Conditions: Platinum Sensitive Recurrent High-grade Serous Ovarian Cancer With Mutated p53
Keywords: Ovarian cancer Ovarian carcinoma High Grade Serous Ovarian Cancer Recurrent Cancer Resistant Cancer
Allocation: RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 247
Healthy volunteers: no

Brief summary:
The purpose of this study is to make a preliminary assessment of the efficacy of a combined APR-246 and carboplatin/PLD chemotherapy regimen, compared with carboplatin/PLD chemotherapy regimen alone, in patients with platinum sensitive recurrent high grade serous ovarian cancer (HGSOC) with mutated p53. In addition, the study aims to assess the safety profile of the combined APR-246 and carboplatin/PLD chemotherapy regimen compared with carboplatin/PLD chemotherapy regimen alone, to evaluate potential biomarkers, and to assess the biological activity in tumor and surrogate tissues. The trial will enroll up to a maximum of 400 patients.

Detailed description:

Arms:
arm 1: Dose escalation of APR-246. arm 2: Experimental arm 3: Active Comparator arm 4: Dose escalation of APR-246. arm 5: Dose escalation of APR-246.

Interventions: intervention 1: APR-246 intervention 2: Carboplatin and Pegylated Liposomal Doxorubicin Hydrochloride (PLD)
Intervention descriptions: intervention 1: Intravenous infusion. intervention 2: Intravenous infusion.

Protocol document:
Prot_SAP_000.pdf: 
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STUDY PROTOCOL 
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a
Phase Ib/II Study of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination
Chemotherapy With or Without APR-246
Protocol No.:
APR-407
EudraCT No.:
2013-001472-38
IND No.:
124,841
Coordinating Investigator:
John A Green
Department of Molecular and Clinical Cancer Medicine
Institute of Translational Medicine
University of Liverpool
Clatterbridge Centre for Oncology
Bebington
Merseyside CH63 4JY, UK
+44 (0)151 482 7793
Sponsor:
Aprea Therapeutics AB   
Nobels väg 3
SE-171 65 Solna
Sweden
+46 (0)8 50884504
Medical Monitor:
Theradex® (Europe) Ltd.
2nd Floor, the Pinnacle
Station Way, Crawley
West Sussex, RH10 1JH, UK
+44 (0)1293 510 319
Current Version:
Version 11.0 
Date:
16 August 2017
CONFIDENTIAL
This document contains strictly confidential information and cannot be disclosed or used, unless 
authorized in writing by Theradex and Aprea Therapeutics AB




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INVESTIGATOR’S STATEMENT
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a
Phase Ib/II Study of Systemic Carboplatin/ Pegylated Liposomal Doxorubicin Combination 
Chemotherapy With or Without APR-246.
This page will be institute specific and should list the investigator that will sign-off the separate protocol 
agreement.
1.
I agree to conduct this study as outlined in the protocol.
2.
I understand that this study will not be initiated without approval of the appropriate 
Institutional Review Committee/Independent Ethics Committee (IRB/IEC), and that all 
administrative requirements of the governing body of the Institution will be complied with 
fully.
3.
Informed written consent will be obtained from all participating patients in accordance with 
institutional guidelines, FDA requirements as specified in Title 21 CFR, Part 50, the 
European Union Directive 2001/20/EC and its associated Detailed Guidances, European 
Union GCP Directive 2005/28/EC, the ICH Guideline for Good Clinical Practice, Section 
4.8, and the terms of the Declaration of Helsinki (2013).
4.
I will enroll patients who meet the protocol criteria for entry.
5.
I understand that my signature on each completed Electronic Case Report Form indicates that 
I have carefully reviewed each page and accept full responsibility for the contents thereof.
6.
I understand that the information presented in this study protocol is confidential, and I hereby 
assure that no information based on the conduct of the study will be released without prior 
consent from the Sponsor unless this requirement is superseded by the Food and Drug 
Administration, a Competent Authority of the European Union or another Regulatory 
Authority.
Investigator Signature
Name:
Title:
Signature
Date
Institution name and address:


Aprea Therapeutics AB
Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
APR-246
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TABLE OF CONTENTS
Page No.
PROTOCOL APPROVAL PAGE ..........................................................................................2
INVESTIGATOR’S STATEMENT........................................................................................3
TABLE OF CONTENTS .........................................................................................................4 
CLINICAL STUDY SYNOPSIS ...........................................................................................10 
LIST OF ABBREVIATIONS ................................................................................................16 
1.0
GENERAL INFORMATION..................................................................................19
1.1
Protocol Number and Title of the Study...................................................................19
1.2
Sponsor .....................................................................................................................19
1.3
Clinical Research Organization ................................................................................19 
1.4
Coordinating Investigator .........................................................................................19 
1.5
Independent Data Monitoring Committee (IDMC)..................................................19 
2.0
INTRODUCTION AND RATIONALE FOR THE STUDY................................21 
2.1
Background Information...........................................................................................21 
2.1.1 General Information .....................................................................................21 
2.1.2 The p53 Protein and APR-246 .....................................................................21 
2.2
Disease Background..................................................................................................22 
2.3
Choice of Patient Population ....................................................................................23 
2.4
Investigational Medicinal Product............................................................................23 
2.5
Preclinical Studies.....................................................................................................24 
2.5.1 Primary Pharmacology of APR-246.............................................................24 
2.5.2 Safety Pharmacology of APR-246 ...............................................................25 
2.5.3 Pharmacokinetics..........................................................................................26 
2.5.4 Toxicology....................................................................................................26 
2.6
Previous Clinical Studies..........................................................................................27
2.7
Rationale for the Current Study................................................................................27 
2.7.1 Preliminary Results from the Current Study, Phase Ib, and Rationale for 
Selected Dose for Phase II Study.............................................................................28 
2.7.1.1
Rationale for a Selected Dose of APR-246...........................................28
2.7.2. Quality of Life Assessment and Rationale for the Selection of the 
Questionnaires..........................................................................................................29 
2.8
Characteristics of a Well-Conducted Trial ...............................................................29 
3.0
TRIAL OBJECTIVES AND ENDPOINTS ...........................................................31 
3.1
Objectives and Endpoints .........................................................................................31 
3.1.1 Primary Objective.........................................................................................31 


Aprea Therapeutics AB
Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
APR-246
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3.1.2
Secondary Objectives ...................................................................................31
3.1.3 Primary Endpoint..........................................................................................31 
3.1.4 Secondary Endpoints....................................................................................31 
4.0
STUDY DESIGN ......................................................................................................33
4.1
Overview of Study Design........................................................................................33
4.2
Randomization/Registration of Patients ...................................................................33
4.3
Shipment of p53 Samples .........................................................................................34 
4.4
Treatment Allocation ................................................................................................34 
4.5
Drug Products ...........................................................................................................34 
4.5.1
Investigational Medicinal Product, APR-246...............................................34
4.5.2
Reference Products Carboplatin and PLD....................................................34
4.6
Duration of Therapy..................................................................................................34 
4.7
End of Study .............................................................................................................34 
4.8
Study Discontinuation by the Sponsor......................................................................34
4.9
Treatment Plan for Patients after the Study..............................................................35 
5.0
SELECTION AND WITHDRAWAL OF PATIENTS .........................................36 
5.1
Inclusion Criteria ......................................................................................................36 
5.2
Exclusion Criteria .....................................................................................................37 
5.3
Withdrawal of Patients and Study Termination........................................................38 
5.4
Compliance with Study Procedures..........................................................................39 
6.0
TREATMENT OF PATIENTS...............................................................................40 
6.1
Drug Supply and Handling Procedures.....................................................................40 
6.1.1 Investigational Medicinal Product, APR-246...............................................40 
6.1.2 Carboplatin ...................................................................................................40 
6.1.3 Pegylated Liposomal Doxorubicin (PLD) Hydrochloride............................40 
6.2
IMP Accountability/Disposition of Clinical Trial Supplies......................................40 
6.3
Method of Assigning Patients to Treatment Groups.................................................41 
6.4
Treatment Administration.........................................................................................42 
6.4.1 Treatment Arm A: APR-246 with carboplatin and PLD..............................42 
6.4.2 Treatment Arm B: Carboplatin and PLD alone............................................43 
6.4.3 Treatment of Adverse Events of the Central Nervous System related to 
APR-246...................................................................................................................43 
6.5
Dose Modifications...................................................................................................44 
6.5.1 Modifications for APR-246 due to Adverse Events during Infusion...........44 
6.5.1.1
APR-246 Infusion and Systemic Chemotherapy Delays......................45
6.5.2 Dose Modifications for Systemic Chemotherapy.........................................45 
6.5.2.1
Hematological Toxicity and Dose Modifications.................................46
6.5.2.2
Non-Hematological Toxicity ................................................................47
6.5.2.2.1
Renal Impairment.............................................................................47
6.5.2.2.2
Hepatic impairment..........................................................................47


Aprea Therapeutics AB
Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
APR-246
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6.5.2.2.3
Cutaneous Toxicity (Palmar-Plantar Erthyrodysesthia (PPE)) ........48
6.5.2.2.4
Stomatitis..........................................................................................48
6.5.2.2.5
Other Grade 3 or 4 Non-hematological toxicities ............................49
6.5.3 Hypersensitivity / Adverse Drug Reactions to Chemotherapy Agents ........49 
6.5.4
Cardiac Safety Monitoring in relation to Treatment with PLD....................50
6.5.5
Action to be taken in the Event of QT/QTc Prolongation............................50
6.6
Concomitant Treatment and Prohibited Medication.................................................50 
6.7
Contraception............................................................................................................51 
7.0
STUDY PROCEDURES ..........................................................................................51
7.1
Schedule of Study Procedures ..................................................................................51
7.2
Detailed Study Evaluations for Arm A and B ..........................................................56
7.2.1 Registration /Informed Consent Form..........................................................56 
7.2.2 Pre-treatment ................................................................................................56 
7.2.3
Randomization..............................................................................................57
7.2.4 All Cycles, Days 1 - 28.................................................................................57 
7.2.5 End of Treatment Visit .................................................................................58 
7.2.6 Follow-up Visits ...........................................................................................59 
7.2.7 After Progression..........................................................................................59 
7.3
Adverse Events .........................................................................................................59 
7.3.1 Definition of Adverse Events .......................................................................59 
7.3.2 Definitions of Serious Adverse Events.........................................................60 
7.3.3 Recording of Adverse Events.......................................................................60 
7.3.3.1
Time Period for Collection of Adverse Events.....................................60
7.3.3.2
Follow-up of Unresolved Adverse Events............................................61
7.3.3.3
Variables ...............................................................................................61
7.3.3.4
Causality Collection..............................................................................62
7.3.3.5
Adverse Events based on Signs and Symptoms ...................................62
7.3.3.6
Adverse Events based on Examinations and Tests...............................62
7.3.3.7
Hy’s Law...............................................................................................62
7.3.3.8
Disease Progression ..............................................................................63
7.3.3.9
New Cancers .........................................................................................63
7.3.3.10 Handling of Deaths ...............................................................................63
7.3.4 Reporting of Serious Adverse Events...........................................................63 
7.4
Pregnancy..................................................................................................................64 
7.4.1 Maternal Exposure........................................................................................64 
8.0
EFFICACY ASSESSMENTS..................................................................................65 
8.1
Definitions.................................................................................................................65 
8.1.1 Measurable Disease......................................................................................65 
8.1.2 Non-measurable Disease ..............................................................................66 
8.1.2.1
Bone Lesions.........................................................................................66


Aprea Therapeutics AB
Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
APR-246
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8.1.2.2
Cystic Lesions.......................................................................................66
8.1.2.3
Lesions with Prior Local Treatment .....................................................66
8.1.3 Target Lesions ..............................................................................................66 
8.1.4 Lymph Node Assessment.............................................................................67 
8.1.5
Non-target Lesions .......................................................................................67
8.2
Guidelines for Evaluation of Measurable Disease....................................................67
8.3
Response Criteria......................................................................................................68 
8.3.1 Evaluation of Target Lesions........................................................................68 
8.3.1.1
Assessment of Target Lymph Nodes....................................................69
8.3.1.2
Target Lesions that Become “Too Small to Measure” .........................69
8.3.1.3
Lesions that Split or Coalesce on Treatment ........................................69
8.3.2 Evaluation of Non-target Lesions.................................................................69 
8.3.2.1
New Lesions..........................................................................................70
8.3.2.2
Evaluation of Best Overall Response by RECIST v1.1........................70
8.3.2.3
Evaluation of Best Overall Response in Patients with Initial 
Measurable Disease and who are also Evaluable by CA-125.............................72
8.3.3 Confirmatory Measurement/Duration of Response......................................73 
8.3.3.1
Confirmation According to RECIST v1.1 ............................................73
8.3.3.2
Definition of Response According to CA-125......................................73
8.3.3.3
Duration of Overall Response...............................................................74
8.3.3.4
Duration of Stable Disease....................................................................74
8.3.4 Progression-free Survival .............................................................................74 
8.3.4.1
According to CA-125..........................................................................................75
8.3.4.2
Evaluation of Progression According to CA-125.................................75
8.4
Pharmacokinetics......................................................................................................76 
8.5
Pharmacodynamics ...................................................................................................77 
8.5.1 Optional Tumor Biopsy................................................................................77 
8.6
Exploratory Biomarker Research..............................................................................78 
8.7
Biological Sample Handling.....................................................................................78 
8.8
Chain of Custody of Biological Samples..................................................................78 
8.9
Withdrawal of Informed Consent for Donated Biological Samples.........................79
9.0
STATISTICS.............................................................................................................80 
9.1
Primary Endpoint......................................................................................................80 
9.2
Secondary Endpoints ................................................................................................80 
9.3
Sample Size...............................................................................................................80 
9.4
Analysis Populations.................................................................................................80 
9.5
Statistical Methods....................................................................................................81 
9.5.1 Safety Analysis.............................................................................................81 
9.5.2 Phase II Analysis ..........................................................................................81 
9.5.2.1
Primary analysis....................................................................................81


Aprea Therapeutics AB
Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
APR-246
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9.5.2.2
Secondary analysis................................................................................82
9.5.3 Pharmacokinetic Analysis ............................................................................82 
9.6
Randomization/Stratification....................................................................................83 
9.7
Statistical Modeling for Interim Analyses ................................................................83 
9.7.1
Control Hazard Model..................................................................................83
9.7.2
Model............................................................................................................84
9.7.3 Quantities of Interest ....................................................................................84 
9.7.3.1
Probability Superior to Control by the Target HR................................84
9.7.3.2
Predictive Probability of Success..........................................................84
9.8
Adaptive Sample Size...............................................................................................85
9.8.1
Timing of Interim Analyses..........................................................................85
9.8.2 Allocation .....................................................................................................85 
9.8.3 Criteria for Stopping Accrual .......................................................................85 
9.8.3.1
Stopping for predicted success..............................................................85
9.8.3.2
Stopping for Small Observed Effect.....................................................85
9.8.3.3
Stopping Boundaries.............................................................................86
9.8.4 Operating Characteristics .............................................................................86 
10.0
QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES.........87 
10.1 Monitoring of the Study and Regulatory Compliance..............................................87 
10.2 Curricula Vitae of Investigators................................................................................87 
10.3 Protocol Modifications..............................................................................................87 
10.4 Publication Policy.....................................................................................................87 
11.0
ETHICAL CONSIDERATIONS ............................................................................88 
11.1 Informed Consent......................................................................................................88 
11.2 Institutional Review Board/Independent Ethics Committee/Regulatory..................88 
11.3 Patient Privacy ..........................................................................................................88 
12.0
DATA HANDLING AND RECORD KEEPING...................................................89 
12.1 Data to be Recorded Directly in the Case Report Form ...........................................89 
12.2 Recording of Data.....................................................................................................89 
12.3 Study Records...........................................................................................................89 
13.0
REFERENCES .........................................................................................................90 
Appendix I: ECOG Performance Status ..............................................................................91 
Appendix II: New York Heart Association Heart Failure Classification..........................92 
Appendix III: Further Guidance on the Definition of a Serious Adverse Event and 
Interpreting the Causality Question .....................................................................................93 
Appendix IV: Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law..........................................................................................................95 


Aprea Therapeutics AB
Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
APR-246
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Appendix V: Statistical Appendix.........................................................................................99 
Appendix VI: GCIG CA-125 Response Definition ............................................................100 
Appendix VII: QOL Questionnaires...................................................................................101 


Aprea Therapeutics AB
Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
APR-246
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CLINICAL STUDY SYNOPSIS
Name of Sponsor:
Aprea Therapeutics AB
Nobels väg 3
SE-171 65 Solna
Sweden
Study phase:
Phase Ib/II Study 
Name of finished product:  APR-246, concentrate for solution for infusion
Name of active ingredient: 2-(hydroxymethyl)-2-(methoxymethyl)-1-azabicyclo[2,2,2]octan-3-one
Title of the study: PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a 
Phase Ib/II Study of Systemic Carboplatin/ Pegylated Liposomal Doxorubicin (PLD) Combination Chemotherapy 
With or Without APR-246.
Investigators and study centers:
Please see Study Operations Manual
Publication (reference): To be confirmed
Clinical phases: Phase Ib/II Study
Study Design:
This study is an open-label, randomized, multi-center Phase II proof-of-concept study with a dose confirmation 
component (dose confirmation component now completed) to assess whether patients with platinum sensitive 
recurrent p53 mutated high grade serous ovarian cancer (HGSOC) will benefit from treatment with APR-246 in 
combination with a carboplatin/pegylated liposomal doxorubicin (PLD) chemotherapy regimen.  
All patients will have pre-screening immunohistochemistry (IHC) test that will determine p53 status and therefore 
the suitability to participate in this study. Patient’s archived sections from the original tumor sample will be 
reviewed by a gynecological pathologist to confirm the diagnosis of HGSOC, and positive staining for p53. 
Patients without positive p53 staining will not be included.
Patients will be randomly assigned in a 1:1 ratio to receive either:
Arm A: APR-246 with the carboplatin/PLD chemotherapy regimen, 
Arm B: Carboplatin/PLD chemotherapy alone. 
The trial will enroll up to a maximum of 400 patients with positive IHC staining for p53. A CT scan/MRI using 
RECIST v1.1 criteria will be performed at pre-treatment, after 2 cycles (8 weeks), 4 cycles (16 weeks), and after 
the last cycle (24 weeks).


Aprea Therapeutics AB
Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
APR-246
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At subsequent follow-up visits, tumor assessments by CT scan/MRI will be performed 2 months (± 2 weeks) after 
the end of treatment visit and every 3 months (± 2 weeks) thereafter, until the documented disease progression, as
determined by the Investigator at each site and defined by RECIST v1.1. 
Optional frozen/fixed core biopsies will be undertaken after randomization, but prior to any infusion, for all 
patients and on day 3 in APR-246 patients.
Objectives, Endpoints and Study Treatment:
Objectives:
Primary Objective:
To assess the efficacy of a combined APR-246 and carboplatin/PLD chemotherapy regimen in patients with 
platinum sensitive recurrent HGSOC with mutated TP53.
Secondary Objective:
To assess the safety profile of the combined APR-246 and carboplatin/PLD chemotherapy regimen compared 
with carboplatin/PLD chemotherapy regimen alone.
To evaluate potential biomarkers.
To assess the biological activity in tumor and surrogate tissues.
To compare quality of life of patients treated with these regimens.
Endpoints:
Primary Endpoint
Progression-free survival (PFS) based on Blinded Independent Central Review (BICR) is the primary 
endpoint and is defined as the number of days from the date of randomization to the date of objective disease 
progression or relapse (according to RECIST v1.1 only) or death due to any cause, whichever occurs first. If 
neither event occurs, PFS will be censored at the date of the last evaluable tumor assessment. Symptomatic 
deterioration is not objective disease progression.  
Secondary Endpoints
Best overall response and overall response rate (according to RECIST v1.1 and GCIG criteria)
Duration of response (complete or partial response) 
PFS by assessment of CA-125 (according to GCIG Criteria)
Overall survival
Safety profile based on AEs and laboratory assessments 
Evaluation of biomarkers and tumor activity based on CA-125
Quality of Life assessment using EORTC Ovarian (QLQ-30 and QLQ-OV28) and the Functional Assessment 
of Cancer Therapy-Ovarian (FACT-O)
Tumor response data will be summarized at each tumor assessment cycle using the following response categories: 
Complete Response (CR), Partial Response (PR), Stable Disease (SD), Progressive Disease (PD) and Non-
Evaluable (NE). Best overall response for a patient is the best response recorded from the start of the treatment 
until disease progression or death. Best overall response will be summarized as the number (%) of patients in each 
category of response (CR, PR, SD, PD, and NE). PR and CR must be confirmed by a repeat assessment at least 28 
days after the criteria are first met for the response to be considered a PR or CR.


Aprea Therapeutics AB
Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
APR-246
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The overall response rate is defined as the percentage of patients with a confirmed response of CR or PR in a 
given population.
The duration of response (confirmed CR or PR) is defined as the number of days from the date of initial response 
(not the confirmation date) to the date of objective disease progression or death due to any cause, whichever 
occurs first. If neither event occurs, duration of response will be censored at the date of the last evaluable tumor 
assessment. Symptomatic deterioration is not objective disease progression.
Overall survival (OS) is defined as the number of days from the date of randomization to the date of death. In the 
event of no death, overall survival will be censored at the last known alive date.
Study Treatment:
Arm A (APR-246). Patients will receive a fixed dose of 4.5 g APR-246 (1.5 g of the dose during first 45 minutes 
followed by 3 g of the dose during 5 hours 15 minutes) on Days 1 to 4, with carboplatin AUC 5 and 
PLD 30 mg/m2 administered concurrently on Day 4 (treatment repeated every 28 days for up to six cycles).
Arm B (Control). Carboplatin AUC 5 and PLD 30 mg/m2 administered on Day 1 of each 28-day cycle, repeated 
for up to six cycles.
Number of patients:
The trial will enroll up to a maximum of 400 patients with positive IHC staining for p53.
Diagnosis and main criteria for inclusion: 
Inclusion criteria:
1.
Archived sections from the original FFPE sample reviewed by a gynecological pathologist confirming 
High Grade Serous Ovarian Cancer, High Grade Serous Peritoneal Cancer or Primary Fallopian Tube 
Cancer, and positive IHC staining for p53 assessed according to defined standard (as detailed in the 
laboratory manual). Cases that do not show p53 staining will not be included.
2.
Radiologically-confirmed Disease Progression between six and twenty-four (6-24) months after a first or 
second platinum based regimen.  
3.
At least a single (RECIST v1.1) measurable lesion.
4.
Adequate organ function prior to registration:
a)
Bone Marrow Reserve:
x109/L,
x109/L,
g/dL.
b)
Hepatic: 
Total bilirubin level < 1.5 x ULN,
ALT and AST < 2.5 x ULN.
c)
Renal: 
Calculated creatinine clearance > 30 mL/min.
d)
Electrolytes 
Potassium within institutional normal ranges.


Aprea Therapeutics AB
Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
APR-246
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5.
Toxicities from previous cancer therapies, excluding alopecia, must have recovered to grade 1 (defined by 
CTCAE version 4.0). Chronic stable grade 2 peripheral neuropathy secondary to neurotoxicity from prior 
therapies may be considered on a case by case basis by the Principal Investigator.
6.
If of childbearing potential, negative pre-treatment serum pregnancy test.
7.
If of childbearing potential, willing to use an effective form of contraception (see below) during 
chemotherapy treatment and for at least six months thereafter.
Such methods include: (if using hormonal contraception this method must be supplemented with a barrier 
method, preferably male condom).
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of
ovulation:
o
Oral
o
Intravaginal
o
Transdermal
Progestogen-only hormonal contraception associated with inhibition of ovulation:
o
Oral
o
Injectable
o
Implantable 
Intrauterine device (IUD) 
Intrauterine hormone-releasing system (IUS)
Bilateral tubal occlusion 
Vasectomized partner 
True sexual abstinence when this is in line with the preferred and usual lifestyle of the patient. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of 
abstinence for the duration of a trial, and withdrawal are not acceptable methods of contraception.
Male condom with spermicide (female condom and male condom should not be used together)
8.
ECOG performance status of 0 to 1 (Appendix I).
9.
10. Written informed consent obtained prior to any screening procedures and in accordance with federal, 
local, and institutional guidelines.
11. Patient has exhausted all available treatments, including surgery, and is considered a suitable candidate to 
receive carboplatin/PLD.
Exclusion criteria:
1.
Prior exposure to cumulative doses of doxorubicin >400 mg/m2 or epirubicin >720 mg/m2.
2.
Confirmed cardiac history of any of the following: 
a)
Myocardial infarct within six months prior to registration,
b)
New York Heart Association Class II or worse heart failure (Appendix II), 
c)
A history of familial long QT syndrome,
d)
Clinically significant pericardial disease, 


Aprea Therapeutics AB
Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
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e)
Electrocardiographic evidence of acute ischemia, 
f)
Symptomatic atrial or ventricular arrhythmias not controlled by medications,
g)
Fridericia’s  correction (QTcF = QT/RR0.33),
h)
Bradycardia (< 40bpm),
i)
Left ventricular ejection fraction (LVEF) < the institution lower limit of normal as assessed by 
ECHO.
3.
Major abdominal surgery or peritonitis within six weeks prior to study treatment.
4.
Unresolved bowel obstruction, sub-occlusive disease or the presence of brain metastases.
5.
History of uncontrolled allergic reactions to carboplatin, platinum containing compounds or mannitol 
and/or hypersensitivity to PLD or to any of the excipients.
6.
Unable to undergo imaging by either CT scan or MRI.
7.
Evidence of any other medical conditions (such as psychiatric illness, infectious diseases, neurological 
conditions, physical examination or laboratory findings) that may interfere with the planned treatment, 
affect patient compliance or place the patient at high risk from treatment related complications.
8.
Breast feeding.
9.
Concurrent malignancy requiring therapy (excluding non-invasive carcinoma or carcinoma in situ).
10. Patients requiring or undergoing concurrent treatment with live vaccines.
11. Patients requiring or undergoing concurrent treatment with phenytoin.
12. Known HIV positive status, active hepatitis B or C status.
13. Is taking any concurrent (or within 4 week prior to registration) anti-cancer therapy, immunotherapy, 
radiotherapy or any ancillary anti-cancer therapy; or any therapy that is considered to be investigational 
(i.e., used for non-approved indications(s) and in the context of a research investigation). Supportive care 
measures are allowed.
14. Patients unable to be regularly followed for any reason (geographic, familiar, social, psychological, 
housed in an institution e.g., prison because of a court agreement or administrative order). Patients who
are dependent on the sponsor/CRO or investigational site as well as on the Investigator.
Test product, dose and mode of administration:
Patients will receive a fixed dose of 4.5 g APR-246 (1.5 g of the dose during first 45 minutes followed by 3 g of 
the dose during 5 hours 15 minutes) if randomized to Arm A.
In all cycles, APR-246 will be administered as a 6-hour infusion daily for four consecutive days (Study Day 1 to 
Day 4).  Carboplatin and PLD will be administered on Day 4 at the same time as the final infusion of APR-246. 
Carboplatin followed by PLD administration should commence 2-hours after the start of the APR-246 infusion.
Further administration of APR-246 (repeated in 28-day cycles) will commence three days prior to subsequent 
chemotherapy cycles, with the fourth dose administered the same day as the chemotherapy.


Aprea Therapeutics AB
Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
APR-246
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Treatment Administration for Patients Receiving APR-246 (Arm A)
Duration of treatment: 
Patients will receive up to six 28-day cycles of the carboplatin/PLD chemotherapy regimen with or without 
APR-246.
Reference therapy, dose and mode of administration:  
Patients randomized to Arm B will not receive APR-246.
Carboplatin and PLD will be administered on Day 1 as per hospital practice. Cycles will be repeated every 28 
days for up to six cycles.
Criteria for evaluation:  
Efficacy:  Patients with measurable disease will be assessed using RECIST (v1.1) criteria and GCIG CA-125
Criteria.
Safety: AEs will be collected throughout the study, from informed consent until 30 days after the last 
administration of study treatment. AEs will be graded according to NCI CTCAE version 4.0. Serious adverse 
events (SAEs) will be reported according to Directive 2001/20/EC and 2005/28/EC and the ICH GCP guidelines.
Sample size calculation:
The phase II portion of this study has a flexible sample size. The purpose is to use a smaller sample size with very 
small or very large observed effect sizes, and a larger sample size where observed effect sizes are promising but 
more data are needed. For small observed effect sizes (with typically smaller sample sizes), the study results will 
have traditional phase II interpretations. However, for moderate/large observed effect sizes (with potentially larger 
sample sizes), the design is intended to provide sufficient evidence to justify regulatory conditional approval.
Study Day -1 1
2
3
4
5
6
7
8
27 28 29 30 31 32 33 34
Carbo/PLD
APR-246 6 hr IV 
infusion per day
Carbo/PLD
APR-246 6 hr IV 
infusion per day


Aprea Therapeutics AB
Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
APR-246
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LIST OF ABBREVIATIONS
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
AML
Acute Myeloid Leukemia
ANC
Absolute Neutrophil Count
APTT
Activated Partial Thromboplastin Time
AST
Aspartate Aminotransferase
AUC
Area Under the Curve
BICR
Blinded Independent Central Review
BW
Body weight
CA-125
Cancer Antigen 125
CD
Candidate Drug
CLL
Chronic Lymphocytic Leukemia
Cmax
Maximal Plasma Concentration
CNS
Central Nervous System
CR
Complete Response
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
DILI
Drug-induced Liver Injury
DNA
Deoxyribonucleic acid
DSMB
Data and Safety Monitoring Board
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EOC
Epithelial Ovarian Cancer
FDA
U.S. Food and Drug Administration
FFPE
Formalin Fixed Paraffin Embedded
GCIG
Gynecologic Cancer Intergroup
GCP
Good Clinical Practice
GFR
Glomerular Filtration Rate
GMP 
Good Manufacturing Practice
HIV
Human Immunodeficiency Virus
HGSOC
High Grade Serous Ovarian Cancer
HL
Hy’s Law
HR
Hazard Ratio
IB
Investigator’s Brochure
IC50
Inhibitory Concentration 50%
ICH
International Council for Harmonization
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee


Aprea Therapeutics AB
Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
APR-246
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IHC
Immunohistochemistry
IMP
Investigational Medicinal Product
INR
International Normalized Ratio
IRB
Institutional Review Board
IUD
Intrauterine Device
IUS
Intrauterine Hormone-releasing System 
IV
Intravenous
IWRS
Interactive Web Response System
LBM
Lean Body Mass
LD
Longest Diameter
LDH
Lactate Dehydrogenase
LVEF
Left Ventricular Ejection Fraction
MedDRA
Medical Dictionary for Regulatory Activities
MHRAUK Medicine and Healthcare Products Regulatory Agency
MQ
Methylene Quinuclidinone
MRI
Magnetic Resonance Imaging
MUGA
Multi Gated Acquisition Scan
NCI
National Cancer Institute
NOAEL
No Observed Adverse Effect Level
OS
Overall Survival
PARP
Poly (adenosine diphosphate [ADP]) Ribose Polymerase 
PD
Progressive Disease
PFI
Platinum-free Interval
PFS
Progression-free survival
PH2RD
Phase II Recommended Dose
PHL
Potential Hy’s Law
PiSARRO
P53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer
PLD
Pegylated Liposomal Doxorubicin 
PPE
Palmar-Plantar Erthyrodysesthia
PPoS
Predicted Probability of Success 
PR
Partial Response
PRIMA
p53 Reactivation and Induction of Massive Apoptosis
QoL
Quality of Life
RECIST
Response Evaluation Criteria In Solid Tumors
SAE
Serious Adverse Event
SaOS-2
Osteosarcoma Cell Line
SD
Stable Disease
TEAE
Treatment-emergent Adverse Event
Tid
Three Times Daily
ULN 
Upper Limit of Normal
ULRR
Upper Limit of Response Range
US
United States
WBC
White Blood Cell Count


Aprea Therapeutics AB
Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
APR-246
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WHO
World Health Organization
Wt
Wild Type


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Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
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1.0
GENERAL INFORMATION
1.1
Protocol Number and Title of the Study
APR-407 PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a 
Phase Ib/II Study of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination 
Chemotherapy With or Without APR-246.  
1.2
Sponsor
This study is being Sponsored by Aprea Therapeutics AB.
Aprea Therapeutics AB
Nobels väg 3
SE-171 65 Solna 
Sweden
Tel.:+46(0)8-50884504
Fax: +46(0)8-52487022
1.3
Clinical Research Organization
Theradex® (Europe) Ltd
2nd Floor, The Pinnacle
Station Way, Crawley
West Sussex
RH10 1JH, UK
Tel.: +44 (0)1293 510 319
Fax: +44 (0)1293 510 322
1.4
Coordinating Investigator 
John A Green
Department of Molecular and Clinical Cancer Medicine
Institute of Translational Medicine
University of Liverpool
Clatterbridge Centre for Oncology
Bebington
Merseyside CH63 4JY, UK
Tel.: +44 (0)151 482 7793
1.5
Independent Data Monitoring Committee (IDMC)
An Independent Data Monitoring Committee (IDMC) will review and evaluate safety data and
reports on cumulated serious adverse events (SAEs). Based on this review the IDMC should provide 


Aprea Therapeutics AB
Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
APR-246
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recommendations to the Sponsor regarding the ongoing scientific and ethical integrity of the study 
and in reference to the study protocol. The members of the IDMC serve in an individual capacity 
and provide their expertise and recommendations. The IDMC Charter will outline the roles and 
responsibilities and serve as the Standard Operating Procedure (SOP) for the IDMC.
The safety and well-being of the trial participants are the most important considerations and should 
prevail over the interests of the science and society.


Aprea Therapeutics AB
Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
APR-246
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2.0
INTRODUCTION AND RATIONALE FOR THE STUDY
2.1
Background Information
2.1.1
General Information
Aprea Therapeutics AB was founded in 2003 by the inventors, Klas Wiman, Galina Selivanova, 
Vladimir Bykov, Staffan Strömblad, Wenjie Bao and Natalia Issaeva together with Karolinska 
Innovations AB. The company is aiming to develop target specific drugs for the treatment of cancer 
by restoration of p53 function. Such treatment should induce massive apoptosis and thus eliminate 
the tumor.
The company has identified molecules that via p53-dependent pathways induce apoptosis in cancer 
cells with mutant or wild type p53. Aprea Therapeutics AB has since its inception confirmed the 
data in house and has screened for novel substances. The compound APR-246 has been selected as 
the company’s first candidate drug (CD).
2.1.2
The p53 Protein and APR-246
P53 was discovered in 1979 as a cellular protein that forms a complex with the viral large T protein 
in SV40-infected cells. Later studies showed that p53 was a tumor suppressor which could inhibit 
cell growth and trigger cell death by apoptosis. TP53, the p53 gene is mutated in almost half of all 
human tumors. The p53 status of a tumor may have a strong impact on sensitivity to commonly used 
anti-cancer drugs and radiotherapy [1]. Thus, p53 is an important clinical marker and also a novel 
therapeutic target. In contrast to other tumor suppressor genes, TP53 is typically inactivated by 
single missense mutations, which is accompanied by loss of the remaining wild type allele. As a 
rule, mutant p53 proteins are deficient for specific DNA binding suggesting that DNA binding and 
transcriptional regulation of target genes are critical functions for p53-mediated tumor suppression
[2].
The fact that TP53 is mutated in around 50% of human tumors, that mutant p53 protein usually 
accumulates at high levels, and that mutant p53-expressing tumors respond poorly to conventional 
therapy makes mutant p53 an attractive target for novel cancer therapy [3]. In hematological
malignancies, between 5 and 20% of the patients carry a TP53 mutation in their malignant cell 
clone. However, for the current indication more than 95% of patients with High Grade Serous 
Epithelial Ovarian Cancer (HGSOC) carry TP53 mutations [4].
Recent studies have demonstrated that restoration of p53 in p53-deficient mouse tumors triggers 
rapid and efficient elimination of the tumor through cell cycle arrest, senescence and/or apoptosis 
[5]. This supports the idea that pharmacological reactivation of p53 should allow efficient 
elimination of tumors with minimal effects on normal cells.
The small molecule PRIMA-1 (later denoted APR-017) was identified in a cellular screen for 
compounds that preferentially induce apoptosis in human tumor cells expressing exogenous mutant 
p53. Optimization of APR-017 resulted in the structural analogue APR-246, the IMP for this study. 
Treatment with APR-246 has been shown to restore sequence specific DNA binding wild type 


Aprea Therapeutics AB
Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
APR-246
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conformation and transcriptional transactivation to mutant p53 protein. Furthermore, APR-246 has 
been shown to synergize with the DNA damaging anti-cancer agents, including platinum
compounds and doxorubicin (See IB).
2.2
Disease Background
Ovarian cancer is the seventh most commonly diagnosed cancer among women in the world,
accounts for an estimated 239,000 new cases and 152,000 deaths worldwide annually [6]. Ovarian 
cancer has been of considerable interest to clinical cancer investigators due to the fact that it is 
among the most chemosensitive of all solid tumors [7]. It is frequently platinum sensitive initially 
and even in advanced disease the accepted management is a combination of surgery and platinum 
based chemotherapy.
Despite the evolution of surgical techniques and ever improving chemotherapy regimens, relapse 
and consequential disease progression remains the most challenging task. Screening has not yet 
proven an effective tool to diagnose patients at an earlier stage in their disease and late diagnosis is 
associated with relapse and death after repeated treatment cycles. The 5 year survival rate remains 
poor at less than 40% and this has remained unchanged for the last 20 years [6]. Thus, there is a 
need for improved treatment of relapsed ovarian cancer. The combination of carboplatin and 
pegylated liposomal doxorubicin is widely used in Europe following results of the multicenter phase 
III CALYPSO study which demonstrated non-inferiority of this combination over the standard 
carboplatin and paclitaxel combination arm in terms of PFS (11.3 months versus 9.4) with lower 
rates of severe and long-lasting side effects [8].
Despite rapid scientific advances in the last decades, it has proved difficult to improve outcomes 
beyond platinum-based therapy introduced in the late 1970s. Cisplatin, and subsequently carboplatin 
has been combined with other agents, especially taxanes to form the backbone of current treatment 
regimes. The combination is effective in first-line, platinum sensitive ovarian cancer, but 
unfortunately since most patients are diagnosed late, recurrence is common. Drug resistance does 
eventually develop due to repeated treatment with the same drugs. With each relapse, the response 
to treatment decreases with lower quality of life.
The median survival time for patients with advanced HGSOC is approximately 44 months. In 
platinum-sensitive cancer, tumor response to first line platinum-based treatment lasts at least 6 
months following initial treatment. In the first line setting, carboplatin, generally in combination 
with a taxane provides impressive results with about a 70% response rate. Patients are retreated at 
relapse with platinum unless the cancer is platinum resistant (i.e. tumor progression within 6 months 
after completing first line treatment). Unfortunately almost 50% of Epithelial Ovarian Cancer (EOC)
patients will relapse within 18 months and 75% by 30 months. The likelihood that a patient will 
respond to the reintroduction of a platinum-based regimen depends on the platinum-free interval 
(PFI), defined as the interval between the last dose of platinum and the time of relapse. Thus, fewer 
patients with a PFI of 6–12 months are expected to respond to the reintroduction of platinum-based 
chemotherapy, compared with patients with a PFI of 18–24 months.
As the majority of patients with advanced ovarian cancer will eventually relapse with incurable and 
terminal disease, there is significant unmet need for improved tools to aid earlier diagnosis and also 


Aprea Therapeutics AB
Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
APR-246
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for establishing more effective alternative treatment options for the late stage resistant patient 
population. As such, there is a need for better first-line therapies that may delay or prevent relapse 
and improve survival rates. An unmet need also exists in the setting of recurrent disease, where 
currently used therapies have little impact on survival. As such the addition of a new drug on the 
market to current standard of care may impact significantly on patient management, given the 
current lack of effective treatment options once patients relapse.
High Grade Serous Ovarian Cancer (HGSOC) accounts for approximately 70% of malignant
ovarian surface epithelial carcinoma in Europe and North America [9]. Mutant TP53 is a hallmark 
of HGSOC, resulting in deregulation of cell cycle checkpoints and uncontrolled tumor cell 
proliferation and thus represents a key driver event. Pathogenic TP53 mutations have been quoted as 
occurring in up to 96% of patients with HGSOC [4]. Rearrangements in TP53 have been shown to 
correlate significantly with resistance to chemotherapy, early relapse and shortened overall survival.
Almost 90% of HGSOC initially present as advanced-stage (stage III of IV) disease [10] thus 
spreading outside the pelvic cavity hence accounting for low median survival times. There is a need 
for improved treatment of HGSOC since present therapies have little impact on survival. APR-246
may offer such an opportunity since it has been shown to induce apoptosis and cell death in cancer 
cells with mutant or otherwise non-functional p53, and in addition to display strong synergistic 
anticancer effects in combination with several conventional chemotherapeutic drugs including 
platinum drugs and doxorubicin.
2.3
Choice of Patient Population
The study population will include patients with platinum sensitive recurrent TP53 mutated HGSOC 
(defined as those patients whose cancer recurs after more than 6 months, but less than 24 months 
since completion of platinum-based chemotherapy), who in the Investigator’s opinion require 
further treatment with combination carboplatin/PLD systemic chemotherapy (stage III-IV). Relapse 
should be verified radiologically and/or by CA-125 using Gynecological Cancer Intergroup (GCIG)
criteria.
2.4
Investigational Medicinal Product
APR-246, 2-hydroxymethyl-2-methoxymethyl-1-azabicyclo [2,2,2] octan-3-one is also called 
PRIMA-1Met in the literature, where PRIMA is an acronym for p53 reactivation and induction of 
massive apoptosis (see IB).
The APR-246 compound has a molecular weight of 199.24 g/mol, is a racemic mixture and is 
isolated as a white powder. The structure of APR-246 can be seen in Figure 1 below.


Aprea Therapeutics AB
Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
APR-246
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OH
N
O
OMe
Figure 1. Structure of APR-246
The IMP should be stored at 2-8 C. The IMP is a concentrated solution which should be diluted 
with sterile 0.9% NaCl solution for infusion before administration. The solution for infusion should 
be prepared with the prescribed dosage for each patient in accordance with the protocol and separate 
technical instruction. After preparation of the ready to use solution for infusion the pH of the 
solution will range from slightly above 4 up to approximately 4.8, depending on dosage. The 
infusion will be slightly hypertonic. The prepared APR-246 study product is to be stored at not more 
than 25 C. The infusion to the patient should be finalized within 24 h from the time of preparation.
APR-246 is a prodrug that is converted to the active compound methylene quinuclidinone (MQ),
responsible for the anticancer effects of APR-246. Ample evidence shows that APR-246 in 
physiological conditions is converted to MQ, which has been shown to bind to cysteines in mutant 
unfolded p53 pushing the protein towards a functional wild type conformation.
2.5
Preclinical Studies
Please refer to the IB for full details.
2.5.1
Primary Pharmacology of APR-246
APR-246 has demonstrated efficacy in various preclinical in vitro, ex vivo, and in vivo cancer 
models, as single substance as well as in combination with several conventional chemotherapeutics. 
In many of these models APR-246 has shown good potency and efficacy and unique 
pharmacological profile in comparison with conventional chemotherapeutic drugs.
APR-246 reduced cell viability in a dose-dependent manner being more potent in SaOS-2-His273 
cells, expressing mutant p53 than in TP53 null cells (lacking p53 expression). It also reduced cell 
viability in a large number of other cancer cell lines with different TP53 status. In ex vivo
experiments with primary cancer cells from patients with acute myeloid leukemia (AML) and 
ovarian cancer, APR-246 reduced cell viability and, in contrast to conventional drugs, was effective 
also in TP53 mutant cancer cells.
A large number of solid cancer cell lines with various cisplatin sensitivity and TP53 status, were 
investigated in combination studies with APR-246 and cisplatin. In the various resistant cell lines 
tested, platinum compounds and doxorubicin showed resistance while the sensitivity for APR-246 
was considerably less affected. Strong synergistic (CI<0.5) effects with APR-246 were observed in 
all cell lines with homozygous hotspot TP53 mutations. These cell lines showed high levels of 


Aprea Therapeutics AB
Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
APR-246
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mutant p53 protein. Synergistic (CI<0.8) or strong synergistic (CI<0.5) effects were observed in 
cancer cell lines with frequently occurring TP53 mutations accumulating moderate levels of mutant
p53. Variable rather than strong synergistic combination effects were observed in the cell lines with 
wild type (wt) p53 and in those in which full length p53 protein is not detectable.
These results are consistent with the proposed dual mechanisms of action of APR-246, and show 
that APR-246 can exert anticancer effects both in cells carrying wt p53 and cells carrying mutant 
p53. Hence, both p53 dependent and independent apoptotic effects contribute to APR-246 efficacy.
Strong synergistic effects were also observed with APR-246 and cisplatin in the OVCAR-3 cell line, 
a cisplatin-resistant ovarian carcinoma cell line, carrying the TP53 hotspot mutation R248Q. 
APR-246 resensitized the OVCAR-3 cancer cells to cisplatin as well as to the anthracycline
doxorubicin; the IC50 value of cisplatin was decreased 5-fold. 
Strong synergistic effects of APR-246 and the DNA-damaging compound doxorubicin were also 
seen in the doxorubicin-resistant A2780ADR ovarian cancer cell line. 
Strong synergy between cisplatin and APR-246 was furthermore shown in a number of primary 
cancer cells from ovarian cancer patients. 
An additive, close to synergistic effect (CI=0.82) in terms of antitumor efficacy was observed with 
APR-246 in combination with cisplatin in a xenograft study using the A2780-CP20 cell line, an 
aggressively growing cisplatin-resistant TP53 mutant ovarian cancer cell line. Ex vivo
immunohistochemical analysis of the tumors showed an increase of active caspase-3 positive cells
confirming that APR-246 induced apoptosis.
2.5.2
Safety Pharmacology of APR-246
APR-246 has been investigated for core safety pharmacology endpoints. The compound induced 
clinical signs indicating adverse reactions on CNS and the respiratory function, after bolus injection 
to mice or as short-term infusion in dogs. These effects were observed in direct connection with the 
dosing and were transient, with a rapid and full recovery after the end of the infusion or after the 
interruption of a non-tolerated dose at a stage of moderate CNS-related clinical signs. Irwin and 
rotarod tests in mice indicate that the CNS toxicity is due to the active moiety MQ and not to any of 
the two enantiomers of the prodrug APR-246.
The severity of clinical signs was directly correlated to the plasma levels. Independently of dose, 
infusion rate or infusion time the plasma threshold for inducing CNS adverse reactions was at least 
100 µg/mL. The infusion rate of 100 mg/kg/h induced no signs related to CNS or respiratory 
function at 200 mg/kg in two independent studies in dogs. Daily infusion for 9 h in 3 cycles of 7 
days at the rate of 100 mg/kg/h giving a total daily dose of 900 mg/kg/day induced no significant 
adverse reactions related to CNS or respiratory function. There were no cardiovascular effects at any 
dose level in a telemetric study and the hERG study was negative up to 100 µM. At the No 
Observed Adverse Effect Level (NOAEL) of 200 mg/kg given as a 30-minute infusion in the 
cardiovascular study the peak plasma level was 154 and 130 µg/mL in male and female dogs, 
respectively.


Aprea Therapeutics AB
Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
APR-246
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It was concluded that cardiovascular and respiratory effects induced by APR-246 were 
concentration dependent. No significant toxicity was observed when infusion was prolonged up to 
9 h at the rate of 100 mg/kg/h (900 mg/kg/day) reaching plasma concentrations around 120 µg/mL.
2.5.3
Pharmacokinetics
The pharmacokinetics of APR-246 has been studied using validated bioanalytical methods. The data 
demonstrate that APR-246 has a low protein binding across species. The terminal plasma half-life 
was about 3 h in mice and 2 to 5 h in dogs. There were no gender differences regarding exposure or
half-life. The exposure was reduced with approximately 50% in mice following a 4-week treatment 
compared with day 1, whereas no clear time-dependency on dose-proportionality was observed in 
dogs in the corresponding 4-week study. Also in the cyclic study, the systemic exposure showed 
dose-proportionality without gender deviations. However, exposure data in the cyclic study in dogs 
demonstrated generally lower exposure on day 7 compared with day 1 after each cycle. A whole 
body quantitative autoradiography study in rats using carbon-14 labeled APR-246 showed that the 
radioactivity was rapidly distributed into the whole body, and was excreted both into the 
gastrointestinal tract and urine.
2.5.4
Toxicology
APR-246 has been investigated for toxicology in agreement with existing regulatory guidelines for 
initiation of early clinical trials in patients with malignancies.
The pre-clinical toxicity data demonstrate that APR-246 induces CNS toxicity in a dose- and rate-
dependent manner. The severity of clinical signs was found to be directly correlated to the plasma 
concentration. With an infusion rate of 400 mg/kg/h during 40 minutes, plasma levels of 
approximately 400 µg/mL were reached without mortality. Based on this carefully monitored 
additional dog study, the CNS toxicity window, from detected mild signs to severe signs, was found 
to be approximately 140 to 400 µg/mL. Independent of dose, infusion rate or infusion time of the 
plasma threshold for inducing CNS adverse reactions was at least 100 µg/mL. The CNS effects 
showed reversibility, for example after interruption of infusion after 40 minutes at the non-tolerated 
rate of 400 mg/kg/h, all animals recovered and had normal movements from 30 minutes after the 
infusion, whereas slight tremor and hypoactivity lasted longer with full recovery after 3 h.
It can be concluded that APR-246 induced clinical signs of adverse reactions when the compound 
was given at high dose levels as bolus injection or short-term infusion. The NOAEL of APR-246 in 
the 4-week repeat dose toxicity study in dogs given as a 2-hour infusion was 200 mg/kg/day. The 
mean systemic exposure at this dose level was 63.7 µg/mL (Cmax) and 129 µg·h/mL (AUC). The 
mean plasma level at the NOAEL of 200 mg/kg in the follow-up dog study was 114 µg/mL (Cmax). 
With prolonged infusion time at the infusion rate of 100 mg/kg/h, APR-246 was well tolerated at 
much higher daily dose concentrations given over 7-days in cycles. No significant toxicity and no 
target organ toxicity were observed at 900 mg/kg/day in the cyclic study. The mean Cmax varied 
between 61 to 185 µg/mL (males) and 65 to 190 µg/mL (females) during the study. The mean AUC 
on day 1 of the 3rd cycle was 1510 µg·h/mL (males) and was 797 µg·h/mL (females).


Aprea Therapeutics AB
Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
APR-246
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2.6
Previous Clinical Studies
The first clinical trial (APR-246-01) was conducted with APR-246 in patients with refractory 
hematological malignancies and prostate cancer. For further information please refer to the IB.
2.7
Rationale for the Current Study
HGSOC accounts for approximately 70% of malignant surface epithelial carcinoma in Europe and
North America [9]. Clinical data shows that TP53 mutations are present in at least 96% of patients 
with HGSOC [4]. Furthermore, TP53 mutations have been shown to correlate significantly with 
resistance to chemotherapy, early relapse and shortened overall survival [11].
Despite the evolution of surgical techniques and ever improving chemotherapy regimens, relapse 
and consequential disease progression remains the most challenging task for ovarian cancer patients.
The combination of carboplatin and pegylated liposomal doxorubicin has shown an improvement in 
PFS (11.3 months versus 9.4) with lower rates of severe and long-lasting side effects, and has been 
accepted as standard of care for patients with platinum-sensitive ovarian cancer, including HGSOC
[8].
APR-246 may offer an opportunity to improve current treatment of HGSOC. The rationale for this 
derives from preclinical evidence that APR-246/MQ (i.e., the active moiety of APR-246) induces 
apoptosis and cell death in cancer cells with mutant or otherwise non-functional p53. Additional to 
the apoptosis-inducing effect as a single substance, APR-246 can act synergistically with platinum 
compounds by reversing the cisplatin sensitivity of cisplatin-resistant TP53 mutant ovarian cancer 
cell lines, resulting in resensitization of cancer cells to cisplatin.
The completed Phase I/II extended exposure study of single agent APR-246 (APR-246-01 
Amendment 6) indicated that prolonged exposure, after 4-hour and 6-hour pulse incubations as 
compared to 2 hours, resulted in stronger apoptotic response. Ten patients have received 6-hour 
infusions and pharmacokinetic, safety and efficacy parameters have been collected. No major safety 
concerns were reported, and 2 patients have shown protocol defined clinical responses.
This study also provided important information about APR-246 and increased knowledge about its 
safety and tolerability, as well as pharmacokinetic (PK) and optimal administration. In summary, the 
results of the extension study suggested that the adapted dose regimen was suitable and that 
APR-246 was well tolerated with limited number of adverse events. The pharmacokinetic data 
suggested time-independent and dose-independent kinetics.
In view of the data accumulated, the starting dose for the PiSARRO study at Cohort 1 was 35.0 
mg/kg/day (approximately 50% of the PH2RD (Phase II recommended dose) dose of 67.5 mg/kg/ 
day) for 6-hours on Days 1 to 4 with carboplatin AUC 5 and PLD 30 mg/m2 on Day 4 within Phase 
Ib of the planned clinical study.


Aprea Therapeutics AB
Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
APR-246
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The purpose of this study is to determine whether patients with platinum sensitive, recurrent, 
HGSOC with TP53 mutations causing overexpressed defect p53 protein, will benefit from treatment 
with APR-246 in combination with the reintroduction of a platinum-based regimen. Focus will be on 
patients with HGSOC with recurrent disease at least 6 months and up to 24 months after platinum
based treatment.
The objectives of the Phase Ib were to find the maximum tolerated dose of APR-246 in this 
combination, to determine PK variables, to follow appropriate biomarkers, and safety.
The Phase II portion of the study is an open-label randomized evaluation of APR-246 in 
combination with a carboplatin/PLD chemotherapy regimen, versus carboplatin/PLD chemotherapy 
regimen alone in patients with HGSOC with TP53 mutation and recurrent disease at least 6 months 
and up to 24 months after platinum based treatment. Antitumor activity will be determined by a CT 
scan/MRI using RECIST v1.1 criteria and with CA-125 using the GCIG criteria. Patients will be 
followed to progression.
2.7.1
Preliminary Results from the Current Study, Phase Ib, and Rationale for Selected Dose 
for Phase II Study
The first phase of this study was designed to determine the dose for the second (randomized) phase 
of the study. In this phase APR-246 was administered IV in combination with carboplatin and PLD 
at 3 dose levels; 35 mg/kg, 50 mg/kg and 67.5 mg/kg, to 27 women with high grade serous ovarian 
cancer, previously treated with platinum-based antineoplastic agents. Each treatment cycle was 
repeated every 28 days to a maximum of six treatment cycles.  
The primary study objectives were an assessment of safety and tolerability and an evaluation of the 
pharmacokinetics of APR-246 in combination. In this first phase of study APR-407, primary study 
end points were dose-limiting toxicity and a safety assessment of the combined APR-246 and 
carboplatin PLD combination together with limited pharmacokinetic profiles.
At the data cut-off point of 12 May 2016, the most commonly reported adverse events were
neutropenia, dizziness, nausea, vomiting, headache, dysgeusia, constipation, diarrhea, depressed 
appetite, anemia, thrombocytopenia device occlusion, mucosal inflammation, pyrexia, and 
abdominal pain. This pattern of toxicity, except for the bone marrow suppression, was similar to that 
reported following treatment with APR-246 alone in study APR-246-01.  
There is no evidence of a pharmacokinetic interaction between APR-246 and carboplatin or PLD 
and no evidence of consistent QTc prolongation at any of the explored dose levels.
2.7.1.1
Rationale for a Selected Dose of APR-246
During the Phase I clinical development, APR-246 dosing was based on mg/kg body weight (BW) 
and 67.5 mg/kg was identified as the maximum tolerated dose when given as a 6-hour infusion. A
population pharmacokinetic (PK) analysis using data from the first 2 clinical studies (67 subjects, 
951 observations) confirms that the influence of BW on the PK of APR-246 is relatively small and 


Aprea Therapeutics AB
Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
APR-246
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that dosing by lean body mass (LBM) could lead to lower variability in the patient exposure 
compared with dosing based on BW. 
However, this analysis also showed that a fixed dose of 4.5 g (split as 1.5 g for the first 45 min and 3 
g for the subsequent 5 h and 15 min) gives the same average exposure in women as 67.5 mg/kg or 
100 mg/kg LBM. The variability with fixed dose is slightly increased, but within acceptable ranges.
(See below table). 
Population PK predictions for women using a fixed dose of 4.5 g vs body weight 
and LBM based dosing
Dosing Regimen
AUC (µg*h/mL)
Cmax (µg/mL)
67.5 mg/kg
552
325 - 852
54.4
31.1 - 85.4
100 mg/kg LBM
549
341 - 820
54.2
32.0 - 82.8
4.5 g fixed
571
311 - 910
57.5
29.6 - 92.4
Data are mean and 90% range (5th percentile-95th percentile)
AUC: Area Under the Curve; Cmax: Maximal Plasma Concentration
In summary, in women a 6-hour infusion of a fixed dose of 4.5 g of APR-246 gives a similar 
average exposure in terms of AUC0-24 and Cmax as the established maximum tolerated dose of 67.5 
mg/kg and the currently used LBM based dose of 100 mg/kg. Since the predicted PK variability is 
also very similar, it is justified to switch to fixed dosing of APR-246 as it will remove the risk for 
miscalculations of the dose and thereby contribute to the safe use of the product.
2.7.2. Quality of Life Assessment and Rationale for the Selection of the Questionnaires
The EORTC QLQ-C30 (including the Ovarian Module QV28) Quality of life (QoL) assessment was 
chosen as it may help determine the intermediate- and long-term effects of protocol treatments
whereas the FACT-O questionnaire was selected in order to determine the impact of the study 
treatments on the emotional, social/family and functional well-being of the patients.
2.8
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/EC and its associated 
Detailed Guidances, European Union GCP Directive 2005/28/EC, the ICH Guideline for 
Good Clinical Practice, Sections 3 and 4, and the terms of the Declaration of Helsinki 
(2013), will be followed.


Aprea Therapeutics AB
Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
APR-246
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4.
Requirements for informed consent in accordance with institutional guidelines, FDA 
requirements as specified in Title 21 CFR, Part 50, the European Union Directive 
2001/20/EC and its associated Detailed Guidances, European Union GCP Directive 
2005/28/EC, the ICH Guideline for Good Clinical Practice, Section 4.8, and the terms of the 
Declaration of Helsinki (2013), will be followed.
5.
Safety data will be recorded and evaluated.
6.
Routine monitoring visits will be conducted by the Sponsor’s representative (Theradex ) to 
ensure data accuracy.
7.
APR-246 accountability will be strictly maintained.
8.
This trial will be conducted according to Good Clinical Practice (GCP), the protocol and 
applicable regulatory requirements.


Aprea Therapeutics AB
Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
APR-246
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3.0
TRIAL OBJECTIVES AND ENDPOINTS
3.1
Objectives and Endpoints
3.1.1
Primary Objective
To assess the efficacy of a combined APR-246 and carboplatin/PLD chemotherapy regimen in 
patients with platinum sensitive recurrent HGSOC with mutated TP53.
3.1.2
Secondary Objectives
To assess the safety profile of the combined APR-246 and carboplatin/PLD chemotherapy 
regimen compared with carboplatin/PLD chemotherapy regimen alone.
To evaluate potential biomarkers.
To assess the biological activity in tumor and surrogate tissues.
To compare quality of life of patients treated with these regimens.
3.1.3
Primary Endpoint
Progression-free survival (PFS) based on Blinded Independent Central Review (BICR) is the 
primary endpoint and is defined as the number of days from the date of randomization to the 
date of objective disease progression or relapse (according to RECIST v1.1 only) or death due to 
any cause, whichever occurs first. If neither event occurs, PFS will be censored at the date of the 
last evaluable tumor assessment. Symptomatic deterioration is not objective disease progression.
3.1.4
Secondary Endpoints
Secondary endpoints include the following:
Best overall response and overall response rate (according to RECIST v1.1 and GCIG Criteria)
Duration of response (complete or partial response) 
PFS by assessment of CA-125 (according to GCIG Criteria)
Overall survival
Safety profile based on AEs and laboratory assessments 
Evaluation of biomarkers and tumor activity based on CA-125
Quality of Life assessment using EORTC Ovarian (QLQ-30 and QLQ-OV28) and the 
Functional Assessment of Cancer Therapy-Ovarian (FACT-O)
Tumor response data will be summarized at each tumor assessment cycle using the following 
response categories: Complete Response (CR), Partial Response (PR), Stable Disease (SD), 
Progressive Disease (PD) and Non-Evaluable (NE). Best overall response for a patient is the best 


Aprea Therapeutics AB
Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
APR-246
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response recorded from the start of the treatment until disease progression or death. Best overall 
response will be summarized as the number (%) of patients in each category of response (CR, PR, 
SD, PD, and NE). PR and CR must be confirmed by a repeat assessment at least 28 days after the 
criteria are first met for the response to be considered a PR or CR.
The overall response rate is defined as the percentage of patients with a confirmed response of CR 
or PR in a given population.
The duration of response (confirmed CR or PR) is defined as the number of days from the date of 
initial response (not the confirmation date) to the date of objective disease progression or death due 
to any cause, whichever occurs first. If neither event occurs, duration of response will be censored at 
the date of the last evaluable tumor assessment. Symptomatic deterioration is not objective disease 
progression.
Overall survival (OS) is defined as the number of days from the date of randomization to the date of 
death. In the event of no death, overall survival will be censored at the last known alive date.


Aprea Therapeutics AB
Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
APR-246
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4.0
STUDY DESIGN
4.1
Overview of Study Design
This study is an open-label, multi-center Phase II proof-of-concept study with a dose confirmation 
component to assess whether patients with platinum sensitive recurrent TP53 mutated high grade 
serous ovarian cancer (HGSOC) will benefit from treatment with APR-246 in combination with a 
carboplatin/PLD chemotherapy regimen. It is planned that patients will receive up to 6 cycles of 
treatment.
Archived sections from the original tumor sample will be reviewed by a gynecological pathologist 
to confirm the diagnosis of HGSOC and positive IHC staining for p53 (please refer to the laboratory 
manual). Patients without positive p53 staining will not be included.
Patients will be randomly assigned in a 1:1 ratio to receive either:
Arm A: APR-246 with the carboplatin/PLD chemotherapy regimen, 
Arm B: Carboplatin/PLD chemotherapy alone. 
Optional frozen/fixed core biopsies will be undertaken after randomization, but prior to any 
infusion, on day 1 for all patients and day 3 in APR-246 patients.
The study will enroll up to 400 patients with positive IHC staining for p53. A CT scan/MRI using 
RECIST v1.1 criteria will be performed at pre-treatment, after 2 cycles (8 weeks), 4 cycles (16 
weeks) and after the last cycle (24 weeks).
At subsequent follow-up visits, tumor assessments by CT scan/MRI will be performed 2 months 
(± 2 weeks) after the end of treatment visit and every 3 months (± 2 weeks) thereafter, until the 
documented disease progression, as determined by the Investigator at each site and defined by 
RECIST v1.1.
All scans for each individual patient should have the same modality (CT or MRI) but CT is 
preferred.
4.2
Randomization/Registration of Patients
Upon completion of all screening evaluations, the center will register the patient using the
Interactive Web Response System (IWRS). After successful completion of patient registration, a 
treatment assignment and randomization number will be issued.
Once the patient is registered through the IWRS, the patient is considered enrolled in the study. 
Specific instructions for the central enrolment and registration procedures are provided to the center
in the Study Operations Manual.
Registered patients will be assigned a unique patient identifier number. If a patient is withdrawn and
replaced (as described in Section 13), the patient identifier number will not be reused.


Aprea Therapeutics AB
Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
APR-246
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4.3
Shipment of p53 Samples
All archived pathology samples will be sent for centralized p53 analysis after registration and 
following local analysis. Labeling and shipment procedures will be provided in a separate 
Laboratory Manual. 
4.4
Treatment Allocation
Patients will be randomized in a 1:1 ratio to receive the carboplatin/PLD chemotherapy regimen 
with or without APR-246. The study treatment will not be blinded. Patients will be registered on-
study as described in Section 4.2; the treatment arm will be automatically allocated during 
registration. 
4.5
Drug Products
4.5.1
Investigational Medicinal Product, APR-246
The study substance APR-246 (2-hydroxymethyl-2-methoxymethyl-1-azabicyclo [2,2,2] octan-3-
one) is isolated as a white powder. APR-246 is prepared from quinuclidin-3-one in one reaction step 
using formaldehyde in methanol and in the presence of potassium carbonate (see IB). The IMP, 
APR-246 concentrate for solution for infusion, will be manufactured by Cobra BioPharma, Matfors 
Sweden.
4.5.2
Reference Products Carboplatin and PLD
Carboplatin and PLD will be supplied by the hospital’s pharmacy and will be administered in 
combination in 28-day cycles for up to 6 cycles.
4.6
Duration of Therapy
Patients will receive up to six 28-day cycles of the carboplatin/PLD chemotherapy regimen, with or 
without APR-246.
4.7
End of Study
The end of the study is defined as the date of the last visit of the last patient taking part in the study.
4.8
Study Discontinuation by the Sponsor
For reasonable cause, either the Investigator or the Sponsor may terminate this study prematurely. 
Written notification of the termination is required. Conditions that warrant termination by the 
Sponsor include, but are not limited to:
The discovery of an unexpected, significant, or unacceptable risk to the patients enrolled in the 
study.


Aprea Therapeutics AB
Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
APR-246
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Failure of the Investigator to enter patients at an acceptable rate.
Insufficient adherence to protocol requirements (non-compliance).
Lack of evaluable and/or complete data.
Decision to modify the developmental plan of the drug.
A decision on the part of the Sponsor to suspend or discontinue development of the drug.
4.9
Treatment Plan for Patients after the Study
It is expected that patients will go on to receive treatment according to usual hospital practice


Aprea Therapeutics AB
Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
APR-246
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5.0
SELECTION AND WITHDRAWAL OF PATIENTS
5.1
Inclusion Criteria
To be eligible to participate in this study, patients must meet all of the following inclusion criteria:
1. Archived sections from the original FFPE sample reviewed by a gynecological pathologist 
confirming High Grade Serous Ovarian Cancer, High Grade Serous Peritoneal Cancer or 
Primary Fallopian Tube Cancer, and positive IHC staining for p53 assessed according to 
defined standard (as detailed in the laboratory manual). Cases that do not show p53 staining 
will not be included.
2. Radiologically-confirmed Disease Progression between six and twenty-four (6-24) months 
after a first or second platinum based regimen.
3. At least a single (RECIST v1.1) measurable lesion.
4. Adequate organ function prior to registration:
a) Bone Marrow Reserve:
Absolute neutrophil 
x109/L,
x109/L,
Hemoglobin
g/dL.
b) Hepatic: 
Total bilirubin level < 1.5 x ULN,
ALT and AST < 2.5 x ULN.
c) Renal: 
Calculated creatinine clearance > 30 mL/min.
d) Electrolytes 
Potassium within institutional normal ranges.
5. Toxicities from previous cancer therapies, excluding alopecia, must have recovered to grade 1 
(defined by CTCAE version 4.0). Chronic stable grade 2 peripheral neuropathy secondary to 
neurotoxicity from prior therapies may be considered on a case by case basis by the Principal 
Investigator.
6. If of childbearing potential, negative pre-treatment serum pregnancy test.
7. If of childbearing potential, willing to use an effective form of contraception (see below) 
during chemotherapy treatment and for at least six months thereafter.
Such methods include: (if using hormonal contraception this method must be supplemented   
with a barrier method, preferably male condom).
Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation:
o
Oral
o
Intravaginal


Aprea Therapeutics AB
Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
APR-246
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o
Transdermal
Progestogen-only hormonal contraception associated with inhibition of ovulation:
o
Oral
o
Injectable
o
Implantable 
Intrauterine device (IUD) 
Intrauterine hormone-releasing system (IUS) 
Bilateral tubal occlusion 
Vasectomized partner 
True sexual abstinence when this is in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods), declaration of abstinence for the duration of a trial, and withdrawal are not 
acceptable methods of contraception.
Male condom with spermicide (female condom and male condom should not be used 
together)
8. ECOG performance status of 0 to 1 (Appendix I).
9.
10. Written informed consent obtained prior to any screening procedures and in accordance with 
federal, local, and institutional guidelines.
11. Patient has exhausted all available treatments, including surgery, and is considered a suitable 
candidate to receive carboplatin/PLD.
5.2
Exclusion Criteria
Patients will be excluded if any of the following exclusion criteria are met:
1. Prior exposure to cumulative doses of doxorubicin >400 mg/m2 or epirubicin >720 mg/m2.
2. Confirmed cardiac history of any of the following:
a) Myocardial infarct within six months prior to registration,
b) New York Heart Association Class II or worse heart failure (Appendix II)
c) A history of familial long QT syndrome,
d) Clinically significant pericardial disease,
e) Electrocardiographic evidence of acute ischemia,
f) Symptomatic atrial or ventricular arrhythmias not controlled by medications,


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Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
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g)
480 msec calculated from a single ECG reading or a mean of 3 ECG readings using 
Fridericia’s correction (QTcF = QT/RR0.33),
h) Bradycardia (<40 bpm),
i)  Left ventricular ejection fraction (LVEF) < the institution lower limit of normal as assessed
by ECHO.
3. Major abdominal surgery or peritonitis within six weeks prior to study treatment.
4. Unresolved bowel obstruction, sub-occlusive disease or the presence of brain metastases.
5. History of uncontrolled allergic reactions to carboplatin, platinum containing compounds or 
mannitol and/or hypersensitivity to PLD or to any of the excipients.
6. Unable to undergo imaging by either CT scan or MRI.
7. Evidence of any other medical conditions (such as psychiatric illness, infectious diseases,
neurological conditions, physical examination or laboratory findings) that may interfere with 
the planned treatment, affect patient compliance or place the patient at high risk from 
treatment related complications.
8. Breast feeding.
9. Concurrent malignancy requiring therapy (excluding non-invasive carcinoma or carcinoma in 
situ).
10. Patients requiring or undergoing concurrent treatment with live vaccines
11. Patients requiring or undergoing concurrent treatment with phenytoin.
12. Known HIV positive status, active hepatitis B or C status.
13. Is taking any concurrent (or within 4 week prior to registration) anti-cancer therapy,
immunotherapy, radiotherapy or any ancillary anti-cancer therapy; or any other therapy that is 
considered to be investigational (i.e., used for non-approved indications(s) and in the context 
of a research investigation). Supportive care measures are allowed.
14. Patients unable to be regularly followed for any reason (geographic, familiar, social, 
psychological, housed in an institution e.g., prison because of a court agreement or 
administrative order). Patients who are dependent on the sponsor/CRO or investigational site 
as well as on the Investigator.
5.3
Withdrawal of Patients and Study Termination
In accordance with the Declaration of Helsinki, each patient is free to withdraw from the study at 
any time without penalty or loss of benefits or other adequate treatments to which he/she is 
otherwise entitled. 
Investigators also have the right to withdraw patients from the study in the event of illness, AEs, or 
other reasons concerning the health or well-being of the patient, or in the case of lack of co-
operation. After withdrawal of a patient, the investigator is responsible for ensuring adequate 


Aprea Therapeutics AB
Protocol No. APR-407
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of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
APR-246
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treatment and follow-up, although every effort should be made to complete all assessments at an 
End of Treatment visit as listed in Section 7.0.
Should a patient decide to withdraw after administration of the investigational medicinal product, or 
should the investigators decide to withdraw the patient, all efforts will be made to complete and 
report the observations up to the time of withdrawal as thoroughly as possible. A complete final 
evaluation at the time of the patient’s withdrawal should be made and an explanation given of why 
the patient is withdrawing or being withdrawn from the study. 
The reason, time, and date for withdrawal must be noted in the eCRF. If the reason for withdrawal is 
a clinical AE, monitoring will continue until the outcome is evident. The specific event must be 
recorded in the eCRF.
Patients who are withdrawn before completion of the first cycle of APR-246, carboplatin and PLD 
as prescribed will be replaced.
The study treatment will be discontinued at any time if any of the following situations occur; in the 
case of study termination by the Sponsor patients will be allowed to continue to receive the standard 
of care:
1. Completed 6 cycles of treatment.
2. Progressive disease per RECIST v1.1 criteria.
3.
Grade 3 APR-246 related toxicity that leads to a delay in dosing and that persists for more 
than 4 weeks from the last planned study drug administration or recurs after the maximum 
dose reduction, despite optimal supportive therapy.
4. Patient refusal.
5. Lost to follow-up/noncompliance.
6. Significant illness that can affect the patient’s ability to comply with study procedures.
7. At the discretion of the Investigator.
8. Pregnancy.
9. Study termination by Sponsor.
5.4
Compliance with Study Procedures
Patients will receive the study treatment as outlined in Section 6.0. The details of the study treatment 
will be documented in the eCRF and IMP accountability forms as applicable.
All study treatment related procedures will be performed in the hospital or clinic by qualified health 
care personnel. All instances of noncompliance and all resulting protocol deviations will be recorded 
in the eCRF.


Aprea Therapeutics AB
Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
APR-246
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6.0
TREATMENT OF PATIENTS
6.1
Drug Supply and Handling Procedures
6.1.1
Investigational Medicinal Product, APR-246
The IMP will be manufactured according to Good Manufacturing Practice (GMP), and labeled
according to GCP, GMP and the national requirements for each site. The labels will comply with the 
legal requirements of the country. They will include storage conditions for the drug but no 
information about the study.
The IMP will be distributed in vials to the pharmacies of each participating study center. The 
APR-246 substance will be diluted in 0.9% sodium chloride solution at the appropriate 
concentration for infusion for each patient.
At the pharmacies, the IMP vials are to be stored at 2-8ºC. At the pharmacies and at the study 
centers, the prepared APR-246 study product (diluted in sodium chloride solution) is to be stored at 
not more than 25ºC. The infusion should be completed within 24h from the time of preparation (see 
Study Manual).
Detailed instructions on vial concentration, preparation and dispensing can be found in the 
Pharmacy File.
6.1.2
Carboplatin
Carboplatin will be provided from the pharmacy stock. The carboplatin bag used for administration 
will be labeled according to the local routines and regulatory requirements. The hospital will be 
responsible for ordering carboplatin. The manufacturer and batch numbers will be documented.
Please refer to the Summary of Product Characteristics for further information on carboplatin.
6.1.3
Pegylated Liposomal Doxorubicin (PLD) Hydrochloride
PLD will be provided from the pharmacy stock. The PLD bag used for administration will be 
labeled according to the local routines and regulatory requirements. The hospital will be responsible 
for ordering PLD. The manufacturer and batch numbers will be documented.  
Please refer to the Summary of Product Characteristics for further information on PLD.
6.2
IMP Accountability/Disposition of Clinical Trial Supplies
IMP accountability records will be maintained for all clinical trial supplies.
IMP accountability records will be kept at the pharmacy and at the study centers. The pharmacy 
must maintain accurate records demonstrating date and amount of IMP received, to whom and by 
whom administered, and accounts of any IMP accidentally or deliberately destroyed.
The Investigator is responsible for keeping records to ensure that:


Aprea Therapeutics AB
Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
APR-246
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a.
Deliveries of IMPs are correctly received and recorded by a designated person.
b.
Study medications are handled and stored safely and properly.
c.
Study medications are dispensed only to study patients in accordance with the 
protocol.
d.
All unused medication and empty containers are stored until they have been checked 
by the study monitor.
e.
It is possible to reconcile records of all used and unused stocks as confirmed by the 
Investigator’s signature.
The IMP is the property of Aprea Therapeutics AB and must not be passed on to third parties. Any 
discrepancies between returned and expected returned IMP should be explained.
6.3
Method of Assigning Patients to Treatment Groups
Up to 400 patients will be centrally registered and randomly assigned study treatment in a 1:1 ratio
to receive either:
Arm A: APR-246 treatment on Days 1 to 4, with carboplatin and PLD administered 
concurrently on Day 4 (treatment repeated every 28 days for up to six cycles) or
Arm B: Carboplatin and PLD alone administered on Day 1 of each 28-day cycle, repeated 
for up to six cycles.
Patients will be stratified at randomization by: 
Platinum-free Interval after previous platinum based regimen. 6-12 months vs. 12-24 months
Prior Lines of Platinum Treatment. One line vs. Two lines
BRCA status. known positive vs. other
The schema for the study is shown in Figure 2 below.


Aprea Therapeutics AB
Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
APR-246
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Figure 2. Phase II Schema
6.4
Treatment Administration
6.4.1
Treatment Arm A: APR-246 with carboplatin and PLD
Patients will receive a fixed dose of 4.5 g APR-246 (1.5 g of the dose during first 45 minutes 
followed by 3 g of the dose during 5 hours 15 minutes) on Days 1 to 4 with carboplatin AUC 5 and 
PLD 30 mg/m2 on Day 4 (Figure 3). Carboplatin and PLD administration to be given on Day 4 only 
should commence 2 hours after the start of the APR-246 infusion. Further administration of 
APR-246 (repeated in 28-day cycles) will commence three days prior to subsequent chemotherapy 
cycles, with the fourth dose administered the same day as the chemotherapy.
Figure 3. Treatment Administration for Patients Receiving APR-246
Note: The entire dose should be given even if the infusion needs to be extended beyond a total time 
of 6 hours (e.g. due to slightly larger start volume in prefilled infusion bags).
Screening
Randomisation
APR-246 +
Carbo/PLD
Carbo/PLD
APR-246 +
Carbo/PLD
APR-246 +
Carbo/PLD
Carbo/PLD
Carbo/PLD
RECIST / CA-125
Disease assessment
2 cycles
2 cycles
2 cycles
Disease
Assessment
Disease
Assessment
Disease
Assessment
Follow-up until 
progression
RECIST / CA-125
Disease assessment
Study Day -1 1
2
3
4
5
6
7
8
27 28 29 30 31 32 33 34
Carbo/PLD
APR-246 6 hr IV 
infusion per day
Carbo/PLD
APR-246 6 hr IV 
infusion per day


Aprea Therapeutics AB
Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
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APR-246 Treatment Duration
Treatment will be repeated every 28 days for up to 6 cycles in the absence of disease progression or 
unacceptable toxicity. Supportive therapy, including growth factors, can be given as per institutional 
standard of care.
Carboplatin Dosing
The dose of carboplatin will be calculated as per standard practice at that hospital. Patients will start 
at carboplatin with an AUC 5.
Pegylated Liposomal Doxorubicin Dosing
The dose of PLD will be calculated based on the body surface of the patients at 30 mg/m2 as per 
standard practice at that hospital.
6.4.2
Treatment Arm B: Carboplatin and PLD alone
Patients will receive carboplatin AUC 5 plus PLD at 30 mg/m2 on Day 1 of each cycle. Treatment 
will be repeated every 28 days for a total of up to six cycles in the absence of disease progression or 
unacceptable toxicity. Supportive therapy will be given as per institutional standard of care. Patients 
randomized to Arm B will not receive APR-246.
Carboplatin Dosing
The dose of carboplatin will be calculated as per standard practice at that hospital. Patients will start 
at carboplatin with an AUC 5.
Pegylated Liposomal Doxorubicin Hydrochloride Dosing
The dose of PLD will be calculated based on the body surface of the patients at 30 mg/m2 as per 
standard practice at that hospital.
6.4.3
Treatment of Adverse Events of the Central Nervous System related to APR-246
If a patient reports any clinical adverse event of any grade during the administration period of 
APR-246 that could be considered to originate from the central nervous system (e.g. dizziness, 
vertigo, nausea) then the patient will be given a rescue medication as per the institutional standard of 
care (Table 1).


Aprea Therapeutics AB
Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
APR-246
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Table 1. Rescue Medications for use with APR-246
Indication
Supportive Measure
Central Nervous System symptoms (Treatment 
and Prevention)
Prochlorperazine 10 mg orally tid a or other as per the 
institutional standard of care
Start Day -1 prior to APR-246 administration
Persistent CNS symptoms
Cyclizine 50 mg IM or other as per the institutional 
standard of care
a.
Prochlorperazine 10 mg orally tid (three times daily). To continue until end of Day 4 of the cycle. When used 
prophylactically for future treatment, start the day prior to the Day 1 administration of APR-246 of each cycle (as 
needed). 
If during the infusion the patient continues to remain symptomatic intramuscular administration of 
cyclizine 50 mg may be considered.
6.5
Dose Modifications
6.5.1
Modifications for APR-246 due to Adverse Events during Infusion
If a patient in Arm A 
-246 infusion, the 
infusion should immediately be stopped. The type, severity and duration of the adverse event should 
be carefully assessed as well as the relationship to APR-246.
If the adverse event is considered to be unrelated to APR-246, the infusion may be resumed within 2 
hours.
If the adverse event is considered to be related to APR-246, as long as all symptoms resolve to 
CTCAE Grade 1 or less within 2 hours, the infusion may be resumed.
In case of re-challenge, the infusion should resume at the same infusion rate (the same dose per time 
unit) as the initial infusion. If no symptoms occur during re-challenge, the infusion can continue 
until the whole dose is given and the treatment can continue according to the protocol. 
If the same symptoms do occur or increase in severity during re-challenge the infusion should be 
stopped. 
If the event lasts longer than 2 hours, then the remainder of the APR-246 infusion for that day 
should be discarded. If the patient has recovered sufficiently by the next day, the remainder of the 
planned course should be administered. 
After an adverse event considered as related, a single level dose reduction of APR-246 is allowed
(Table 2). The rationale for the suggested dose reductions is the steep relation between Cmax and 
dose, revealed by modeling based on an extended population PK analysis (Section 2.7.1.1). If more 
than two dose reductions of APR-246 are required, APR-246 must be discontinued.
The type, severity and duration of the symptoms, adverse event and infusion timings (start and stop) 
should be carefully documented in the patient’s medical charts as per trial procedures.


Aprea Therapeutics AB
Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
APR-246
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Table 2. Dose Modifications of APR-246
Dose Modification
APR-246 Dose
Current Dose Level 
(DL)
APR-246 4.5 g
1.5 g (for first 45 minutes ) + 3 g (for 5 hours 15 minutes)
First dose reduction 
DL-1
APR-246 4.0 g
1.33 g (for first 45 minutes) + 2.67 g (for 5 hours 15 minutes)
Second dose DL-2
APR-246 3.5 g
1.16 g (for first 45 minutes) + 2.34 g (for 5 hours 15 minutes)
The rationale behind this dose reduction scheme is the steep relation between Cmax and dose, e.g. the suggested 11% 
and 22% reductions in dose result in 19% and 33% lowering of the average Cmax, respectively (Section 2.7.1.1).
6.5.1.1
APR-246 Infusion and Systemic Chemotherapy Delays
The days 1 to 4 APR-246 administration, together with the day 4 chemotherapy, are to be regarded 
as one treatment cycle and must be administered consecutively.
On day 1, prior to APR-246 administration, the hematological status of the patient should be 
assessed. If the patient has any hematological adverse event that would prevent systemic 
chemotherapy administration on day 4, the APR-246 infusion and systemic chemotherapy should be 
delayed until recovery (see Section 6.5.2.1).
If a patient has any adverse event on days 2, 3 or 4 prior to the APR-246 infusion which, in the 
opinion of the Investigator, would prevent systemic chemotherapy administration, the remainder of 
the planned APR-246 administration should be stopped. Once the patient has recovered sufficiently 
to receive chemotherapy, the whole treatment cycle (consisting of days 1-4 APR-246 and day 4 
chemotherapy) should be restarted as previously planned. 
If APR-246 and/or systemic chemotherapy are delayed, the reasons for delay should be recorded in 
eCRF.
6.5.2
Dose Modifications for Systemic Chemotherapy
For typical hematological (Table 3 and Table 4) and non-hematological (Section 6.5.2.2) adverse 
events seen with carboplatin and PLD, the dose modifications specified below should be applied.
However, if any adverse events occur that are not typical or that are considered unusual, the Sponsor 
should be consulted prior to re-treating the patient.
If due to adverse events the patient is unable to continue treatment with PLD, the Investigator may 
consider continuing with carboplatin monotherapy and APR-246 in Arm A to a total of six cycles 
(including all prior combination chemotherapy cycles).


Aprea Therapeutics AB
Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
APR-246
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If due to adverse events the patient is unable to continue chemotherapy with both PLD and 
carboplatin, the patient may continue monotherapy APR-246 up to 6 courses in total if the following 
criteria are met:
There is CA-125 reduction suggestive of treatment benefit (eligible patients)
Latest radiological scans shows evidence of response
Patient is evaluated as not having symptoms suggestive of progressive disease
The Investigator assessment is that APR-246 monotherapy is of continued benefit to the 
patient
APR-246 administration has been approved by the Sponsor.
6.5.2.1
Hematological Toxicity and Dose Modifications
The absolute neutrophil count (ANC) must be 
1.50 x 109/L and the platelet count must be 
100 x 109/L in order to administer full doses of carboplatin and PLD in each cycle as assessed on 
day 1. In the event of an ANC < 1.0 x 109/L, hematological assessment should be performed twice a 
week until recovery of ANC to >1.0 x 109/L. Patients should be monitored prior to each dose for 
platelet and neutrophil counts, and at the discretion of the Investigator, if necessary, the dose of 
carboplatin and/or PLD may be either reduced or withheld in the presence of hematological toxicity 
according to the following scale (Table 3):
Table 3. Dose Modification of Systemic Chemotherapy for Hematological Toxicities
Hematological Assessment on Day 1 of a Cycle:
ANC (x 109 /L)
Platelet Count (x 109 /L)
Dose Modification
and
Administer full dose of Carboplatin and PLD
<1.5
and/or
<100
Delay cycle for 7 days. If within normal acceptable 
parameters (as above) proceed with dose reductions 
of carboplatin to AUC 4 and PLD 25 mg/m2.
Dose reduction to carboplatin AUC 4 and PLD 25 mg/m2 is also required in the following circumstances:
ANC < 0.5 x 109 /L for > 7 days
°C and ANC < 1.0 x 109 /L)
Platelets < 25 x 109 /L, or bleeding requiring a platelet transfusion
Growth factors:
For patients who have a prolonged neutropenia, Investigators may administer growth factors to 
aid white cell count recovery. This should be given per the package insert.
Patients who the Investigator considers to be at risk for developing neutropenia (considering 
bone marrow tolerance with prior chemotherapy or neutropenia while on the PiSARRO study)


Aprea Therapeutics AB
Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
APR-246
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that could affect their ability to receive study treatment per the study protocol, should consider 
administering prophylactic growth factor per the package insert.
For patients in Arm A:
If hematological recovery is inadequate by Day 42 of any cycle, the Investigator should discuss 
appropriate patient management with the Sponsor before allowing the patient to continue with 
study drug treatment. If the patient is showing signs of response, the Investigator may retain the 
patient in the study, but should assess the potential for further prolonged periods of marrow 
suppression and the associated adverse events as part of this decision process. 
In the event that a patient requires a second dose reduction of systemic chemotherapy or the 
initial recovery of hematologic parameters took longer than 14 days even with growth factor 
support, the Investigator may also consider a single level reduction in the dose of APR-246 in 
conjunction with a further dose reduction of chemotherapy per Table 4.
Table 4. Dose Modification of Systemic Chemotherapy for Hematological Toxicities in Arm A
Chemotherapy Modification
Treatment Delay
APR-246 Dose Modification
Initial Dose Reduction
Less than 14 days
None
14 days or more
Reduce one level
Second Dose Reduction
Any
Reduce one level
For patients in Arm B:
If hematological recovery is inadequate by Day 42 of any cycle after cycle 2, the Investigator 
should discuss appropriate patient management with the Sponsor.
6.5.2.2
Non-Hematological Toxicity
Please see relevant sections below for specific management.
Patients unable to be dosed within 4 weeks of scheduled therapy should be discussed with the 
Sponsor to decide if to still proceed in the study.
6.5.2.2.1 Renal Impairment
The carboplatin dose should be calculated based on GFR. If renal function drops less than 
20 mL/min, the patient should be discontinued from treatment with carboplatin.
Dose modifications should not be required for PLD in patients with renal impairment.
6.5.2.2.2 Hepatic impairment
PLD can be administered to patients with liver metastases with concurrent elevation of bilirubin and 
liver enzymes up to 4 x the upper limit of the normal range. See Table 5 below. 


Aprea Therapeutics AB
Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
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Carboplatin: Transient increases in liver enzymes have been seen although no dose reduction is 
usually required. In severe hepatic dysfunction consider a dose reduction after discussing with the 
Sponsor.
Table 5. Dose Modification of PLD for Hepatic Impairment
Total bilirubin (mg/dL)
Total bilirubin (µmol/L)
PLD Dose
< 1.2
<20.52
100%
1.2 - 3.0 
20.52 – 51.3
75%*
>3.0
> 51.3
50%*
*If the patient tolerates the first dose without an increase in serum bilirubin or liver enzymes, the dose for the next 
cycle can be increased to the next dose level, i.e., if reduced by 25% for the first dose, increase to full dose for cycle 2; 
if reduced by 50% for the first dose, increase to 75% of full dose for cycle 2. The dosage can be increased to full dose 
for subsequent cycles if tolerated.
6.5.2.2.3 Cutaneous Toxicity (Palmar-Plantar Erthyrodysesthia (PPE)) 
Treat symptoms accordingly. Follow dosing guideline as per Table 6.
Table 6. Dose Modification of PLD for Cutaneous Toxicity
Time after prior PLD Dose
Toxicity Grade at
Current 
Assessment 
After Day 28 (week 4)
Days 35 and 42 (week 5)
> Day 42 (week 6)
Grade 1 
Redose unless patient has 
experienced a previous Grade 3 
or 4 skin toxicity, in which case 
wait an additional week
Redose unless patient has 
experienced a previous Grade 3 
or 4 skin toxicity, in which case 
wait an additional week
Decrease dose by 25 %; 
return to 4 week interval
Grade 2
Wait an additional week
Wait an additional week
Decrease dose by 25 %; 
return to 4 week interval
Grade 3 
Wait an additional week
Wait an additional week
Stop PLD
Grade 4 
Wait an additional week
Wait an additional week
Stop PLD
Grade 1 - mild erythema, swelling, or desquamation not interfering with daily activities
Grade 2 - erythema, desquamation, or swelling interfering with, but not precluding normal physical activities; small 
blisters or ulcerations less than 2 cm in diameter
Grade 3 - blistering, ulceration, or swelling interfering with walking or normal daily activities; cannot wear regular 
clothing
Grade 4 - diffuse or local process causing infectious complications, or a bedridden state or hospitalization
6.5.2.2.4 Stomatitis
Refer to Table 7. If delay has been necessary due to stomatitis, a change of cycle interval to five 
weeks is allowed if the Investigator judges it to be in the patient’s best interests.


Aprea Therapeutics AB
Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
APR-246
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Table 7. Dose Modification of PLD for Stomatitis
Time after prior PLD Dose
Toxicity Grade at Current 
Assessment 
After Day 28 (week 4)
Days 35 and 42 (week 5)
> Day 42 (week 6)
Grade 1 
Redose unless patient has 
experienced a previous 
Grade 3 or 4 stomatitis in 
which case wait an 
additional week
Redose unless patient has 
experienced a previous 
Grade 3 or 4 stomatitis in 
which case wait an 
additional week
Decrease dose by 25 %; 
return to 4 week interval
Grade 2
Wait an additional week
Wait an additional week
Decrease dose by 25 %; 
return to 4 week interval
Grade 3 
Wait an additional week
Wait an additional week
Stop PLD
Grade 4 
Wait an additional week
Wait an additional week
Stop PLD
Grade 1 - painless ulcers, erythema, or mild soreness
Grade 2 - painful erythema, edema, or ulcers, but can eat
Grade 3 - painful erythema, edema, or ulcers, but cannot eat
Grade 4 - requires parenteral or enteral support
6.5.2.2.5 Other Grade 3 or 4 Non-hematological toxicities
Table 8. Other Grade 3 or 4 Non-hematological Toxicities
Grade 3 toxicity
(except nausea & vomiting)
Reduce dose of PLD to 20 mg/m2 and/or reduce dose of 
carboplatin to AUC 4 provided toxicity has resolved to 
Grade 1.
If further toxicity occurs, an additional reduction may be 
made after discussion with Sponsor
Grade 4 toxicity
(except nausea & vomiting)
Withhold treatment and discuss with Sponsor
6.5.3
Hypersensitivity / Adverse Drug Reactions to Chemotherapy Agents
All patients will be carefully monitored for clinical features of hypersensitivity reactions. Should a 
hypersensitivity reaction to carboplatin occur during infusion, this must be discontinued and an 
attempt at desensitization may be made subsequently if deemed appropriate by the Investigator in 
discussion with the patient. The timing of this will be at the discretion of the Investigator depending 
on the initial dose of carboplatin received.
Desensitization should be performed according to local practices and monitoring. 
The desensitization procedure should take place with resuscitation facilities within easy access with 
regular observations and a trained nurse present throughout administration of APR-246 and 
chemotherapy. If at any point during the dose escalation allergic signs or symptoms are apparent, the 
carboplatin infusion must be discontinued.


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Protocol No. APR-407
PiSARRO: p53 Suppressor Activation in Recurrent High Grade Serous Ovarian Cancer, a Phase Ib/II Study 
of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
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All subsequent cycles should then be given using this procedure.
If it is not possible for the patient to continue to receive carboplatin due to unmanageable 
hypersensitivity, the Investigator in consultation with the Sponsor can consider either to remove the 
patient from the study or change to cisplatin monotherapy. Cisplatin monotherapy will be 
administered in place of the combination chemotherapy on day 4 of all remaining treatment cycles, 
up to a maximum of 6 cycles (including prior combination chemotherapy).
The cisplatin monotherapy should be administered, monitored and modified according to the local 
practices at the investigational site.
6.5.4
Cardiac Safety Monitoring in relation to Treatment with PLD
Whenever cardiomyopathy is suspected, i.e., the left ventricular ejection fraction (LVEF) has 
substantially decreased relative to pre-treatment values and/or LVEF is lower than a prognostically 
relevant value (e.g., < 45%), the benefit of continued therapy must be carefully evaluated against the 
risk of developing irreversible cardiac damage. Cardiology consultation is recommended.
6.5.5
Action to be taken in the Event of QT/QTc Prolongation
Although the risk of QT/QTc prolongation is considered to be very low, in the event of prolongation 
of the QT/QTc interval > 500 msec or an increase of > 60 msec over baseline, study treatment 
should be discontinued and appropriate close (continuous) ECG monitoring in a hospital setting 
should be initiated until the opinion of a cardiologist is obtained.
6.6
Concomitant Treatment and Prohibited Medication
Patients are allowed to receive supportive care therapies (including cytokine, growth factors) 
concomitantly during the trial.  
No anti-cancer therapy other than that given in this clinical trial; no immunotherapy; no hormonal 
cancer therapy; no radiation therapy (except palliative); and no experimental medications are 
permitted during the trial. All alternative therapies must first be approved by the Sponsor.
No poly (adenosine diphosphate [ADP]) ribose polymerase inhibitors are permitted until progression 
of disease (PD).
Concomitant use of paracetamol (acetaminophen) based compounds is allowed. However, caution 
should be taken when co-administrating APR-246 with high doses of paracetamol (i.e. 4 g/24 hrs).
Use of paracetamol must be terminated if any liver function tests increase above normal ranges is 
detected. 
Any disease progression that requires other specific antitumor therapy will be cause for 
discontinuation from the trial.
Antioxidants: Concomitant intake of acetylcysteine or other antioxidants might have a negative 
effect on the treatment efficacy and is therefore not recommended.


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Protocol No. APR-407
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of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
APR-246
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Anticoagulant therapy: Patients who are taking warfarin may participate in this trial; however, it is 
recommended that prothrombin time (INR and APTT) be monitored carefully at least once per week 
for the first month, then monthly if the INR is stable. Subcutaneous heparin is permitted.
Concurrent or procedural medications or therapy given to or taken by the patient will be recorded in 
the CRF along with the indication. All concomitant medications should be recorded for up to 30
days following the last protocol treatment. After this period, only relevant medication (e.g. 
medication in patients with treatment related AEs) will be recorded in the CRF.
Both generic and trade names may be recorded. However, the generic name is generally preferred 
because of its specificity, whereas trade names are preferred for combination products.
The potential interaction of APR-246 with other medicinal products has not been investigated.
6.7
Contraception
Female patients of childbearing potential (defined as < 2 years after last menstruation and not 
surgically sterile) and their male partners must use a highly effective method of contraception 
resulting in a low failure rate (i.e. less than 1% per year) during chemotherapy treatment and for at 
least six months thereafter. These methods of contraception according to the note for guidance on 
non-clinical safety studies for the conduct of human trials for pharmaceuticals (CPMP/ICH/286/95, 
modification) include consistent and correct use of hormone containing implants and injectables, 
combined oral contraceptives, hormone containing intrauterine devices, barrier methods with 
spermicide, true sexual abstinence when this is in line with the preferred and usual lifestyle of the 
patient and partner with vasectomy. Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods), declaration of abstinence for the duration of a trial, and withdrawal are not 
acceptable methods of contraception. If using hormonal contraception this method must be 
supplemented with a barrier method, preferably male condom (female condom and male condom 
should not be used together).
7.0
STUDY PROCEDURES
7.1
Schedule of Study Procedures
Study evaluations are summarized in the Table 9 and Table 10 below and described in Sections 7.2
through 7.2.7.
The Principal Investigator is responsible for ensuring that all staff involved in the study are familiar 
with the content of this section.


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of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
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Table 9. Schedule of Study Evaluations in Arm A
Pre-treatment
1
Cycle 1 
Cycle 2 and subsequent cycles
EoT14
FU15
Day
1
2
3
4
5
1
2
3
4
5
25-
28
Eligibility Criteria
X
Registration/Randomization and 
Informed Consent
X
Medical History 
X
X*
Quality of Life Questionnaires
X
X10
X
X9
Tumor Assessment2
X
X
X
X
Physical Exam/ECOG
X
X*
X
X
X11
Vital Signs
X
X
X
X
X
X
X
X
X
Hematology/Coagulation
X
X*
X*
X
Blood Chemistry
X
X*
X*
X
Creatinine Clearance
X
CA-125
X*
X*
X
X8
Urinalysis
X
X*
X*
Serum Pregnancy Test  (women of
child bearing potential)
X
LVEF3
X
X3
ECG4
X
X
Tumor Biopsy5 (optional)
X
X
Exploratory Biomarkers
X
X
X
X13
X7
X7
X7,13
X
X8
Administer APR-246
X
X
X
X
X
X
X
X
Administer Chemotherapy
X
X
Adverse Events and Concomitant 
Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
Survival
X12
Pharmacokinetics6
X
X
X
Examinations marked * need not be repeated if already performed within 3 days prior to Day 1.
1.
Pre-treatment evaluations are to be performed within 28 days of Day 1 of Cycle 1. 
2.
A CT scan/MRI should be performed at pre-treatment (within 4 weeks prior to day 1 of study treatment) and at the end of 
cycle 2 (within 7 days prior to the start of cycle 3), and at the end of cycle 4 (within 7 days prior to the start of cycle 5), after 
the last cycle, 2 months (± 2 weeks) after the end of treatment (EoT) visit and every 3 months (± 2 weeks) thereafter, until 
the documented disease progression, as determined by the Investigator at each site and defined by RECIST v1.1.
Confirmatory scans to be done at least 28 days after scan performed post last treatment cycle for all patients initially 
assessed as having a radiological response.
3.
LVEF assessed by echocardiography between day 21 of cycle 2 and start of cycle 3, and day 21 of cycle 4 and start of cycle 
5. LVEF is mandatory before each additional administration of PLD that exceeds a lifetime cumulative anthracycline dose 
of 450 mg/m2. Additional echocardiograms can be conducted if clinically indicated per institutional practices.


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4.
ECG will be monitored as per the standard of care for PLD treatment.
5.
One tumor biopsy to be performed within 4 weeks prior to day 1 APR-246 infusion and one tumor biopsy to be performed 
cycle 1, day 3, per laboratory manual (optional).
6.
For sparse PK sampling schedule on Cycle 1, days 1, 2, and 4, please refer to Section 8.4.
7.
Only Cycle 2 day 1, 4, 5 and Cycle 6, day 1.
8.
Blood samples should be taken at each follow up visit until progression, as per laboratory manual.
9.
To be performed the first 4 follow up visits only.
10. QoL to be performed at each radiological tumor assessment time point.
11. Physical examination only, excludes ECOG.
12. Patients to be followed until death. Survival after progression will be monitored (e.g. via telephone, via General Practitioner 
or via review of medical records) every 6 months. The start date of the first subsequent treatment will be collected and 
recorded.
13. 18-72h after the end of infusion of APR-246.
14. End of treatment (EoT) visit should take place 7 days after the completion of 6 cycles of chemotherapy (between day 28 and 
day 35 of cycle 6) or up to 30 ± 2 days after the last administration of APR-246 if treatment is stopped early for any reasons.
15. The first follow-up visit should commence 2 months (± 2 weeks) after the EoT visit. Subsequent follow-up visits should be 
performed every 3 months (± 2 weeks) until documented disease progression as defined by RECIST v1.1.


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Table 10. Schedule of Study Evaluations in Arm B
Pre-treatment 1
Cycle 1 
Cycle 2 and subsequent 
cycles 
EoT13
FU14
Day
1
2
3
4
1
2
3
4
25-
28
Eligibility Criteria
X
Registration/Randomization and 
Informed Consent
X
Medical History 
X
X*
Quality of Life Questionnaires
X
X9
X
X8
Tumor Assessment2
X
X
X
X
Physical Exam/ECOG
X
X*
X
X
X10
Vital Signs
X
X
X
Hematology/Coagulation
X
X*
X*
X
Blood Chemistry
X
X*
X*
X
Creatinine Clearance
X
CA-125
X*
X*
X
X7
Urinalysis
X
X*
X*
Serum Pregnancy Test (women of child 
bearing potential)
X
LVEF3
X
X3
ECG4
X
X
Tumor Biopsy (optional)
X5
Exploratory Biomarkers
X
X
X12
X6
X6,12
X
X7
Administer Chemotherapy
X
X
Adverse Events and Concomitant 
Medication
X
X
X
X
X
X
X
X
X
Survival
X11
Examinations marked with * need not be repeated if already performed within 3 days prior to Day 1.
1.
Pre-treatment evaluations are to be performed within 28 days of Day 1 of Cycle 1. 
2.
For patients in Arm B: A CT scan/MRI should be performed at pre-treatment (within 4 weeks prior to day 1 of 
chemotherapy administration) and at the end of cycle 2 (within 7 days prior to the start of cycle 3), and at the end of cycle 4 
(within 7 days prior to the start of cycle 5), after the last cycle, 2 months (± 2 weeks) after the EoT visit and every 3 months 
(± 2 weeks) thereafter, until the documented disease progression, as determined by the Investigator at each site and defined 
by RECIST v1.1. Confirmatory scans to be done at least 28 days after scan performed post last treatment cycle for all 
patients initially assessed as having a radiological response.
3.
LVEF assessed by echocardiography between day 21 of cycle 2 and start of cycle 3, and day 21 of cycle 4 and start of cycle 
5. LVEF is mandatory before each additional administration of PLD that exceeds a lifetime cumulative anthracycline dose 
of 450 mg/m2. Additional echocardiograms can be conducted if clinically indicated per institutional practices.
4.
ECG will be monitored as per the standard of care for PLD treatment.
5.
One tumor biopsy to be performed within 4 weeks prior to day 1 chemotherapy administration (optional).


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6.
Only cycle 2 days 1 and 2, and cycle 6 day 1. 
7.
Blood samples should be taken at each follow up visit until progression, as per laboratory manual.
8.
To be performed at the first 4 follow up visits only.
9.
QoL to be performed at each radiological disease assessment time point.
10. Physical examination only, excludes ECOG.
11. Patients to be followed until death. Survival after progression will be monitored (e.g. via telephone, via General Practitioner 
or via review of medical records) every 6 months. The start date of the first subsequent treatment will be collected and 
recorded.
12. 18-72h after the end of infusion of chemotherapy.
13. EoT visit should take place 7 days after the completion of 6 cycles of chemotherapy (between day 28 and day 35 of cycle 6) 
or up to 30 ± 2 days after the last administration of APR-246 if treatment is stopped early for any reasons.
14. The first follow-up visit should commence 2 months (± 2 weeks) after the EoT visit. Subsequent follow-up visits should be 
performed every 3 months (± 2 weeks) until documented disease progression as defined by RECIST v1.1. 


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7.2
Detailed Study Evaluations for Arm A and B 
The following sections provide details of the study evaluations to be conducted pre-treatment,
during study and in follow-up. Please refer to Table 9 for Arm A and Table 10 for Arm B for a 
complete schedule assessments required.
7.2.1
Registration /Informed Consent Form
Prior to performing any procedures or assessments, the nature of the study and the potential risks
associated with the trial will be explained to all patient candidates and written informed consent will 
be obtained. Patients who choose to participate will have to consent to the biobanking program and
will be asked to sign the mandatory section in the main study consent form related to biobank 
samples. Evaluations obtained as part of routine medical care and performed during the screening 
period may be used in place of the study specific evaluations. Patients will acknowledge and agree 
to the possible use of this information for the study by giving informed consent. 
7.2.2
Pre-treatment
All pre-treatment evaluations are to be performed within 28 days of day 1 unless otherwise noted. 
Please see Table 9 and Table 10 for treatment windows for individual evaluations.
Eligibility criteria: Including archived tumor sample review for positive IHC staining for 
p53.
Medical history.
Quality of Life Questionnaires
Tumor assessment: CT scan/MRI.
Physical examination: Height, weight, body surface area, and description of external signs 
of cancer. 
ECOG performance status.
Vital signs: Heart rate, blood pressure, respiratory rate and temperature. 
Hematology: Hemoglobin, hematocrit, MCV, platelet count, WBC and WBC differentials.
Coagulation: INR and APTT, if patient is receiving warfarin assessments should be done 
weekly. 
Blood chemistry: Sodium, potassium, calcium, magnesium, chloride, glucose, creatinine, 
total bilirubin, aspartate transaminase [AST], alanine transaminase [ALT], urea, total protein, 
albumin and lactic dehydrogenase [LDH], direct bilirubin and uric acid.  
Creatinine clearance: Calculated as per hospital practice.
Urinalysis: Dipstick for protein, glucose, bilirubin and blood (perform microscopy if more 
than one positive dipstick test).
Serum pregnancy test: For patients with reproductive potential.
LVEF: Assessed by echocardiography within 4 weeks prior to Day 1. MUGA may be used 


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as an alternative.
ECG: Standard 12-lead ECG.
Exploratory biomarkers: Archive pathology samples and blood samples to be sent for p53 
centralized analysis after registration. Refer to laboratory manual for detailed instructions.
Adverse events: from the date the Informed Consent form is signed. 
Concomitant medication.
7.2.3
Randomization
Randomization: Optimally performed prior to any biopsy. See Section 4.4 for procedure.
Tumor biopsy (optional): Arm A tumor biopsy to be performed within 28 days prior to 
cycle 1 day 1 APR-246 infusion. Arm B tumor biopsy to be performed within 28 days prior 
to cycle 1 chemotherapy administration. 
7.2.4
All Cycles, Days 1 - 28
Day 1 examinations marked * do not need to be repeated if already performed within 3 days prior to 
day 1 cycle 1.
Medical history: Only cycle 1*.
QoL questionnaires: To be completed at each radiological tumor assessment time point.
Tumor Assessments: CT scan/MRI at the end of cycle 2 (within 7 days prior to the start of 
cycle 3) and at the end of cycle 4 (within 7 days prior to the start of cycle 5).
Physical examination: Day 1*. Height, weight, body surface area, and description of 
external signs of cancer. 
ECOG performance status: Day 1. 
Vital signs: Arm A on Days 1, 2, 3 and 4. Arm B only on Day 1. Heart rate, blood pressure, 
respiratory rate and temperature. 
Hematology: Day 1* (repeat to follow up on AEs as appropriate). Hemoglobin, hematocrit, 
MCV, platelet count, WBC and WBC differentials.
Coagulation: Day 1*. INR and APTT, if patient is receiving warfarin assessments should be 
done weekly. 
Blood chemistry: Day 1*. (repeat to follow up on AEs as appropriate). Sodium, potassium, 
calcium, magnesium, chloride, glucose, creatinine, total bilirubin, aspartate transaminase 
[AST], alanine transaminase [ALT], urea, total protein, albumin, lactic dehydrogenase 
[LDH], direct bilirubin and uric acid.  
CA-125: Day 1*
Urinalysis: Day 1*. Dipstick for protein, glucose, bilirubin and blood (perform microscopy 
if more than one positive dipstick test).
LVEF: Assessed by echocardiography between day 21 of cycle 2 and start of cycle 3, and
day 21 of cycle 4 and start of cycle 5. LVEF is mandatory before each additional 


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administration of PLD that exceeds a lifetime cumulative anthracycline dose of 450 mg/m2.
Additional echocardiograms can be conducted if clinically indicated per institutional 
practices.
Tumor biopsy (optional): Arm A only. One tumor biopsy to be performed optimally at the 
end of APR-246 infusion on day 3 of the first cycle, however a biopsy obtained at the end of 
the APR-246 infusion on day 2 is acceptable. Refer to laboratory manual for detailed 
instructions.
Pharmacokinetics: Arm A only. On Cycle 1, days 1, 2, and 4; please refer to Section 8.4 for 
PK sampling time points.
Exploratory biomarkers: Arm A blood samples. Cycle 1 on days 1, 4 and 5. Cycle 2 on 
days 1, 4 and 5. Cycle 6 on day 1. Arm B blood samples. Cycle 1 and 2 on days 1 and 2.
Cycle 6 on day 1. Refer to laboratory manual for detailed instructions.
APR-246 administration: Arm A only on days 1, 2, 3 and 4.
Chemotherapy administration (Carboplatin and PLD): Arm A on day 4. Arm B on day 
1.
Adverse Events: All adverse events since the last visit should be recorded. Even though pre-
medicated, patients should be closely monitored.
Concomitant medications.
7.2.5
End of Treatment Visit
This visit should take place 7 days after the completion of 6 cycles of chemotherapy (between day 
28 and day 35 of cycle 6) or up to 30 ± 2 days after the last administration of APR-246 if treatment 
is stopped early for any reasons.  
Physical examination*: Height, weight, body surface area, and description of external signs 
of cancer. 
QoL questionnaires
Tumor Assessment: CT scan/MRI. If the patient has stopped APR-246 treatment prior to 
completion of 6 cycles, tumor assessment should be performed at end of treatment visit if not 
done at the last cycle.
ECOG performance status.
Hematology: Hemoglobin, hematocrit, MCV, platelet count, WBC and WBC differentials.
Coagulation: INR and APTT, if patient is receiving warfarin assessments should be done 
weekly. 
Blood chemistry: Sodium, potassium, calcium, magnesium, chloride, glucose, creatinine, 
total bilirubin, aspartate transaminase [AST], alanine transaminase [ALT], urea, total protein, 
albumin and lactic dehydrogenase [LDH], direct bilirubin and uric acid.  
CA-125.
ECG: Standard 12-lead ECG.
Exploratory biomarkers: Blood Sample. Refer to laboratory manual for detailed 
instructions.


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7.2.6
Follow-up Visits
The first follow-up visit should commence 2 months (± 2 weeks) after the end of treatment visit.
Subsequent follow-up visits should be performed every 3 months (± 2 weeks) until documented 
disease progression, as defined by RECIST v1.1.
Physical examination: Description of external signs of cancer until progression.
QoL questionnaires (first four follow up visits only)
CA-125: Disease will be followed by GCIG Criteria until progressive disease and then 
confirmed by CT scan/MRI.
Exploratory biomarkers: Blood samples taken at each visit until progression. Refer to 
laboratory manual for detailed instructions.
Tumor Assessment (by CT/MRI): Tumor assessments by a CT scan/MRI will be 
performed 2 months (± 2 weeks) after the end of treatment visit and every 3 months (± 2 
weeks) thereafter, until the documented disease progression, as defined by RECIST v1.1.
All patients will be followed until initial progression. Information on survival and subsequent 
therapies will be collected. 
7.2.7
After Progression
Survival after progression will be monitored every 6 months. This can be done remotely (e.g. via 
telephone, via General Practitioner or via review of medical records). The start date of the first 
subsequent treatment will be collected and recorded.
7.3
Adverse Events
7.3.1
Definition of Adverse Events
An adverse event (AE) is the development of an undesirable medical condition or the deterioration 
of a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product. An undesirable medical condition can be 
symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results 
of an investigation (e.g., laboratory findings, electrocardiogram). In clinical studies, an AE can 
include an undesirable medical condition occurring at any time, including run-in or washout periods, 
even if no study treatment has been administered.
Any deterioration of the disease under study and associated symptoms or findings should not be 
regarded as an AE as far as the deterioration can be anticipated (see Section 7.3.3.8).
The term adverse event is used generally to include any AE whether serious or non-serious.


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of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
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7.3.2
Definitions of Serious Adverse Events
A serious adverse event (SAE) is an AE occurring during any study phase (i.e., run-in, treatment, 
washout, follow-up), that fulfills one or more of the following criteria:
Results in death
Is immediately 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)
Requires in-patient hospitalization or prolongation of existing hospitalization, unless the 
hospitalization is for:
o
Routine treatment or monitoring of the disease under study, including hospitalization 
due to trial related procedures (e.g. APR-246 administration) not associated with any 
deterioration of the patient’s status;
o
Elective treatment (planned before signing Informed Consent) for a pre-existing 
condition that is unrelated to the disease under study and has not worsened since 
signing Informed Consent;
o
Treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions for an SAE;
o
Social reasons, respite care in the absence of a medical condition.
Results in persistent or significant disability/incapacity or substantial disruption of the ability 
to conduct normal life functions
Is or results in a congenital abnormality or birth defect
Is an important medical event (may not be immediately life-threatening or result in death or 
hospitalization) that may jeopardize the patient or may require medical intervention to 
prevent one of the outcomes listed above.
For further guidance on the definition of a SAE, see Section 7.3.3.10 below and also Appendix III of 
this Clinical Study Protocol.
7.3.3
Recording of Adverse Events
7.3.3.1
Time Period for Collection of Adverse Events
AEs will be collected throughout the study, from informed consent until 30 days after the last 
administration of study treatment.
SAEs occurring in this period should be reported to the Theradex® Safety Desk in the usual manner 
(see Section 7.3.4).
Events which are unequivocally due to a worsening of a patient’s condition, attributable to the 
disease for which the investigational product is being studied, which occur after informed consent 
but before the patient is registered, should not be reported as an AE or SAE during the study.


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of Systemic Carboplatin/Pegylated Liposomal Doxorubicin Combination Chemotherapy With or Without 
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7.3.3.2
Follow-up of Unresolved Adverse Events
All AEs should be followed until they are resolved or until the end of treatment (EoT) visit, 
whichever comes first. All AEs that are still ongoing after the EoT visit, should be followed on a 
regular basis, according to the Investigator’s clinical judgment, until the event has resolved or until 
the Investigator assesses it as chronic and all queries have been resolved. After the EoT visit, AEs 
that are unrelated to APR-246 (serious or non-serious) or related but not serious, do not require 
further recording in the eCRF. For related SAEs that have been resolved, the event resolved date and 
the outcome of resolved or resolved with sequelae, as appropriate, should be recorded on the eCRF 
and the SAE Report Form. The Sponsor retains the right to request additional information for any 
patient with ongoing AE(s) at the end of the study, if judged necessary.
If an Investigator learns of any SAEs, including death, at any time following 30 days after the last 
administration of study treatment and he/she considers there is a reasonable possibility that the SAE 
is related to the study treatment, the Investigator should notify Theradex® Safety Desk.
7.3.3.3
Variables
The following variables will be collected for each AE: 
AE diagnosis/description
The date the AE started and stopped
CTCAE version 4.0 grade
Whether the AE is serious or not and the reason(s) it is serious
Investigator causality rating against the investigational product (yes or no) 
Action taken with regard to study treatment
Outcome
For SAEs other variables will be collected including treatment given for the event.
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria in Section 7.3.2. An AE of severe intensity need not 
necessarily be considered serious. For example, nausea that persists for several hours may be 
considered severe nausea, but not a SAE. On the other hand, a stroke that results in only a limited 
degree of disability may be considered a mild stroke but would be a SAE.
The grading scales found in the current National Cancer Institute CTCAE version 4.0 will be 
utilized for all events with an assigned CTCAE grading. For those events without assigned CTCAE 
grades, the recommendation in the CTCAE criteria that converts mild, moderate, and severe events 
into CTCAE grades should be used. A copy of the current CTCAE version can be downloaded from 
the Cancer Therapy Evaluation Program website (http://ctep.cancer.gov).


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7.3.3.4
Causality Collection
The Investigator will assess causal relationship between investigational product and each AE, and 
answer ‘yes’ or ‘no’ to the question: ‘Do you consider that there is a reasonable possibility that the 
event may have been caused by the study treatment?’
For SAEs causal relationship will also be assessed for other medication and study procedure(s).
A guide to the interpretation of the causality question is found in Appendix III of this Clinical Study 
Protocol.
7.3.3.5
Adverse Events based on Signs and Symptoms
All AEs spontaneously reported by the patient or reported in response to the open-ended and non-
leading verbal questioning from the study personnel (e.g., “How are you feeling?” “Have you had 
any health problems since the previous visit/you were last asked?”), or revealed by observation will 
be collected and recorded in the eCRF. Where possible a diagnosis should be recorded, rather than 
recording a list of signs and symptoms. However, if a diagnosis is known and there are other signs 
or symptoms that are not generally part of the diagnosis, the diagnosis and each sign or symptom 
will be recorded separately.
7.3.3.6
Adverse Events based on Examinations and Tests
The results from protocol mandated laboratory tests, vital signs, ECGs and other safety assessments 
will be summarized in the Clinical Study Report. Deterioration as compared to pre-treatment in 
these parameters will therefore only be reported as AEs if they fulfill any of the criteria for a SAE or 
are the reason for modifying the study treatment unless clearly due to progression of disease under 
study (see Section 7.3.3.8).
If deterioration in a laboratory value, vital sign, ECG, or other safety assessment is associated with 
clinical events, the clinical event will be reported as an AE and the associated laboratory result or 
other finding will be considered as additional information. Wherever possible the reporting 
Investigator will use the clinical, rather than the laboratory term (e.g., anemia versus low 
hemoglobin value). In the absence of clinical events, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s).
Deterioration of a laboratory value that is unequivocally due to disease progression should not be 
reported as an AE.
Any new or aggravated clinically relevant abnormal medical finding at a physical examination as 
compared with the pre-treatment assessment will be reported as an AE.
7.3.3.7
Hy’s Law
Cases where a patient shows elevations in liver biochemistry may require further evaluation and 
occurrences of AST or ALT elevations in liver biochemistry that may require further evaluation


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should be reported as SAEs. Please refer to Appendix IV for further instruction on cases of increases 
in liver biochemistry and evaluation of Hy’s Law.
7.3.3.8
Disease Progression
Disease progression can be considered as a worsening of a patient’s condition attributable to the 
disease for which the investigational product is being studied. It may be an increase in the severity 
of the disease under study and/or increases in the symptoms of the disease. The development of 
new, or progression of existing metastasis to the primary cancer under study should be considered as 
disease progression and not an AE. Events that are unequivocally due to disease progression 
should not be reported as AEs during the study.
7.3.3.9
New Cancers
The development of a new cancer should be regarded as an AE and will generally meet at least one 
of the serious criteria. New cancers are those that are not the primary reason for the administration 
of the study treatment and have been identified after the patient’s inclusion in this study. They do 
not include metastases of the original cancer.
7.3.3.10 Handling of Deaths
All deaths that occur during the study, or within the 30-day follow-up period after the administration 
of the last dose of investigational product, should be reported as follows:
Death, which is unequivocally due to disease progression, should be communicated to the study 
monitor at the next monitoring visit and should be documented in the eCRF module, but should 
not be reported as a SAE during the study.
Where death is not clearly due to disease progression of the disease under study the AE causing 
the death should be reported to the Theradex® Safety Desk as an SAE within 24 hours. The 
report should contain a comment regarding the co-involvement of progression of disease, if 
appropriate, and should assign a single primary cause of death together with any contributory 
causes.
Deaths with an unknown cause should always be reported as a SAE but every effort should be 
made to establish a cause of death. A post-mortem may be helpful in the assessment of the cause 
of death, and if performed a copy of the post-mortem results (with translation of important parts 
into English) should be reported in an expedited fashion to the Theradex® Safety Desk within the 
usual timeframes.
7.3.4
Reporting of Serious Adverse Events
All SAEs have to be reported to the Theradex® Safety Desk, whether or not considered causally 
related to the investigational product, or to the study procedure(s). All SAEs will be recorded in the 
eCRF.
If any SAE occurs in the course of the study (from signing of informed consent up to 30 days after 
last dose), then Investigators or other site personnel must inform the Theradex® Safety Desk


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immediately, or no later than 24 hours of when he or she becomes aware of it.
For fatal or life-threatening adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately. Investigators or other site personnel must inform the 
Theradex® Safety Desk of any follow-up information on a previously reported SAE immediately, or 
no later than 24 hours of when he or she becomes aware of it.
All SAEs require that a Serious Adverse Event Report Form be completed and forwarded either via 
fax or as a PDF via email to the Theradex® Safety Desk at the fax number or email listed below 
within 24 hours of becoming aware of the event. The fax and telephone numbers listed below may 
be used during both business and non-business hours. During non-business hours a recorded 
message will provide the caller with the contact information for the on-call monitor.
EU and US sites will report SAEs to:
Theradex® (Europe) Ltd. Safety Desk
Telephone: +44 (0) 1293 510 319
Fax: +44 (0) 1293 510322
Email: SafetyDeskEurope@theradex.co.uk
7.4
Pregnancy
All pregnancies and their subsequent outcome (spontaneous miscarriage, elective termination, 
ectopic pregnancy, normal birth or congenital abnormality) should be reported to the Theradex®
Safety Desk using the appropriate forms.
7.4.1
Maternal Exposure
If a patient becomes pregnant during the course of the study investigational product should be 
discontinued immediately.
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product under study may have interfered with the effectiveness of a contraceptive 
medication. Congenital abnormalities/birth defects and spontaneous miscarriages should be reported 
and handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of a pregnancy should be followed up and documented even if the patient was withdrawn 
from the study.
If a pregnancy occurs during exposure to investigational product or in the 30 days after 
discontinuing investigational product, then Investigators or other site personnel must inform the 
Theradex® Safety Desk immediately, or no later than 24 hours of when he or she becomes aware 
of it.
The same timelines apply when outcome information is available.


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8.0
EFFICACY ASSESSMENTS
Patients with measurable disease will be assessed by standard criteria. 
For patients in Arm A or Arm B: A CT scan/MRI should be performed at pre-treatment (within 4 
weeks prior to day 1 of study treatment) and at the end of cycle 2 (within 7 days prior to the start of 
cycle 3), and at the end of cycle 4 (within 7 days prior to the start of cycle 5), and after the last 
cycle. At subsequent follow-up visits, tumor assessments by CT scan/MRI will be performed 2
months (± 2 weeks) after the end of treatment visit and every 3 months (± 2 weeks) thereafter, until 
the documented disease progression, as determined by the Investigator at each site and defined by 
RECIST v1.1.
Central reading for all scans will be performed during the study. After CT/MRI acquisition, the 
exam will be transferred for central reading by two expert readers (see Radiology Manual for 
further details). The central reader will visualize the image in order to evaluate the clinical response 
based on RECIST v1.1 criteria. The central review will be performed in batches throughout the 
study. Treatment decisions should be based upon results of the local review.
8.1
Definitions
Response and progression will be evaluated in this study using the international criteria (version 1.1) 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee [14] and 
CA-125 definitions for response and progression agreed by the Gynecological Cancer Intergroup 
(GCIG) [12].
Changes in only the largest diameter (unidimensional measurement) of the tumor lesions are used in 
the RECIST v1.1 criteria. Note: Lesions are either measurable or non-measurable using the criteria 
provided below. The term “evaluable” in reference to measurability will not be used because it does 
not provide additional meaning or accuracy.
8.1.1
Measurable Disease
Measurable disease is defined by the presence of at least one measurable lesion. Measurable lesions 
are defined as those that can be accurately measured in at least one dimension [longest diameter 
(LD) in the plane of measurement to be recorded] with a minimum size of: 
10 mm by CT scan (CT scan slice thickness no greater than 5 mm)
10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured with 
calipers should be recorded as non-measurable)
20 mm by chest x-ray
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a lymph node 
must be 
15 mm in short axis when assessed by CT scan (CT scan slice thickness no greater than 
5 mm).


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8.1.2
Non-measurable Disease
All other lesions (or sites of disease), including small lesions (longest diameter < 10 mm or 
pathological lymph nodes with 
10 to < 15 mm short axis) are considered non-measurable disease. 
Lesions 
considered 
truly
non-measurable
include: 
leptomeningeal 
disease, 
ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal 
masses/abdominal organomegaly identified by physical exam and not followed by CT or MRI.
Bone lesions, cystic lesions and lesions previously treated with local therapy must be considered as 
follows:
8.1.2.1
Bone Lesions
Bone scan, PET scan or plain films are not considered adequate imaging techniques to measure 
bone lesions. However, these techniques can be used to confirm the presence or disappearance 
of bone lesions.
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross sectional imaging techniques (i.e., CT scan or MRI) can be considered 
as measurable lesions if the soft tissue component meets the definition of measurability 
described above.
Blastic bone lesions are non-measurable.
8.1.2.2
Cystic Lesions
Lesions that meet the criteria for radiographically defined simple cysts should not be considered 
malignant lesions (neither measurable nor non-measurable) since they are, by definition, simple 
cysts.
‘Cystic lesions’ thought to represent cystic metastases can be considered measurable lesions, if 
they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions.
8.1.2.3
Lesions with Prior Local Treatment
Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been demonstrated 
progression in the lesion. 
8.1.3
Target Lesions
All measurable lesions up to a maximum of two lesions per organ and five lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at pre-treatment. Target lesions should be selected on the basis of their size (lesions with 
the longest diameter) and their suitability for accurate repeated measurements (either by imaging 


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techniques or clinically). A sum of the diameters (longest for non-nodal lesions, short axis for nodal 
lesions) for all target lesions will be calculated and reported as the pre-treatment sum diameters. The 
pre-treatment sum diameters will be used as reference by which to characterize the objective tumor
response.
8.1.4
Lymph Node Assessment
For lymph nodes, measurements should be made of the short axis, which is defined as perpendicular 
to the LD of node assessed in the plane of measurement:
Target lesion if short axis 
15 mm
Non-target lesion if short axis is 10 but < 15 mm
Normal if short axis < 10 mm
For pre-treatment, add the actual short axis measurement to the sum of LD of non-nodal lesions.
8.1.5
Non-target Lesions
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at pre-treatment. Measurements of these lesions are 
not required and these lesions should be followed as “present,” “absent,” or in rare cases 
“unequivocal progression.” In addition, it is possible to record multiple non-target lesions involving 
the same organ as a single item on the case report form (e.g., ‘multiple enlarged pelvic lymph nodes’ 
or ‘multiple liver metastases’).
8.2
Guidelines for Evaluation of Measurable Disease
All measurements should be taken and recorded in metric notation using a ruler or calipers. All pre-
treatment evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment.
(Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable. If the Sponsor/Investigator thinks it appropriate to include them, the 
conditions under which such lesions should be considered must be defined in the protocol.) 
The same method of assessment and the same technique (CT and/or MRI) should be used to 
characterize each identified and reported lesion at pre-treatment and during follow-up. Imaging-
based evaluation is preferred to evaluation by clinical examination when both methods have been 
used to assess the antitumor effect of a treatment.
Clinical lesions. Clinical lesions will only be considered measurable when they are superficial and
10 mm diameter as assessed using calipers (e.g., skin nodules). In the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended. When lesions can be evaluated by both clinical exam and imaging, imaging 
evaluation should be undertaken since it is more objective and may be reviewed at the end of the 
study.


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Chest x-ray. Chest CT is preferred over chest x-ray, particularly when progression is an important 
endpoint. Lesions on chest x-ray may be considered measurable if they are clearly defined and 
surrounded by aerated lung. 
Conventional CT scan and MRI. This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. When CT scans have slice 
thickness > 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. 
MRI is acceptable in certain situations (e.g., for body scans).
Ultrasound (US). US should not be used to measure tumor lesions. US examinations cannot be 
reproduced in their entirety for independent review at a later date because they are operator 
dependent. If new lesions are identified by US, confirmation by CT or MRI is advised. If there is 
concern about radiation exposure at CT, MRI may be used instead of CT.
Endoscopy, Laparoscopy. The utilization of these techniques for objective tumor evaluation is not 
advised. However, such techniques can be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials where recurrence following complete response 
or surgical resection is an endpoint.
Tumor markers. Tumor markers alone cannot be used to assess objective tumor response. If 
markers are initially above the upper normal limit, they must normalize for a patient to be 
considered in complete clinical response. 
Cytology, Histology. These techniques can be used to differentiate between partial responses (PR) 
and complete responses (CR) in rare cases (e.g., residual lesions in tumor types such as germ cell 
tumors, where known residual benign tumors can remain).
8.3
Response Criteria
8.3.1
Evaluation of Target Lesions
Complete Response (CR):
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to 
< 10 mm.
Partial Response (PR):
At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the pre-treatment sum diameters.


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Progressive Disease (PD):
At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the 
pre-treatment sum if that is the smallest). In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: the appearance of one or more 
new lesions is also considered progression.)
Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
diameters while on study.
8.3.1.1
Assessment of Target Lymph Nodes
Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded (measured in the same anatomical plane as the pre-treatment exam), even if the nodes 
regress to below 10 mm on study. In order to qualify for CR, each node must achieve a short axis 
< 10 mm. For PR, SD and PD, the actual short axis measurement of the nodes is to be included in 
the sum of target lesions.
8.3.1.2
Target Lesions that Become “Too Small to Measure”
All lesions (nodal and non-nodal) recorded at pre-treatment should have their actual measurements 
recorded at each subsequent evaluation, even when very small (e.g., 2 mm). If it is the opinion of the 
radiologist that the lesion has disappeared, the measurement should be recorded as 0 mm. If the 
lesion is believed to be present and is faintly seen but too small to measure, a default value of 5 mm 
should be assigned.  
8.3.1.3
Lesions that Split or Coalesce on Treatment
When non-nodal lesions fragment, the longest diameters of the fragmented portions should be added 
together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between them may 
be maintained that would aid in obtaining diameter measurements of each individual lesion. If the 
lesions have truly coalesced such that they are no longer separable, the vector of the longest 
diameter should be the maximal longest diameter for the ‘coalesced lesion.’
8.3.2
Evaluation of Non-target Lesions
Complete Response (CR):
Disappearance of all non-target lesions and normalization of tumor
marker level. All lymph nodes must be non-pathological in size 
(< 10 mm short axis).
Non-CR/Non-PD:
Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits.


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Progressive Disease (PD):
Unequivocal progression of existing non-target lesions. To achieve 
‘unequivocal progression’ on the basis of the non-target disease, 
there must be an overall level of substantial worsening in non-
target disease such that, even in the presence of SD or PR in target 
disease, the overall tumor burden has increased sufficiently to 
merit discontinuation. (Note: the appearance of one or more new 
lesions is also considered progression.)
8.3.2.1
New Lesions
The finding of a new lesion should be unequivocal (i.e., not attributed to differences in scanning 
technique, change in imaging modality, or findings thought to represent something other than tumor,
such as a ‘new’ healing bone lesion). A lesion identified on a follow-up study in an anatomical 
location that was not scanned at pre-treatment is considered a new lesion and will indicate disease 
progression. If a new lesion is equivocal, continued therapy and follow-up evaluation will clarify if 
it represents truly new disease. If repeat scans confirm this is definitely a new lesion, then 
progression should be declared using the date of the initial scan.
8.3.2.2
Evaluation of Best Overall Response by RECIST v1.1
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). The patient’s best overall response assignment will depend on 
findings of both target and non-target disease and will also take into consideration the appearance of 
new lesions. 
It is assumed that at each protocol-specified time point, a response assessment occurs. Table 11
provides a summary of the overall response status calculation at each time point for patients who 
have measurable disease at pre-treatment. When patients have non-measurable disease, Table 12
should be used.


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Table 11. Time Point Response: Patients with Target (+/- non-target) Disease
Target Lesions
Non-target 
Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR / non-
PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not 
all evaluated
No
PR
SD
Non-PD or not 
all evaluated
No
SD
Not all 
evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR=complete response, PR=partial response, SD=stable disease
PD=progressive disease, NE=inevaluable
Table 12. Time Point Response: Patients with Non-target Disease Only
Non-target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR / non-PD
No
Non-CR / non-PD*
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR=complete response; PD=progressive disease; NE=inevaluable
* Non-CR/non-PD is preferred over SD for non-target disease
Best response determination for studies where confirmation of CR or PR is required: Complete or 
partial responses may be claimed only if the criteria for each are confirmed by a repeat assessment at 
least 4 weeks later. In this circumstance, the best overall response can be interpreted as in Table 13.


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Table 13. Best Overall Response when Confirmation of CR and PR is Required
Overall response
First time point
Overall response
Subsequent time point
BEST overall response
CR
CR
CR
CR
PR
SD, PD or PR*
CR
SD
SD provided minimum criteria for SD duration met, otherwise PD
CR
PD
SD provided minimum criteria for SD duration met, otherwise PD
CR
NE
SD provided minimum criteria for SD duration met, otherwise NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD duration met, otherwise PD
PR
NE
SD provided minimum criteria for SD duration met, otherwise NE
NE
NE
NE
CR=complete response; PR=partial response; SD=stable disease; PD=progressive disease; NE=inevaluable
* If CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting 
PR criteria relative to pre-treatment, makes the disease PD at that point (since disease must have reappeared 
after CR). Best response would depend on whether minimum duration for SD was met. However, sometimes 
‘CR’ may be claimed when subsequent scans suggest small lesions were likely still present and in the fact 
patient had PR, not CR, at the first time point. Under these circumstances, the original CR should be changed to 
PR and the best response is PR.
8.3.2.3
Evaluation of Best Overall Response in Patients with Initial Measurable Disease and 
who are also Evaluable by CA-125
For patients who are measurable by one or both of the criteria and who may have events at different 
time points evaluation should be determined according to Table 14. In patients who have measurable 
disease by both criteria, the date of response will be the date of the earlier of the 2 events if this 
approach to combined response reporting is to be used. 
In the combined assessment of CA-125 and RECIST v1.1 response, the following algorithm applies 
when determining the best overall response:
If patients have progressive disease (PD) according to RECIST v1.1 within 28 days of 
CA-125 response, they are clas
If the PD according to RECIST v1.1 is longer than 28 days before or after the CA-125
Patients whose best response according to RECIST v1.1 is stable disease but who have a 
CA-125
CA-125 responders.


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Table 14. Best Overall Response in Patients with Initial Measurable Disease and Evaluable by CA-125,
Combining Both Criteria
Target 
Lesion *
Non Target *
New Lesion
CA-125
Overall Best
Response
CR
CR
No
Normal
CR
Best 
RECIST 
v1.1 
response for CR and PR 
also requires it to be 
confirmed 
and 
maintained for at least 28 
days
CR
Non CR Non PD
No
Not PD
PR
CR
CR
No
PR not normal
PR
CR
NE
No
PR
PR
PR
Non-PD or NAE
No
Not PD
PR
NAE
Non PD
No
PR
PR
PD or New >28 days from CA-125 PR‡
PR
PR
SD§
Non PD
No
PR
PR
SD§
Non-PD or NAE
No
Not PR and not 
PD
SD
PD or New < 28 days from CA-125 PR‡
PR
PD
PD 
Any
Yes or No
Any
PD
Any
PD
Yes or No
Any
PD
Any
Any
Yes
Any
PD
Any
Any
Yes or No
PD
PD
*According to RECIST v1.1 criteria
‡Patients who have a CA-125 response that occurs more than 28 days from PD according to RECIST v1.1 are 
considered a PR, according to best response, but PD if the RECIST v1.1 PD is within 28 days of CA-125 response.
§ For SD, follow-up measurements must have met the SD criteria at least once after study entry at a minimum interval 
of not less than 6-8 weeks 
NE Not evaluated; NAE not all evaluated.
8.3.3
Confirmatory Measurement/Duration of Response
8.3.3.1
Confirmation According to RECIST v1.1
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by repeat 
assessments that should be performed no less than 4 weeks after the criteria for response are first 
met. In the case of SD, follow-up measurements must have met the SD criteria at least once after 
study entry at a minimum interval of not less than 6-8 weeks.
8.3.3.2
Definition of Response According to CA-125
A CA-125
CA-125 levels from a pretreatment 
least 28 days. Patients can be 
evaluated according to CA-125 only if they have a pretreatment sample that is at least twice the 
upper limit of the reference range and within 2 weeks before starting the treatment.


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To calculate CA-125 responses accurately, the following rules apply:
Intervening samples and the 28-
(within an assay variability of 10%) the previous sample.
Variations within the reference range of CA-125 levels will not interfere with the response 
For each patient, the same assay method must be used, and the assay must be tested in a 
quality control scheme.
Patients are not evaluable by CA-125 if they have received mouse antibodies [unless the 
[12]] or if 
there has been medical and/or surgical interference with their peritoneum or pleura during 
the previous 28 days (e.g., paracentesis). If assessing therapy that includes 2 treatment 
modalities for relapse (e.g., surgery and chemotherapy), any CA-125 response results from 
both treatment modalities. CA-125 cannot distinguish between the effects of the 2 
treatments.
The date when the CA-125
CA-125 response. 
8.3.3.3
Duration of Overall Response
The duration of overall response is measured from the time measurement criteria are met for CR or 
PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started).
The duration of overall CR is measured from the time measurement criteria are first met for CR until 
the first date that recurrent disease is objectively documented.
8.3.3.4
Duration of Stable Disease
Stable disease is measured from the start of the treatment until the criteria for progression are met, 
taking as reference the smallest measurements recorded since the treatment started.
8.3.4
Progression-free Survival
Progression-free survival (PFS) is defined as the time from randomization to the time of disease 
progression or relapse (according to RECIST v1.1. PFS by CA-125 criteria is a separate secondary 
endpoint) or death, or to the date of last tumor assessment without any such event (censored 
observation) and includes any of the following
Occurrence (clinically or imaging signs) of any new lesion
Increase in measurable and/or non-measurable tumor as defined by the RECIST v1.1 criteria
CA-125 elevation as defined by the GCIG criteria


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Deterioration in general health attributable to the disease.
8.3.4.1
Progression on Therapy and Recurrence after Therapy According to 
CA-125
v1.1 but can also be based on 
serum CA-125
change in tumor size should always take precedence over CA-125
measurable disease is reducing in size during treatment but the CA-125 results suggest progression 
is stable but CA-125
discussed with the Sponsor. If patients are having routine CA-125 measurements as part of follow-
up, the date of progression is likely to be several months earlier than symptoms or signs of 
progression develop [15]. Therefore, when categorizing patients according to time to progression, it 
CA-125 alone, CA-125 and 
symptoms, and RECIST v1.1). 
8.3.4.2
Evaluation of Progression According to CA-125
Progression or recurrence based on serum CA-125
on the basis of a 
progressive serial elevation of serum CA-125 according to the following criteria and Table 15:
A. Patients with elevated CA-125 pretreatment and normalization of CA-125 must show 
evidence of CA-125 greater than, or equal to, 2 times the upper limit of the reference range 
on 2 occasions at least 1 week apart or
B. Patients with elevated CA-125 before treatment, which never normalizes, must show 
evidence of CA-125 greater than, or equal to, 2 times the nadir value on 2 occasions at least 
1 week apart or
C. Patients with CA-125 in the reference range before treatment must show evidence of CA-125
greater than, or equal to, 2 times the upper limit of the reference range on 2 occasions at least 
1 week apart.
CA-125
noted. Patients are not evaluable by CA-125 if they have received mouse antibodies (unless the 
d by human antimouse antibody) or if there has been
medical and/or surgical interference with their peritoneum or pleura (e.g., paracentesis) during the 
previous 28 days.
A patient may be declared to have PD on the basis of either the objective RECIST v1.1 criteria or 
the CA-125 criteria. The date of progression will be the date of the earlier of the 2 events if both are 
documented.


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For the purposes of study objectives and analysis of the study end-points, PD will declared based on 
objective RECIST v1.1 data only. PFS by CA-125 criteria is a separate secondary end-point.
Table 15. Definition of Progression after First-line Therapy in Ovarian Cancer as Proposed by the GCIG
GCIG 
Subcategorized 
group
RECIST
Measurable/non-measurable disease
CA-125
A
Compared to baseline (or lowest sum while on 
study if less than baseline), a 20% increase in sum 
of longest diameters (RECIST v1.1 definition)
or
Any new lesions (measurable or non-measurable).
or
Unequivocal increase in non-target disease.
Date of PD: date of documentation of
increase or new lesions
AND/
OR
CA-125 >2x ULRR 
documented on two 
occasions*
Date of PD: first date of 
the CA-125 elevation to 
> 2x ULRR
B
As for A
CA-125 > 2x nadir value 
on two occasions*
Date of PD: first date of 
the CA-125 elevation to 
> 2x nadir value
C
As for A
As for A
CA-125 levels sampled after patients received mouse antibodies (unless the assay used has been shown not to be 
peritoneum or pleura during the previous 28 days should not be taken into account.
*Repeat CA-125
CA-125 level.
8.4
Pharmacokinetics
Sparse blood sampling for APR-246 pharmacokinetic (PK) measurements will be performed from
all patients in Arm A at days 1, 2 and 4 in Cycle 1 (Table 16).
Please refer to the laboratory manual for detail instructions on processing of the pharmacokinetic 
samples.


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Table 16: Sparse PK Blood Sampling Time Points for APR-246 in Cycle 1 (Arm A)
Day 1
Before infusion
0-2 h prior APR-246 infusion (nominal time point 0 h)
At end of rapid phase
45 min (at the end of first part of infusion) (nominal time point 0.75 h)
At end of infusion
5 min relative to the end of infusion (nominal time point 6 h)
After infusion
30-60 min AFTER infusion (nominal time point 7 h)
Day 2
Before infusion
0-2 h prior APR-246 infusion (nominal time point 24 h)
Day 4
Before infusion
0-2 h prior APR-246 infusion (nominal time point 0 h)
At end of rapid phase
45 min (at the end of first part of infusion) (nominal time point 0.75 h)
At end of infusion
5 min relative to the end of infusion (nominal time point 6 h)
After infusion
30-60 min AFTER infusion (nominal time point 7 h)
8.5
Pharmacodynamics
8.5.1
Optional Tumor Biopsy
Archived tumor tissue (FFPE sections) from all patients will be reviewed by a gynecological
pathologist to confirm the diagnosis of high grade serous ovarian cancer, and positive IHC staining 
for p53. In addition, these samples will be used to determine p53 status by a central laboratory.
Additional analysis may include biomarkers and evaluation of tumor cell DNA. 
Optional paired tumor biopsies will be collected in Arm A: one prior to treatment and the other 
during treatment (optimally within the last 30 minutes of the APR-246 infusion on day 3 of the first 
cycle, however a biopsy obtained at the end of the APR-246 infusion on day 2 is acceptable). For 
Arm B, one tumor biopsy to be performed prior to chemotherapy.
Two tumor cores will be taken at each biopsy, one will be flash frozen and one will be formalin 
fixed.
The choice of the tumor lesion is at the Investigator’s discretion. If either tumor biopsy fails, the 
patient can still be included in the trial. The reasons for failure to obtain a biopsy must be recorded 
in the eCRF. If the pre-treatment tumor biopsy is not obtained, no further tumor biopsies will be 
attempted.
Any lesion that is used for biopsy purposes should be recorded as a non-target lesion only.
The following assessments may be performed by Aprea Therapeutics AB or a central laboratory 
appointed by Aprea Therapeutics AB (please refer to Laboratory Manual).
Immunohistochemistry for tumor cellularity and p53 protein staining and other IHC markers 
(i.e. BRCA1, ER stress markers)
RNA/DNA extraction for microarray tumor gene expression profiling
Proteomics - Lysates for reverse phase proteomics 
Specimens may be stored for future evaluation of APR-246 in target tissue.


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The quality and quantity of the biopsy will determine which analyses are to be performed. The 
mutational analyses will be done in batches and the results will not be reported to the trial site
during the treatment period.
8.6
Exploratory Biomarker Research
Serum, plasma, whole blood and tumor samples will be collected from all patients and stored for
retrospective exploratory analyses. These analyses may include (but are not necessarily limited to):
Predictive markers of efficacy, tolerability and clinical pharmacology
Biomarkers of acquired or innate resistance to APR-246
Circulating free tumor DNA
The results of the exploratory biomarker research will be reported separately and will not be part of 
the Clinical Study Report.
A blood sample will be taken pre-treatment for collection of germ line DNA in order to allow 
comparison of germ-line and tumor cell DNA sequence.
The results of exploratory biomarker research may be pooled with data from other studies with 
APR-246 to generate hypotheses to be tested in future studies.
8.7
Biological Sample Handling
Details of sample collection, processing, shipping and storage will be described in the Laboratory 
Manual. Each sample for exploratory research will be identified with the study number and patient 
enrolment number. In this way exploratory biomarker and genetic data may be correlated with 
clinical data. Samples will be destroyed in the case of withdrawal of consent and regulatory audit 
enabled. Where genetic analysis will be undertaken the processes adopted for the coding and storage 
of samples will be more stringent in order to maintain patient confidentiality. As an added 
precaution, irrespective of the type of sample, the DNA sample will be assigned a unique number 
replacing the information on the sample tube. Thereafter, the DNA sample will be identifiable by the 
unique DNA number only. The DNA number will be used to identify the sample and corresponding 
data at the Aprea Therapeutics AB’s designated contract laboratory. No personal details identifying 
the individual will be available to any person (Aprea Therapeutics AB or contract laboratory staff) 
working with the DNA. The samples and data for genetic analysis in this study will be single coded. 
The link between the patient enrolment code and the DNA number will be maintained and stored in 
a secure environment, with restricted access. The link will be used to identify the relevant DNA 
samples for analysis, facilitate correlation of genotypic results with clinical data, allow regulatory 
audit and to trace samples for destruction in the case of withdrawal of consent when the patient has 
requested disposal/destruction of collected samples not yet analyzed.
8.8
Chain of Custody of Biological Samples
A full chain of custody is maintained for all samples throughout their lifecycle. The Principal 
Investigator at each center keeps full traceability of collected biological samples from the patients 


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while in storage at the center until shipment or disposal (where appropriate) and keeps 
documentation of receipt of arrival. The Principal Investigator will also ensure that access to the 
samples while in storage at the study center will be limited only to those people for whom access is 
required. The sample receiver keeps full traceability of the samples while in storage and during use 
until used or disposed of or until further shipment and keeps documentation of receipt of arrival. 
Aprea Therapeutics AB keeps oversight of the entire life cycle through internal procedures, 
monitoring of study sites and auditing of external laboratory providers. Samples retained for further 
use will be registered in the Aprea Therapeutics AB biobank system during the entire life cycle.
Samples will be stored for up to 15 years.
8.9
Withdrawal of Informed Consent for Donated Biological Samples
If a patient withdraws consent to the use of voluntarily donated biological samples, then the samples 
will be disposed of/destroyed, and the action documented. If samples are already analyzed, Aprea 
Therapeutics AB is not obliged to destroy the results of this research. As collection of the genetic 
blood sample is a voluntary part of the study then the patient may continue in the study. 


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9.0
STATISTICS
9.1
Primary Endpoint
The primary endpoint is progression-free survival (PFS) based on BICR and is defined as the 
number of days from the date of randomization to the date of objective disease progression or 
relapse (according to RECIST v1.1 only) or death due to any cause, whichever occurs first. If 
neither event occurs, PFS will be censored at the date of the last evaluable tumor assessment. 
Symptomatic deterioration is not objective disease progression.
9.2
Secondary Endpoints
Secondary endpoints include:
Best overall response and overall response rate (according to RECIST v1.1 and GCIG Criteria)
Duration of response (complete or partial response)
PFS by assessment of CA-125 (according to GCIG Criteria)
Overall survival
Safety profile based on AEs and laboratory assessments
Evaluation of biomarkers and tumor activity based on CA-125
Quality of Life assessment  using EORTC Ovarian (QLQ-30 and QLQ-OV28) and the 
Functional Assessment of Cancer Therapy-Ovarian (FACT-O)
9.3
Sample Size 
Adaptive Sample Size
The trial will enroll up to a maximum of 400 patients, randomized between two arms (treatment and 
control).
This phase II study has a flexible sample size. The purpose is to use a smaller sample size with very 
small or very large observed effect sizes, and a larger sample size where observed effect sizes are 
promising but more data are needed. For small observed effect sizes (with typically smaller sample 
sizes), the study results will have traditional phase II interpretations. However, for moderate/large 
observed effect sizes (with potentially larger sample sizes), the design is intended to provide 
sufficient evidence to justify regulatory conditional approval.
9.4
Analysis Populations
All randomized subjects will be analyzed according to the group in which they were randomized.
Intent-to-Treat (ITT): All randomized patients will be included in the intent-to-treat (ITT) 
population. The ITT population will serve as the primary analysis population for efficacy.


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Safety Evaluable Population: All randomized patients who received any amount of study medication 
(APR-246, carboplatin, or PLD) will be considered evaluable for safety, regardless of the duration 
of treatment. This population will be used to summarize all safety parameters.
Efficacy Evaluable Population: All randomized patients with pre-treatment measurable disease by 
RECIST v1.1 who have at least one radiographic assessment after pre-treatment or discontinue 
study medication early due to disease progression and have a TP53 mutation will be considered 
evaluable for efficacy. The efficacy-evaluable population will be the secondary analysis population 
for efficacy. 
9.5
Statistical Methods
All demographic data and disease-related characteristics will be summarized using descriptive
statistics (count and percent, mean, median, standard deviation, minimum, maximum), separately for 
phase Ib and phase II parts of the study.
9.5.1
Safety Analysis
Safety data will be summarized for the safety evaluable population. These data will include adverse 
events and laboratory parameters. Adverse event terms will be coded using the Medical Dictionary 
for Drug Regulatory Activities (MedDRA®, version 16.0 or higher). Adverse events will be 
summarized by body system, preferred term, severity, and relationship to treatment. Serious adverse 
events, deaths, and AEs leading to early discontinuation of study drug will be summarized. 
Laboratory parameters will be summarized by maximum NCI-CTCAE-4.0 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. 
Data summaries will include only treatment-emergent adverse events (TEAEs), defined as events 
occurring on or after Day 1 Cycle 1 up to and including 30 days after last dose.
9.5.2
Phase II Analysis
9.5.2.1
Primary analysis
At the final analysis (which occurs after 12 months of follow-up after the last patient is enrolled), a 
one-sided p-value is calculated for a stratified logrank test comparing treatment versus control. This 
corresponds to a formal test of the null hypothesis that the survival (event free) distribution of the 
treatment group is less than or equal to the survival distribution of the control group, i.e. 
where 
and 
are the survival distributions for the treatment and control groups, 
respectively, and 
denotes observation time. The stratification factors for the test include 


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previous PFI (6-12, 12-24 months), BRCA status (known positive versus other) and prior lines of 
platinum-based treatment (1,2). The treatment will be considered superior to control if the 
corresponding one-sided p-value is less than or equal to 0.023. If the p-value is greater than 0.023
but less than 0.10, there may be sufficient promise to conduct another trial. The significance level of 
0.023 is selected to control the overall Type I error of the adaptive design to be less than 0.025, as 
shown via simulation.
9.5.2.2
Secondary analysis
Tumor response data will be summarized at each tumor assessment cycle using the following 
response categories: Complete Response (CR), Partial Response (PR), Stable Disease (SD), 
Progressive Disease (PD) and Non-Evaluable (NE). Best overall response for a patient is the best 
response recorded from the start of the treatment until disease progression or death. Best overall 
response will be summarized as the number (%) of patients in each category of response (CR, PR, 
SD, PD, and NE). PR and CR must be confirmed by a repeat assessment at least 28 days after the 
criteria are first met for the response to be considered a PR or CR.
The overall response rate is defined as the percentage of patients with a confirmed response of CR 
or PR in a given population.
The duration of response (confirmed CR or PR) is defined as the number of days from the date of 
initial response (not the confirmation date) to the date of objective disease progression or death due 
to any cause, whichever occurs first. If neither event occurs, duration of response will be censored at 
the date of the last evaluable tumor assessment. Symptomatic deterioration is not objective disease 
progression.
Overall survival (OS) is defined as the number of days from the date of randomization to the date of 
death. In the event of no death, overall survival will be censored at the last known alive date.
PFS by assessment of CA-125 will be analyzed. CA-125 progression is defined according to the 
Gynecologic Cancer InterGroup (GCIG) criteria. The relationship between CA-125 progression and 
radiological disease progression will be evaluated.
PFS, OS and duration of response will be analyzed using Kaplan-Meier methodology. Kaplan Meier 
curves will be plotted. Median survival and duration times will be estimated and their 95% 
confidence intervals based on Brookmeyer-Crowley methodology will be calculated. In addition, 
hazard ratios and 95% confidence intervals will be provided. For the overall response rate and 
categorical response rates, 95% confidence intervals will be calculated based on Clopper-Pearson 
methodology.
9.5.3
Pharmacokinetic Analysis
APR-246 concentrations will be determined by a validated HPLC tandem mass spectrometry 


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(LC/MS/MS) method and calculated PK parameters (Cl, Vss, Cmax, AUC0-24, AUC0- and t1/2) of 
APR-246 will be determined.
Individual and mean profiles of APR-246 concentrations will be presented graphically. Protocol-
specified blood sampling times will be used in the graphical presentation.
No formal statistical analysis beyond descriptive statistics is planned. For each PK parameter, 
individual and mean data and summary statistics (including number of patients, arithmetic mean, 
geometric mean, SD, CV, median, Min and Max) will be presented.
9.6
Randomization/Stratification
In Phase II, patients will be centrally randomized in a 1:1 ratio to receive the carboplatin/PLD 
chemotherapy regimen with or without APR-246. Permuted block randomization will be used to 
randomize patients to study treatment. Study treatment will not be blinded.
The stratification factors to be used are: 
Platinum-free interval after previous platinum based regimen. >6-12 months vs. >12 to <24 
months
Prior Lines of Platinum Treatment. One line vs. two lines
BRCA status. Known positive vs. Other
9.7
Statistical Modeling for Interim Analyses 
Although the final analysis for the primary endpoint is a frequentist (stratified logrank) test, the 
model underlying the adaptive sample size selection is Bayesian in nature. As shown via simulation 
in the Appendix V , the design has control of Type I error rate.
9.7.1
Control Hazard Model
Let 
be the progression event time (in months) for the primary endpoint for the ith patient, where 
an event represents a negative outcome for the patient. We model the event times for the control arm 
as piecewise exponential: 
where 
represents the set of baseline hazard rates (events per month) within each 
segment. The hazard is assumed to be constant within each segment, , and modeled with prior 
where the gamma distribution has the following density function: 


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The 4 segments of the model are defined in Table 17, along with the parameters of the non-
informative prior distributions. 
Table 17. Prior Parameters for the Control Hazard Model
Segment ( )
Interval(months)
1
0 - 6
1
1
2
6 - 12 
1
1
3
12 - 18 
1
1
4
18 -
1
1
9.7.2
Model
The event times for the treatment group is also modeled as piecewise exponential, with hazard rates 
where 
is the log hazard ratio for treatment relative to control. By convention, hazard ratios less 
than one indicate treatment benefit. The log hazard ratio has the non-informative prior 
and is assumed to be constant over time.
9.7.3
Quantities of Interest
9.7.3.1 Probability Superior to Control by the Target HR
Let the event hazard ratio for treatment versus control be denoted by HR 
. At each interim 
analysis, we calculate the probability of being superior to control by assessing the posterior 
distribution of the hazard ratio relative to a targeted 0.8: 
9.7.3.2 Predictive Probability of Success
At each interim analysis, we also calculate the predictive probability of success (PPoS) if accrual is 
halted at the current sample size and all patients are followed for a minimum of 12 months. For each 
iteration in the MCMC algorithm after burn-in, event times are imputed for each patient without an 
observed event among patients current enrolled, creating a single imputed data set for each MCMC 
iteration. A stratified logrank test is performed on each imputed data set, and PPoS is equal to the 
proportion of imputed trials with a one-sided p-value less than 0.023.
Although not currently included in the simulations, PPoS will also use longitudinal modeling of CA-
125 to better inform the predictive probability calculation. Neither the CA-125 data nor the 
longitudinal model will be included in the final analysis; rather the data are used to better inform the 


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decision of stopping accrual for predicted success.
9.8
Adaptive Sample Size
The design uses adaptive sample size selection. This section will describe the allocation and 
decision rules. 
9.8.1
Timing of Interim Analyses
Interim analyses will occur when 150, 200, 250, 300, and 350 patients are enrolled.
9.8.2
Allocation
The trial will enroll up to a maximum of 400 patients, with randomization to treatment and control 
in a fixed 1:1 ratio. Stratified randomization will be used. The stratification factors are prior lines of 
platinum-based treatment (1,2), platinum free interval (6-12, 12-24 months) and BRCA status 
(known positive versus other).
9.8.3
Criteria for Stopping Accrual
9.8.3.1 Stopping for predicted success
At each interim analysis beginning at 200 patients enrolled, the trial may stop enrollment for 
expected success if 
where 
= 0.95 for each interim. If a success stopping rule is met, then a final analysis will be 
conducted 12 months after the last patient is enrolled. Additionally, data will remain blinded and the 
Sponsor will be informed by the DSMB that the study has reached a stopping boundary for 
predicted success. The trial will not stop for predicted success unless at least 200 patients are 
enrolled, per safety concerns.  Hence, the first interim at 150 patients will only stop for a small 
observed effect.  
9.8.3.2 Stopping for Small Observed Effect
At each interim analysis beginning at 150 patients enrolled, the trial may stop enrollment early for a 
small observed effect size if 
where 
= 0.30 for each interim. If this stopping rule is met, the Sponsor will be informed by the 
DSMB that the study has reached a stopping boundary for a small observed effect. The Sponsor may 
then choose to unblind data and release results prior to 12 months after the last patient is enrolled.  If 


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data are unblinded and results are released, regulatory approval will not be sought and results may 
be used for the planning of future trials. Otherwise, the Sponsor may choose to continue to follow 
currently enrolled patients in a blinded manner until 12 months after the last patient is enrolled.
9.8.3.3 Stopping Boundaries
The stopping boundaries for the interim analyses are provided in Table 18.
Table 18. Stopping Boundaries for Success and Small Effect Size
Interim 
150
0.30 
-
200
0.30
0.95
250
0.30
0.95
300
0.30
0.95
350
0.30
0.95
9.8.4
Operating Characteristics
Complete operating characteristics (including power and Type I error) are provided in the Statistical 
Appendix (See Appendix V) for a variety of scenarios. In general the design has about 0.70 power 
for detecting a hazard ratio of 0.70 or smaller with one-sided Type I error less than 0.025.


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10.0
QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES
10.1 Monitoring of the Study and Regulatory Compliance
The project manager, or designee, will make an initiation site visit to each institution to review the 
protocol and its requirements with the Investigator(s), inspect the drug storage area, and fully inform 
the Investigator of his/her responsibilities and the procedures for assuring adequate and correct 
documentation. During the initiation site visit the case report forms (CRFs) will be reviewed. Other 
pertinent study materials will also be reviewed with the Investigator’s research staff. During the 
course of the study, the monitor will make regular site visits in order to review protocol compliance, 
examine CRFs and individual patient’s medical records and assure that the study is being conducted 
according to pertinent regulatory requirements. All CRF entries will be verified with source 
documentation. The review of medical records will be done in a manner to assure that patient 
confidentiality is maintained. 
10.2 Curricula Vitae of Investigators
All Principal Investigators and Sub-investigators will be required to provide a current signed and 
dated curriculum vitae and evidence of GCP training to Theradex .
10.3 Protocol Modifications
No modification of the protocol should be implemented without the prior written approval of the 
Sponsor or the Sponsor’s representative (Theradex ). Any such changes which may affect a 
patient’s treatment or informed consent, especially those increasing potential risks, must receive 
prior approval by the IRB/IEC. The exception to this is where modifications are necessary to 
eliminate an immediate hazard to trial patients, or when the change involves only logistical or 
administrative aspects of the trial (e.g. change in monitor, change in telephone number). Other 
administrative revisions which may impact the clinical portion of a study will be duly reported to the 
IRB/IEC by the Principal Investigator.
10.4 Publication Policy
This is a collaborative EUTROC study. The first publication will include all patients. Centers
recruiting 10 evaluable patients will be entitled to nominate one co-author. The highest recruiting 
center would be entitled to be the first author on the first publication of the phase 2 study. However, 
the Chief Investigator would be the senior author. Contribution to sample collection and analysis for 
the translational components of the study will be assessed on a case by case basis. The Investigator 
agrees to inform the Sponsor of any other publication or presentations on the study. All manuscripts, 
abstracts or presentations (in outline form with copies of slides if available) will be submitted to the 
Sponsor and Theradex
at least 30 days prior to the submission of the data for publication in order 
for the Sponsor to protect proprietary information. The Sponsor will review the submitted material 
within a reasonable period of time and will not unreasonably withhold publication permission.


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11.0 ETHICAL CONSIDERATIONS
11.1 Informed Consent
The Investigator will obtain written informed consent from each patient, or their authorized 
representative, participating in the study. The form must be signed, witnessed and dated prior to any 
study-specific procedures being performed. The informed consent form will contain all the Essential 
Elements of Informed Consent set forth in 21 CFR, Part 50, the European Union Directive 
2001/20/EC and its associated Detailed Guidances, European Union GCP Directive 2005/28/EC, the 
ICH Guideline for Good Clinical Practice, Section 4.8, and the terms of the Declaration of Helsinki 
(2013). Copies of the signed document should be given to the patient and filed in the Investigator’s 
study file, as well as the patient’s medical record if in conformance with the institution’s Standard 
Operating Procedures. 
In cases where minors or incapacitated patients are to be included, two sets of information sheets 
might be needed according to national regulations (not applicable for the PiSARRO). In addition to 
the information given to the patient’s parent or legal representative, the patient should be given 
information according to his/her capacity to understand. This information should include, where 
appropriate, a statement that the patient’s decision not to participate or to withdraw from a trial will 
be respected, even if consent is given by the parent/legal representative.
In all instances the Principal Investigator or an appropriately qualified delegee should consent the 
patient to the study. The patient should be given adequate time to read the information provided and 
consider whether she wants to participate in the study.  
Only adult women who are mentally competent will be in enrolled and treated in this study. 
11.2 Institutional Review Board/Independent Ethics Committee/Regulatory 
The study will not be initiated without approval of the appropriate Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) and compliance with all administrative 
requirements of the governing body of the institution as well as the national Competent Authority 
(CA) in each country. This protocol, consent procedures, and any amendments must be approved by 
the IRB/IEC/CA 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/CA will be 
kept informed by the Investigator, Theradex or the Sponsor, as required by national regulations, as
to the progress of the study as well as to any serious and unexpected adverse events. 
11.3 Patient Privacy 
In order to maintain patient confidentiality, all case report forms, study reports and communications 
relating to the study will identify patients by initials and assigned patient numbers; patients should 


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not be identified by name. In accordance with local, national or federal regulations, the Investigator 
will allow the Sponsor or designee personnel access to all pertinent medical records in order to 
verify the data gathered on the case report forms and to audit the data collection process. Regulatory 
agencies such as the US Food and Drug Administration (FDA) and the UK Medicine and Healthcare 
Products Regulatory Agency (MHRA) may also request access to all study records, including source 
documentation for inspection. Clinical information will not be released without the written 
permission of the patient as outlined in the patient consent form.
12.0 DATA HANDLING AND RECORD KEEPING
12.1 Data to be Recorded Directly in the Case Report Form
Not applicable.
12.2 Recording of Data
Data collected during the study will be recorded in the patient’s electronic Case Report Form 
(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 in a timely manner. Should any value be 
significantly different from normal, the Investigator will comment in the appropriate sections 
provided in the CRF.
The Investigator will provide access to his/her original records to permit a representative from the 
Sponsor to verify the proper transcription of data.  
12.3 Study Records
European laws require that the Investigator maintain all study records (excluding the patient’s 
medical files, see below):
- for at least 15 years after completion or discontinuation of the trial,
- or for at least two years after the granting of the last marketing authorization in the European 
Community (EC) and where there are no pending or contemplated marketing applications in the EC,
- or for at least two years after the formal discontinuation of clinical development of the 
investigational product.
Patient’s medical files should be retained in accordance with applicable legislation and in 
accordance with the maximum period of time permitted by the hospital, institution or private 
practice.


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13.0
REFERENCES
1.
Brown, J.M. and B.G. Wouters, Apoptosis, p53, and Tumor Cell Sensitivity to Anticancer 
Agents. Cancer Research, 1999. 59(7): p. 1391-1399.
2.
van Oijen, M.G.C.T. and P.J. Slootweg, Gain-of-Function Mutations in the Tumor 
Suppressor Gene p53. Clinical Cancer Research, 2000. 6(6): p. 2138-2145.
3.
Wiman, K.G., Strategies for therapeutic targeting of the p53 pathway in cancer. Cell Death 
Differ, 2006. 13(6): p. 921-6.
4.
Ahmed, A.A., et al., Driver mutations in TP53 are ubiquitous in high grade serous 
carcinoma of the ovary. The Journal of Pathology, 2010. 221(1): p. 49-56.
5.
Kastan, M.B., Wild-Type p53: Tumors Can't Stand It. Cell, 2007. 128(5): p. 837-840.
6.
Reid, B. M., Permuth, J. B., & Sellers, T. A. Epidemiology of ovarian cancer: a review.
Cancer Biology & Medicine, 2017. 14(1), 9–32. 
7.
Hennessy, B.T., R.L. Coleman, and M. Markman, Ovarian cancer. The Lancet, 2009.
374(9698): p. 1371-1382.
8.
Pujade-Lauraine, E., et al., Pegylated Liposomal Doxorubicin and Carboplatin Compared 
With Paclitaxel and Carboplatin for Patients With Platinum-Sensitive Ovarian Cancer in 
Late Relapse. Journal of Clinical Oncology, 2010. 28(20): p. 3323-3329.
9.
Seidman, J.D., et al., The Histologic Type and Stage Distribution of Ovarian Carcinomas of 
Surface Epithelial Origin. International Journal of Gynecologic Pathology, 2004. 23(1): p. 
41-44.
10.
Risch, H.A., et al., Prevalence and Penetrance of Germline BRCA1 and BRCA2 Mutations in 
a Population Series of 649 Women with Ovarian Cancer. American journal of human 
genetics, 2001. 68(3): p. 700-710.
11.
Reles, A., et al., Correlation of p53 Mutations with Resistance to Platinum-based 
Chemotherapy and Shortened Survival in Ovarian Cancer. Clinical Cancer Research, 2001. 
7(10): p. 2984-2997.
12.
Rustin, G.J., et al., Definitions for response and progression in ovarian cancer clinical trials 
incorporating RECIST 1.1 and CA 125 agreed by the Gynecological Cancer Intergroup 
(GCIG). Int J Gynecol Cancer, 2011. 21(2): p. 419-23.
13.
Hume, R., Prediction of lean body mass from height and weight. J Clin Pathol, 1966. 19(4): 
p. 389-91.
14.
Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: Revised RECIST 
guideline (version 1.1). European journal of cancer (Oxford, England : 1990), 2009. 45(2): p. 
228-247.
15.
Rustin, G.J., et al., Early versus delayed treatment of relapsed ovarian cancer (MRC 
OV05/EORTC 55955): a randomised trial. Lancet, 2010. 376(9747): p. 1155-63.


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Appendix I: 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 house work, office work.
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% 
of waking hours.
4
Completely disabled.  Cannot carry on any self-care.  Totally confined to 
bed or chair.
5
Dead.


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Appendix II: New York Heart Association Heart Failure Classification
Functional Capacity 
Objective Assessment 
Class I. Patients with cardiac disease but without 
resulting limitation of physical activity. Ordinary 
physical activity does not cause undue fatigue, 
palpitation, dyspnea, or anginal pain.
A. No objective evidence of cardiovascular 
disease.
Class II. Patients with cardiac disease resulting 
in slight limitation of physical activity. They are 
comfortable at rest. Ordinary physical activity 
results in fatigue, palpitation, dyspnea, or anginal 
pain.
B. Objective evidence of minimal cardiovascular 
disease.
Class III. Patients with cardiac disease resulting 
in marked limitation of physical activity. They 
are comfortable at rest. Less than ordinary 
activity causes fatigue, palpitations, dyspnea, or 
anginal pain.
C. Objective evidence of moderately severe 
cardiovascular disease.
Class IV. Patients with cardiac disease resulting 
in inability to carry on any physical activity 
without discomfort. Symptoms of heart failure or 
the anginal syndrome may be present even at rest. 
If any physical activity is undertaken, discomfort 
is increased.
D. Objective evidence of severe cardiovascular 
disease
The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of 
Diseases of the Heart and Great Vessels. 9th ed. Boston, Mass: Little, Brown & Co; 1994:253-256


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Appendix III: Further Guidance on the Definition of a Serious Adverse Event and 
Interpreting the Causality Question
Further Guidance on the Definition of a Serious Adverse Event
Life threatening
‘Life-threatening’ means that the patient was at immediate risk of death from the AE as it occurred 
or it is suspected that use or continued use of the product would result in the patient’s death. ‘Life-
threatening’ does not mean that had an AE occurred in a more severe form it might have caused 
death (e.g. hepatitis that resolved without hepatic failure).
Hospitalization
Out-patient treatment in an emergency room is not in itself a serious AE, although the reasons for it 
may be (e.g. bronchospasm, laryngeal edema). Hospital admissions and/or surgical operations 
planned before or during a study are not considered AEs if the illness or disease existed before the 
patient was enrolled in the study, provided that it did not deteriorate in an unexpected way during 
the study.
Important medical event or medical intervention
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life-threatening or result in 
death, hospitalization, disability or incapacity but may jeopardize the patient or may require medical 
intervention to prevent one or more outcomes listed in the definition of serious. These should 
usually be considered as serious. Simply stopping the suspect investigational medicinal product 
(IMP) does not mean that it is an important medical event; medical judgment must be used.
Examples of such events are:
Angioedema not severe enough to require intubation but requiring i.v. hydrocortisone 
treatment,
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine,
Intensive treatment in an emergency room or at home for allergic bronchospasm,
Blood dyscrasias (e.g. neutropenia or anemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalization,
Development of drug dependency or drug abuse.
A Guide to Interpreting the Causality Question
The following factors should be considered when deciding if there is a “reasonable possibility” that 
an AE may have been caused by the IMP.
1. Time Course. Exposure to suspect IMP. Has the patient actually received the suspect IMP? 
Did the AE occur in a reasonable temporal relationship to the administration of the suspect 
IMP?


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2. Consistency with known drug profile. Was the AE consistent with the previous knowledge 
of the suspect IMP (pharmacology and toxicology) or drugs of the same pharmacological 
class? OR could the AE be anticipated from its pharmacological properties?
3. Dechallenge experience. Did the AE resolve or improve on stopping or reducing the dose of 
the suspect IMP?
4. No alternative cause. The AE cannot be reasonably explained by another etiology such as the 
underlying disease, other drugs, other host or environmental factors.
5. Rechallenge experience. Did the AE reoccur if the suspect IMP was reintroduced after 
having been stopped? Rechallenge is not normally recommended or supported.
6. Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship?
A “reasonable possibility” could be considered to exist for an AE where one or more of these factors 
exist. In contrast, there would not be a “reasonable possibility” of causality if none of the above 
criteria apply or where there is evidence of exposure and a reasonable time course but any 
dechallenge (if performed) is negative or ambiguous or there is another more likely cause of the AE.
In difficult cases, other factors could be considered such as:
Is this a recognized feature of overdose of the IMP
Is there a known mechanism?
Ambiguous cases should be considered as being a “reasonable possibility” of a causal relationship 
unless further evidence becomes available to refute this. Causal relationship in cases where the 
disease under study has deteriorated due to lack of effect should be classified as no reasonable 
possibility.


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Appendix IV: Actions Required in Cases of Increases in Liver Biochemistry and Evaluation of 
Hy’s Law
1.
Introduction
This Appendix describes the process to be followed in order to identify and appropriately report 
cases of Hy’s Law.  It is not intended to be a comprehensive guide to the management of elevated 
liver biochemistries.  
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry. The Investigator is responsible for determining whether a patient meets potential Hy’s 
Law (PHL) criteria at any point during the study.
The Investigator participates, together with Aprea Therapeutics AB’s representatives, in review and 
assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria are met.  HL 
criteria are met if there is no alternative explanation for the elevations in liver biochemistry other 
than Drug Induced Liver Injury (DILI) caused by the Investigational Medicinal Product (IMP). 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for reporting 
Adverse Events (AE) and Serious Adverse Events (SAE) according to the outcome of the review 
and assessment in line with standard safety reporting processes.
2.
Definitions
Potential Hy’s Law (PHL)
Norm
following the start of study medication  irrespective of an increase in Alkaline Phosphatase (ALP).
Hy’s Law (HL)
ther reason, other than the IMP, 
can be found to explain the combination of increases, eg, elevated ALP indicating cholestasis, viral 
hepatitis, another drug.  
For PHL and HL the elevation in transaminases must precede or be coincident with (i.e. on the same 
day) the elevation in TBL, but there is no specified timeframe within which the elevations in 
transaminases and TBL must occur.
3.
Identification of potential hy’s law cases
In order to identify cases of PHL it is important to perform a comprehensive review of laboratory 
data for any patient who meets any of the following identification criteria in isolation or in 


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combination:
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will:
Determine whether the patient meets PHL criteria (see Section 2 of this Appendix for definition) 
by reviewing laboratory reports from all previous visits
Promptly enter the laboratory data into the laboratory CRF
4.
Follow-up
1.1. Potential Hy’s Law Criteria not met
If the patient does not meet PHL criteria the Investigator will:
Perform follow-up on subsequent laboratory results according to the guidance provided in the 
Clinical Study Protocol.
1.2. Potential Hy’s Law Criteria met
If the patient does meet PHL criteria the Investigator will:
Determine whether PHL criteria were met at any study visit prior to starting study treatment (See 
Section 6 of this Appendix)
Notify the Theradex representative who will then inform Aprea Therapeutics AB
The Medical Monitor contacts the Investigator, to provide guidance, discuss and agree an approach 
for the study patients’ follow-up and the continuous review of data.  Subsequent to this contact the 
Investigator will:
Monitor the patient until liver biochemistry parameters and appropriate clinical symptoms and 
signs return to normal or baseline levels, or as long as medically indicated 
Investigate the etiology of the event and perform diagnostic investigations as discussed with the 
Medical Monitor. 
Complete the relevant eCRF pages as information becomes available 
If at any time (in consultation with the Medical Monitor) the PHL case meets serious criteria, 
report it as an SAE using standard reporting procedures
5.
Review and Assessment of potential Hy’s law cases
The instructions in this Section should be followed for all cases where PHL criteria are met.
No later than 3 weeks after the biochemistry abnormality was initially detected, the Medical Monitor 
contacts the Investigator in order to review available data and agree on whether there is an 
alternative explanation for meeting PHL criteria other than DILI caused by the IMP.  The Medical 


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Monitor and Aprea Therapeutics AB will also be involved in this review together with other patient
matter experts as appropriate.  
According to the outcome of the review and assessment, the Investigator will follow the instructions 
below.
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:
If the alternative explanation is not an AE, record the alternative explanation on the appropriate 
CRF
If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF accordingly and 
follow the SAE reporting processes as defined in Section 7.3.4 of this protocol
If it is agreed that there is no explanation that would explain the ALT or AST and TBL elevations 
other than the IMP:
Report an SAE (report term ‘Hy’s Law’) according to Theradex standard processes 
o
The ‘Medically Important’ serious criterion should be used if no other serious criteria 
apply
o
As there is no alternative explanation for the HL case, a causality assessment of ‘related’ 
should be assigned.
If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary to assess 
whether or not the case meets the criteria for HL, then it is assumed that there is no alternative 
explanation until such time as an informed decision can be made:
Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and causality 
assessment as per above
Continue follow-up and review according to agreed plan.  Once the necessary supplementary 
information is obtained, repeat the review and assessment to determine whether HL criteria are 
met.  Update the SAE report according to the outcome of the review
6.
Actions required when potential Hy’s law criteria are met before and after starting study 
treatment 
This section is applicable to patients who meet PHL criteria on study treatment having previously 
met PHL criteria at a study visit prior to starting study treatment.
At the first on study treatment occurrence of PHL criteria being met the Investigator will:
Determine if there has been a significant change in the patients’ condition# compared with the 
last visit where PHL criteria were met#
o
If there is no significant change no action is required
o
If there is a significant change notify the Theradex representative, , then follow the 
subsequent process described is Section 1.2 of this Appendix


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# A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any of the 
individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in 
combination, or a clinically relevant change in associated symptoms.  The determination of whether 
there has been a significant change will be at the discretion of the Investigator, this may be in 
consultation with the Medical Monitor if there is any uncertainty.
7.
Actions required for repeat episodes of potential hy’s law
This section is applicable when a patient meets PHL criteria on study treatment and has already met 
PHL criteria at a previous on study treatment visit.
The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) of PHL is 
based on the nature of the alternative cause identified for the previous occurrence.  
The Investigator should determine the cause for the previous occurrence of PHL criteria being met 
and answer the following question:
Was the alternative cause for the previous occurrence of PHL criteria being met found to be the 
disease under study e.g. chronic or progressing malignant disease, severe infection or liver 
disease,  or did the patient meet PHL criteria prior to starting study treatment and at their first on 
study treatment visit as described in Section 6 of this Appendix.
If No: follow the process described in Section 1.2 of this Appendix
If Yes:
Determine if there has been a significant change in the patient’s condition# compared with when 
PHL criteria were previously met
If there is no significant change no action is required
If there is a significant change follow the process described in Section 1.2 of this Appendix
# A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any of the 
individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in 
combination, or a clinically relevant change in associated symptoms.  The determination of whether 
there has been a significant change will be at the discretion of the Investigator; this may be in 
consultation with the Medical Monitor if there is any uncertainty.
8.
References
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing clinical 
evaluation’:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UC
M174090.pdf


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Appendix VI: GCIG CA-125 Response Definition


Copyright © 2011 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.


Copyright © 2011 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.


Copyright © 2011 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.


Copyright © 2011 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.


Copyright © 2011 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.


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Appendix VII: QOL Questionnaires


FACT-O (Version 4) 
English (Universal) 
16 November 2007 
Copyright  1987, 1997 
Page 1 of 3 
 
 
Below is a list of statements that other people with your illness have said are important. Please circle 
or mark one number per line to indicate your response as it applies to the past 7 days.
 
 
 
 
PHYSICAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GP1 
I have a lack of energy .......................................................
0 
1 
2 
3 
4 
GP2 
I have nausea......................................................................
0 
1 
2 
3 
4 
GP3 
Because of my physical condition, I have trouble 
meeting the needs of my family.........................................
 
0 
1 
 
2 
3 
4 
GP4 
I have pain..........................................................................
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of treatment .........................
0 
1 
2 
3 
4 
GP6 
I feel ill ...............................................................................
0 
1 
2 
3 
4 
GP7 
I am forced to spend time in bed........................................
0 
1 
2 
3 
4 
SOCIAL/FAMILY WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GS1 
I feel close to my friends....................................................
0 
1 
2 
3 
4 
GS2 
I get emotional support from my family ............................
0 
1 
2 
3 
4 
GS3 
I get support from my friends.............................................
0 
1 
2 
3 
4 
GS4 
My family has accepted my illness ....................................
0 
1 
2 
3 
4 
GS5 
I am satisfied with family communication about my 
illness..................................................................................
 
0 
1 
 
2 
3 
4 
GS6 
I feel close to my partner (or the person who is my main 
support) ..............................................................................
 
0 
1 
 
2 
3 
4 
Q1 
Regardless of your current level of sexual activity, please 
answer the following question. If you prefer not to answer it, 
please mark this box           and go to the next section. 
 
 
 
 
 
GS7 
I am satisfied with my sex life ............................................
0 
1 
2 
3 
4 


FACT-O (Version 4) 
English (Universal) 
16 November 2007 
Copyright  1987, 1997 
Page 2 of 3 
 
 
Please circle or mark one number per line to indicate your response as it applies to the past 7 
days.
 
 
EMOTIONAL WELL-BEING 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GE1 
I feel sad ..............................................................................
0 
1 
2 
3 
4 
GE2 
I am satisfied with how I am coping with my illness..........
0 
1 
2 
3 
4 
GE3 
I am losing hope in the fight against my illness..................
0 
1 
2 
3 
4 
GE4 
I feel nervous.......................................................................
0 
1 
2 
3 
4 
GE5 
I worry about dying.............................................................
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get worse............................
0 
1 
2 
3 
4 
 
 
 
 
FUNCTIONAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GF1 
I am able to work (include work at home) ..........................
0 
1 
2 
3 
4 
GF2 
My work (include work at home) is fulfilling.....................
0 
1 
2 
3 
4 
GF3 
I am able to enjoy life..........................................................
0 
1 
2 
3 
4 
GF4 
I have accepted my illness...................................................
0 
1 
2 
3 
4 
GF5 
I am sleeping well ...............................................................
0 
1 
2 
3 
4 
GF6 
I am enjoying the things I usually do for fun ......................
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life right now..............
0 
1 
2 
3 
4 
 


FACT-O (Version 4) 
English (Universal) 
16 November 2007 
Copyright  1987, 1997 
Page 3 of 3 
 
 
Please circle or mark one number per line to indicate your response as it applies to the past 7 
days.
 
 
 
 
 
ADDITIONAL CONCERNS
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
O1 
I have swelling in my stomach area ....................................
0 
1 
2 
3 
4 
C2 
I am losing weight...............................................................
0 
1 
2 
3 
4 
C3 
I have control of my bowels................................................
0 
1 
2 
3 
4 
O2 
I have been vomiting...........................................................
0 
1 
2 
3 
4 
B5 
I am bothered by hair loss ...................................................
0 
1 
2 
3 
4 
C6 
I have a good appetite .........................................................
0 
1 
2 
3 
4 
C7 
I like the appearance of my body ........................................
0 
1 
2 
3 
4 
BMT5 
I am able to get around by myself.......................................
0 
1 
2 
3 
4 
B9 
I am able to feel like a woman ............................................
0 
1 
2 
3 
4 
O3 
I have cramps in my stomach area ......................................
0 
1 
2 
3 
4 
BL4 
I am interested in sex...........................................................
0 
1 
2 
3 
4 
BMT7 
I have concerns about my ability to have children..............
0 
1 
2 
3 
4 
 


ENGLISH 
 
EORTC QLQ-C30 (version 3)  
 
We are interested in some things about you and your health. Please answer all of the questions yourself by circling the 
number that best applies to you. There are no "right" or "wrong" answers. The information that you provide will 
remain strictly confidential. 
 
Please fill in your initials: 
 
Your birthdate (Day, Month, Year): 
 
Today's date (Day, Month, Year):  
31 
 
__________________________________________________________________________________________ 
 
 
Not at 
A 
Quite 
Very 
 
 
All 
Little 
a Bit 
Much 
1. 
Do you have any trouble doing strenuous activities,  
 
like carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
 
2. 
Do you have any trouble taking a long walk? 
1 
2 
3 
4 
 
3. 
Do you have any trouble taking a short walk outside of the house? 
1 
2 
3 
4 
 
4. 
Do you need to stay in bed or a chair during the day? 
1 
2 
3 
4  
 
5. 
Do you need help with eating, dressing, washing  
 
yourself or using the toilet? 
1 
2 
3 
4 
 
 
During the past week:  
Not at 
A 
Quite 
Very 
 
 
All 
Little 
a Bit 
Much 
 
6. 
Were you limited in doing either your work or other daily activities? 
1 
2 
3 
4 
 
7. 
Were you limited in pursuing your hobbies or other 
 
leisure time activities? 
1 
2 
3 
4 
 
8. 
Were you short of breath? 
1 
2 
3 
4 
 
9. 
Have you had pain? 
1 
2 
3 
4 
 
10. Did you need to rest? 
1 
2 
3 
4 
 
11. Have you had trouble sleeping? 
1 
2 
3 
4 
 
12. Have you felt weak? 
1 
2 
3 
4 
 
13. Have you lacked appetite? 
1 
2 
3 
4 
 
14. Have you felt nauseated? 
1 
2 
3 
4 
 
15. Have you vomited? 
1 
2 
3 
4 
 
16. Have you been constipated? 
1 
2 
3 
4 
 
 
Please go on to the next page 
 


ENGLISH 
 
© Copyright 1995 EORTC Quality of Life Group. All rights reserved. Version 3.0 
 
 
 
During the past week:  
Not at 
A 
Quite 
Very 
 
 
All 
Little 
a Bit 
Much 
 
17. Have you had diarrhea? 
1 
2 
3 
4 
 
18. Were you tired? 
1 
2 
3 
4 
 
19. Did pain interfere with your daily activities? 
1 
2 
3 
4 
 
20. Have you had difficulty in concentrating on things, 
 
like reading a newspaper or watching television? 
1 
2 
3 
4 
 
21. Did you feel tense? 
1 
2 
3 
4 
 
22. Did you worry? 
1 
2 
3 
4 
 
23. Did you feel irritable? 
1 
2 
3 
4 
 
24. Did you feel depressed? 
1 
2 
3 
4 
 
25. Have you had difficulty remembering things? 
1 
2 
3 
4 
 
26. Has your physical condition or medical treatment 
 
interfered with your family life? 
1 
2 
3 
4 
 
27. Has your physical condition or medical treatment 
 
interfered with your social activities? 
1 
2 
3 
4 
 
28. Has your physical condition or medical treatment 
 
caused you financial difficulties? 
1 
2 
3 
4 
 
 
For the following questions please circle the number between 1 and 7 that  
best applies to you 
 
29. How would you rate your overall health during the past week? 
 
 
 1 
2 
3 
4 
5 
6 
7 
 
 Very poor 
 
 
 
 
 
Excellent 
 
 
30. How would you rate your overall quality of life during the past week? 
 
 
 1 
2 
3 
4 
5 
6 
7 
 
 Very poor 
 
 
 
 
 
Excellent