination 
• 
Height: historical record can be used from up to 1 year in the past. 
• 
Weight  
• 
ECOG performance status (Appendix II) 
• 
Vital signs, including blood pressure, heart rate, respiration rate and temperature 
• 
Hematology, including complete blood count with WBC differential.  
• 
Serum chemistry, including sodium, potassium, magnesium, phosphorus, chloride, CO2, blood 
urea nitrogen (BUN), creatinine, glucose, calcium, albumin, total protein, total bilirubin, AST, 
ALT, alkaline phosphatase, uric acid and lactate dehydrogenase (LDH). 
• 
Creatinine CL (Cockcroft-Gault method; Appendix I) 
• 
Serum or urine beta-human chorionic gonadotrophin (βhCG) must be performed within 
7 days prior to study treatment initiation for female patients of childbearing potential. 
• 
HBV/HCV test: Patients with prior exposure to hepatitis B (i.e., positive anti-hepatitis B core 
antibody) must demonstrate hepatitis B PCR to be negative during screening period and 
undergo prophylaxis and monitoring for hepatitis B according to institutional guidelines. 
Reflex PCR testing is required if serology is positive. 
• 
ECG: standard 12-lead ECGs with patient in a semi-recumbent position in triplicate. 
• 
Clinical toxicity assessment 
• 
Concomitant medication review 
• 
Baseline tumor assessment. Responses will be assessed according to disease specific 
response criteria via blood, BM, and imaging (PET/CT), as appropriate, on Day 1 (±14 days) of 
Cycles 4, 7, 13, 19, 22 and 25. If IV contrast is contraindicated, CT without contrast can be used. 
For patients with BM disease, BM assessments will be done at Day 1 (±14 days) of Cycles 7, 13 
and 25 and if required to confirm CR. 
 
6.4 
APR-246 Monotherapy Lead-in 
6.4.1 
Day 1 
• 
Clinical toxicity assessment 
• 
Concomitant medications review 
• 
Physical examination 


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• 
Weight 
• 
ECOG performance status (Appendix II) 
• 
Vital signs, including blood pressure, heart rate, respiration rate and temperature, collected 
2 hours into APR-246 infusion (±30 min) and at EOI (±30 min) 
• 
Hematology, including complete blood count with WBC differential. Hematology test should 
be completed before and approximately 4 hours after APR-246 administration 
• 
Serum chemistry, including sodium, potassium, magnesium, phosphorus, chloride, CO2, BUN, 
creatinine, glucose, calcium, albumin, total protein, total bilirubin, AST, ALT, alkaline 
phosphatase, uric acid and LDH 
• 
APR-246 IV administration  
• 
ECG: standard 12-lead ECGs with patient in semi-recumbent position before and after APR-246 
infusion, per Table 19 
• 
Blood samples for APR-246 PK, per Table 18 
• 
Blood samples for PD, per Table 18 
• 
Blood sample for GSH assay (prior to and approximately 4 hours after APR-246 IV infusion). 
Sample is collected and sent to LabCorp following sites standard practice. 
 
6.4.2 
Day 2 
• 
Clinical toxicity assessment 
• 
Concomitant medications review 
• 
Vital signs, including blood pressure, heart rate, respiration rate and temperature, collected 
2 hours (±30 min) and 6 hours (±30 min) after APR-246 PO administration 
• 
Hematology, including complete blood count with WBC differential. Hematology test should 
be completed before and approximately 10 hours after APR-246 PO administration 
• 
APR-246 PO administration 
• 
ECG: standard 12-lead ECGs with patient in semi-recumbent position before and after APR-246 
infusion, per Table 19 
• 
Blood samples for APR-246 PK, per Table 18 
• 
Blood samples for PD approximately 10 hours after APR-246 administration PO), per 
Table 18Blood sample for GSH assay (prior to and approximately 10 hours after APR-246 
administration PO). Sample is collected and sent to LabCorp following sites standard practice. 
 
 
6.4.3 
Day 3 
• 
Hematology, including complete blood count with WBC differential (approximately 24 hours 
after APR-246 PO administration).  
• 
Blood samples for APR-246 PK, per Table 18 
• 
Blood samples for PD (approximately 24 hours after APR-246 PO administration), per Table 18 
• 
Blood sample for GSH assay (approximately 24 hours after APR-246 PO administration). 
Sample is collected and sent to LabCorp following sites standard practice. 
 


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6.5 
Cycle 1 (Venetoclax Ramp-up, Weeks 1-5) 
6.5.1 
Day 1 
• 
Physical examination: Day 1 
• 
Weight: Day 1 
• 
ECOG performance status (Appendix II): Day 1 
• 
Vital signs, including blood pressure, heart rate, respiration rate and temperature 
• 
Hematology, including complete blood count with WBC differential. Hematology test should 
be completed before and after APR-246 administration on Day 1 
• 
Serum chemistry including sodium, potassium, magnesium, phosphorus, chloride, CO2, BUN, 
creatinine, glucose, calcium, albumin, total protein, total bilirubin, AST, ALT, alkaline 
phosphatase (for TLS assessment), uric acid and LDH: Day 1  
• 
Concomitant medications review 
• 
Clinical toxicity assessment 
• 
APR-246 IV administration: Day 1 
• 
ECG before and after APR-246 administration, see Table 19 (Day 1) 
• 
Venetoclax is given PO at the dose of 20 mg during Week 1, 50 mg during Week 2, 100 mg 
during Week 3, 200 mg during Week 4, and 400 mg during Week 5. Each dose should be given 
once daily at approximately the same time every day, with a meal and water. Please see 
current prescribing information for venetoclax. 
• 
Optional hospitalization for the first dose of 20 and 50 mg of venetoclax beginning the evening 
prior to the dose of venetoclax and continuing for 24 hours after, at the discretion of the 
treating Investigator. 
• 
Blood samples for PD, per Table 18 (Day 1) 
• 
Blood sample for GSH assay (prior to and approximately 4 hours after APR-246 IV infusion on 
Day 1). Sample is collected and sent to LabCorp following sites standard practice. 
 
6.5.2 
Day 8 
• 
Vital signs 
• 
APR-246 IV administration  
• 
ECG before and after APR-246 administration, see Table 19 
• 
Venetoclax is given PO at the dose of 20 mg during Week 1, 50 mg during Week 2, 100 mg 
during Week 3, 200 mg during Week 4, and 400 mg during Week 5. Each dose should be given 
once daily at approximately the same time every day, with a meal and water. Please see 
current prescribing information for venetoclax. 
• 
Clinical toxicity assessment 
• 
Concomitant medications review 
 
6.5.3 
Day 15 
• 
Vital signs 
• 
APR-246 IV administration  
• 
ECG before and after APR-246 administration, see Table 19  
• 
Venetoclax is given PO at the dose of 20 mg during Week 1, 50 mg during Week 2, 100 mg 
during Week 3, 200 mg during Week 4, and 400 mg during Week 5. Each dose should be given 


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once daily at approximately the same time every day, with a meal and water. current 
prescribing information for venetoclax. 
• 
Hematology, including complete blood count with WBC differential 
• 
Serum chemistry, including sodium, potassium, magnesium, phosphorus, chloride, CO2, BUN, 
creatinine, glucose, calcium, albumin, total protein, total bilirubin, AST, ALT, alkaline 
phosphatase (for TLS assessment), uric acid and LDH 
• 
Clinical toxicity assessment 
• 
Concomitant medications review 
 
6.6 
Cycles 2-7  
6.6.1 
Day 1 
• 
Clinical toxicity assessment 
• 
Concomitant medications review 
• 
Physical examination 
• 
Weight 
• 
ECOG performance status (Appendix II) 
• 
Vital signs 
• 
Hematology, including complete blood count with WBC differential 
• 
Serum chemistry, including sodium, potassium, magnesium, phosphorus, chloride, CO2, BUN, 
creatinine, glucose, calcium, albumin, total protein, total bilirubin, AST, ALT, alkaline 
phosphatase, uric acid and LDH 
• 
ECG, per Table 19 
• 
APR-246 IV administration  
• 
Blood sample for APR-246 PK, per Table 18 
• 
Venetoclax is given PO at the dose of 400 mg (or tolerable dose following 5-week ramp-up) 
once daily at approximately the same time every day, with a meal and water. 
 
6.6.2 
Day 2 
• 
Clinical toxicity assessment 
• 
Concomitant medications review 
• 
Vital signs 
• 
Venetoclax is given PO at the dose of 400 mg (or tolerable dose following 5-week ramp up) 
once daily at approximately the same time every day, with a meal and water. 
• 
Rituximab administered intravenously at 500 mg/m2 
 
6.6.3 
Day 8 (±3 Days)  
• 
Clinical toxicity assessment 
• 
Concomitant medications review 
• 
Vital signs, including blood pressure, heart rate, respiration rate and temperature, collected 
2 hours into APR-246 infusion (±30 min) and at EOI (±30 min) 
• 
Hematology, including complete blood count with WBC differential  


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• 
Serum chemistry, including sodium, potassium, magnesium, phosphorus, chloride, CO2, BUN, 
creatinine, glucose, calcium, albumin, total protein, total bilirubin, AST, ALT, alkaline 
phosphatase, uric acid and LDH 
• 
APR-246 IV administration  
• 
Blood sample for APR-246 PK, per Table 18 
• 
Venetoclax is given PO at the dose of 400 mg (or tolerable dose following 5-week ramp up) 
once daily at approximately the same time every day, with a meal and water 
 
6.6.4 
Day 15 (±3 Days)  
• 
Clinical toxicity assessment 
• 
Concomitant medications review 
• 
Vital signs, including blood pressure, heart rate, respiration rate and temperature, collected 
2 hours into APR-246 infusion (±30 min) and at EOI (±30 min) 
• 
Hematology, including complete blood count with WBC differential  
• 
Serum chemistry, including sodium, potassium, magnesium, phosphorus, chloride, CO2, BUN, 
creatinine, glucose, calcium, albumin, total protein, total bilirubin, AST, ALT, alkaline 
phosphatase, uric acid and LDH 
• 
APR-246 IV administration  
• 
Blood sample for APR-246 PK, per Table 18 
• 
Venetoclax is given PO at the dose of 400 mg (or tolerable dose following 5-week ramp up) 
once daily at approximately the same time every day, with a meal and water 
 
6.7 
Tumor Assessment (Cycles 4, 7, 10, 13, 19, 22 and 25) 
• 
Tumor assessment is performed on Day 1 (±14 days) of Cycles 4, 7, 10, 13, 19, 22 and 25. 
Response to study treatment will be assessed via blood, BM, and imaging (PET/CT), as 
appropriate. If IV contrast is contraindicated, CT without contrast can be used. For patients 
with BM disease, BM assessments will be done at Day 1 (±14 days) of Cycles 7, 13 and 25 and 
if required to confirm CR. For patients who achieve CR, imaging may be omitted and MRD 
assessment will be completed using flow cytometry and/or molecular techniques. 
 
6.8 
Cycle 8 and Beyond 
6.8.1 
Day 1 
• 
Clinical toxicity assessment 
• 
Concomitant medications review 
• 
Physical examination 
• 
Weight 
• 
ECOG performance status (Appendix II) 
• 
Vital signs 
• 
Hematology, including complete blood count with WBC differential 
• 
Serum chemistry, including sodium, potassium, magnesium, phosphorus, chloride, CO2, BUN, 
creatinine, glucose, calcium, albumin, total protein, total bilirubin, AST, ALT, alkaline 
phosphatase, uric acid and LDH 
• 
APR-246 IV administration  


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• 
ECG before and after APR-246 administration, see Table 19  
• 
Blood sample for APR-246 PK, per Table 18 
• 
Venetoclax is given PO at the dose of 400 mg (or tolerable dose following 5-week ramp up) 
once daily at approximately the same time every day, with a meal and water 
 
 
6.8.2 
Day 8 (±3 Days)  
• 
Clinical toxicity assessment 
• 
Concomitant medications review 
• 
Vital signs, including blood pressure, heart rate, respiration rate and temperature, collected 
2 hours into APR-246 infusion (±30 min) and at EOI (±30 min) 
• 
Hematology, including complete blood count with WBC differential  
• 
Serum chemistry, including sodium, potassium, magnesium, phosphorus, chloride, CO2, BUN, 
creatinine, glucose, calcium, albumin, total protein, total bilirubin, AST, ALT, alkaline 
phosphatase, uric acid and LDH 
• 
APR-246 IV administration  
• 
Venetoclax is given PO at the dose of 400 mg (or tolerable dose following 5-week ramp up) 
once daily at approximately the same time every day, with a meal and water 
 
6.8.3 
Day 15 (±3 Days)  
• 
Clinical toxicity assessment 
• 
Concomitant medications review 
• 
Vital signs, including blood pressure, heart rate, respiration rate and temperature, collected 
2 hours into APR-246 infusion (±30 min) and at EOI (±30 min) 
• 
Hematology, including complete blood count with WBC differential  
• 
Serum chemistry, including sodium, potassium, magnesium, phosphorus, chloride, CO2, BUN, 
creatinine, glucose, calcium, albumin, total protein, total bilirubin, AST, ALT, alkaline 
phosphatase, uric acid and LDH 
• 
APR-246 IV administration  
• 
Venetoclax is given PO at the dose of 400 mg (or tolerable dose following 5-week ramp up) 
once daily at approximately the same time every day, with a meal and water 
 
6.9 
End of Treatment Visit 
This visit should take place within 28 days of the last dose of study treatment, if treatment is stopped 
early for any reasons.   
 
• 
Physical examination 
• 
Weight  
• 
Vital signs 
• 
ECOG performance status (Appendix II) 
• 
Hematology, including complete blood count with WBC differential 
• 
Serum chemistry, including sodium, potassium, magnesium, phosphorus, chloride, CO2, BUN, 
creatinine, glucose, calcium, albumin, total protein, total bilirubin, AST, ALT, alkaline 
phosphatase, uric acid and LDH 


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• 
Clinical toxicity assessment up to 30 days after the last dose 
• 
ECG, per Table 19 
• 
Disease assessment 
• 
Concomitant medications review 
 
6.10 Long-Term Follow-Up 
Long-term follow-up can be done remotely (e.g., via telephone, via local practitioner or via review of 
medical records). After a patient is removed from the study, the patient will be followed until death. If 
a patient has withdrawn consent from study, then follow-up has to cease on the date when consent 
for study was withdrawn. Off-treatment data on OS will be updated every 3 months or until death or 
withdrawal of consent for study participation, whichever occurs first. If a patient is removed from the 
study due to unacceptable AEs, the event(s) will be followed until resolution or stabilization of the AE. 
Patients who respond and discontinue study treatment for reasons other than disease progression 
should have response assessments and survival should be collected every 2 months until disease 
progression or death, whichever occurs first. After disease progression, data for survival should be 
collected every 3 months until death or withdrawal of consent for study participation. 
 
7.0 STUDY ASSESSMENTS 
7.1 
Safety Assessments 
7.1.1 
Safety Analysis 
Safety data will be tabulated for all patients and include vital signs, laboratory parameters, and AEs. 
 
7.1.2 
Reporting of Adverse Events 
7.1.2.1 
Adverse Events 
An AE is any untoward medical occurrence in a patient administered a pharmaceutical product that 
does not necessarily have a causal relationship with the treatment. An AE can be any unfavorable and 
unintended sign (including a laboratory finding), symptom or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product.  
 
The AE reporting period starts at the time of study treatment initiation. For the time period from 
signing of informed consent up to receipt of the first dose of APR-246, non-serious events should be 
recorded as medical history on the appropriate eCRF page within the clinical database. SAEs that occur 
during the screening period are required to be reported and should include an assessment on 
whether the SAE was related to a protocol-defined procedure or activity. AEs will be collected for up 
to 30 days after the last dose of study treatment, unless the patient has withdrawn consent for study 
participation or started a new anti-cancer treatment for the disease under study, whichever occurs 
first. Hospitalization to start new anti-cancer treatment for primary disease after confirmed 
progression/relapse does not meet criteria for AE or SAE. 
 
Progression of primary disease and events unequivocally related only to progression of primary 


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disease do not need to be reported on the AE CRF page. Progression of primary disease should be 
reported on a response assessment eCRF. 
 
At each evaluation, patients should be interviewed in a non-directed manner to elicit potential adverse 
reactions from the patient. The occurrence of an AE will be based on changes in the patient’s physical 
examination, laboratory results, and/or signs and symptoms. 
 
All AEs (except laboratory abnormalities that are assessed as not clinically significant by the 
Investigator), regardless of causal relationship, are to be recorded in the eCRF and source 
documentation. The Investigator must determine the intensity of any AEs according to the NCI CTCAE 
version 5.0 and their causal relationship to each study medication administered that has been 
administered to the patient at the time of event onset. 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.  
AEs will be followed until resolution or stabilization while the patient remains on-study. Once the 
patient is removed from study treatment, 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. 
 
7.1.2.2 
AE Relationship Attribution Definitions 
An AE is considered to be associated with the use of the study treatment if the attribution is 
determined as possible or definite.  
 
The relationship of each AE to study treatment should be evaluated by the Investigator using the 
following criteria:  
 
• 
Definitely related: A clinical event, including laboratory test abnormality, occurring in a 
plausible time relationship to the medication administration, and which cannot be explained 
by concurrent disease or other drugs or chemicals. The response to withdrawal of the drug 
should be clinically plausible.  
• 
Possibly related: A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to the medication administration, but which could also be explained by concurrent 
disease or other drugs or chemicals. Information on the drug withdrawal may be lacking or 
unclear.  


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• 
Unlikely related: A clinical event, including laboratory test abnormality, with little or no 
temporal relationship to medication administration, and which other drugs, chemicals, or 
underlying disease provide plausible explanations.  
• 
Not related: A clinical event, including laboratory test abnormality that has no temporal 
relationship to the medication or has more likely alternative etiology. 
 
7.1.2.3 
Definition of an Unexpected Adverse Event 
An unexpected AE is defined as any adverse drug experience, the specificity or severity of which is not 
consistent with the reference safety information in the current Investigator Brochure for a study 
product or products administered to a patient; or, if an Investigator Brochure is not available, the 
specificity or severity of which is not consistent with the risk information described in this protocol or 
in the regulatory agency study authorization application.  
 
For study treatments used in this protocol that have been approved for use in the US by the FDA (i.e., 
venetoclax, and rituximab), the reference safety information that will be used for making 
expectedness decisions is the most current version of the product USPI that can be found on the FDA 
website.   
 
Unexpected, as used in this definition, refers to an adverse drug experience that has not been 
previously observed (e.g., included in the IB40 or other product reference safety information such as 
the USPI) rather than from the perspective of such experience not being anticipated from the 
pharmacological properties of the pharmaceutical product. 
 
7.1.2.4 
Serious Adverse Event 
An SAE is defined as any untoward medical occurrence that at any dose: 
 
1. 
Results in death, 
2. 
Is life-threatening (i.e., the patient was at risk of death at the time of the event. It does not 
refer to an event which hypothetically might have caused death if it was more severe), 
3. 
Requires inpatient hospitalization or prolongation of existing hospitalization excluding that for 
pain management, disease staging/re-staging procedures, or catheter placement, for 
administration of study treatments, or for pre-existing condition or elective surgery that was 
planned prior to study enrollment, unless associated with other serious events, 
4. 
Results in persistent or significant disability/incapacity, or 
5. 
Is a congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious adverse drug events when, based on appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed above. 
 
SAEs during the screening period that are assessed as related to a study procedure or activity should 
be reported to the Sponsor. 
 


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7.1.2.5 
Pregnancy 
Any pregnancy detected during the study, or that occurs within 30 days after stopping study 
medication, must be reported immediately to the Investigator. Pregnancy, in and of itself, is not 
regarded as an AE, unless there is suspicion that study medication may have interfered with the 
effectiveness of a contraceptive medication. If the patient becomes pregnant while on-study, the study 
drug should be immediately discontinued. Pregnancy information about a female patient or a female 
partner of a male patient should be reported immediately from the time the Investigator first becomes 
aware of a pregnancy or its outcome. This will be performed by the Investigator per instructions from 
the Sponsor’s monitoring CRO.  
 
Any pregnancy complication, spontaneous abortion, elective termination of a pregnancy for medical 
reasons, outcome of stillbirth, congenital anomaly/birth defect, or SAE in the mother will be recorded 
as an SAE and will be reported as described in Section 7.1.2.6.  
 
7.1.2.6 
Reporting of Serious Adverse Events 
AEs classified as serious require expeditious handling and reporting to Sponsor’s monitoring CRO to 
comply with regulatory requirements. 
 
For any SAE that occurs while a patient is on-study; within 30 days of the last study treatment 
administration, regardless of any opinion as to the relationship of the SAE to the study treatment; or 
if any SAE that the Investigator feels is related to the study treatment occurs later than 30 days after 
the last study treatment administration, the Sponsor’s monitoring CRO must be notified immediately 
(within 24 hours of becoming aware of the event). The primary mechanism for reporting an SAE to the 
Sponsor will be the electronic data collection tool. An SAE eCRF should be completed in the electronic 
data capture (EDC) system within 24 hours of site becoming aware of the event. EDC Alerts will be sent 
to Safety desk for all SAEs. 
 
If the EDC system is inaccessible/unavailable, then the site will use the paper SAE form in order to 
report the SAE within 24 hours. Emailing the paper SAE forms is the preferred method of notification.           
 
SAEs will be reported to the following email address: 
 
       
7.1.2.7 
Safety Monitoring Plan  
The Medical Monitor is responsible for ongoing safety monitoring for the study per the detailed safety 
plan. This monitoring will include a review of all SAEs as they are reported by the study site. The 
Medical Monitor will also be in contact with site monitors and will be available to discuss any issues 
concerning safety with site staff. Safety data will be reviewed periodically by 
 
and the Sponsor Medical Officer. 
 
The DRT consisting of the Medical Monitor, Site Principal Investigators, and other clinical research 
personnel that the Sponsor may deem appropriate will hold DRMs on an interim basis at a frequency 
dependent on study accrual. At these meetings, the DRT will review AEs and DLTs and any available 
PK and/or PD data and make recommendations regarding the recommended dose of APR-246. All 
accumulated safety data will be discussed during DRMs. 


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The DRT will produce summaries or minutes of these meetings. These summaries will be available for 
inspection when requested by any of the regulatory bodies charged with the safety of human patients 
and the integrity of data. 
 
7.2 
Efficacy Assessments 
7.2.1 
Complete Remission Rate  
CR rate will be defined as the proportion of patients who achieve CR. The rate of MRD-negative CR is 
defined as the proportion of patients who achieve MRD-negative CR. 
 
7.2.2 
Duration of Response 
Duration of response (DOR) will be measured from the time of initial response to disease progression 
or death. 
 
7.2.3 
Objective Response Rate 
ORR, defined as the proportion of patients achieving CR or partial response, measured per Lugano 
criteria (see Appendix V). 
 
7.2.4 
Overall Survival 
OS is defined for all enrolled patients, as measured from the date of enrollment until the date of 
death. 
 
7.3 
Progression-Free Survival 
PFS is defined for each patient as the time from start of treatment to the date of the first documented 
progression or death due to any cause. Patients who die without a reported prior progression will be 
considered to have progressed on the date of their death. Patients who did not progress or die will 
be censored on the date of their last evaluable tumor assessment. Patients who started any 
subsequent therapy without a prior reported progression will be censored at the last evaluable tumor 
assessment prior to the initiation of the subsequent anticancer therapy. 
 
7.4 
Pharmacokinetic and Pharmacodynamic Evaluation 
APR-246 will be administered in a 7-day monotherapy cycle on Days 1 and 2, via IV and PO route, 
respectively. PK samples for APR-246 measurements will be taken on Day 1 pre-dose, at the end of 
the infusion and 1, 2 and 4 hours after the end of the infusion, and 24 hours after the end of the 
infusion prior to APR-246 PO administration on Day 2, as well as 0.5, 1, 1.5, 2, 3, 4, 6, 10 and 24 hours 
after the oral administration on Day 2. Following review of the initial PK profiles after oral 
administration, the PK sampling scheme will be reviewed and optimized. Unnecessary samples will be 
removed from the schedule and sampling times changed (the total number of samples specified 
below will not be exceeded). 


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Blood samples for PD markers and GSH will be collected as follows: on Day 1 pre-dose and 4 hours 
after the end of the infusion; on Day 2 prior to oral administration as well as 10 and 24 hours after the 
oral administration.    
In addition, blood samples for PD and GSH markers will be collected on Cycle 1 Day 1 pre-dose and 4 
hours after the end of the infusion. 
Table 18: PK, PD, and Glutathione Blood Sampling Timepoints for APR-246 
 
PK and PD Blood Sampling Timepoints 
APR-246 PK and PD Sample Collection 
APR-246 Monotherapy Lead-In 
Period 
Cycle 
1 
Cycle 2 
Cycles 
3+ 
D1a 
D2b 
D3 
D1 
D
1 
D
8 
D
15 
D1 
PK 
PD 
PK 
PD 
PK 
PD 
PD 
PK 
PK 
PK 
PK 
Prior to APR-246 administration b,c 
× 
×d 
×b 
×d 
×c 
×d 
×d 
× 
× 
× 
 
After APR-246 administration (<5 min 
after end of IV infusion [EOI]) 
× 
 
 
 
 
 
 
× 
× 
× 
× 
0.5 h after APR-246 administration 
 
 
× 
 
 
 
 
 
 
 
 
1 h (±5 min) after APR-246 administration 
× 
 
× 
 
 
 
 
× 
× 
× 
 
1.5 h (±5 min) after APR-246 
administration 
 
 
× 
 
 
 
 
 
 
 
 
2 h (±5 min) after APR-246 administration 
× 
 
× 
 
 
 
 
 
 
 
 
3 h (±15 min) after APR-246 
administration 
 
 
× 
 
 
 
 
 
 
 
 
4 h (±15 min) after APR-246 
administration 
× 
×d 
× 
 
 
 
×d 
 
 
 
 
6 h (±15 min) after APR-246 
administration 
 
 
× 
 
 
 
 
 
 
 
 
10 h (±1 h) after APR-246 administration 
 
 
× 
×d 
 
 
 
 
 
 
 
a PK samples are collected at time points related to IV administration of APR-246 on Day 1 of monotherapy lead-in period 
b PK samples are collected at time points related to PO administration of APR-246 on Day 2 of monotherapy lead-in period with 
the exception of the pre-dose sample collected 24 h after IV administration of APR-246 on Day 1 (prior to PO administration of 
APR-246 on Day 2) 
c Sample collected 24 h (±1 h) after PO administration of APR-246 on Day 2 of monotherapy lead-in period 
d Blood sample for glutathione assay and hematology 
 
On Day 1, 8 and 15 of Cycle 2, venetoclax will be taken 1 hour prior to administration of the APR-246 
infusion. Please refer to Sections 2.5 and 5.4, regarding the risk of certain drugs and foods influencing 
the PK of venetoclax such as grapefruits (see Appendix VII). The time of venetoclax administration on 
the PK sampling day will be recorded to allow popPK evaluation of venetoclax, if deemed necessary. 
          


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7.5 
Electrocardiographic Assessment 
Table 19 describes the routine ECG requirements. 
Table 19. ECG Assessment Requirements 
Time Point 
ECG, number 
Timing 
Baseline/Screening 
Triplicate 
Within 28 days of study treatment 1 
APR-246 Monotherapy 
Lead-In 
Triplicate 
Pre-dose; at the end of the infusion (±30 min) 2 
Cycle 1, Day 1, 8 and 15 
Triplicate 
Pre-dose; at the end of the infusion (±30 min) 
Cycles 2+, Day 1 
Triplicate 
Pre-dose; at the end of the infusion (±30 min) 
 
End of Treatment 
Triplicate 
Within 28 days of the last dose of APR-246 
1 Baseline/Screening registration is for eligibility purpose and should be performed before the patient is approved and 
registered in IWRS to start any treatment on study, i.e., 28 days prior to the first dose of venetoclax in ramp-up. 
2 On Day 2 of the APR-246 monotherapy lead-in period, ECG is obtained prior to PO administration of APR-246, and then 6 
hours after APR-246 administration. 
 
If repeated QTcF measurements show a stable QTcF <470 msec, unless due to BBB and/or pacemaker, 
with no significant change at the EOI during several cycles of treatment, reducing the number of ECGs 
performed in the study may be discussed with the Medical Monitor. 
If a patient starts treatment with another medication known to prolong QT interval at any time during 
the study therapy, an additional pre- and post-dose (6 hours after start of infusion, ±30 min) ECG 
should be performed on the next treatment day. 
Please consult Section 5.3.1 for additional requirements for proceeding with treatment with APR-246. 
 
8.0 STATISTICS 
Continuous variables will be presented by n, mean, median, standard deviation and range (minimum 
and maximum), and categorical variables will be presented by count and percentage of patients as 
appropriate. Data will be presented by dose escalation cohort. All patient data, efficacy and safety 
data will be summarized and listed.   
 
8.1 
Sample Size 
A total of up to 48 evaluable patients will be included in the study. 
 
Patients with RT will be enrolled and receive APR-246 at the assigned dose cohort level. Dose 
escalation will proceed in a 3 + 3 design. Cohorts will consist of 3-6 patients and 10 additional patients 
may be enrolled at the MTD. Approximately 6 + 6 + 6 (18) DLT evaluable patients will be enrolled. In 
the event Dose Level 3 is declared the MTD, up to 10 additional patients may be enrolled at Dose 
Levels 1 and 2 to gain additional safety, PK, and/or PD data to help define the recommended dose of 
APR-246 in this combination. 
 


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8.2 
Analysis Populations 
Safety population: Patients will be evaluable for safety if they receive at least one dose of APR-246. The 
safety population will be the primary analysis population used for all analyses such as patient 
disposition, patient demographics, exposure, safety parameters and efficacy parameters. The safety 
population will be the primary analysis population for efficacy. 
 
Efficacy evaluable (EE) population: All patients who complete at least one treatment cycle of APR-246 
and venetoclax and rituximab and who have at least one post-treatment clinical response assessment. 
The EE population will be the secondary analysis population for efficacy. 
 
PD population: Patients will be evaluable for PD if at least one sample for PD evaluation has been 
obtained after administration of APR-246. 
 
PK population: Patients will be evaluable for PK if at least one sample for PK evaluation has been 
obtained. 
 
8.3 
Endpoints 
8.3.1 
Primary 
1. PD analysis of circulating peripheral blood cells to determine effects of APR-246 on cellular 
viability and apoptosis. 
2. Frequency of TEAEs and SAEs related to APR-246 in combination with venetoclax and 
rituximab therapy. 
3. The highest tested dose of APR-246 with acceptable toxicity (the dose producing <33% of DLT). 
 
8.3.2 
Secondary  
1. PK parameters: Cmax, AUC, Vd and CL of APR-246, and Cmax, time to maximum concentration 
(Tmax), and AUC of venetoclax. 
2. PD analysis of circulating peripheral blood cells to determine effects of APR-246 on cellular 
viability and apoptosis (PK/PD Substudy of APR-246 Monotherapy). 
3. PK parameters after oral dosing: Cmax, Tmax, AUC, relative bioavailability (F), apparent volume 
of distribution (Vd/F) and apparent clearance (CL/F) of APR-246, (PK/PD Substudy of APR-246 
Monotherapy). 
4. CR rate, defined as the proportion of patients who achieve CR as per response criteria. 
5. ORR, defined as the proportion of patients achieving a response, as per response criteria. 
6. DOR, defined as the time from documentation of tumor response to disease progression or 
death as a result of any cause. 
7. PFS, defined as the time from the first study dose date to the date of first documentation of 
confirmed disease progression or death (whichever occurs first). 
 
8.3.3 
Exploratory 
The exposure response relationship for safety and efficacy of APR-246 when combined with 
venetoclax and rituximab therapy. 
 


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8.4 
Safety Stopping Criteria 
The study will implement the following stopping criteria: 
 
• 
Any death occurring between receipt of the first dose of APR-246 through 30 days of last dose 
of study treatment which is not clearly and solely due to underlying disease. 
• 
A medically equivalent SAE experienced by >1 patient, which is not clearly and solely due to 
underlying disease. 
• 
A severe AE (NCI-CTCAE toxicity grade >3) experienced by >2 patients that does not return to 
grade ≤1 or baseline within 7 days. 
• 
A grade ≥3 neurologic AE that does not return to grade ≤1 or baseline within 7 days. 
 
If a stopping criterion is met, enrollment will be temporarily suspended. The DRT will perform a 
prompt cumulative review of safety data and the circumstances of the event(s) in question to 
determine whether dosing and/or the protocol should be modified. 
 
8.5 
Futility Criteria 
As this is a phase 1 study intended to determine the recommended dose of APR-246 in combination 
with venetoclax and rituximab in a limited number of patients with RT, futility criteria based on efficacy 
are not included. 
 
8.6 
Safety 
Safety data will be summarized for the safety population. These data will include AEs, laboratory 
parameters, electrocardiogram, and physical exam findings. AE terms will be coded using the Medical 
Dictionary for Drug Regulatory Activities (MedDRA)®, version 22.0 or higher. AEs will be summarized 
by SOC, preferred term, severity, and relationship to treatment. SAEs, deaths, and AEs leading to early 
discontinuation of study treatment will be summarized. Laboratory parameters will be summarized 
by maximum NCI-CTCAE version 5.0 severity grade and also by change from pre-treatment to 
scheduled time points using descriptive statistics. Laboratory parameter listings will include the 
normal ranges for each parameter. Each value will be classified as falling above, below, or within the 
normal range.  
 
Only SAEs related to study screening procedures from the time of signing informed consent and AEs 
from the time of first dose of APR-246, throughout study enrollment, and up to 30 days after last dose 
of study treatment are to be collected. Data summaries will include only TEAEs, defined as events 
occurring at the start of APR-246 infusion in the monotherapy lead-in or Cycle 1, Day 1 up to and 
including 30 days after last dose of study treatment. 
 
8.7 
Efficacy 
CR rate will be summarized for the safety and EE patients as the proportion (%) of patients with CR. In 
addition to presenting the CR rate, its associated exact 95% CI will also be presented. 
 
DOR is defined as the time from the date when criteria for response are met to the date of disease 


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progression or death due to any cause, whichever occurs first. Patients alive with no disease 
progression will have their DOR censored at the date of the last clinical assessment. The duration of 
CR will be summarized by providing the median DOR together with associated 95% CI, using Kaplan-
Meier methodology. 
 
ORR will be summarized in number (%) of patients in each category of responses and ORR will be 
analyzed by using a similar method to the one used for the CR rate. ORR is defined as the number of 
patients who achieve CR and partial remission (PR) measure per Lugano criteria (see Appendix V). 
 
Survival data are collected at treatment and follow-up periods. Patients will be followed until death or 
withdrawal of consent from the study, whichever occurs first.  
 
OS is defined as the number of days from the first day of treatment to the date of death due to any 
cause. Kaplan-Meier methodology will be utilized. 
 
PFS is defined as the time from the first day of treatment to disease progression or death due to any 
cause, whichever occurs first. If neither event occurs, PFS will be censored at the date of the last clinical 
assessment. Kaplan-Meier methodology will be utilized. 
 
8.8 
Pharmacodynamic Analysis 
PD analysis will be conducted using flow cytometry of circulating CLL/RT cells before and after 
treatment with APR-246 during monotherapy and the first day of combination treatment ramp-up to 
assess viability and apoptosis. Descriptive statistics (mean, standard deviation, CV% mean, geometric 
mean, CV% geometric mean) will be utilized to compare the post- and pre-treatment samples and the 
differences at each dose cohort level will be tested for relationship to dose. 
 
8.9 
Pharmacokinetic Analysis 
Concentrations of APR-246 will be determined using validated bioanalytical methods.  
 
During the APR-246 monotherapy cycle, PK sampling for APR-246 will be performed on Day 1 and 2. 
Noncompartmental  PK analysis will be used to determine Cmax, Tmax, AUC and bioavailability after oral 
dosing for decision making on dose escalation of the oral dose. 
 
PK sampling for APR-246 will be performed during Cycle 2, on Day 1, 8 and 15 and on Day 1 from 
Cycle 3 onwards. 
 
PK sampling for venetoclax and rituximab will not be performed for this study. 
 
The PK of APR-246 will be summarized using descriptive statistics (mean, standard deviation, CV% 
mean, geometric mean, CV% geometric mean). The concentration data for APR-246 will be evaluated 
using (popPK analysis in combination with data from other studies. 
 
APR-246 AUC and Cmax will then be tested for association with signs of efficacy and safety. If an 
observable trend exists, a PK/PD model will be developed to evaluate the exposure-response 
relationship between APR-246 plasma exposure and outcome measures. Demographic and clinical 


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data (ethnicity, current age, body weight, sex, disease status, etc.) will be utilized to assess interpatient 
variability in the PK and PK/PD relationships. 
 
 
9.0 QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES 
9.1 
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 eCRFs 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 eCRFs and 
individual patient’s medical records and assure that the study is being conducted according to 
pertinent regulatory requirements. All eCRF entries will be verified with source documentation. The 
review of medical records will be done in a manner to assure that patient’s confidentiality is 
maintained.  
 
9.2 
Curricula Vitae and Financial Disclosure of Investigators  
All Principal Investigators will be required to provide a current signed and dated curriculum vitae, a 
completed FDA Form 1572 and a financial disclosure statement to Sponsor’s monitoring CRO. All 
Sub-Investigators will be required to provide a current curriculum vitae and a financial disclosure 
statement to Sponsor’s monitoring CRO. 
 
9.3 
Protocol Modifications 
No modification of the protocol should be implemented without the prior written approval of the 
Sponsor or the Sponsor’s representative. Any such changes which may affect a patient’s treatment or 
informed consent, especially those increasing potential risks, must receive prior approval by the 
IRB/IEC. The exception to this is where modifications are necessary to eliminate an immediate hazard 
to trial patients, or when the change involves only logistical or administrative aspects of the trial (e.g., 
change in monitor, change in telephone number). Other administrative revisions which may impact 
the clinical portion of a study will be duly reported to the IRB/IEC by the Principal Investigator. 
 
9.4 
Publication Policy 
The publication of the results of the study will be subject to the terms and conditions of the clinical 
trial agreement between the Sponsor and Investigators. Sponsor approval is required for publication 
of any data from this trial.  
 
10.0 ETHICAL CONSIDERATIONS 
10.1 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 


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informed consent form will contain all the Essential Elements of Informed Consent set forth in 21 CFR, 
Part 50, the European Union Directive 2001/20/EC and its associated Detailed Guidances, European 
Union GCP Directive 2005/28/EC, the ICH Guideline for GCP, Section 4.8, and the terms of the 
Declaration of Helsinki (2013). Copies of the signed document should be given to the patient and filed 
in the Investigator’s study file, as well as the patient’s medical record if in conformance with the 
institution’s Standard Operating Procedures.  
 
10.2 Institutional Review Board/Independent Ethics Committee 
The study will not be initiated without approval of the appropriate IRB/IEC and compliance with all 
administrative requirements of the governing body of the institution. This protocol, consent 
procedures, and any amendments must be approved by the IRB/IEC in compliance with current 
regulations of the FDA and the European Union as applicable and in accordance with ICH/GCPs. A 
letter of approval will be sent to the Sponsor prior to initiation of the study and when any subsequent 
modifications are made. The IRB/IEC will be kept informed by the Investigator, Sponsor’s monitoring 
CRO or the Sponsor, as required by national regulations, as to the progress of the study as well as to 
any serious and unexpected AEs.  
 
10.3 Patient Privacy  
In order to maintain patient confidentiality, all eCRFs, study reports and communications relating to 
the study will identify patients by initials and assigned patient numbers; patients should not be 
identified by name. In accordance with local, national or federal regulations, the Investigator will allow 
the Sponsor or designee personnel access to all pertinent medical records in order to verify the data 
gathered on the eCRFs and to audit the data collection process. Regulatory agencies such as the US 
FDA may also request access to all study records, including source documentation for inspection. 
Clinical information will not be released without the written permission of the patient as outlined in 
the patient consent form. 
 
11.0 DATA HANDLING AND RECORD KEEPING 
11.1 Data to be Entered Directly in the Case Report Form 
The eCRF will be the source record. 
 
11.2 Recording of Data 
Data collected during the study will be entered in the patient’s eCRF 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 eCRF 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 eCRF.  
 
The Investigator will provide access to his/her original records to permit a representative from the 
Sponsor to verify the proper transcription of data.  
 


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11.3 Study Records 
U.S. Federal laws require that an Investigator maintain all study records for the indication under 
investigation for two years following the date a Product Licensing Application is approved or, if no 
application is to be filed or if the application is not approved for such indication, until two years after 
the investigation is discontinued and the FDA is notified. 
 
 


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Gonzalez D, Martinez P, Wade R, et al. Mutational status of the TP53 gene as a predictor of response 
and survival in patients with chronic lymphocytic leukemia: Results from the LRF CLL4 trial. J Clin Oncol. 
2011;29(16):2223-2229. doi:10.1200/JCO.2010.32.0838 
18.  
Stilgenbauer S, Schnaiter A, Paschka P, et al. Gene mutations and treatment outcome in chronic 
lymphocytic leukemia: Results from the CLL8 trial. Blood. 2014;123(21):3247-3254. doi:10.1182/blood-
2014-01-546150 
19.  
An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta-
analysis of individual patient data. Lancet Oncol. 2016;17(6):779-790. doi:10.1016/S1470-2045(16)30029-
8 
20.  
Rossi D, Khiabanian H, Spina V, et al. Clinical impact of small TP53 mutated subclones in chronic 
lymphocytic leukemia. Blood. 2014;123(14):2139-2147. doi:10.1182/blood-2013-11-539726 
21.  
Sorror ML, Storer BE, Sandmaier BM, et al. Five-year follow-up of patients with advanced chronic 
lymphocytic leukemia treated with allogeneic hematopoietic cell transplantation after nonmyeloablative 
conditioning. J Clin Oncol. 2008;26(30):4912-4920. doi:10.1200/JCO.2007.15.4757 
22.  
Stilgenbauer S, Zenz T, Winkler D, et al. Subcutaneous alemtuzumab in fludarabine-refractory chronic 
lymphocytic leukemia: Clinical results and prognostic marker analyses from the CLL2H study of the 
German chronic lymphocytic leukemia study group. J Clin Oncol. 2009;27(24):3994-4001. 
doi:10.1200/JCO.2008.21.1128 
23.  
Dreger P, Döhner H, Ritgen M, et al. Allogeneic stem cell transplantation provides durable disease 
control in poor-risk chronic lymphocytic leukemia: Long-term clinical and MRD results of the German 
CLL Study Group CLL3X trial. Blood. 2010;116(14):2438-2447. doi:10.1182/blood-2010-03-275420 
24.  
Pettitt AR, Jackson R, Carruthers S, et al. Alemtuzumab in combination with methylprednisolone is a 
highly effective induction regimen for patients with chronic lymphocytic leukemia and deletion of TP53: 
Final results of the National Cancer Research Institute CLL206 Trial. J Clin Oncol. 2012;30(14):1647-1655. 
doi:10.1200/JCO.2011.35.9695 
25.  
Dreger P, Schnaiter A, Zenz T, et al. TP53, SF3B1, and NOTCH1 mutations and outcome of 
allotransplantation for chronic lymphocytic leukemia: six-year follow-up of the GCLLSG CLL3X trial. 
Blood. 2013;121(16):3284-3288. doi:10.1182/blood-2012-11-469627 
26.  
Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid 
leukemia. N Engl J Med. 2014;371(3):213-223. doi:10.1056/NEJMoa1400376 
27.  
Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic 
leukemia. N Engl J Med. 2014;370(11):997-1007. doi:10.1056/NEJMoa1315226 
28.  
Jones JA, Robak T, Brown JR, et al. Efficacy and safety of idelalisib in combination with ofatumumab for 
previously treated chronic lymphocytic leukaemia: an open-label, randomised phase 3 trial. Lancet 
Haematol. 2017;4(3):e114-e126. doi:10.1016/S2352-3026(17)30019-4 


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29.  
O’Brien S, Jones JA, Coutre SE, et al. Ibrutinib for patients with relapsed or refractory chronic lymphocytic 
leukaemia with 17p deletion (RESONATE-17): a phase 2, open-label, multicentre study. Lancet Oncol. 
2016;17(10):1409-1418. doi:10.1016/S1470-2045(16)30212-1 
30.  
O’Brien SM, Lamanna N, Kipps TJ, et al. A phase 2 study of idelalisib plus rituximab in treatment-naïve 
older patients with chronic lymphocytic leukemia. Blood. 2015;126(25):2686-2694. doi:10.1182/blood-
2015-03-630947 
31.  
Sharman JP, Coutre SE, Furman RR, et al. Final results of a randomized, phase III study of rituximab with 
or without idelalisib followed by open-label idelalisib in patients with relapsed chronic lymphocytic 
leukemia. J Clin Oncol. 2019;37(16):1391-1402. doi:10.1200/JCO.18.01460 
32.  
Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax in relapsed or refractory chronic lymphocytic 
leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol. 2016;17(6):768-778. 
doi:10.1016/S1470-2045(16)30019-5 
33.  
Zelenetz AD, Barrientos JC, Brown JR, et al. Idelalisib or placebo in combination with bendamustine and 
rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia: interim results from a 
phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2017;18(3):297-311. 
doi:10.1016/S1470-2045(16)30671-4 
34.  
Pospisilova S, Gonzalez D, Malcikova J, et al. ERIC recommendations on TP53 mutation analysis in 
chronic lymphocytic leukemia. Leukemia. 2012;26(7):1458-1461. doi:10.1038/leu.2012.25 
35.  
Jain P, O’Brien S. Richter’s transformation in chronic lymphocytic leukemia. Oncol (United States). 
2012;26(12). doi:10.1016/j.leukres.2004.09.008 
36.  
Ding W. Richter transformation in the era of novel agents. Hematol (United States). 2018;2018(1):256-263. 
doi:10.1182/asheducation-2018.1.256 
37.  
Jain N, Keating MJ. Richter transformation of CLL. Expert Rev Hematol. 2016;9(8):793-801. 
doi:10.1080/17474086.2016.1199948 
38.  
Parikh SA. Chronic lymphocytic leukemia treatment algorithm 2018. Blood Cancer J. 2018;8(10). 
doi:10.1038/s41408-018-0131-2 
39.  
Rossi D, Gaidano G. Richter syndrome: Pathogenesis and management. Semin Oncol. 2016;43(2):311-
319. doi:10.1053/j.seminoncol.2016.02.012 
40.  
Aprea Therapeutics. APR-246 Investigator’s Brochure Version 14.0. 2021. 
41.  
Lehmann S, Bykov VJN, 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. J Clin Oncol. 
2012;30(29):3633-3639. doi:10.1200/JCO.2011.40.7783 
42.  
European Medicines Agency. ICH E9 (R1) addendum on estimands and sensitivity analysis in clinical 
trials to the guideline on statistical principles for clinical trials - Step 2b. 2017;44(August):1-23. 
43.  
Deneberg S, Cherif H, Lazarevic V, et al. An open-label phase I dose-finding study of APR-246 in 
hematological malignancies. Blood Cancer J. 2016;6(7):e447. doi:10.1038/bcj.2016.60 
44.  
Sallman DA, DeZern AE, Garcia-Manero G, et al. Eprenetapopt (APR-246) and Azacitidine in TP53-Mutant 
Myelodysplastic Syndromes. J Clin Oncol. January 2021:JCO2002341. doi:10.1200/JCO.20.02341 


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45.  
Cluzeau T, Sebert M, Rahmé R, et al. Eprenetapopt Plus Azacitidine in TP53-Mutated Myelodysplastic 
Syndromes and Acute Myeloid Leukemia: A Phase II Study by the Groupe Francophone des 
Myélodysplasies (GFM). J Clin Oncol. February 2021:JCO2002342. doi:10.1200/JCO.20.02342 
46.  
Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax–Rituximab in Relapsed or Refractory Chronic 
Lymphocytic Leukemia. N Engl J Med. 2018;378(12):1107-1120. doi:10.1056/NEJMoa1713976 
47.  
FDA, CDER. Venetoclax Prescribing Information. www.fda.gov/medwatch. Accessed June 24, 2019. 
48.  
Genentech. Rituximab. Highlights of Prescribing Information. 2010:1-35. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/103705s5311lbl.pdf. 
49.  
Deneberg S, Cherif H, Lazarevic V, et al. An open-label phase I dose-finding study of APR-246 in 
hematological malignancies. Blood Cancer J. 2016;6(7):e447. doi:10.1038/bcj.2016.60 
50.  
Jaskova Z, Pavlova S, Malcikova J, Brychtova Y, Trbusek M. PRIMA-1MET cytotoxic effect correlates with 
p53 protein reduction in TP53-mutated chronic lymphocytic leukemia cells. Leuk Res. 2020;89. 
doi:10.1016/j.leukres.2019.106288 
51.  
Aprea Therapeutics. APR-246 Investigator’s Brochure v10.1. 2019:168. 
52.  
FDA. Venetoclax Prescribing Information.; 2016. 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208573s000lbl.pdf. 
53.  
Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax–Rituximab in Relapsed or Refractory Chronic 
Lymphocytic Leukemia. N Engl J Med. 2018;378(12):1107-1120. doi:10.1056/NEJMoa1713976 
54.  
Roselló S, Blasco I, García Fabregat L, Cervantes A, Jordan K, ESMO Guidelines Committee. Management 
of infusion reactions to systemic anticancer therapy: ESMO Clinical Practice Guidelines†. Ann Oncol. 
2017;28(suppl_4):iv100-iv118. doi:10.1093/annonc/mdx216 
55.  
Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and 
response assessment of hodgkin and non-hodgkin lymphoma: The lugano classification. J Clin Oncol. 
2014;32(27):3059-3067. doi:10.1200/JCO.2013.54.8800 
56.  
Venetoclax. Highlights of Prescribing Information. Updated 5/2020.; 2020. www.fda.gov/medwatch. 
Accessed September 17, 2020. 
 


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


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


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APPENDIX III - Acceptable Contraceptive Methods 
● 
Male or female condom with or without spermicide 
● 
Cervical cap, diaphragm or sponge with spermicide 
Highly Effective Contraceptive Methods That Are User Dependent a  
Failure rate of <1% per year when used consistently and correctly. 
● 
Combined (estrogen- and progesterone-containing) hormonal contraception b 
○ 
Oral  
○ 
Intravaginal  
○ 
Transdermal  
○ 
Injectable 
● 
Progestogen-only hormonal contraception b 
○ 
Oral  
○ 
Injectable  
Highly Effective Methods That Have Low User Dependency  
Failure rate of <1% per year when used consistently and correctly. 
● 
Progesterone-only contraceptive implant b, c  
● 
Intrauterine hormone-releasing system (IUS) b  
● 
Intrauterine device (IUD) 
● 
Bilateral tubal occlusion 
● 
Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the 
sole male sexual partner of the female of childbearing potential and the absence of sperm has 
been confirmed. If not, an additional highly effective method of contraception should be used.  
● 
Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the participant.)  
Notes:  
Use should be consistent with local regulations regarding the use of contraceptive methods for 
participants of clinical studies. 
a) Typical use failure rates are lower than perfect-use failure rates (i.e., when used consistently and 
correctly).  
b) If hormonal contraception efficacy is potentially decreased due to interaction with study 
treatment, condoms must be used in addition to the hormonal contraception during the 
treatment period and for at least 120 days, (corresponding to time needed to eliminate study 
treatment plus 30 days for study treatments with genotoxic potential) after the last dose of the 
study treatment. 
c) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable hormonal contraceptives are limited to those which inhibit ovulation.  
 
 


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


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APPENDIX V - Lugano Criteria for RT Patients 55 
Response and Site 
PET-CT-Based Response 
CT-Based Response 
Complete 
Complete metabolic response 
Complete radiologic response (all of the following) 
Lymph nodes and extra-
lymphatic sites 
Score 1, 2, or 3* with or without a residual mass 5 PS† 
It is recognized that in Waldeyer’s ring or extranodal 
sites with high physiologic uptake or with activation 
within spleen or marrow (e.g., with chemotherapy or 
myeloid colony-stimulating factors), uptake may be 
greater than normal mediastinum and/or liver. In this 
circumstance, complete metabolic response may be 
interred if uptake at sites of initial involvement is no 
greater than surrounding normal tissue even if the 
tissue has high physiologic uptake 
Target nodes/nodal masses must regress to ≤ 
1.5 cm in LDi 
No extralymphatic sites of disease 
Nonmeasured lesion 
Not applicable 
Absent 
Organ enlargement 
Not applicable 
Regress to normal 
New lesions 
None 
None 
Bone marrow 
No evidence of FDG-avid disease in marrow 
Normal by morphology; if indeterminate, IHC 
negative 
Partial 
Partial metabolic response 
Partial remission (all of the following) 
Lymph nodes and extra-
lymphatic sites 
Score of 4 or 5† with reduced uptake compared with 
baseline and residual mass(es) of any size 
At interim, these findings indicate responding disease 
At end of treatment, these findings indicate residual 
disease 
 
≥ 50% decrease in SPD of up to 6 target 
measurable nodes and extranodal sites 
When a lesion is too small to measure on CT, 
assign 5 mm × 5 mm as the default value 
When no longer visible, 0 x 0 mm 
For a node > 5 mm × 5 mm, but smaller than 
normal, use actual measurement for calculation 
Nonmeasured lesions 
Not applicable 
Absent/normal, regressed, but no increase 
Organ enlargement 
Not applicable 
Spleen must have regressed by >50% in length 
beyond normal 
New lesions 
None 
None 


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Bone marrow 
Residual uptake higher than uptake in normal 
marrow but reduced compared w/ baseline (diffuse 
uptake compatible w. reactive changes from 
chemotherapy allowed). If there are persistent focal 
changes in the marrow in the context of a nodal 
response, consideration should be given to further 
evaluation w/ MRI or biopsy or an interval scan 
Not applicable 
No response or stable disease 
No metabolic response 
Stable disease 
Target nodes/nodal masses, 
extranodal lesions 
Score 4 or 5 with no significant change in FDG uptake 
from baseline at interim or end of treatment 
<50% decrease from baseline in SPD of up to 6 
dominant, measurable nodes and extranodal 
sites; no criteria for progressive disease are met 
Non measure lesions 
Not applicable 
No increase consistent with progression 
Organ enlargement 
Not applicable 
No increase consistent with progression 
New lesions 
None 
None 
Bone marrow 
No change from baseline 
Not applicable 
Progressive disease 
Progressive metabolic disease 
Progressive disease requires at least 1 of the 
following 
Individual target 
nodes/nodal masses 
Score 4 or 5 with an increase in intensity of uptake 
from baseline and/or 
PPD progression: 
Extranodal lesions 
New FDG-avid foci consistent with lymphoma at 
interim or end-of-treatment assessment 
An individual node/lesion must be abnormal with: 
LDi >1.5 cm and 
Increase by ≥50% from PPD nadir and an increase 
in LDi or SDi from nadir 
0.5 cm for lesions ≤2 cm 
1.0 cm for lesions >2 cm 
In the setting of splenomegaly, the splenic length 
must increase by >50% of the extent of its 
prior increase beyond baseline (e.g., a 15-cm 
spleen must increase to >16 cm). If no prior 
splenomegaly, must increase by at least 2 cm 
from baseline 
New or recurrent splenomegaly 


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Non measured lesions 
None 
New or clear progression of preexisting 
nonmeasured lesions 
New lesions 
New FDG-avid foci consistent with lymphoma rather 
than another etiology (e.g., infection, inflammation). If 
uncertain regarding etiology of new lesions, biopsy or 
interval scan may be considered 
Regrowth of previously resolved lesions 
A new node >1.5 cm in any axis 
A new extranodal site >1.0 cm in any axis; if <1.0 
cm in any axis, its presence must be 
unequivocal and must be attributable to 
lymphoma 
Assessable disease of any size unequivocally 
attributable to lymphoma 
Bone marrow 
New or recurrent FDG-avid foci 
New or recurrent involvement 
 
Revised Response Criteria (Table Key) 
 
Abbreviations: 5PS, 5-point scale, CT computed tomography; FDG, fluorodeoxyglucose; IHC, immunohistochemistry; LDi, longest transverse diameter of a 
lesion; MRI, magnetic resonance imaging; PET, positron emission tomography; PPD cross product of the LDi and perpendicular diameter; SDi, shortest axis 
perpendicular to the LDi; SPD, sum of the product of the perpendicular diameters for multiple lesions. 
* A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an interim scan. However, in trials involving 
PET where de-escalation is investigated, it may be preferable to consider a score of 3 as inadequate response (to avoid undertreatment). Measured dominant 
lesions: Up to 6 of the largest dominant nodes, nodal masses, and extranodal lesions selected to be clearly measureable in two diameters. Nodes should 
preferably be from disparate regions of the body and should include, where applicable, mediastinal and retroperitoneal areas. Non-nodal lesions include 
those preferably be from disparate regions of the body and should include, where applicable, mediastinal and retroperitoneal areas. Non-nodal lesions 
include those in solid organs (e.g., liver, spleen, kidneys, lungs), GI involvement, cutaneous lesions, or those noted on palpation. Nonmeasure lesions: Any 
disease not selected as measure, dominant disease and truly assessable disease should be considered not measured. These sites include any nodes, nodal 
masses, and extranodal sites not selected as dominant or measurable or that do not meet the requirements for measurability but are still considered 
abnormal, as well as truly assessable disease, which is any site of suspected disease that would be difficult to follow quantitatively with measurement, 
including pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot be confirmed and followed by 
imaging. In Waldeyer’s ring or in extranodal sites (e.g., GI tract, liver, bone marrow), FDG uptake may be greater than in the mediastinum with complete 
metabolic response, but should be no higher than surrounding normal physiologic uptake (e.g., with marrow activation as a result of chemotherapy or 
myeloid growth factors). 
† PET 5 PS: 1, no uptake above background; 2 uptake ≤ mediastinum; 3, uptake > mediastinum but ≤ liver; 4, uptake moderately > liver; 5, uptake markedly 
higher than liver and/or new lesions; X, new areas of uptake unlikely to be related to lymphoma. 
 
 
 


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APPENDIX VI - Dose Modifications of Venetoclax with Use of CYP3A or P-gp 
Inhibitors 
Concomitant use of venetoclax with strong CYP3A inhibitors at initiation and during ramp-up phase 
is contraindicated. Concomitant use of venetoclax with strong CYP3A inhibitors increases 
venetoclax exposure (i.e., Cmax and AUC) and may increase the risk for TLS at initiation and during 
ramp-up phase. For patients who have completed the ramp-up phase and are on a steady daily 
dose of venetoclax, reduce the venetoclax dose by at least 75% when strong CYP3A inhibitors must 
be used concomitantly.  
 
Avoid concomitant use of venetoclax with moderate CYP3A inhibitors or P-gp inhibitors. Consider 
alternative treatments. If a moderate CYP3A inhibitor or a P-gp inhibitor must be used, reduce the 
venetoclax dose by at least 50%. Monitor these patients more closely for signs of toxicities.  
 
Resume the venetoclax dose that was used prior to initiating the CYP3A inhibitor or P-gp inhibitor 
2 to 3 days after discontinuation of the inhibitor.  
 
The recommendations for managing drug-drug interactions are summarized in the table below. 
 
Co-administered drug 
Initiation and Ramp-Up Phase 
Steady Daily Dose (After Ramp-
Up Phase) 
Posaconazole 
Day 1 – 10 mg 
Day 2 – 20 mg 
Day 3 – 50 mg 
Day 4 – 70 mg 
Reduce venetoclax dose to 70 mg. 
Other strong CYP3A inhibitor 
Day 1 – 10 mg 
Day 2 – 20 mg 
Day 3 – 50 mg 
Day 4 – 100 mg 
Reduce venetoclax dose to 100 
mg. 
Moderate CYP3A inhibitor 
Reduce the venetoclax dose by at least 50% 
P-gp inhibitor 
 
Warfarin 
Concomitant use of venetoclax increases warfarin Cmax and AUCinf, which may increase the risk of 
bleeding. Closely monitor international normalized ratio (INR) in patients using warfarin 
concomitantly with venetoclax. 
 
P-gp Substrates 
Concomitant use of venetoclax increases Cmax and AUCinf of P-gp substrates, which may increase 
toxicities of these substrates. Avoid concomitant use of venetoclax with a P-gp substrate. If a 
concomitant use is unavoidable, separate dosing of the P-gp substrate at least 6 hours before 
venetoclax. 
 
Please refer to the venetoclax USPI56 for additional details on drug-drug interactions. 
 
Below (Table 20) are examples of CYP3A inhibitors and inducers (strong and moderate); however, 


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this is not an exhaustive list. 
 
Table 20. CYP3A Inhibitors and Inducers 
CYP3A Inhibitors 
Strong CYP3A Inhibitors 
Moderate CYP3A Inhibitors 
boceprevir, cobicistat, danoprevir and ritonavir, 
elvitegravir and ritonavir, indinavir and ritonavir, 
itraconazole, ketoconazole, lopinavir and ritonavir, 
paritaprevir and ritonavir and (ombitasvir and/or 
dasabuvir), posaconazole, ritonavir, saquinavir and 
ritonavir, telaprevir, tipranavir and ritonavir, 
telithromycin, troleandomycin, voriconazole 
aprepitant, ciprofloxacin, conivaptan, crizotinib, 
cyclosporine, diltiazem, dronedarone, 
erythromycin, fluconazole, fluvoxamine, imatinib, 
tofisopam, verapamil 
 
CYP3A Inducers 
Strong CYP3A Inducers 
Moderate CYP3A Inducers 
apalutamide, carbamazepine, enzalutamide, 
mitotane, phenytoin, rifampin, St. John’s wort 
 
bosentan, efavirenz, etravirine, phenobarbital, 
primidone 
Note: In addition to the medications listed above, patients taking venetoclax should not consume grapefruit, grapefruit 
products, Seville oranges, (including marmalade containing Seville oranges), or star fruit. 
 
 
 
 
 


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VENETOCLAX DRUG DIARY 
 
Instructions:  
You will use this diary to record each dose of venetoclax that you take. You should also use 
this diary to record any side effects that you experience and medications that you take other 
than the venetoclax. Please be sure to bring this diary with you to your next clinic visit. 
 
Venetoclax:  
• 
Venetoclax is taken once a day every day, approximately 24 hours apart. 
• 
Venetoclax should be taken with food. Venetoclax can be taken before or after start 
of APR-246 infusion (±2 hours). 
• 
If you forget to take a dose of venetoclax and it is within 8 hours of when it should 
have been taken, you should take the dose. If it has been more than 8 hours, you 
should skip that dose and take the next dose at the next regular time.  
• 
If you vomit after taking a dose of venetoclax, you should not make up the dose or 
take additional pills, you should take the next dose at the next regular time.  
• 
Always bring your pill bottles (including those that are empty) and your diary with you 
to each clinic visit.   
 
Your study doctor will make sure you reach the required dose of venetoclax slowly, over the 
period of 5 weeks called ramp-up, as shown in the table below. 
 
Week Number 
Venetoclax Daily Dose 
Week 1 
20 mg 
Week 2 
50 mg 
Week 3 
100 mg 
Week 4 
200 mg 
Week 5 and beyond 
400 mg 
 
 
If you have any questions, please ask a study team member or your doctor. 


Aprea Therapeutics  
Protocol Number A20-11197  
Phase 1 Study of APR-246 with 
Venetoclax-Based Therapy in NHL 
 
1197_CSP_7.0 
 
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 Patient Number:   __________ 
 
Patient Initials:   __________ 
 
Cycle Number:  _______ 
Start Date: _______________ 
 
Venetoclax tablets to take at each dose:  20 mg = _____ 
50 mg = _____ 
100 mg = _____ 
 
 
 
 
 
 
 
 
Other information/Comments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY STAFF USE ONLY 
 
Staff member reviewing diary at end of study 
cycle: 
 
 


Aprea Therapeutics  
Protocol Number A20-11197  
Phase 1 Study of APR-246 with 
Venetoclax-Based Therapy in NHL 
 
1197_CSP_7.0 
 
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VENETOCLAX DRUG DIARY (continued)  
 
Patient Number/Initials:  ____________________ 
 
Cycle:  _____ 
 
Cycle 
Day 
Date 
Taken 
Time 
Taken 
Number of 
venetoclax 
tablets taken 
Dose 
taken 
Comments 
(Side effects, complaints, other 
medications) 
1 
 
 
 
 
 
2 
 
 
 
 
 
3 
 
 
 
 
 
4 
 
 
 
 
 
5 
 
 
 
 
 
6 
 
 
 
 
 
7 
 
 
 
 
 
8 
 
 
 
 
 
9 
 
 
 
 
 
10 
 
 
 
 
 
11 
 
 
 
 
 
12 
 
 
 
 
 
13 
 
 
 
 
 
14 
 
 
 
 
 
15 
 
 
 
 
 
16 
 
 
 
 
 
17 
 
 
 
 
 
18 
 
 
 
 
 
19 
 
 
 
 
 
20 
 
 
 
 
 
21 
 
 
 
 
 
22 
 
 
 
 
 
23 
 
 
 
 
 
24 
 
 
 
 
 
25 
 
 
 
 
 
26 
 
 
 
 
 
27 
 
 
 
 
 
28 
 
 
 
 
 
 
* NOTE: Add additional days in case needed due to scheduling delay or dose modifications. 


 
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APPENDIX VII - Patient Handout: Prohibited Medications 
PROHIBITED MEDICATIONS  
 
One of the medications you are receiving during this clinical trial, venetoclax, interacts with some 
drugs that are processed by your liver. Because of this, it is very important to tell your study doctors 
about all of your medicine before you start this study. It is also very important to tell them if you 
stop taking any regular medicine, or if you start taking a new medicine while you take part in this 
study. When you talk about your medicine with your study doctor, include medicine you buy 
without a prescription at the drug store (over-the-counter remedy), or anything that you buy from 
the health food store or grocery store (herbal supplement). Many health care prescribers can write 
prescriptions. You must also tell your other prescribers (doctors, physicians’ assistants or nurse 
practitioners) that you are taking part in a clinical trial.  
 
Bring this paper with you.  
 
• 
Venetoclax is processed by a certain enzyme in the liver called CYP3A4. Drugs that 
increase the activity of this enzyme are called “inducers”, and drugs that decrease the 
activity of this enzyme are called “inhibitors”. Venetoclax must be used very carefully with 
other medicines that are inducers or inhibitors of CYP3A4. Venetoclax may also interact 
with other drugs that are processed by the liver. 
• 
You and healthcare providers who prescribe drugs for you must be careful about adding 
or removing any drug in this category. 
Before you start the study, your study doctor will work with your regular prescriber to switch the 
following medications if you are taking them:  
 
Avoid strong CYP3A inhibitors, i.e., clarithromycin, indinavir, itraconazole, ketoconazole, 
lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, 
telithromycin, and voriconazole. Avoid grapefruits and grapefruit juice. If a strong CYP3A inhibitor 
must be co-administered, the dose of venetoclax should be reduced. If the strong inhibitor is 
discontinued, the dose of venetoclax should be increased (after 3 to 5 half-lives of the inhibitor) to 
the dose used prior to initiation of the strong inhibitor. 
 
Avoid strong CYP3A inducers, i.e., phenytoin, rifampin, enzalutamide, and St John’s wort. 
 
Avoid P-gp inhibitors, i.e., amiodarone, carvedilol, clarithromycin, dronedarone, itraconazole, 
lapatinib, lopinavir and ritonavir, propafenone, quinidine, ranolazine, ritonavir, saquinavir and 
ritonavir, telaprevir, tipranavir and ritonavir, verapamil. 
 
Avoid P-gp substrates with narrow therapeutic index, i.e., amitriptyline, carbamazepine, clonidine, 
ciclosporin, digitoxin, digoxin, imipramine, phenobarbital, phenytoin, quinidine. 
 
Your regular prescribers should look at these websites: https://www.crediblemeds.org 
http://medicine.iupui.edu/clinpharm/ddis/table.asp to see if any medicine they want to prescribe 
is on a list of drugs to avoid. Your study doctor may also have a list of medications for you to show 
your regular prescribers instead of, or in addition to, this website.   
 
Eating grapefruit, grapefruit containing products, Seville oranges (including marmalade made with 
Seville oranges), and starfruit is prohibited while you are taking venetoclax as these may increase 
the amount of venetoclax in your blood. Please discuss any questions about prohibited foods with 
your study doctor.  


 
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Other medicines can be a problem with your study drugs. 
o 
You should check with your doctor or pharmacist whenever you need to use an over-the-
counter medicine or herbal supplement. 
o 
Your regular prescriber should check a medical reference or call your study doctor before 
prescribing any new medicine for you. Your study doctor’s name is _______________ and he or she 
can be contacted at _______________________. 
 
 
 
 
 
 
 
 
 
 
 
 
 


Aprea Therapeutics  
Protocol Number A20-11197  
Phase 1 Study of APR-246 with 
Venetoclax-Based Therapy in NHL 
 
1197_CSP_7.0 
 
1 of 107 
Confidential - Entire Page 
Phase 1 Study of APR-246 in Combination with Venetoclax and Rituximab Therapy in 
Patients with Richter’s Transformed Non-Hodgkin’s Lymphomas 
 
 
Protocol No.: 
A20-11197 
 
IND No.: 
147956 
 
 
 
 
 
Sponsor: 
Aprea Therapeutics, Inc. 
 
 
 
 
 
 
 
Responsible Medical Officer: 
Eyal C. Attar, M.D. 
 
 
Medical Monitor: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This document contains strictly confidential information and cannot be disclosed or used, 
unless authorized in writing by Aprea Therapeutics, Inc.