Clinical trial NCT01713582
Conditions: Acute Myeloid Leukemia Diffuse Large B-cell Lymphoma Acute Lymphoblastic Leukemia Multiple Myeloma
Sponsor: Oncoethix GmbH, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Start date: 2012-12-14; Completion date: 2017-01-20
Enrollment: 141 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary purpose of this study was to determine the recommended dose (RD) of birabresib (MK-8628) /OTX015 for further phase II studies, in participants with acute leukemia (AL) including acute myeloid leukemia (AML; de novo and secondary to a myelodysplastic syndrome) and acute lymphoblastic leukemia (ALL) or other hematologic malignancies (OHM) including diffuse large B cell lymphoma (DLBCL) and multiple myeloma (MM). The first phase of the study will be a dose escalation phase to determine the Phase II RD using dose-limiting toxicities (DLTs). Once the RD is determined, participants will be enrolled in an expansion phase at the RD to determine preliminary efficacy in AL and OHM cohorts. Participants received therapy in 21-day cycles until disease progression, intolerable toxicity, or treatment interruption for \>2 weeks due to toxicity.

Detailed description:

Arms: arm 1: Participants received 10 mg birabresib/OTX015 administered orally (PO), once daily (QD), in a fasted state on Days 1 to 14 of a 21-day cycle. arm 2: Participants received 20 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 14 of a 21-day cycle. arm 3: Participants received 40 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 14 of a 21-day cycle. arm 4: Participants received 20 mg birabresib/OTX015 administered PO, twice a day (BID), with the first daily dose in a fasted state, on Days 1 to 21 of a 21-day cycle. arm 5: Participants received 80 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 14 of a 21-day cycle. arm 6: Participants received 40 mg birabresib/OTX015 administered PO, twice a day (BID), with the first daily dose in a fasted state, on Days 1 to 14 of a 21-day cycle. arm 7: Participants received 120 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 14 of a 21-day cycle. arm 8: Participants received 120 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 21 of a 21-day cycle. arm 9: Participants received 160 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 14 of a 21-day cycle. arm 10: Participants received 80 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 14 of a 21-day cycle. arm 11: Participants received 80 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 14 of a 21-day cycle. arm 12: Participants received 10 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 21 of a 21-day cycle. arm 13: Participants received 20 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 21 of a 21-day cycle. arm 14: Participants received 40 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 21 of a 21-day cycle. arm 15: Participants received 80 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 21 of a 21-day cycle. arm 16: Participants received 40 mg birabresib/OTX015 administered PO, BID, with the first daily dose in a fasted state, on Days 1 to 21 of a 21-day cycle. arm 17: Participants received 120 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 21 of a 21-day cycle. arm 18: Participants received 120 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 14 of a 21-day cycle. arm 19: Participants received 120 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 5 of a 7-day cycle. arm 20: Participants received 120 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 7 of a 21-day cycle arm 21: Participants received 80 mg birabresib/OTX015 administered PO, QD, in a fasted state on Days 1 to 14 of a 21-day cycle.
Interventions: intervention 1: OTX015/Birabresib
Intervention descriptions: intervention 1: OTX015/Birabresib 10 mg, 20 mg, or 40 mg capsules administered orally

Protocol documents:
Prot_001.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Official Protocol Title: A phase I, dose-finding study of the bromodomain (Brd) inhibitor 
OTX015/MK-8628 in haematological malignancies 
 
 
NCT number: 
NCT01713582
Document Date: 
18-Dec-2015


CONFIDENTIAL 
 
  
 
The information in this document is the property of OncoEthix and is confidential. Neither the document nor the information  
contained therein may be reproduced or disclosed outside OncoEthix without their written consent. 
Sponsor : ONCOETHIX GmbH, a wholly owned subsidiary of Merck, Sharp & Dohme 
Corp 
CLINICAL STUDY PROTOCOL 
OTX015_104/MK-8628-001 
EUDRACT number: 2012-003380-22 
A phase I, dose-finding study of the bromodomain (Brd) inhibitor OTX015/MK-8628 
in haematological malignancies 
 
Coordinating investigator (for France): 
 
Tel: 
 / Fax: 
 
E-mail : 
 
 
 
 
 
Sponsor Medical Expert 
 
Merck Research Laboratories, Oncology Product 
Development 
126 E. Lincoln Avenue, RY34-B184, Rahway, NJ 
07065, US 
Tel: 
 Fax: 
 
E-mail: 
 
 
CRO Medical Monitor 
 
OTD (Oncology Therapeutic Development) SARL 
100 rue Martre, 92110 Clichy, France  
Tel : 
 / Fax : 
mail: 
 
 
CRO Project Leader 
 
OTD (Oncology Therapeutic Development) SARL,       
100 rue Martre  92110 Clichy – France.                            
Tel : 
 Mobile: 
        
Fax : 
 
E-mail: 
 
 
 
Date of issue: 
18 December, 2015  
Version N° : J 
Amendment 9 
 
 
 
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CONFIDENTIAL 
 
  
 
The information in this document is the property of OncoEthix and is confidential. Neither the document nor the information  
contained therein may be reproduced or disclosed outside OncoEthix without their written consent. 
STUDY PROTOCOL AGREEMENT FORM 
 
I, ------------------------------------------------------, Principal Investigator, have examined this 
Oncoethix’ Study Protocol OTX015_104/MK-8628-001 Version J, dated 18 December 2015, 
entitled:  
A phase I, dose-finding study of the bromodomain (Brd) inhibitor OTX015/MK-8628 in 
haematologic malignancies  
I confirm that I have read the above protocol. The information it contains is consistent with the 
current risk-benefit evaluation of the investigational product. 
I understand it, and I agree to conduct the study according to this protocol and to comply with its 
requirements, subject to scientific, ethical and safety considerations. More specifically, I will 
work according to the principles of GCP as described in CPMP/ICH/135/95 and 21 CFR parts 50, 
54, 56, and 312 and according to applicable local requirements. 
 
I understand that, I must keep confidential the information contained in the study documents that I 
have been or will be provided with. 
 
I understand that, should the decision be made by the Sponsor to terminate prematurely or 
suspend the study at any time for whatever reason; such decision will be communicated to me in 
writing. Conversely, should I decide to withdraw from execution of the study I will communicate 
immediately such decision in writing to the Sponsor. 
 
Furthermore, by the present, I am committed to enrol the first patient in this Study within a month. 
 
FOR THE SPONSOR 
INVESTIGATOR 
 
 
 
 
ONCOETHIX 
 
 
 
 
 
 
CRO Medical Project Leader 
 
 
 
 
 
 
Name: 
 
Name: 
 
 
 
 
 
 
Date : 
 
 
d 
m 
y 
 
 
 
 
d 
m 
y 
 
 
 
Signature: 
 
Signature: 
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ONCOETHIX                                                             CONFIDENTIAL 
Clinical Study Protocol  OTX015_104                       Date: 18 December 2015                    Document Status: Version J 
The information in this document is the property of OncoEthix and is confidential. Neither the document nor the information  
contained therein may be reproduced or disclosed outside OncoEthix without their written consent. 
 
Page 3 
TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ................................................................................................................................. 9 
ABBREVIATIONS AND DEFINITIONS ........................................................................................................ 21 
1 
INTRODUCTION AND STUDY RATIONALE .................................................................................... 24 
1.1 
BACKGROUND INFORMATION (SEE INVESTIGATOR’S BROCHURE FOR DETAILS) ................ 24 
1.1.1 Name and description of the investigational product OTX015 (formerly known as Y-803) ................ 24 
1.1.2 Summary of findings from nonclinical studies that potentially have clinical significance .................... 25 
1.1.2.1 
Bromodomains (brd) of the Bromodomain and Extra Terminal (BET) proteins as Cancer 
Targets ................................................................................................................................................ 25 
1.1.2.2 
Interaction of OTX015 with BRD2/3/4 ............................................................................................ 26 
1.1.2.3 
Effects of OTX015 on Cell Cycle .................................................................................................... 28 
1.1.2.4 Antitumor Effects of OTX015 ............................................................................................................. 28 
1.1.2.5 
Nonclinical Safety Evaluation of OTX015 ...................................................................................... 29 
1.1.3 Phase 1 clinical Studies in healthy Volunteers ..................................................................................... 31 
1.1.4 Summary of the known and potential risks and benefits, if any, to human subjects ............................ 34 
1.2 
JUSTIFICATION OF THE STUDY AND OF THE STUDY DESIGN ................................................... 35 
1.2.1   Justification of selecting patients with hematological malignancies ................................................... 35 
1.2.2 Justification of the new drug product formulation ................................................................................ 35 
1.2.3 Justification of the starting dose .......................................................................................................... 36 
1.2.4 Justification of the schedule of administration and of various schedules according to the 
treated condition .................................................................................................................................. 37 
1.2.5 Justification of two parallel dose escalation subsets ............................................................................ 37 
1.3 
CONCLUSION .................................................................................................................................... 37 
2 
STUDY OBJECTIVES ........................................................................................................................ 38 
2.1 
PRIMARY OBJECTIVE ....................................................................................................................... 38 
2.2 
SECONDARY OBJECTIVES .............................................................................................................. 38 
2.3 
EXPLORATORY ................................................................................................................................. 38 
3 
STUDY DESIGN, DURATION AND DATES ...................................................................................... 38 
3.1 
STUDY DESIGN ................................................................................................................................. 38 
3.1.1 Dose escalation part ........................................................................................................................... 38 
3.1.2 Expansion part .................................................................................................................................... 39 


ONCOETHIX                                                             CONFIDENTIAL 
Clinical Study Protocol  OTX015_104                       Date: 18 December 2015                    Document Status: Version J 
The information in this document is the property of OncoEthix and is confidential. Neither the document nor the information  
contained therein may be reproduced or disclosed outside OncoEthix without their written consent. 
 
Page 4 
3.2 
DEFINITION OF DOSE LIMITING TOXICITIES (DLTS) .................................................................... 40 
3.2.1 Non-hematological DLTs ..................................................................................................................... 40 
3.2.2 Hematological DLTs ............................................................................................................................ 41 
3.2.2.1 
In patients with acute leukemia ...................................................................................................... 41 
3.2.2.2 
In patients with other hematological malignancies ......................................................................... 41 
3.3 
INDEPENDENT SAFETY MONITORING COMMITTEE (SMC) ......................................................... 41 
3.4 
STUDY DURATION AND DATES ....................................................................................................... 42 
4 
SELECTION OF SUBJECTS ............................................................................................................. 43 
4.1 
NUMBER OF SUBJECTS ................................................................................................................... 43 
4.2 
INCLUSION CRITERIA ....................................................................................................................... 43 
4.3 
EXCLUSION CRITERIA ...................................................................................................................... 45 
4.4 
SUBJECTS OF REPRODUCTIVE POTENTIAL ................................................................................. 46 
5 
STUDY TREATMENT ......................................................................................................................... 47 
5.1 
DETAILS OF STUDY TREATMENT ................................................................................................... 47 
5.2 
DOSAGE SCHEDULE ........................................................................................................................ 47 
5.2.1 Prophylactic medication regimen ........................................................................................................ 47 
5.2.2 Body surface area/weight adjustment ................................................................................................. 47 
5.2.3 Schedule ............................................................................................................................................. 47 
5.2.4 Dose .................................................................................................................................................... 49 
5.2.4.1 
Dose escalation .............................................................................................................................. 49 
5.2.4.2 
Dose adaptation ............................................................................................................................. 50 
5.2.5 Supportive care guidelines in case of study treatment toxicity ........................................................... 52 
5.3 
TREATMENT DURATION .................................................................................................................. 52 
5.4 
TREATMENT ASSIGNMENT ............................................................................................................. 52 
5.5 
PACKAGING AND LABELING ............................................................................................................ 54 
5.6 
CAPSULE STRENGTHS .................................................................................................................... 54 
5.7 
SUPPLIES AND ACCOUNTABILITY .................................................................................................. 54 
5.8 
COMPLIANCE ..................................................................................................................................... 55 
6 
PRIOR AND CONCOMITANT ILLNESSES AND TREATMENTS .................................................... 56 
6.2 
PRIOR AND CONCOMITANT MEDICAL CONDITIONS .................................................................... 56 
6.3 
PRIOR AND CONCOMITANT MEDICATIONS .................................................................................. 56 


ONCOETHIX                                                             CONFIDENTIAL 
Clinical Study Protocol  OTX015_104                       Date: 18 December 2015                    Document Status: Version J 
The information in this document is the property of OncoEthix and is confidential. Neither the document nor the information  
contained therein may be reproduced or disclosed outside OncoEthix without their written consent. 
 
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6.3.1 Forbidden concomitant medications / treatments ............................................................................... 56 
6.3.2 Allowed concomitant medications / treatments ................................................................................... 57 
7.2 
DESCRIPTION OF STUDY DAYS ...................................................................................................... 57 
7.2.1 Pre-study screening ............................................................................................................................ 57 
7.2.2 Evaluation during each study visit during study treatment .................................................................. 59 
7.2.3 End of therapy ..................................................................................................................................... 60 
7.2.4 Follow-up ............................................................................................................................................. 61 
7.3 
METHODS .......................................................................................................................................... 61 
7.3.1 Efficacy data ........................................................................................................................................ 61 
7.3.1.1 
Tumor assessment methods .......................................................................................................... 61 
7.3.1.2 
Tumor assessment criteria ............................................................................................................. 62 
7.3.1.3 
Overall survival (OS) ...................................................................................................................... 62 
7.3.2 Safety data .......................................................................................................................................... 62 
7.3.2.1 
Clinical Safety ................................................................................................................................. 62 
7.3.2.2 
Laboratory measurements ............................................................................................................. 62 
7.3.3 Pharmacokinetics (PK) ........................................................................................................................ 63 
7.3.3.1 
PK sampling schedule .................................................................................................................... 63 
7.3.3.1.1 
Blood collection schedule ............................................................................................................ 63 
7.3.3.1.2 
Fresh tumor cells ......................................................................................................................... 64 
7.3.3.2 
Assay method: ................................................................................................................................ 64 
7.2.4.7 Pharmacokinetic analysis: ................................................................................................................. 65 
7.3.4 Pharmacodynamic assessment .......................................................................................................... 65 
7.3.4.1 
Fresh tumor cells ............................................................................................................................ 65 
7.3.5 Pharmacokinetic / pharmacodynamic relationship .............................................................................. 65 
7.3.6 Tumor phenotype/Predictive factors of clinical activity ....................................................................... 65 
7.3.6.1 
Archived tumor material ................................................................................................................. 65 
7.3.6.2 
Fresh tumor cells ............................................................................................................................ 66 
8 
ASSESSMENT OF SAFETY .............................................................................................................. 66 
8.1 
ADVERSE EVENT DEFINITIONS (21 CFR§312.32) ......................................................................... 66 
8.2 
DOCUMENTATION OF ADVERSE EVENTS ..................................................................................... 68 
8.2.1 AE Grade ............................................................................................................................................. 69 
8.2.2 AE Severity .......................................................................................................................................... 69 
8.2.3 Adverse event relationship to study treatment or procedure .............................................................. 69 
8.3 
EVENTS OF CLINICAL INTEREST .................................................................................................... 70 
8.4 
IMMEDIATE REPORTING BY INVESTIGATOR TO SPONSOR ....................................................... 71 
8.5 
PERIOD OF OBSERVATION ............................................................................................................. 72 


ONCOETHIX                                                             CONFIDENTIAL 
Clinical Study Protocol  OTX015_104                       Date: 18 December 2015                    Document Status: Version J 
The information in this document is the property of OncoEthix and is confidential. Neither the document nor the information  
contained therein may be reproduced or disclosed outside OncoEthix without their written consent. 
 
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9 
STUDY TREATMENT DISCONTINUATION ...................................................................................... 73 
10 
EMERGENCY PROCEDURES ........................................................................................................... 75 
10.1 EMERGENCY SPONSOR CONTACT................................................................................................ 75 
10.2 EMERGENCY IDENTIFICATION OF INVESTIGATIONAL PRODUCTS ........................................... 75 
11 
STATISTICAL PROCEDURES .......................................................................................................... 75 
11.1 ANALYSIS VARIABLES/ STUDY ENDPOINTS ................................................................................. 75 
11.2 ANALYSIS POPULATIONS ................................................................................................................ 75 
11.3 STATISTICAL METHODS .................................................................................................................. 76 
11.4 INTERIM ANALYSIS ........................................................................................................................... 76 
11.5 SAMPLE SIZE JUSTIFICATION ......................................................................................................... 76 
12 
ETHICAL AND LEGAL ASPECTS ..................................................................................................... 77 
12.1 GOOD CLINICAL PRACTICE ............................................................................................................. 77 
12.2 DELEGATION OF INVESTIGATOR DUTIES ..................................................................................... 77 
12.3 SUBJECT INFORMATION AND INFORMED CONSENT .................................................................. 77 
12.4 CONFIDENTIALITY ............................................................................................................................ 78 
12.5 APPROVAL OF THE CLINICAL STUDY PROTOCOL AND AMENDMENTS ................................... 78 
12.6 ONGOING INFORMATION FOR INDEPENDENT ETHICS COMMITTEE/ INSTITUTIONAL 
REVIEW BOARD AND HEALTH AUTHORITIES ............................................................................... 78 
12.7 CLOSURE OF THE STUDY ............................................................................................................... 79 
12.8 RECORD RETENTION ....................................................................................................................... 79 
12.9 LIABILITY AND INSURANCE ............................................................................................................. 79 
12.10 FINANCIAL DISCLOSURE ................................................................................................................. 80 
13 
STUDY MONITORING AND AUDITING ............................................................................................ 81 
13.1 STUDY MONITORING AND SOURCE DATA VERIFICATION ......................................................... 81 
13.2 ON-SITE AUDITS/INSPECTIONS ...................................................................................................... 81 
14 
DOCUMENTATION AND USE OF STUDY FINDINGS ..................................................................... 81 
14.1 DOCUMENTATION OF STUDY FINDINGS ....................................................................................... 81 
14.2 CONFIDENTIALITY/USE OF STUDY FINDINGS .............................................................................. 82 


ONCOETHIX                                                             CONFIDENTIAL 
Clinical Study Protocol  OTX015_104                       Date: 18 December 2015                    Document Status: Version J 
The information in this document is the property of OncoEthix and is confidential. Neither the document nor the information  
contained therein may be reproduced or disclosed outside OncoEthix without their written consent. 
 
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15 
REFERENCES .................................................................................................................................... 83 
16 
APPENDICES ..................................................................................................................................... 85 
16.1  APPENDIX I:  ECOG PERFORMANCE STATUS ............................................................................... 85 
16.2 APPENDIX II: CALCULATION OF THE RENAL CLEARANCE ......................................................... 85 
16.3 APPENDIX III:  PATIENT REGISTRATION FORM ............................................................................ 86 
16.4 APPENDIX IV:  PHARMACOKINETICS : SAMPLING SCHEDULE, SAMPLING METHOD, 
STORAGE AND SHIPMENT GUIDELINES ....................................................................................... 87 
16.5 APPENDIX V: ARCHIVED TUMOR TISSUE AND COLLECTION OF FRESH TUMOR 
BIOPSY/CELLS FOR PHARMACODYNAMIC BIOMARKERS, PREDICTIVE BIOMARKER 
AND INTRACELLULAR PHARMACOKINETICS. ............................................................................... 90 
ANATOMIA PATOLOGICA GENERALE E ONCOGENETICA MOLECOLARE - U .................................. 91 
1.1.1 To : 
 ................................................................................................................. 91 
16.6  APPENDIX VI: PATIENT INFORMATION LEAFLET (PIL) AND INFORMED CONSENT FORM 
(ICF) .................................................................................................................................................... 94 
16.7 APPENDIX VII: PATIENT’S DIARY ...................................................................................................... 95 
16.8 APPENDIX VIII: SAFETY MONITORING COMMITTEE COMPOSITION AND CHART ...................... 96 
16.9 APPENDIX IX: CURICULUM VITAE OF INVESTIGATORS AND SAFETY MONITORING 
COMMITTEE MEMBERS ................................................................................................................... 98 
16.10  APPENDIX X: SUMMARY OF STANDARD RESPONSE CRITERIA FOR ACUTE 
LEUKEMIA, MALIGNANT LYMPHOMA, AND MULTIPLE MYELOMA .............................................. 99 
16.11 APPENDIX XI: LIST (NON EXHAUSTIVE) OF DRUGS AND OTHER SUBSTANCES 
INTERFERING WITH CYTOCHROME P450 3A4 AND 2A6 (CYP3A4 AND CYP2A6) ................... 104 
16.12 APPENDIX XII: GUIDANCE FOR POTENTIAL DRUG-INDUCED LIVER INJURY (DILI)I .............. 105 
1.1.1 Purpose ............................................................................................................................................. 105 
1.1.2 Introduction ........................................................................................................................................ 105 
1.1.3 Close Observation Recommendations ............................................................................................. 106 
1.1.4 Hepatic Assessment Flow Chart ....................................................................................................... 107 
1.1.5 Factors to Consider in Assessing Potential DILI ............................................................................... 107 
1.1.5.1 
Study Medication .......................................................................................................................... 107 
1.1.5.2 
Treatment ..................................................................................................................................... 107 
1.1.5.3 
Signs and Symptoms (associated with the potential DILI event) ................................................. 107 
1.1.5.4 
Confounding Variables ................................................................................................................. 108 
1.1.5.5 
Evaluation algorithm for potential DILI if there are no other clinical reasons ............................... 109 
1.1.5.6 
Potential diagnosis ....................................................................................................................... 111 
1.1.5.7 
Overall clinical impression ............................................................................................................ 111 
1.1.5.8 
Treatment plan ............................................................................................................................. 111 
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ONCOETHIX                                                             CONFIDENTIAL 
Clinical Study Protocol  OTX015_104                       Date: 18 December 2015                    Document Status: Version J 
The information in this document is the property of OncoEthix and is confidential. Neither the document nor the information  
contained therein may be reproduced or disclosed outside OncoEthix without their written consent. 
 
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1.1.6 Contacts ............................................................................................................................................ 111 
1.1.7 References ........................................................................................................................................ 111 


ONCOETHIX                                                             CONFIDENTIAL 
Clinical Study Protocol  OTX015_104                       Date: 18 December 2015 
   Document Status: Version J 
 
The information in this document is the property of OncoEthix and is confidential. Neither the document nor the 
information contained therein may be reproduced or disclosed outside OncoEthix without their written consent 
 
Page 9 
PROTOCOL SYNOPSIS 
 
Title 
A phase I, dose-finding study of the bromodomain (Brd) inhibitor OTX015/MK-8628 in haematological 
malignancies 
Study code: OTX015_104/MK-8628-001 
Investigator(s), study site(s) 
• 
 France 
• 
 France 
• 
 Switzerland 
• 
 France 
• 
 France 
• 
 France 
• 
 France 
• 
 France 
• 
 United Kingdom 
• 
 Canada 
Objectives 
 
               Primary: 
               To determine the recommended dose (RD) of OTX015/MK-8628 for further phase II studies, in 
patients with acute leukemia and in patients with other hematological malignancies, 
Secondary: 
• To assess the safety profile of OTX015/MK-8628 as a single agent in patients with 
haematological malignancies  
• To assess pharmacokinetics (PK) of OTX015/MK-8628 in patients 
with 
haematological malignancies and PK/safety relationship 
• To assess pharmacodynamics (PD) of OTX015/MK-8628 in patients with 
haematological malignancies, PD/safety and PK/PD relationships  
• To detect clues of clinical antitumor activity 
       Exploratory: 
• To detect predictive factors of clinical activity 
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ONCOETHIX                                                             CONFIDENTIAL 
Clinical Study Protocol  OTX015_104                       Date: 18 December 2015 
   Document Status: Version J 
 
The information in this document is the property of OncoEthix and is confidential. Neither the document nor the 
information contained therein may be reproduced or disclosed outside OncoEthix without their written consent 
 
Page 10 
Study design: Multicenter, dose finding, open label, phase I b study in successive cohorts of 3 patients. 
Dose escalation part:  
• 
Two dose escalation subsets will be assessed independently in parallel: patients with acute leukemia 
(AL) and patients with other hematological malignancies.   
• 
In each subset, patients will be enrolled by successive cohorts of 3 patients. 
• 
Three patients will be initially treated at the starting dose level (DL) in each subset. If no dose limiting 
toxicity (DLT) is observed among these 3 patients during the first cycle of treatment (i.e. the first 21 
days following study treatment initiation, regardless of the treatment schedule), the next 3 patients will 
be treated at the DL immediately above, according to the dose escalation schedule defined below. In the 
absence of DLT observed at the current DL, the dose will be doubled. 
• 
At each DL in each subset, the second patient enrolled will not start the study treatment before the first 
treated patient of the cohort will have completed at least 2 weeks of treatment (i.e. 14 consecutive daily 
administrations). The first patient enrolled into a higher DL cohort will not start the study treatment 
before the last treated patient in the DL immediately below will have completed one cycle of study 
treatment (21 days following study treatment initiation, regardless of the treatment schedule). 
• 
If one out of 3 patients of a cohort experiences a DLT during the first cycle (i.e. the first 21 days 
following study treatment initiation, regardless of the treatment schedule), 3 additional patients will be 
entered at this DL. If no more than 1/6 treated and evaluable patient experience a DLT, the dose 
escalation will proceed to the DL immediately above. As soon as a DLT is observed, the magnitude of 
dose escalation will follow a Fibonacci-like model (see below). If more than one patient out of 6 (or 
more than one out of 3) experiences a DLT, the DL will be considered exceeding the maximum 
tolerated dose (MTD) for this subset.  
• 
Patients not evaluable for DLT (i.e. those having received less than 85% of the intended cumulative 
dose during the first 21 days) and who have not experienced a DLT, will be replaced. 
• 
The dose escalation will be stopped independently in each subset upon decision of the Safety 
Monitoring Committee (SMC). This decision could be taken if one of the following conditions is met: 
o 
A DL exceeding the MTD has been reached 
o 
Biological activity (PD) or sustained biologically active concentrations (PK) 
of OTX015/MK-8628 have been achieved 
o 
Or any other unforeseen condition, which, in the judgment of the SMC, 
would prevent, or would not deserve, further dose escalation. 
• 
In the absence of other data (PD or PK) suggesting a lower RD, the MTD will be considered the RD. At 
least 6 evaluable patients will be enrolled at the supposed RD (one DL below the dose exceeding the 
MTD) in each subset. The RD will be confirmed for each subset if no more than 1/6 patient experiences 
a DLT. Otherwise the DL immediately below will be explored with a minimum of 6 evaluable patients. 
Expansion part   
• 
Once the RD will be established with at least 3 patients having received at least 2 cycles of study 
treatment for each subset, the study will be prolonged with expansion cohorts in selected patients to 
confirm feasibility, safety, PK and PD at the RD. At least 12 evaluable patients with acute leukemia 
will be treated at the RD established for patients with acute leukemia. At least 12 evaluable patients 
with diffuse large B-cell lymphoma (DLBCL) or multiple myeloma (MM) will be treated at the RD 
established for patients with other hematological malignancies. Additional expansion cohorts may be 
decided by the SMC, based upon the data collected during the dose escalation phase. 
 
 
 
 


ONCOETHIX                                                             CONFIDENTIAL 
Clinical Study Protocol  OTX015_104                       Date: 18 December 2015 
   Document Status: Version J 
 
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Page 11 
Inclusion criteria 
1. Signed informed consent prior to beginning protocol specific procedures.  Patients registered for this trial 
must be treated and followed at the participating centers.   
2. Histologically or cytologically proven hematological malignancy, or confirmed multiple myeloma using 
standard diagnosis criteria. For the dose finding part, any refractory/relapsing hematological malignancy 
will be accepted. For the expansion cohorts, only patients with selected hematological malignancies will be 
enrolled : acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), DLBCL and MM) and/or 
other diseases, as decided by the SMC after closure of the dose finding part. 
3. Patient having failed all standard therapies or for whom standard treatment are contra-indicated: 
• 
For acute leukemia: patients < 60 years old in second or further relapse or relapsing after allogeneic 
stem cell transplantation (aSCT) regardless of number of relapses;  patients > 60 years old in first 
relapse with a disease-free interval (DFI) < 12 months, or further relapse ; irrespective of age, in 
patients relapsing after aSCT, the time elapsed since aSCT should be > 90 days. Patients with 
Philadelphia chromosome positive (Ph+) and/or bcr-abl+ B-cell ALL must have received at least 
two lines of therapy, including 2 bcr-abl tyrosine-kinase (TK) inhibitors (among imatinib, nilotinib 
and dasatinib), or only one line including one TK inhibitor, if the relapse/refractoriness is associated 
with the detection of a resistance mutation to these inhibitors. 
• 
For MM: patients adequately exposed to at least one alkylating agent, one corticosteroid, one 
immunomodulatory drug (IMiD) and bortezomib,  
• 
For lymphomas: patients having failed 2 standard lines of therapy (at least one containing an anti-
CD20 antibody if B-cell lymphoma), or for whom such treatment is contra-indicated. 
4. Patients with evaluable disease 
• 
AL patients must have > 5% bone marrow blasts at study entry, without alternative causality (e.g. bone 
marrow regeneration)  
• 
Lymphoma patients must have at least one non-irradiated tumor mass > 15 mm (long axis of lymph 
node) or > 10 mm (short axis of lymph node or extranodal lesions) on spiral CT-scan.  
• 
Patients with MM must have at least one of the following: serum monoclonal component > 1g/dL 
(IgG), or > 0.5g/dL (IgA), or Bence-Jones (BJ) proteinuria > 200mg/24h, or measurable plasmacytoma 
(not previously irradiated). 
5. Patients > 18 years old. 
6. Life expectancy of at least 3 months   
7. ECOG performance status of 0 to 2  
8. Off previous therapy for at least 3 weeks, or 5 half-lives of previously administered drug, whichever is 
longer, prior to first study treatment administration, except 1) hydroxyurea given to control 
hyperleukocytosis that should be stopped 48 hours prior to start study medication and 2) rituximab, which 
should be stopped for at least 3 weeks, regardless of half-life 
9. Recovery from the non-hematological toxic effects of prior treatment to grade < 1, according to NCI-CTC 
classification, except alopecia. 
10. Bone marrow function:  
• 
For patients with acute leukemia: No limitation 
• 
For patients with other hematological malignancies: Neutrophils ≥ 1.0 x 109/L, platelets ≥ 150 x 109/L 
(without transfusion), hemoglobin ≥8 g/dL (4 weeks without transfusion) 
11. Calculated creatinine clearance ≥ 30 mL/min (Cockroft & Gault formula, or MDRD formula for patients 
aged > 65 years).  
12. Adequate LFTs: Total bilirubin < institutional upper normal limit (UNL) (or ≤ 2 x UNL in cases of liver 
involvement); ALAT/ASAT ≤ 3 x UNL; if alkaline phosphatase (ALP) > 2.5 X ULN, then liver fraction 
should be ≤ 2.5 X ULN. 
13. Serum albumin > 28 g/L 
14. International normalized ratio (INR) or prothrombin time (PT) and activated partial thromboplastin time 
(aPTT) ≤1.5 X ULN 
15. Complete baseline disease assessment workup prior to first study treatment administration. 
 


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Exclusion criteria 
1. History of prior malignancy other than those previously treated with a curative intent more than 5 years ago 
and without relapse (any tumor) or basal cell skin cancer, in situ cervical cancer, superficial bladder cancer, 
or high grade intestinal polyps treated adequately, regardless of the disease-free interval. 
2. Pregnant or lactating women or women of childbearing potential not using adequate contraception. Male 
patients not using adequate contraception. 
3. Patients with peripheral cytopenias (i.e. auto-immune hemolytic anemia or thrombocytopenia) 
4. Patients with acute promyelocytic leukemia or with clinically uncontrolled (i.e. with bleeding) disseminated 
intravascular coagulation (DIC) 
5. MM patients with POEMS syndrome or plasma cell leukemia. 
6. Patient with chronic graft versus host disease (GVHD) or on immunosuppressive therapy for the control of 
GVHD 
7. Uncontrolled leptomeningeal disease. 
8. Other tumor location necessitating an urgent therapeutic intervention (palliative care, surgery or radiation 
therapy), such as spinal cord compression, other compressive mass, uncontrolled painful lesion, bone 
fracture, etc..) 
9. Uncontrolled disease-related metabolic disorder (e.g. hypercalcemia) 
10. Patients unable to swallow oral medications, or patients with gastrointestinal condition (e.g. malabsorption, 
resection…) deemed to jeopardize intestinal absorption. 
11. Other serious illness or medical conditions, which, in the investigator’s opinion could hamper 
understanding of the study by the patient, patient’s compliance to study treatment, patient’s safety or 
interpretation of study results. These conditions include (but are not restricted to): 
a) Congestive heart failure or angina pectoris except if medically controlled.  Previous history of 
myocardial infarction within 1 year from study entry, uncontrolled hypertension or arrhythmias. 
b) Existence of significant neurologic or psychiatric disorders impairing the ability to obtain consent. 
c) Uncontrolled infection. 
 d)  Known HIV positivity 
12. Concurrent treatment with other experimental therapies or participation in another clinical trial within 21 
days prior to first study treatment administration, or 5 half-lives of previously administered drugs, 
whichever is longer. 
13. Concurrent treatment or within 21 days prior to first study treatment administration with any other 
anticancer therapy, except hydroxyurea to reduced hyperleukocytosis. 
14. Concomitant treatment with corticosteroids except if chronic treatment with corticosteroids ≤ 30 mg of 
methylprednisolone daily or equivalent. 
15. Patients taking concomitant strong CYP3A4 interacting drugs (see Appendix XI) 
16. Patients with prior irradiation on more than 30% of bone marrow reserves (including Total Body 
Irradiation), regardless of washout period, and patients having received high dose chemotherapy followed 
by autologous stem cell transplantation less than 90 days prior to first OTX015/MK-8628 dosing. 
Treatment 
• 
Patients should receive the study treatment within 7 days after registration. 
• 
All patients will be hospitalized for at least 8 hours after the first study drug administration to check 
vital signs and ECG and collect PK blood samples around the anticipated Tmax.  
• 
Patients will take OTX015/MK-8628 orally, daily in a fasted state just before lunch, at least 3 hours 
after breakfast end (except outpatient who must take the study medication before breakfast at the 
hospital on day 1). The schedule of administration will initially depend on the indication: 
- 
patients with acute leukemia will initially take OTX015/MK-8628, over 14 consecutive days 
followed by a 7-day rest period. Upon SMC decision, patients with acute leukemia will take 
OTX015/MK-8628 continuously without planned rest period, like patients with other hematological 
malignancies. 
- 
patients with other malignancies will take OTX015/MK-8628 continuously without planned 
rest period 
- 
In all cases, one cycle = 21 days by convention. 
• 
The initial daily schedule of administration will be once a day at the first DL. Based upon PK and PD 
results, this schedule could be modified (e.g. b.i.d.by SMC decision) for further patients.  For the BID 
schedule, patients will take their medication in a fasted state around 8 a.m. (+ 2 hours) and 8 p.m. (+ 2 


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Clinical Study Protocol  OTX015_104                       Date: 18 December 2015 
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Page 13 
hours). 
• 
Treatment will be interrupted in case of toxicity according to guidelines (see dose and schedule 
adaptation). 
• 
Enrolled patients will receive OTX015/MK-8628 at the DL they were assigned at study entry 
throughout the study, or at reduced dose according to toxicity encountered.  
• 
However, in exceptional circumstances, intra-patient dose escalation could be allowed, provided all the 
following conditions are met: 1) The patient did not experience toxicity of grade > 1 while treated at 
the initial dose for at least 2 cycles; 2) The dose immediately above has already been tested and is 
considered safe (i.e. at least 3 patients were treated over 3 weeks and no DLT was observed, or at least 
6 were treated over 3 weeks and no more than one of them has experienced a DLT); 3) the patient has 
experienced stable disease so far (no response and no progression); 4) the investigator considers that 
the patient could benefit from dose increment and 5) the SMC agrees. 
• 
Treatment will be definitely discontinued upon patient’s request, or in case of disease progression, 
intolerable toxicity, treatment interruption > 2 weeks due to toxicity (except in case of suspicion of 
hematological DLT in acute leukemia, where treatment interruption for 3 weeks is allowed to confirm 
DLT), recurrence of the same toxicity despite dose reduction, specific liver toxicities (see Dose and 
Schedule Adaptation below), lack of compliance, or major protocol deviation. 
• 
Dosing not performed at the same time (+ 2 hours) as the other days will be omitted. 
• 
Omitted or vomited doses will not be replaced. 
 
The recommended dose (RD) for expansion cohorts for both acute leukemia and other hematologic 
malignancies is 80 mg QD days 1 to 14 of 21-day cycles (2 weeks ON/one week OFF) 
 
Dose & schedule adaptation  
Study product dosing (OTX015/MK-8628) will be interrupted in case of: 
Non-hematological toxicities: 
• 
any grade 3-4 non hematological toxicity despite adequate medication, regardless of duration;  
• 
grade 3-4 asymptomatic non hematological laboratory abnormal values, deemed related to study 
medication,  lasting > 7 days. This definition applies for patients with lab values grade < 1 at baseline. 
For patients with grade 2 values at baseline, only grade 4 lasting > 7 days will be considered DLT, 
unless the SMC considers the event clinically significant. See below for liver function tests. 
• 
Any prolonged grade 2 toxicity (lasting more than 2 weeks), leading to treatment interruption and/or 
dose reduction. 
Hematological toxicities: 
-- Patients with acute leukemia: 
• 
pancytopenia with a hypocellular bone marrow and no marrow blasts lasting for ≥ 6 weeks after the 
start of a cycle.   
- Patients with other hematological malignancies: 
• 
any grade 3  neutropenia, with fever or infection; any grade 3 thrombocytopenia with bleeding,  
• 
any grade 4 neutropenia or thrombocytopenia, lasting > 3 days. 
OTX015/MK-8628 dosing will be resumed when all toxic events have resolved to grade < 1 (or to the baseline 
value) at a reduced dose : at the DL immediately below during the dose escalation phase.  
 
During the cohort expansion phase, patients initially treated at 80 mg will have their dose reduced to 60 mg QD 
(2 weeks ON/1 week OFF) at the first occurrence of toxicity, then to 40 mg QD (2 weeks ON/1 week OFF) if 
the same toxicity recurs. 
 
In all cases 
• 
Dosing interruption for > 2 weeks due to toxicity, recurrence of the same toxicity with the same 
severity despite one dose reduction, or specific liver toxicities* will lead to definitive study treatment 
discontinuation, unless the investigator thinks the patient’s best interest is to pursue study treatment, 
with sponsor’s agreement. 
* Any of the following liver test abnormalities** (see Appendix 16.12) 
- 
ALT or AST > 8 x ULN  
- 
ALT or AST > 5 x ULN for > 2 weeks 
- 
ALT or AST > 3 x ULN AND (total bilirubin > 2 x ULN OR INR > 1.5) 


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Clinical Study Protocol  OTX015_104                       Date: 18 December 2015 
   Document Status: Version J 
 
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Page 14 
- 
ALT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash and/or eosinophilia (> 5%), unless the investigator assesses the rash or fatigue to 
be related to OTX015 and not related to liver impairment with sponsor’s agreement. 
**Note: All patients with these liver test abnormalities should be monitored weekly until all abnormalities 
return to normal or to the baseline state. For patients with isolated total bilirubin increases >2 x ULN or 2 x 
baseline (if elevated at baseline), except if associated with direct bilirubin ≤ ULN, monitoring should be every 2 
weeks until bilirubin returns to normal or to the baseline state. Drug induced liver injury (DILI) may develop or 
progress even after the causative drug has been stopped. Results should be recorded on the CRF and in the 
database. See guidelines on the handling of these events (potential Hy’s law cases).  
Premedication 
No premedication is planned at the first cycle, in the first 3 patients. Decision of further systematic 
premedication should be taken by the SMC. 
Dose escalation scheme:  
• 
The starting dose will be 10 mg/day (once a day, flat dose, without adaptation for body weight or 
surface area),  
• 
DLTs will be collected during the first cycle (21 days after the first OTX015/MK-8628 administration) 
The dose escalation scheme will be as follows for each subset (AL and other hematological malignancies). The 
magnitude of dose escalation between two consecutive dose levels will depend upon the occurrence or not of 
DLT at the current DL. 
Dose Level 
 
 
 
1 (starting dose) (mg) 
10 
 
 
2 
20 
 
 
3 
30 
40 
 
4 
40 
60 
80 
5 
50 
80 
120 
Dose escalation schedule: 
Doubling the dose in the absence of DLT (grey boxes). 
Fibonacci-like model once at least one  DLT occurs (white boxes) 
 
• 
Dose escalation will be stopped by SMC decision separately and independently for the two subsets 
when RD is deemed to be reached or exceeded.  
• 
If and when the decision of exploring a BID schedule is taken by the SMC after the assessment of dose 
level Xmg once-a-day, the first BID dose level explored will be X/2 mg twice-a-day (e.g. if the last 
once-a day dose level explored = 80mg → the first BID dose level explored = 40mg x 2/day). Then, 
further dose escalation with the BID schedule will proceed as described in the table above (e.g. if the 
first BID dose level explored= 40mg x 2/day, then the next dose level explored will be 80mg x 2/day if 
no DLT was observed at 40mg x 2/day, or 60mg x 2 if one DLT was observed).  
When the decision of delivering OTX015/MK-8628 continuously to AL patients is taken by the SMC, 
ongoing AL patients having received at least one intermittent cycle (14 days ON/7 days OFF) without 
DLT will be proposed to receive further cycles without planned interruption (21days ON) at the same 
daily dose. When sufficient safety data will have been collected with the continuous schedule both in 
AL patients and in patients with other hematologic malignancies, the SMC may allow further cohorts 
of AL patients to receive continuous OTX015/MK-8628 treatment from cycle 1. 
• 
RD will be defined either by the MTD, or, in the absence of DLT, based upon PK and/or PD 
considerations or other unforeseen condition (see Study Design). 
The final decision of further escalating the dose and, finally, of stopping dose escalation, determining the RD 
and starting expansion cohorts enrollment will be left to the discretion of the SMC. According to the nature, 
suspected relationship to study drug, or other clinical considerations, the SMC will make ad-hoc decisions, such 
as replacing inevaluable patients, adding more patients at the same DL, adding intermediate DLs, not 
considering a given DLT as clinically relevant for the determination of the RD. Serial assessments of PK/PD 
results will be forwarded to the SMC and will be taken into account for the determination of the RD, especially 
if no DLT occurs.  


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Clinical Study Protocol  OTX015_104                       Date: 18 December 2015 
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Page 15 
Safety Monitoring Committee (SMC) 
The SMC will be composed of the principal investigators (PI) of each participating center, the pharmacokinetics 
(PK) specialist, the medical and safety representatives of the Sponsor and one independent expert in 
oncology/hematology phase I development. All decisions taken by the SMC and their rationale will be recorded 
in meeting minutes that will be integrated in the final clinical study report. 
Definition of dose limiting toxicities (DLTs) 
The DLTs are identical to the events leading to treatment interruption and dose adjustment (see Dose & 
schedule adaptation), as well as any other unforeseen drug-related AE (including liver function test 
abnormalities as reported in Dose and Schedule Adaptation) resulting in study drug discontinuation or 
interruption with/without dose reduction. But only such AEs occurring during cycle 1 (or the first 21 days 
following the first dosing of OTX015) are considered DLT, except the hematologic DLT for patients with acute 
leukemia that must be confirmed after 6 weeks of treatment, 
Treatment compliance 
Patients will record daily in a specific diary, the number of capsules swallowed, time of intake, as well as 
possible reactions, including vomiting, and their time of occurrence. At each study visit the hospital pharmacist 
of the study center will provide the patient with the needed number of capsules for the visit interval and retrieve 
the unused capsules that will be kept until study end for accountability by the study monitor. 
Number of subjects  
The total number of patients enrolled will depend on the number of DLs explored and of DLT encountered. 
Approximately 80 evaluable patients will be enrolled in the dose escalation part  (40 by subset acute 
leukemias/other hematological malignancies) 
At least 12 evaluable patients by expansion cohorts will be enrolled in at least 3 expansion cohorts 
The total number of evaluable patients is estimated to be 125. 
Pharmacokinetics (PK) 
Blood collection: 
• 
Once-a-day schedule 
Three patients by DL will have complete PK sampling, consisting of 7 blood draws of 3 mL each at days 1 and 
2 (T0, T1h, T4h, T8h, T12h and T24h, plus one sampling ay either T10h or T16h). Complete PK sampling will 
be performed preferably in patients hospitalized due to medical reasons. All other patients enrolled at this DL 
will have limited PK sampling, consisting of 5 blood draws on day 1 (T0, T1h, T4h, T6h and T8h). Patients 
enrolled into the same DL across both dose escalation subsets (AL/other hematological malignancies) will be 
considered for the selection of the 3 patients with complete PK sampling. 
In addition, all patients will have blood sampling at T0 (just before drug intake) on days 8, 15 and 22. 
 
• 
Twice-a-day (BID) schedule 
All patients will have complete PK consisting of 8 blood draws of 3 mL each on days 1 and 2 (T0, 
T20min±5min, T1h±10min, T2h15min±10min, T3h15min±10min, T9h+1h, T12h±15min (before drug intake) 
and T24h (before drug intake)). Patients will be hospitalized for 24 hours for PK sampling.  
In addition, all patients will have blood sampling at T0 (just before drug intake) on days 8, 15 and 22.  
 
Fresh tumor collection : 
OTX015/MK-8628 concentration will be measured in tumor cells. 
• 
Patients with AL will have one bone marrow (3mL) or one blood (7mL) sample of at day 8.  
• 
Patients with other hematological malignancies* (optional): If a tumor is easily accessible to tumor cell 


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Clinical Study Protocol  OTX015_104                       Date: 18 December 2015 
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Page 16 
collection using non invasive method (i.e., skin or superficial lymph node deposits), optional tumor 
core biopsy will be strongly encouraged, with patient’s express additional consent at baseline, and on 
D15 + 7 days. 
Assay method: Ultra Performance Liquid Chromatography with tandem Mass Spectrometry detection (UPLC-
MS/MS). 
Pharmacokinetic/safety correlations: The incidence and severity of AEs will be compared to Cmax, CL and 
AUC of OTX015/MK-8628. 
Pharmacodynamics (PD) 
Potential biomarkers will be explored in tumor cells, including c-MYC and BRD2, 3 and 4. 
• 
Patients with AL will have 2 bone marrow (3mL each) and blood (15mL each) samples  at screening 
and at day 8.  
• 
Patients with other hematological malignancies* (optional): If a tumor is easily accessible to tumor cell 
collection using non invasive method (i.e, skin or superficial lymph node deposits), optional tumor 
core biopsy will be strongly encouraged, with patient’s express additional consent, for intra tumor PK 
at baseline, and on D15 + 7 days. 
 
PD/safety correlation: The incidence and severity of AEs will be compared to the most pertinent biomarker(s), 
if any.  
PK/PD correlation: Cmax, CL and AUC of OTX015/MK-8628 will be compared to the most pertinent 
biomarker(s), if any. 
As far as possible the same cytology/tissue samples will be used for intratumor PK and PD 
 
Predictive biomarkers   
• 
Available archived tumor material (lymphoma) will be collected, as well as fresh tumor material at 
baseline (leukemic blasts or optional biopsy for other hematological malignancies) to preliminary detect 
predictive factors of OTX015/MK-8628 clinical antitumor activity. The availability of a paraffin-
embedded block is a pre-requisite for inclusion of patients with lymphoma into the study if no fresh 
tumor cells/tissue are available.  
 
Study endpoints 
• 
Primary: the primary endpoint for the determination of the RD will be DLT 
• 
Secondary: treatment-emergent adverse events (TEAEs), PK and PD parameters, laboratory results, 
tumor response assessment (according to most recently published standard criteria) (see details by 
disease in the core protocol), tumor-related symptoms, PS. 
• 
Exploratory: tumor phenotype, Karyotype, molecular biology… 
Safety parameters 
Safety will be assessed on every patient having received the study treatment.  It will be evaluated on: 
• 
Vital signs (temperature, breath rate, blood pressure and heart rate), physical examination, within 1 week 
prior to the first study drug administration and then weekly for 3 weeks, and then every 21 days.  
• 
In addition, vital signs will be collected immediately before, then, 1 and 2 hours  (around the Tmax) after 
the first study drug administration on day 1 
• 
ECG will be performed within one week prior to the first study drug administration, immediately before, 
then, 1 and 2 hours (around Tmax) after study drug administration at days 1. 
• 
Echocardiography, with measurement of LVEF will be performed at baseline and at the end of treatment. 
• 
AEs will be recorded and graded according to the NCI-CTC (v4.03). 


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Page 17 
Laboratory tests 
• Hematology: 
Complete blood cell counts (CBC): platelets, WBC and differential and hemoglobin, INR, will be performed 
within 7 days prior to the first study drug administration, then at day 1, then weekly during the first 3 weeks 
and then every 3 weeks thereafter. In case of grade >2 hematologic toxicity CBC will be performed twice a 
week until recovery to grade < 2. In case of neutropenia/thrombocytopenia grade 4, CBC will be performed 
at least every other day until recovery to grade < 3. In addition, in case of thrombocytopenia grade 4 lasting 
> 3 days, a bone marrow aspiration is to be performed. In case of fever ≥ 38°C, infection, purpura or 
bleeding, additional CBC should be done as clinically indicated. 
• 
Biochemistry: 
LDL, HDL, β2-microglobulin (only for patients with myeloma),Serum creatinine, glucose, ionogram 
(sodium, potassium, chloride, HCO3- (bicarbonate)), calcium, phosphorus, magnesium, total protein, 
albumin, AP, ASAT, ALAT, total bilirubin, LDH, CPK and CRP will be performed within 7 days prior to 
the first OTX015/MK-8628 intake, then at day 1, then weekly during the first 3 weeks, and then every 3 
weeks thereafter. 
In addition, apolipoprotein A-1 (Apo A1) will be assessed within 7 days prior to first OTX015/MK-8628 
intake and at day 22 only 
• Urinalysis: 
Dipsticks for protein, glucose and blood at day 1, 2,  8, 15, 22, then every 3 weeks 
Efficacy parameters 
• 
Tumor response will be evaluated using standard criteria for lymphoma, acute leukemia and multiple 
myeloma.  
• 
Any clue of anti-tumor activity will be quantified and recorded, even though it does not meet criteria 
for response 
• 
Overall survival (OS) 
Statistical considerations: 
This is an exploratory Phase I study aimed to assess the pharmacological effects of OTX015/MK-8628 in 
humans with hematological malignancies. The small subject sample size by cohort does not allow for statistical 
hypotheses. The decisions will be taken by a board of experts (SMC) and the recommended dose will be 
validated in further studies. 
Study duration and dates 
Enrolment:  24-26 months according to the number of DLs explored. 
First-patient in: January 2013 
Last patient in: December 2014- January 2016 
End of study follow-up: January – May 2016 
 
 


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Clinical Study Protocol  OTX015_104                       Date: 18 December 2015 
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disclosed outside OncoEthix without their written consent 
 
 
Page 18 
STUDY SCHEDULE 
Overall Study Flow Chart 
 
PARAMETERS 
BASELINE 
to be done within 7 days prior 
to first study drug 
administration (except tumor 
imaging, bone marrow biopsy 
and LVEF within 30 days and 
informed consent and blasts 
sampling within 14 days) 
DURING STUDY TREATMENT 
END OF STUDY 
TREATMENT 
D1 
D8 
D15 
D22 
q3 wks 
from 
day 22 
onward 
V1 
V2 
V3 
V4 
V5 and 
higher 
EOT  
Informed consent 
x 
 
 
 
 
 
 
History incl. baseline concomitant 
illnesses; , Height  
 
x 
 
 
 
 
 
 
Pregnancy test 
x 
 
 
 
 
 
 
Availability of archived biopsy for 
lymphoma 
x 
 
 
 
 
 
 
Physical examination (ECOG Performance 
Status (PS), Weight, clinical tumor 
measurement) 
x 
x 
x 
x 
x 
x 
x 
Vital Signs 
x 
x (1) 
x 
x 
x  
x 
x 
12-lead ECG 
x 
x (1) 
 
 
x  
x 
x 
Baseline symptoms / Adverse events  
x 
x 
x 
x 
x 
x 
x 


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ONCOETHIX                                                             CONFIDENTIAL 
Clinical Study Protocol  OTX015_104                       Date: 18 December 2015 
   Document Status: Version J 
 
The information in this document is the property of OncoEthix and is confidential. Neither the document nor the 
information contained therein may be reproduced or disclosed outside OncoEthix without their written consent 
 
 
Page 21 
ABBREVIATIONS AND DEFINITIONS 
ABC 
Activated B-cell-like 
AE 
Adverse Event 
AL 
Acute leukemia 
ALCL 
Anaplastic Large Cell Lymphoma 
ALL 
Acute lymphoblastic leukemia 
AML 
Acute myeloid leukemia 
ANC 
Absolute neutrophil count 
ALAT 
Serum alanine aminotransferase 
ALP 
Alkaline Phosphatase 
APO A1 
Apolipoprotein A-1 
aPTT 
activated partial thromboplastin time 
ASAT 
Serum aspartate aminotransferase 
AUC 
Area under the plasma concentration vs time curves 
BA 
Bioavailability 
BCC 
Blood Cell Counts 
BET 
Bromodomain and Extra Terminal 
BJ 
Bence Jones protein 
BP 
Blood pressure 
Brd 
Bromo domains 
BSA 
Body surface area 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CL 
Total plasma clearance 
Cmax 
Peak concentration  
Cmin 
Residual/trough concentration 
CPK 
Creatine phospho kinase 
CR 
Complete Response 
CRF 
Case report form 
CT-scan 
Computerized tomography scan 
CYP 
Cytochrome P 
DCF 
Data Correction Form 
DIC 
Disseminated Intravascular coagulation 
DILI 
Drug Induced Liver Injury 


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ONCOETHIX                                                             CONFIDENTIAL 
Clinical Study Protocol  OTX015_104                       Date: 18 December 2015 
   Document Status: Version J 
 
The information in this document is the property of OncoEthix and is confidential. Neither the document nor the 
information contained therein may be reproduced or disclosed outside OncoEthix without their written consent 
 
 
Page 23 
PR 
Partial Response 
PS 
Performance Status 
PT 
Prothrombin Time 
PVP 
PolyVinyl Pyrolidone 
RD 
Recommended dose 
SAE 
Serious adverse event 
SAERF 
Serious adverse event Report Form 
SAR 
Suspected Adverse reaction 
SD 
Stable Disease 
SMC 
Safety Monitoring Committee 
SMZL 
Splenic Marginal Zone Lymphoma 
SUSAR 
Serious, unexpected suspect adverse reaction 
t1/2 
Terminal half-life 
TEAE 
Treatment emergent adverse event 
Tmax 
Time to peak concentration 
UNL 
Upper Normal Limit 
UPN 
Unique Patient Number 
UPLC-MS/MS 
Ultra Performance Liquid Chromatography, with tandem Mass Spectrometry detection 
US 
Ultrasound 
Vss 
Volume of distribution at steady state 
WHO 
World Health Organization 


ONCOETHIX                                                             CONFIDENTIAL 
Clinical Study Protocol  OTX015_104                       Date: 18 December 2015 
   Document Status: Version J 
 
The information in this document is the property of OncoEthix and is confidential. Neither the document nor the 
information contained therein may be reproduced or disclosed outside OncoEthix without their written consent 
 
 
Page 24 
1 
INTRODUCTION AND STUDY RATIONALE 
1.1 
BACKGROUND INFORMATION (SEE INVESTIGATOR’S BROCHURE FOR DETAILS) 
1.1.1 Name and description of the investigational product OTX015 (formerly known as Y-
803) 
 OTX015 is a synthetic small molecule targeted to bromodomains (BRD) 2, 3 and 4 of the 
tandem-BRD-containing family of transcriptional regulators known as the BET (bromodomain 
and extraterminal) proteins. The structure is summarized below: 
 
Chemical name: 
2-[(6S)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo- 
                                    [4,3-a][1,4]diazepin-6-yl]-N-(4-hydroxyphenyl)acetamide dihydrate 
 
I.N.N.:                         Not yet issued 
 
Molecular mass:           528.02 
Molecular formula:       C25H22ClN5O2S • 2H2O 
Structural formula: 
 
OTX015 is administered orally. It is provided size 3 gelatin capsules containing 10 mg,20 mg or 
40 mg OTX015 (free base) as a solid molecular dispersion with HPMCAS-M, mixed with lactose 
monohydrate, microcrystalline cellulose, Ac-Di-Sol, colloidal silicon dioxide, and magnesium 
stearate 5712. 
White opaque capsules are used for 10 mg and 40 mg strength and green opaque capsules are used for 
20 mg strength. 
Capsules are to be swallowed with little water, in a fasted state. They must not be open or chewed. 


ONCOETHIX                                                             CONFIDENTIAL 
Clinical Study Protocol  OTX015_104                       Date: 18 December 2015 
   Document Status: Version J 
 
The information in this document is the property of OncoEthix and is confidential. Neither the document nor the 
information contained therein may be reproduced or disclosed outside OncoEthix without their written consent 
 
 
Page 25 
1.1.2 Summary of findings from nonclinical studies that potentially have clinical 
significance 
1.1.2.1 Bromodomains (brd) of the Bromodomain and Extra Terminal (BET) proteins as 
Cancer Targets 
 
 The bromodomain (BRD) containing family of proteins [Belkina 2012] recognizes acetylated 
lysine residues within histone proteins and functions as a scaffold for the assembly of 
macromolecular complexes that alter chromatin accessibility to transcription factors and also 
allows the recruitment or activation of RNA polymerases. The tandem BRD-containing family of 
transcriptional regulators known as the BET (bromodomains and extraterminal) proteins, which 
comprise BRD2, BRD3, BRD4, and BRDt (also called BRD6) in humans, have emerged as major 
epigenetic regulators of proliferation, differentiation, and human cancer and also have been 
associated with predisposition to dyslipidemia or improper regulation of adipogenesis, elevated 
inflammatory profile, and increased susceptibility to autoimmune diseases [Denis 2010]. The four 
BET proteins exhibit similar gene arrangements, domain organizations, and some functional 
properties. With the exception of BRDt, which is expressed specifically in ovary and testis, BRDs 
2, 3, and 4 are widely distributed.  
Experimental evidence suggests a role for both BRD2 and BRD4 in oncogenesis. Both BRD2 
(Nakamura et al 2007) and BRD4 (Dey et al 2003) bind acetylated histones and mobilize 
chromatin modification (Wu & Chiang 2007) to control cell cycle (Denis et al 2000; Dey et al 
2000). Additionally, both BRD2 (Kanno et al 2004) and BRD4 (Dey et al 2009) remain 
mitotically associated with chromatin.  
BRD2 is a nuclear-localized serine-threonine kinase that has elevated activity in human leukemias 
(Denis & Green 1996; Rachie et al 1993). BRD2 was shown to synergistically transactivate cell 
cycle regulatory genes including cyclin D1, cyclin A, cyclin E, and dihydrofolate reductase in 
combination with Ras or MEKK through E2Fs (Denis et al 2000). Subsequently, it was shown 
that BRD2 associates with a transcription complex containing E2F1, E2F2, TBP, and chromatin 
remodeling machines (Denis et al 2000, 2006) and serves as a bridge between E2F1 and TBP 
(Peng et al 2006). Taken together, these findings indicate that BRD2 can serve as a transcription 
regulator and a contributing element in oncogenesis.  
BRD4 is a critical mediator of transcriptional elongation, functioning to recruit the positive 
transcription elongation factor complex (P-TEFb) (Yang 2005; Yang et al 2005). Functional 
studies have suggested that BRD4 plays an important role in the regulation of growth-associated 
genes at the M/G1 boundary by retaining P-TEFb at the promoters of key regulatory genes 
throughout mitosis (Dey et al 2009; Yang et al 2008). Additionally, BRD4 is a transcriptional 
coactivator of NF-κB via specific binding to acetylated RelA (Huang et al 2011). Taken together, 
these findings indicate that BRD4 can serve as a transcription regulator and a contributing element 
in oncogenesis.  
Recent studies showed that a small molecule inhibitor of the BET family elicited rapid and potent 
abrogation of MYC gene transcription in a range of leukemia and lymphoma cell lines, resulting 
in G1 arrest and extensive apoptosis (Mertz et al 2011). While the BET inhibitor suppressed MYC 
transcription in the context of translocation, amplification, or with an unaltered, wild-type MYC 


ONCOETHIX                                                             CONFIDENTIAL 
Clinical Study Protocol  OTX015_104                       Date: 18 December 2015 
   Document Status: Version J 
 
The information in this document is the property of OncoEthix and is confidential. Neither the document nor the 
information contained therein may be reproduced or disclosed outside OncoEthix without their written consent 
 
 
Page 26 
locus, cells exhibited a range of sensitivity to BET-inhibitor-dependent MYC suppression. 
Exogenous expression of MYC from an artificial promoter that is resistant to BET regulation 
significantly protected cells from cell cycle arrest and growth suppression by the BET inhibitor. 
MYC suppression was accompanied by deregulation of the MYC transcriptome, including potent 
reactivation of the p21 tumor suppressor (Mertz et al 2011). Treatment with a small molecule 
BET inhibitor also resulted in significant antitumor activity in mouse models of Raji Burkitt’s 
lymphoma and MV4-11 AML (Mertz et al 2011). These findings were the first to demonstrate 
that pharmacologic inhibition of MYC is achievable by targeting BET bromodomains [Delmore 
2011].  
1.1.2.2 Interaction of OTX015 with BRD2/3/4 
Binding of OTX015 to BRDs 2, 3, and 4 in Jurkat cells nuclear extract was demonstrated by a pull 
down assay using biotinylated OTX015 and streptavidin resin. CHO cells transfected with expression 
plasmids for Flag-tagged BRD 2, 3, or 4 or vector alone, europium-conjugated anti-Flag antibody, 
XL-665-conjugated streptavidin, and biotinylated OTX015 were incubated at room temperature for 
0.5 to 2 hours and fluorescence was measured by time-resolved fluorescence energy transfer (TR-
FRET). Results showed that OTX015 binds to similarly to all three BRDs, with EC
50s from 10 to 19 
nM (Figure 1 and Table 1).  
 
OTX015 (nmol/L) 
Figure 1. Binding of Biotinylated OTX015 to BRD2/3/4  
Expression vector-transfected CHO cell lysate (4-fold dilution), FLAG-BRD2-transfected cell lysate (20-fold 
dilution), FLAG-BRD3-transfected cell lysate (22-fold dilution), and FLAG-BRD4-transfected cell lysate (4-fold 
dilution) were incubated with biotinylated OTX015, europium-conjugated anti-FLAG antibody, and XL-665 
conjugated streptavidin for 30 minutes at room temperature. Binding was measured by TR-FRET.  
Binding of biotinylated OTX015 to BRDs 2, 3, and 4 was inhibited by addition of OTX015 in a 
concentration-dependent manner, suggesting competitive inhibition.  
The effect of OTX015 on binding of acetylated histone H4 (AcH4) to BRDs 2, 3, and 4 was 
measured using a similar system, by incubating biotin conjugated-AcH4, BRD-expressing CHO 
cell lysate, europium-conjugated anti-Flag antibody, and XL-665-conjugated streptavidin and then 
measuring fluorescence by TR-FRET. Percent binding was calculated by defining the value of the 


ONCOETHIX                                                             CONFIDENTIAL 
Clinical Study Protocol  OTX015_104                       Date: 18 December 2015 
   Document Status: Version J 
 
The information in this document is the property of OncoEthix and is confidential. Neither the document nor the 
information contained therein may be reproduced or disclosed outside OncoEthix without their written consent 
 
 
Page 27 
sample without biotin conjugated AcH4 as 0% and the sample without OTX015 as 100% binding. 
Results showed that OTX015 inhibited BRD2, 3, 4 binding to AcH4 with similar effect, with 
IC50s from 92 to 112 nM (Table 1 and Figure 2).  
 
OTX015 (nmol/L)  
 
Figure 2. Inhibition of the BRD-AcH4 Binding by OTX015  
Various concentrations of OTX015 were mixed with biotinylated AcH4 and then incubated with FLAG-BRD2- (8-
fold dilution), FLAG-BRD3- (8-fold dilution), or FLAG-BRD4- (2.5-fold dilution)-transfected CHO cell lysate, 
europium conjugated anti-FLAG antibody, and XL-665-conjugated streptavidin for 2 hours at room temperature. 
Fluorescence was measured by TR-FRET Biotinylated H4 was used instead of AcH4 as a negative control. Percent of 
binding was calculated as 100 x [(count of sample minus count of sample without AcH4 sample) / (count without 
OTX015 sample minus count without AcH4 sample)] The columns represent mean ± SEM of three independent 
experiments. The mean value of the OTX015 treatment group and the control group was compared by Dunnett’s 
multiple comparison test; NS: no significant difference, **: p<0.01.  
 
 
Table 1: Interaction of OTX015 with BRDs 2/3/4 
 
BRD  
EC
50 (nmol/L)  
for OTX015 binding  
(mean ± SEM)  
IC
50 (nmol/L)  
for OTX015 inhibition of 
BRD-AcH4 binding  
(mean, 95% CI)  
2  
9.95 ±0.90  
91.8 (79.9 – 105.5)  
3  
13.37 ± 0.89  
111.5 (100.9 – 123.3)  
4  
18.61 ± 2.56  
95.5 (72.8 – 125.1)  
 
 


ONCOETHIX                                                             CONFIDENTIAL 
Clinical Study Protocol  OTX015_104                       Date: 18 December 2015 
   Document Status: Version J 
 
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information contained therein may be reproduced or disclosed outside OncoEthix without their written consent 
 
 
Page 28 
 
1.1.2.3 Effects of OTX015 on Cell Cycle 
It was reported that a BRD4 shRNA vector stably knocked down BRD4 protein expression by 
~90% in NIH3T3 cells (Mochizuki et al 2008). BRD4 knockdown cells were growth impaired and 
grew more slowly than control cells. When synchronized by serum starvation and released, BRD4 
knockdown cells were arrested at G1, via inhibition of cyclin D1 gene expression, whereas control 
cells progressed to S phase (Mochizuki et al 2008). In analogous experiments, cell cycle analysis 
showed that OTX015 treatment induced G1 arrest of NIH3T3 cells synchronized in the G0 phase 
by serum starvation. After serum stimulation for 10 hours, Western blot and RT-PCR analysis 
showed that OTX015 inhibited both protein and mRNA expression of cyclin D1. 
1.1.2.4 Antitumor Effects of OTX015 
Against a panel of human tumor cell lines, OTX015 showed antiproliferative effects against a 
variety of hematological malignancies, including leukemias (ALL, AML, CML), lymphomas 
(ALCL, DLBCL, MCL, SMZL), and multiple myeloma, with GI50s ranging from 0.04 to 2.9 μM. 
OTX015 was also highly effective against the Ty82 midline carcinoma cell line with a BRD4-
NUT fusion gene (GI50 of 0.04 μM). Most solid tumor cell lines did not respond to OTX015, 
though hepatocellular carcinoma, ovarian cancer, and some breast cancer cell lines were sensitive 
(GI50 s ranging from 0.25 to 0.94 μM).  
More detailed examination of the effects on OTX015 on hematologic malignancies in vitro 
showed that OTX015 treatment induced G1 arrest and down-regulation of MYC mRNA and 
putative MYC target genes in most cell lines examined, including 4 of 4 AML lines, 3 of 3 ALL 
lines, 7 patient-derived primary AML cells, 9 of 11 diffuse large B-cell lymphoma lines, 5 of 8 
anaplastic large T-cell lymphoma lines, 3 of 3 splenic marginal zone lymphoma lines, and 3 of 3 
multiple myeloma lines. OTX015 treatment induced apoptosis in leukemia cell lines and patient 
blasts, but not in lymphoma and multiple myeloma cell lines. Induction of apoptosis in leukemia 
is not reversible after washout of OTX015 at 6 or 24 hours, while inhibition of proliferation in 
lymphoma cell lines is reversible after washout. There was no obvious correlation between 
sensitivity to OTX015 and BET expression in cell lines. In sensitive lines, MYC down-regulation 
was observed after as little as 30 minutes exposure, but reversed within 2 to 4 hours after wash-
out in lymphoma cells,. 
The in vivo efficacy of OTX015 was demonstrated in the Ty82 human BRD4-NUT t(15;19) 
midline carcinoma xenograft model in female BALC/c-nu/nu mice. Animals were inoculated in 
the right flank with exponentially growing Ty82 cells (1 x 10
7 cells/0.1 mL in serum-free RPMI-
1640 medium with 10% Matrigel). When tumors reached a mean size of >100 mm
3 (usually at 7 
days after implantation), mice were grouped (6/group) according to tumor size and body weight 
and treatment was initiated with 0 (placebo), 10 mg/kg qd, 30 mg/kg qd, 100 mg/kg qd, or 10 
mg/kg bid OTX015 by gavage for 14 consecutive days. Body weights were measured at the time 
of grouping and prior to dosing each day and tumor size was measured by digital caliper on Days 


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1, 5, 9, 12, and 15. On Day 15 animals were euthanized by cervical dislocation and tumors, 
spleens, and livers were excised and weighed.  
The mean relative tumor growth rates based on tumor volumes on Day 15 for mice treated with 0, 
10, 30, 100 mg/kg and 10 mg/mg bid of OTX015 were 6.13 ± 0.51, 3.74 ± 0.30, 3.26 ± 0.58, 2.10 
± 0.28, and 3.00 ± 3.56, respectively (Figure 3). Compared with the placebo control, mice 
receiving 10, 30, 100 mg/kg and 10 mg/kg bid of OTX015 had tumor growth inhibition rates of 
46.6%, 55.9%, 78.6%, and 61.1%, respectively. All treatment groups showed a significant 
reduction in tumor growth compared with vehicle control (Dunnett’s test, p<0.01). 
 
Figure 3. Effects of OTX015 on Growth of Ty82 Human BRD4-NUT/t(15;19) Midline 
Carcinoma Xenografts in BALBc/nu/nu Mice 
The Ty82 model was repeated to assess the effects of OTX015 combined with docetaxel. Results 
showed that (1) docetaxel alone was not effective in this model; (2) OTX015 was effective, with 
BID dosing as effective as once daily dosing (i.e., 56% TGI at 50 mg/kg qd vs. 55% TGI at 25 
mg/kg BID) and (3) combination treatment was more effective than either agent alone, with cures 
achieved using 50 mg/kg qd x 14 or 25 mg/kg BID x14 OTX015 combined with 10 mg/kg IV q7d 
x2 docetaxel. 
1.1.2.5 Nonclinical Safety Evaluation of OTX015 
The safety of OTX015 was evaluated in both safety pharmacology and toxicology studies, 
conducted in accordance with ICH Guidance S9: Nonclinical Evaluation for Anticancer 
Pharmaceuticals. 
Safety pharmacology studies showed that OTX015 had no effects on general safety assessments at 
doses up to 10 mg/kg PO. OTX015 had no effect on hERG current at concentration up to 580 nM 


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and no effects on respiration rate, blood pressure, heart rate, and electrocardiogram in anesthetized 
dogs at doses up to 3 mg/kg IV. 
The adverse effects of OTX015 were evaluated in 28-day repeated oral dose toxicity studies with 
28-day recovery in both rats (12-18/sex/group dosed at 0, 3, 10, 30, and 60 mg/kg/day) and dogs 
(3-5/sex/group dosed at 0, 1, 3, 10, and 20 mg/kg/day) and in chronic 26-week studies in rats 
(14/sex/group dosed at 0, 3, 10, and 30 mg/kg/day) and 52-week studies in dogs (4/sex/group 
dosed at 0, 0.6, 2, and 6 mg/kg/day). Studies were conducted using a solid dispersion formulation 
of 10% or 25% OTX015:PVP, either suspended in water for administration to rats or combined 
with lactose, corn starch, crystalline cellulose, and calcium carmelose excipient and filled into 
gelatin capsules for administration to dogs. 
The no-observed adverse effect levels (NOAELs) in rats were 10 mg/kg/day, corresponding with 
a mean Day 28 AUC0-24h of 1045 ng•h/mL, for 4-week dosing and 10 mg/kg/ day, 
corresponding with a mean Day 182 AUC0-24h of 1522 ng•h/mL, for 26-week dosing. The 
NOAELs in dogs 
were 3 mg/kg/day, corresponding with a mean Day 28 AUC 
0-24h of 922 ng•h/mL, for 4-week dosing; 3 mg/kg/day, corresponding with a mean Day 91 
AUC0-24h of 938 ng•h/mL, for 13-week dosing; and 2 mg/kg/day, corresponding with a mean 
Day 365 AUC0-24h of 447 ng•h/mL, for 52-week dosing. Virtually identical AUCs were obtained 
in rats and dogs corresponding with the NOAELs for 28-day dosing (mean AUC0-24h of 1045 
and 922 ng•h/mL for rats and dogs, respectively), while higher AUCS were obtained at the 
NOAELS for chronic dosing for rats compared to dogs (mean Day 182 AUC0-24h of 1522 
ng•h/mL in rats and mean Day 365 AUC0-24h of 447 ng•h/mL in dogs). 
From the 4-week repeated dose toxicity studies, the highest non-severely toxic dose (HNSTD) 
was 30 mg/kg/day in rats, corresponding with a mean Day 28 AUC0-24h of 6715 ng•h/mL, and 
10 mg/kg/day in dogs, corresponding with a mean Day 28 AUC0-24h of 4377 ng•h/mL. 
Considering results from the 28-day repeated dose and chronic toxicity studies, the main target 
organ toxicity was the digestive system, particularly liver. Other organs which should be 
monitored are lymphoid tissues, hematopoietic organs, lungs, and reproductive organs in males. 
Briefly: 
• Digestive system: In both rats and dogs, clinical signs of loose stools and diarrhea were 
accompanied by histopathologic findings of mononuclear cell infiltration of the lamina propria 
mucosa and degeneration of the epithelium of the small and large intestine. In chronic toxicity 
studies, abnormal liver function tests were observed in both rats (decreased total protein and 
albumin) and dogs (increased SGOT and SGPT), accompanied by histological findings of 
pigment deposition in perilobular Kupffer cells in livers of both species and cholestasis and 
vacuolization of the centrilobular hepatocytes in livers of dogs. Prolonged APTT in both species 
was observed after 28-day dosing in rats and after both 28-day and chronic dosing in dogs. 
• Hematopoietic system: Both rats and dogs showed decreased platelets and lymphocytes after 28-
day dosing, accompanied by histopathologic findings of depletion of lymphocytes in the spleen 
and mesenteric and submandibular lymph nodes and myeloid hypoplasia in the bone marrow of 
femur and sternum. Rats showed decreased RBC after both 28-day and chronic dosing, 
accompanied by histopathologic findings of extramedullary hematopoiesis in spleen after chronic 
dosing. 


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• Lungs: In rats, histopatholoic exams showed intra-aveolar foamy macrophages in lungs and 
bronchus in both sexes after both 28-day and chronic dosing; these were resolved after one month 
recovery in the 28-day study. 
• Reproductive organs in males: In male dogs, histopathologic exams showed tubular 
degeneration of testes after both 28-day and chronic dosing and bilateral decrease of sperm in the 
epididymides after chronic dosing. 
OTX015 showed no genotoxic effects in the standard panel of in vitro and in vivo tests. From 
reproductive and developmental toxicity assessments in rats, the non-toxic dose for reproductive 
performance was considered to be 30 mg/kg/day for males and 10 mg/kg/day for females and the 
non-toxic dose for embryonic growth and development was 10 mg/kg/day. From reproductive and 
developmental toxicity assessments in rabbits, the non-toxic dose for reproductive function of 
dams and growth and development of embryos and fetuses was considered to be 3 mg/kg/day. 
1.1.3 Phase 1 clinical Studies in healthy Volunteers 
Three studies have been conducted in a total of 114 healthy volunteers:  
• Study Y-803-E01 (“E01 Study”) was a double-blind, randomized study to evaluate the safety, 
tolerability, and pharmacokinetics of single ascending oral doses of 2.5, 5, 10, 20, 40, 80, 120 
and 180 mg OTX015 compared with placebo in healthy adults;  
• Study Y-803-E02 (“E02 Study”) was an open label, randomized, three-way crossover study to 
assess the bioavailabilty of a single oral dose of 20 mg OTX015 in healthy male subjects in the 
fasted state and before and after food, with at least a 10 day wash-out between doses; and  
• Study Y-803-E04 (“E04 Study”) was a double-blind, placebo-controlled repeat dose study to 
assess the safety, tolerability, and pharmacokinetics of OTX015 following a single oral dose on 
Day 1 and once daily oral doses of 10, 20, and 40 mg OTX015 for 10 days (Days 4-13) in 
healthy male subjects.  
All three studies were performed using a capsule containing microcrystalline cellulose spheres 
coated with an ethanolic solution of OTX015, triethyl citrate, aminoalkyl methacrylate copolymer 
RS, and methacrylic acid copolymer, which was spray dried and mixed with excipients including 
talc, magnesium alunimometasilicate, and light anhydrous silicic acid.  
Each study assessed safety, tolerability, and plasma and urinary pharmacokinetics of OTX015 and 
its two main metabolites, the glucuronide conjugate and an oxidation product termed M1. 
Additionally, the single dose studies assessed fecal excretion of OTX015 and the M1 metabolite.  
The main findings for these studies are summarized in Table 2 and described briefly below.  
Pharmacokinetics  
Following administration of single oral doses of OTX015 to fasted subjects, plasma 
concentrations of OTX015 increased slowly, reaching Cmax at a median of 4 to 6 hours. 
Thereafter, plasma levels declined slowly for all dose levels, maintaining levels about 50%-60% 
of Cmax at 12 hours post-dose and 25%-30% of Cmax at 24 hours post-dose. Semi-logarithmic 
plasma concentration-time curves gave an apparent monophasic decline, with mean t1/2 ranging 
from 12.0 to 16.3 hours for all dose levels. The mean t1/2 and median tmax were statistically 


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constant. Exposure (Cmax, AUC0-24h, and AUC0-∞ ) increased in a dose proportional manner over 
the range from 2.5 to 80 mg. The MRT, Cl, Cl/F, Vz/F ranged from 17.8 to 21.4 h, from 0.11 to 
0.20 L/h, from 28.2 to 54.0 L/h, and from 477.6 to 1159.6 L, respectively. The mean cumulative 
fecal excretion of OTX015 ranged from 54% to 88% of the administered dose for all dose levels, 
while the mean cumulative urinary excretion of OTX015 and its metabolites was less than 4.1% 
of the dose for all dose levels.  
Overall, the pharmacokinetics of OTX015 appeared to be independent of dose and repeated 
dosing. Analysis of pre-dose plasma levels on Days 5 through 12 (for repeated dosing from Days 
4 -13) showed steady-state to be achieved by Day 6, after 24 hours of dosing (i.e. the second 
consecutive day of repeated treatment), at each dose level. Geometric mean pre-dose (trough) 
plasma concentrations at steady state ranged from 3.9 to 4.9 ng/mL for the 10 mg dose, from 5.9 
to 8.5 ng/mL for the 20 mg dose, and from. 13.6 to 22.4 ng/mL for the 40 mg dose; for each dose 
level the pre-dose plasma concentrations were constant. Statistical analysis of the first and last 
dose across all dose levels showed t1/2, MRT, Cl/F, and Vz/F to be independent of dose, with no 
differences between the first and last dose. 
Interestingly, the mean Cmax of 52-66 ng/mL achieved with 40mg repeated dosing, was 
equivalent to approximately 100nM, an active concentration against hematological malignancies 
in in vitro experiments. 
Intake of a high-fat breakfast after and before administration decreased plasma OTZ015 
concentration: Cmax by 45% and 47%, AUC0-24h by 35% and 38%, and AUC0-∞ by 20% and 
27%, respectively, compared to the fasted state using geometric means. Cmax and AUCs in fed 
states were not bioequivalent to the fasted states (90% CI not within the range 80% to 125%). 
However, dosing after food was bioequivalent to dosing before food for Cmax and AUC0-24h 
and the deviation from bioequivalence criteria was small (90%CI 78.9% - 107.3%). The tmax of 
OTX015 was prolonged by food intake after and before administration, from 6h (fasted state) to 
9h and 10h, respectively, while the MRT was constant for all dosing conditions. Urinary excretion 
also was reduced by food intake before and after administration: OTX015 by 10% and 9%, M1 
metabolite by 22% and 24%, and OTX015 conjugate by 18% and 21%. Fecal excretion of 
OTX015 and its metabolites was only slightly lowered by food intake. 
Mean plasma concentrations of the OTX015 glucuronide conjugate and M1 oxidized metabolite 
were parallel to OTX015 for all dosing conditions and dose levels. In Cmax and AUC, the 
OTX015 glucuronide conjugate ranged from 50%-73% and from 40%-64% of the OTX015 level, 
respectively, while the M1 metabolite ranged from 3% to 5% and from 3% to 6% of the OTX015 
level, respectively. 
Safety and Tolerability 
A total of 92 healthy volunteers (86 males, 6 females) received at least one dose of OTX015 in the 
three Phase 1 studies, while 22 males received at least one dose of placebo. Overall, OTX015 was 
well tolerated. No severe or serious adverse events (AEs) were reported. The most frequent AEs, 
occurring in ≥3% of subjects receiving OTX015, were headache (17% of subjects), abdominal 
pain/discomfort (14%), diarrhea/loose stools (8%), rhinitis (5%), constipation (4%), myalgia 
(4%), back pain (3%), and paresthesia (3%). With the exception of one mild headache, all of these 
events were both mild and transient. These AEs occurred with similar frequency among subjects 
receiving placebo, i.e., headache (17% of subjects), diarrhea/loose stools (17%), and abdominal 
pain/discomfort (13%).


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Table 2: Summary of previous clinical experience in humans (healthy volunteers) 
Study design 
Single-dose, dose escalation, double blind study vs 
placebo 
(study E01) 
Repeated dose (10 consecutive days) , dose 
escalation, double-blind study vs placebo 
(study E04) 
Open label, randomized, 3-way crossover, food-
effect study 
(study E02) 
N.subjects (M/F) 
72 (64/8) 
24 (24/0) 
18 (18/0) 
Dose levels tested (mg) 
2.5, 5, 10, 20, 40, 80,120, 180 (placebo 2 subjects 
/DL); fasted  
10, 20, 40 (placebo 2 subjects /DL); fasted 
20 
Safety data 
Mild –moderate headaches and GI symptoms .  
A similar percentage of subjects had AES on 
placebo (33% [6/18]) and at 120 mg (33% [2/6]).  
No dose-related laboratory, ECG, or vital signs 
changes  
Mild (98%) –moderate (2%) headaches and GI 
symptoms. A similar percentage of subjects had 
AEs on placebo (67% [4/6]) and 40 mg (100% [6/6]). 
No dose-related laboratory, ECG, or vital signs 
changes  
Mild –moderate headaches and GI symptoms.  
The percentage of subjects with AEs was higher in 
the fasted state (44% [8/18]) than before food (17% 
[3/18]) and after food (39% [7/18]).  
MTD 
Not reached 
Not reached 
Not applicable 
PK results 
Exposure (C
max, AUC) increased in a dose 
proportional manner over the range from 2.5 to 80 
mg. Mean C
max (ng/mL) ranged from 5.0 ± 1.4 (2,5 
mg dose) to 210 ± 67 ng/mL (80 mg dose). Mean 
AUC
0-∞ (ng•h/mL) ranged from 95 ± 30 (2.5 mg 
dose) to 3585 ± 1100 (180 mg dose).  
Following administration, plasma levels of OTX015 
increased slowly, reaching C
max at a median of 4 to 
6 hours. Thereafter, plasma levels declines slowly, 
maintaining levels abot 50%-60% of C
max at 12 
hours post-dose and 25%-30% of C
max at 24 hours 
post-dose. The median t
max (4-6 hours) and mean 
t
1/2 (12.0 – 16.1 hours) were statistically constant. 
Mean MRT ranged from 18.3 to 20.5 h and mean 
Cl/F ranged from 28.2 to 54.0 L/h.  
OTX015 OK appeared to be independent of dose 
and repeated dosing. Analysis of pre-dose plasma 
levels on Days 5 through 12 (for repeated dosing 
from Days 4 – 13) showed steady state to be 
achieved by approximately Day 6, after 24 hours of 
dosing, at each dose level. Geometric mean pre-
dose (trough) plasma concentrations at steadt state 
ranged from 3.9 to 4.9 ng/mL for the 10 mg dose, 
from 5.9 to 8.5 ng/mL for the 20 mg dose, and from 
13.6 to 22.4 ng/mL for the 40 mg. dose; for each 
dose level, the pre-dose plasma concentrations 
were statistically constant. Statistical analysis of the 
first and last dose across all dose levels showed t
1/2, 
MRT, Cl/F, and Vz/F to be independent of dose, 
with no differences between the first and last dose.  
High fat breakfast taken before or after OTX015 
intake decreased Cmax by 45 and 47% and AUC 0-∞  
by 20 and 27%, respectively. 
Tmax was delayed from 6h (fasted state) to 9 and 
10 h with breakfast before and after OTX015 intake, 
respectively 
MTD: maximum tolerated dose             PK: pharmacokinetic


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1.1.4 Summary of the known and potential risks and benefits, if any, to human subjects 
In three Phase 1 studies in healthy volunteers, no major toxicities were reported following 
administration of single oral doses up to 180 mg OTX015 and oral doses of 10 to 40 mg/day 
administered over 10 consecutive days. No severe AE, no SAE, and no AE leading to study 
treatment discontinuation were reported. The maximum tolerated dose (MTD) was not reached. 
The main toxicities were mild (about 90% of AEs) to moderate headaches and miscellaneous 
gastrointestinal (GI) events, mainly abdominal pain and loose stools. Based on these results, the 
expected toxicities at low doses are headache, abdominal pain, diarrhea, nausea, vomiting, 
constipation, dizziness, and myalgias.  
Considering the results from 28-day repeated dose and chronic toxicity studies in rats and dogs, 
the main target organ toxicity is the digestive system, particularly liver. Other organs which 
should be monitored are lymphoid tissues, hematopoietic organs, lungs, and reproductive organs 
in males. Briefly:  
• Digestive system: In both rats and dogs, clinical signs of loose stools and diarrhea were 
accompanied by histopathologic findings of mononuclear cell infiltration of the lamina propria 
mucosa and degeneration of the epithelium of the small and large intestine. In chronic toxicity 
studies, abnormal liver function tests were observed in both rats (decreased total protein and 
albumin) and dogs (increased SGOT and SGPT), accompanied by histological findings of 
pigment deposition in perilobular Kupffer cells in livers of both species and cholestasis and 
vacuolization of the centrilobular hepatocytes in livers of dogs. Prolonged APTT in both species 
was observed after 28-day dosing in rats and after both 28-day and chronic dosing in dogs.  
• Hematopoietic system: Both rats and dogs showed decreased platelets and lymphocytes after 28-
day dosing, accompanied by histopathologic findings of depletion of lymphocytes in the spleen 
and mesenteric and submandibular lymph nodes and myeloid hypoplasia in the bone marrow of 
femur and sternum. Rats showed decreased RBC after both 28-day and chronic dosing, 
accompanied by histopathologic findings of extramedullary hematopoiesis in spleen after chronic 
dosing.  
• Lungs: In rats, histopatholoic exams showed intra-alveolar foamy macrophages in lungs and 
bronchus in both sexes after both 28-day and chronic dosing; these were resolved after one month 
recovery in the 28-day study.  
• Reproductive organs in males: In male dogs, histopathologic exams showed tubular 
degeneration of testes after both 28-day and chronic dosing and bilateral decrease of sperm in the 
epididymides after chronic dosing. There is no evidence of reversibility of this effect. Male 
patients should therefore be informed of the risk of definite infertility. 
No phototoxicity studies have been performed yet. However OTX015 absorbs light in the range of 
290 and 400 nm with a molar extinction coefficient (MEC) of >1000 L mol-1 cm-1. 
Recommendation to avoid sun exposure should be made until results of phototoxicity studies are 
available. 


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The present study plans to continue dose escalation, possibly up to MTD, in order to achieve 
higher systemic exposures than those obtained in the healthy volunteer studies and thereby 
optimize antitumor activity. Accordingly, the target organ toxicities observed in nonclinical 
studies may be expected, with target organs including digestive tract, liver, lungs, lymphoid 
tissues, hematopoietic organs, and reproductive organs in males.  
In addition, other unexpected toxicities may occur. Patients with advanced, multi-treated, life-
threatening diseases will be treated, who might tolerate OTX015 differently than healthy 
volunteers.  
1.2 
JUSTIFICATION OF THE STUDY AND OF THE STUDY DESIGN 
1.2.1   Justification of selecting patients with hematological malignancies 
Hematological malignancies are heterogeneous diseases. There is increasing evidence in 
preclinical models that brd inhibition can lead to anti tumor activity against various illnesses from 
acute leukemia [Redner 1999; Zuber 2011; Dawson 2011; Blobel 2011]  to lymphoma [OTX015 
Investigator’s Brochure]. and myeloma [Delmore 2011] [OTX015 Investigator’s Brochure ]. It is 
known that in many hematological malignancies, the oncogenesis is driven by the oncogene c-
Myc [Boxer 2001 ; Vita & Henriksson 2006; Mertz 2011; Delmore 2011 ; Cuccuini 2012]. It has 
been shown that brd inhibition was frequently associated with c-Myc, and downstream targets 
downregulation [Mertz 2011]. 
Though a significant proportion of patients with acute leukemia and lymphoma can be cured or 
can benefit of prolonged overall survival with current therapies, the majority of patients with 
hematological malignancies will die from their disease. The level of unmet medical need is 
therefore very high and innovative new drugs are eagerly expected. 
1.2.2 Justification of the new drug product formulation 
The drug product formulation used in the healthy volunteer studies was designed to deliver the 
active agent to the lower intestine for treatment of inflammatory bowel disease. For treatment of 
cancer, it is desirable for have a formulation that achieves the highest possible systemic levels of 
active agent. A bioavailability study in dogs comparing the clinical formulation used for the 
healthy volunteer studies (Eudragit; microcrystalline cellulose spheres coated with an ethanolic 
solution of OTX015, triethyl citrate, aminoalky methacrylate copolymer RS, and methacrylic acid 
copolymer, spray dried and mixed with talc, magnesium aluminometasilicate, and light anhydrous 
silicic acid) and the formulation used for nonclinical safety studies (25% OTX015:PVP in ethanol, 
spray dried and mixed with lactose, corn starch, crystalline cellulose, and carmellose calcium) 
found 16%-17% bioavailability (mean Cmax of 211 ng/mL and mean AUC0-24h of 833 ng•h/mL at 3 
mg/kg) for the clinical formulation compared with 30%-40% bioavailability (mean Cmax of 414 
ng/mL and mean AUC0-24h of 1787 ng•h/mL at 3 mg/kg) for the nonclinical formulation. The 2-
fold higher systemic exposure achieved with the solid dispersion OTX015:PVP formulation used 


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in nonclinical safety studies compared with the formulation used in the healthy volunteer studies 
was consistent with the design of the clinical formulation. 
Although the solid dispersion OTX015:PVP formulation achieved adequate systemic exposure, 
polyvinyl pyrrolidone (PVP) is hygroscopic, so screening was performed to identify an alternative 
excipient for a solid dispersion formulation for clinical studies in cancer patients. A bioavailability 
study in dogs of the solid dispersion OTX015:PVP formulation used in nonclinical safety studies 
and the solid dispersion OTX015:HPMCAS-MG formulation to be used in the clinical studies in 
cancer patients found comparable (not statistically different) bioavailability for both the PVP solid 
dispersion (mean Cmax of 487 ng/mL and mean AUC0-24h of 1555 ng•h/mL at 3 mg/kg) and the 
HPCMAS solid dispersion (mean Cmax of 371 ng/mL and mean AUC0-24h of 1970 ng•h/mL at 3 
mg/kg). Accelerated stability studies have confirmed that the solid dispersion PVP formulation 
absorbs some moisture, while the solid dispersion HPMCAS formulation does not. 
1.2.3  Justification of the starting dose 
Traditionally, for first-in-human oncology trials in patients with advanced and/or metastatic 
disease the starting dose is calculated based on the maximally tolerated dose (MTD) or highest 
non-severely toxic dose (HNSTD) in the most sensitive species in 28-day repeated dose 
toxicology studies [CHMP/SWP/997/96; Senderowitz 2010]. In the case where rodents are the 
most sensitive species, the starting dose in humans is one-tenth the rodent MTD or LD10. In the 
case where dogs are the most sensitive species, the starting dose in humans is one-sixth the dog 
HNSTD or MTD. In 28-day repeated dose toxicity studies of OTX015, the MTD in rats was 30 
mg/kg/day, corresponding to a mean Day 28 AUC0-24h of 6715 ng•h/mL, and the HNSTD in dogs 
was 10 mg/kg/day, corresponding to a mean Day 28 AUC0-24h of 4377 ng•h/mL. Based on the 
MTD in rats and using a conversion factor of 6 from mg/kg to mg/m
2 in rats and assuming a mean 
BSA of 1.5 m
2 for humans, the starting dose is calculated as 27 mg [i.e., (30 x 6 x 1.5)/10]. Based 
on the HNSTD in dogs and using a conversion factor of 20 from mg/kg to mg/m
2 in dogs and 
assuming a mean BSA of 1.5 m
2 for humans, the starting dose is calculated as 50 mg [i.e., (10 x 
20 x 1.5)/6]. The most conservative estimate, based on the MTD in rats, gives a starting dose of 
27 mg in humans. As noted above, the bioavailabilites in dogs found for the solid dispersion 
OTX015:PVP formulation used in nonclinical safety studies and the solid dispersion 
OTX015:HPMCAS formulation to be used in clinical studies in cancer patients were not 
statistically different, so a starting dose of 27 mg can be justified.  
However, a starting dose of 10 mg will be used, based on the following considerations: (1) in the 
healthy volunteer studies, a dose of 40 mg/day over 10 consecutive days was well tolerated, with 
no severe AEs or dose-limiting toxicities; (2) patients with advanced hematologic malignancies 
may tolerate treatment less well than healthy volunteers, justifying a starting dose one level below 
the highest repeated dose administered to healthy volunteers, or 20 mg/day, and (3) the systemic 
bioavailability in dogs of the formulation to be used in studies in cancer patients is 2-fold higher 
than the formulation used in healthy volunteers, so a dose of 10 mg/day using the new formulation 
is expected to give a systemic exposure comparable to the dose of 20 mg/day using the 
formulation in the healthy volunteer study.  


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1.2.4 Justification of the schedule of administration and of various schedules according to 
the treated condition 
In vitro experiments of OTX015 against lymphoma and leukemia cells have shown that c-Myc 
downregulation and anti-proliferative effect were reversible after washout [OTX015 Investigator’s 
Brochure]. Thus, a continuous exposure is deemed appropriate for an optimal antitumor effect. An 
intermittent schedule (14 days ON/ 7 days OFF every 21 days) was initially deemed more 
appropriate for the assessment of toxic effects in acute leukemia patients, known to experience 
many disease-related AEs. After the assessment of 3 dose levels with both an intermittent and a 
continuous schedule, showing the tolerance and feasibility of a continuous schedule and 
accumulating evidence that a continuous exposure to adequate concentrations of OTX015 is 
required for an optimal antitumor activity, the same continuous schedule will be finally delivered 
to all patients. 
 
1.2.5 Justification of two parallel dose escalation subsets 
Patients with relapsed/refractory acute leukemia usually experience severe/life-threatening AEs 
associated to disease-related severe bone marrow failure (especially fever, sepsis and 
hemorrhages) sometimes associated with metabolic disorders (hyperuricemia, hyperkalemia, 
hypocalcemia, renal failure, metabolic acidosis…). Thus, it is difficult to assess the relationship of 
treatment emergent AEs to a new medication having yet an undefined safety profile. Especially, 
hematological toxicities in acute leukemia cannot be assessed according to the same guidelines as 
other hematological malignancies, such as lymphoma or myeloma, without or with only 
mild/moderate bone marrow failure. Because peripheral blood cell counts (BCC) are usually 
extremely low at study entry in patients with acute leukemia, bone marrow toxicity cannot be 
assessed based upon decrease of BCC on study treatment. Hence it is not possible to pool and 
assess together acute leukemia and other malignancies in very small patient cohorts of 3-6 patients 
to assess toxicities and establish a reliable recommended dose. 
Therefore, dose escalations and the safety and pharmacokinetics of OTX015 will be evaluated 
separately in patients with acute leukemia on one hand, and in patients with other hematological 
malignancies on the other hand. 
1.3 
CONCLUSION   
OTX015 is a new innovative compound acting through Brd inhibition and epigenetic modulation 
of gene expression with promising anti-tumor activities in various hematological malignancies. It 
has been already tested in human healthy volunteers and was well tolerated at doses which 
achieved plasma concentration in the range of active concentration against in vitro tumor models. 
The antitumor effect is often associated with c-Myc down-regulation. 
This clinical study is aimed at assessing the recommended dose (RD), the safety profile, PK and 
PD of OTX015 in patients with refractory/relapsed hematological malignancies, and to detect 
clues of clinical anti-tumor activity. 


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2 
STUDY OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
To determine the recommended dose (RD) of OTX015/MK-8628 for further phase II studies, in 
patients with acute leukemia and in patients with other hematological malignancies. 
2.2 
SECONDARY OBJECTIVES 
The secondary objectives of the study are: 
• To assess the safety profile of OTX015/MK-8628 as a single agent in patients with 
haematological malignancies  
• To assess pharmacokinetics (PK) of OTX015/MK-8628 in patients with haematological 
malignancies and PK/safety relationship 
• To assess pharmacodynamics (PD) of OTX015/MK-8628 in patients with 
haematological malignancies, PD/safety and PK/PD relationships  
• To detect clues of clinical antitumor activity 
2.3 
EXPLORATORY  
• To detect predictive factors (among patient or tumor characteristics) of clinical activity 
3 
STUDY DESIGN, DURATION AND DATES 
3.1 
STUDY DESIGN 
This is a multicenter, multinational dose finding, open label, phase Ib study.  
3.1.1 Dose escalation part 
• Two dose escalation subsets will be assessed independently in parallel: patients with acute 
leukemia and patients with other hematological malignancies.   
• Patients will be enrolled by successive cohorts of 3 patients in each dose escalation subset. 
• Three patients will be initially treated at the starting dose level (DL) in each subset. If no dose 
limiting toxicity (DLT) is observed among these 3 patients during the first cycle of treatment 
(i.e. the first 21 days following study treatment initiation, regardless of the treatment 
schedule), the next 3 patients will be treated at the DL immediately above, according to the 
dose escalation schedule defined in section 5.2.4.1. In the absence of DLT observed at the 
completed DL, the dose will be doubled. 


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• At each DL in each subset, the second patient enrolled will not start the study treatment before 
the first treated patient of the cohort will have completed at least 2 weeks of treatment (i.e. 14 
consecutive daily administrations). The first patient enrolled in a higher DL cohort will not 
start the study treatment before the last treated patient in the DL immediately below will have 
completed at least one cycle of study treatment (i.e. 21 days following study treatment 
initiation, regardless of the treatment schedule).. 
• If one out of 3 patients of a cohort experiences a DLT during the first cycle (i.e. 21 days 
following study treatment initiation, regardless of the treatment schedule), 3 additional 
patients will be entered at this DL. If no more than 1/6 treated and evaluable patient 
experience a DLT, the dose escalation will proceed to the DL immediately above. As soon as 
a DLT is observed, the magnitude of dose escalation will follow a Fibonacci-like model. (see 
section 5.2.4.1). 
• 
 If more than one patient out of 6 (or more than one out of 3) patients experiences a DLT, the 
DL will be considered exceeding the maximum tolerated dose (MTD) for this subset.  
• Patients not evaluable for DLT are those having received less than 85% of the intended 
cumulative dose during the first 21 days (i.e. those receiving less than 18 days of treatment for 
the continuous, 21-day schedule or less than 12 days of treatment for the intermittent, 14 days 
ON/ 7 days OFF schedule) and who have not experienced a DLT, will be replaced. 
• The dose escalation will be stopped independently in each subset upon decision of the Safety 
Monitoring Committee (SMC). This decision could be taken if one of the following conditions 
is met: 
- 
A DL exceeding the MTD has been reached 
- 
Biological activity (PD) or sustained biologically active concentrations (PK) of 
OTX015/MK-8628 have been achieved 
- 
Or any other unforeseen condition, which, in the judgment of the SMC, would prevent, 
or would not deserve, further dose escalation. 
• In the absence of other data (PD or PK) suggesting a lower RD, the MTD will be considered 
the RD (one DL below the dose exceeding the MTD) in each subset. At least 6 evaluable 
patients will be enrolled at the supposed RD. The RD will be confirmed for each subset if no 
more than 1/6 patient experiences a DLT. Otherwise the DL immediately below will be 
explored with a minimum of 6 patients treated. 
 
3.1.2 Expansion part   
• Once the RD will be established with at least 3 patients having received at least 2 cycles of 
study treatment in each subset, the study will be prolonged with expansion cohorts in 
selected patients to confirm feasibility, safety, PK and PD at the RD. At least 12 evaluable 
patients with acute leukemia will be treated at the RD established for patients with acute 


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Page 40 
leukemia. At least 12 evaluable patients with lymphoma and at least 12 patients with 
multiple myeloma will be treated at the RD established for patients with other 
hematological malignancies. Additional expansion cohorts may be decided by the SMC, 
based upon the data collected during the dose escalation phase. 
 
 
3.2 
DEFINITION OF DOSE LIMITING TOXICITIES (DLTS) 
DLTs are defined as any of the following treatment-related adverse events occurring in the first 
cycle (during the first 21 days following study treatment initiation (except hematological toxicity 
in AL patients confirmed at day 43, see below), regardless of the administration schedule), 
leading to dose modifications, study treatment interruption or discontinuation, unless a 
relationship to study medication can be definitely ruled out.  
DLTs will be reported immediately to the sponsor using Serious Adverse Events Report Forms 
(SAERF) with reason for seriousness: “other important medical event” if there is no other reason 
for seriousness. 
3.2.1 Non-hematological DLTs 
• Any grade 3 or 4 non-hematological event (regardless of duration), unless it was not optimally 
treated with supportive care (e.g. grade 3 vomiting not adequately treated according to 
antiemetic standard of care). 
• Grade 3-4 asymptomatic laboratory abnormal values lasting > 7 days. This definition applies 
for patients with lab values grade < 1 at baseline. For patients with grade 2 values at baseline, 
only grade 4 lasting > 7 days will be considered DLT, unless the SMC considers the event 
clinically significant. See below for liver function tests*. 
• Any prolonged grade 2 toxicity (lasting more than 2 weeks) leading to treatment interruption 
and/or dose reduction 
 
* Any of the following liver test abnormalities** (see Appendix 16.12) 
- 
ALT or AST > 8 x ULN  
- 
ALT or AST > 5 x ULN for > 2 weeks 
- 
ALT or AST > 3 x ULN AND (total bilirubin > 2 x ULN OR INR > 1.5) 
- 
ALT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%), unless the 
investigator assesses the rash or fatigue to be related to OTX015 and not related to liver 
impairment with sponsor’s agreement. 
**Note: All patients with these liver test abnormalities should be monitored weekly until all 
abnormalities return to normal or to the baseline state. For patients with isolated total bilirubin 
increases >2 x ULN or 2 x baseline (if elevated at baseline), except if associated with direct 
bilirubin ≤ ULN, monitoring should be every 2 weeks until bilirubin returns to normal or to the 
baseline state. Drug induced liver injury (DILI) may develop or progress even after the causative 


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Page 41 
drug has been stopped. Results should be recorded on the CRF and in the database. See guidelines 
on the handling of these events (potential Hy’s law cases).  
 
Investigators must be warned about qualifying fatigue/asthenia as a DLT. Grade 3 fatigue/asthenia 
deemed to be related to the study medication is a DLT as per protocol. However, multiple causal 
events, often intricate, may result in severe fatigue/asthenia in cancer patients participating to a 
phase I clinical trial, including disease progression, concomitant medications, concomitant 
medical conditions, anxiety, depression, transportation, etc. 
3.2.2 Hematological DLTs 
3.2.2.1 In patients with acute leukemia 
• Pancytopenia with a hypocellular bone marrow and no marrow blasts lasting for ≥ 6 weeks 
after the start of a cycle. DLT will be suspected in case of pancytopenia with a hypocellular 
bone marrow and no marrow blast on bone marrow aspiration on day 22, but confirmed on 
bone marrow aspiration on day 43. Decision of adding or not patients in the cohort will be 
based on day 22 findings.   
3.2.2.2 In patients with other hematological malignancies 
• Any grade 3  neutropenia, with fever or infection; any grade 3 thrombocytopenia with 
bleeding,  
• 
Any grade 4 neutropenia or thrombocytopenia, regardless of symptoms and lasting > 3 days. 
 
3.3 
INDEPENDENT SAFETY MONITORING COMMITTEE (SMC) 
The SMC will be composed of the principal investigators (PI) of each participating center, the 
pharmacokinetics (PK) specialist, the medical and safety representatives of the Sponsor and one 
independent expert in oncology/hematology phase I development (see Appendix VIII, section 
16.8). All decisions taken by the SMC and their rationale will be recorded in meeting minutes that 
will be integrated as appendix in the final Clinical Study Report. 
The SMC will be responsible for the following decisions: 
• Proceeding to the next higher DL or stop dose escalation 
• Definitely ruling out a relationship of an adverse event (AE) to study medication 
• Adding patients at a given DL, if appropriate 
• Modifying the treatment schedule of administration (e.g. BID) or shifting from an 
intermittent schedule to a continuous schedule 
• Determining the RD  


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• Starting enrollment into expansion cohorts and determining the number of cohorts 
• Closing patient enrollment 
• Taking any decision aimed at improving participating patients’ safety. 
In addition, according to the nature, suspected relationship to study drug, or other clinical 
considerations, the SMC will make ad-hoc decisions, such as replacing inevaluable patients, 
adding more patients at the same DL, adding intermediate DLs, not considering a given DLT as 
clinically relevant for the determination of the RD. Serial assessments of PK and, if possible, PD 
results will be forwarded to the SMC and will be taken into account for the determination of the 
RD, especially if no DLT occurs. 
 
3.4 
STUDY DURATION AND DATES 
The duration of this study will depend upon the number of DLTs encountered and the number of 
dose levels explored. 
It is anticipated to be 40 months, with subject enrolment starting in January 2013 and ending 
January 2016 and a minimum follow-up over 1 month after the last patient entered (end of study 
May 2016).   
The study will be closed after the last visit of the last patient still on study. 


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Clinical Study Protocol  OTX015_104                       Date: 18 December 2015 
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Page 43 
4 
SELECTION OF SUBJECTS 
4.1 
NUMBER OF SUBJECTS 
The total number of patients enrolled will depend on the number of DLs explored and of DLT 
encountered. 
Approximately 80 evaluable patients will be enrolled in the dose escalation part (40 by subset 
acute leukemias/other hematological malignancies). 
At least 12 evaluable patients will be enrolled by expansion cohorts in at least 3 expansion cohorts 
The total number of evaluable patients is estimated to be approximately 125. 
4.2 
INCLUSION CRITERIA 
Subjects meeting all of the following criteria will be considered for enrollment into the study: 
1. Signed informed consent must be obtained for all subjects at enrollment into the study (see 
section 12.3), i.e. prior to beginning protocol specific procedures. Patients registered for 
this trial must be treated and followed at the participating center. 
2. Histologically or cytologically proven hematological malignancy or confirmed multiple 
myeloma according to standard diagnosis criteria [Durie, 2006]. For the dose escalation 
part, any refractory/relapsing hematological malignancy (having failed all standard 
therapies) will be accepted. For the expansion cohorts, only patients with selected 
hematological malignancies will be enrolled: At least 4 diseases are foreseen, but 
additional medical conditions may be decided by the SMC: acute myelocytic leukemia 
(AML), acute lymphocytic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), 
multiple myeloma (MM). Acute leukemia (AL) is defined according to the WHO 2008 
classification [Vardiman, 2009]. Acute myeloblastic leukemia (AML) and B-cell or T-cell 
acute lymphoblastic leukemia (ALL), de novo, as well as secondary AL (i.e. 
transformation of a pre-existing myelodysplastic syndrome, chronic myelogenous 
leukemia or other myeloproliferative neoplasms) may be enrolled. For lymphoma, an 
archived formaldehyde-fixed paraffin-embedded block must be available. 
3. Patient with resistant/refractory disease, having failed all standard therapies or for whom 
standard treatments are contra-indicated. 
DEFINITION OF RESISTANT/REFRACTORY DISEASE 
 
• 
Acute Leukemia: Patients < 60 years old in second or further relapse, or relapsing after 
allogeneic stem cell transplantation (aSCT) regardless of number of relapses; patients > 
60 years old in first relapse with a disease-free interval (DFI) < 12 months; or further 
relapse; irrespective of age, in patients relapsing after aSCT, the time elapsed since aSCT 
should be > 90 days. Patients with philadelphia chromosome positive (Ph+) and/or bcr-


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abl+ B-cell ALL must have received at least two lines of therapy, including 2 bcr-abl 
tyrosine-kinase (TK) inhibitors (among imatinib, nilotinib and dasatinib), or only one line 
including one TK inhibitor, if the relapse/refractoriness is associated with the detection of 
a resistance mutation to these inhibitors. 
• Lymphomas: Patients having failed 2 standard lines of therapy, or for whom such 
treatment is contra-indicated. B-cell lymphoma patients must have received at least one 
anti-CD20 monoclonal antibody-based regimen. 
• Multiple myeloma: Patients adequately exposed to at least one alkylating agent, one 
corticosteroid, one immunomodulatory drug (IMiD) and bortezomib, or for whom one or 
more of such treatments are contra-indicated. 
 
4. Patients with evaluable disease:  
• AL patients must have > 5% bone marrow blasts at study entry, without alternative 
causality (e.g. marrow regeneration), or reappearance of blasts in peripheral blood, or 
evaluable extramedullary disease  [Döhner, 2010]. In case of low marrow blast count 
(5-10%), relapse should be confirmed by a second myelogram. 
• Lymphoma patients must have at least one non-irradiated tumor mass > 15 mm (long 
axis of lymph node) or > 10 mm (short axis of lymph node or extranodal lesions) on 
spiral CT-scan.  
• Patients with MM must have at least one of the following: serum monoclonal 
component > 1g/dL (IgG), or > 0.5g/dL (IgA), or Bence-Jones (BJ) proteinuria > 
200mg/24h, or measurable plasmacytoma (not previously irradiated). 
5. Patients > 18 years old. 
6. Life expectancy of at least 3 months  
7. ECOG performance status (PS) of 0 to 2  
8. Off previous anti-tumor therapy for at least 3 weeks, or 5 half-lives of previously 
administered drug, whichever is longer, prior to first study treatment administration, 
except 1) hydroxyurea given to control hyperleukocytosis that should be stopped 48 hours 
prior to start study medication and 2) rituximab which should be stopped for at least 3 
weeks, regardless of half-life. 
9. Recovery from the non-hematological toxic effects of prior treatment to grade < 1, 
according to NCI-CTC classification, except alopecia. 
10. Bone marrow function 
• For patients with AL: no limitation 
• For patients with other hematological malignancies: Absolute neutrophil count (ANC) 
> 1.0 x 109/L, platelets > 150 x 109/L, hemoglobin ≥8 g/dL (4 weeks without 
transfusion)   
11.  Calculated creatinine clearance > 30 mL/min (Cockroft & Gault formula, or MDRD 
formula for patients aged > 65 years).  


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12. Adequate LFTs: Total bilirubin < institutional upper normal limit (UNL) (or ≤ 2 x UNL in 
cases of liver involvement); ALAT/ASAT ≤ 3 x UNL (or ≤ 5 x UNL in case of liver 
involvement). 
13. Serum albumin > 28 g/L 
14. International normalized ratio (INR) or prothrombin time (PT) and activated partial 
thromboplastin time (aPTT) ≤1.5 X ULN. 
15. Complete baseline disease assessment workup (including bone marrow examination and 
tumor imaging for lymphomas; bone marrow aspiration for AL, measurement of serum M-
component and/or BJ proteinuria, imaging of bone lesions and bone marrow aspiration or 
biopsy for MM) prior to first study treatment administration. 
4.3 
EXCLUSION CRITERIA 
Subjects presenting with any of the following will not be included in the study: 
 
1. History of prior malignancy other than those previously treated with a curative intent more 
than 5 years ago and without relapse (any tumor) or basal cell skin cancer, in situ cervical 
cancer, superficial bladder cancer, or high grade intestinal polyps treated adequately, 
regardless of the disease-free interval. 
2. Pregnant or lactating women or women of childbearing potential not using adequate 
contraception. Male patients not using adequate contraception. 
3. Patients 
with 
peripheral 
cytopenias 
(i.e. 
auto-immune 
hemolytic 
anemia 
or 
thrombocytopenia). 
4. Patients with acute promyelocytic leukemia or with clinically uncontrolled (i.e. with 
bleeding) disseminated intravascular coagulation (DIC). 
5. MM patients with POEMS syndrome or plasma cell leukemia 
6. Patient with chronic graft versus host disease (GVHD) or on immunosuppressive therapy 
for the control of GVHD 
7. Uncontrolled leptomeningeal disease. 
8. Uncontrolled disease-related metabolic disorder (e.g. hypercalcemia) 
9. Other tumor location necessitating an urgent therapeutic intervention (palliative care, 
surgery or radiation therapy), such as spinal cord compression, other compressive mass, 
uncontrolled painful lesion, bone fracture, etc..) 
10. Patients unable to swallow oral medications, or patients with gastrointestinal condition 
(e.g. malabsorption, resection…) deemed to jeopardize intestinal absorption. 
11. Other serious illness or medical conditions, which, in the investigator’s opinion, could 
hamper understanding of the study by the patient, patient’s compliance to study treatment, 
patient’s safety, or interpretation of study results. These conditions include (but are not 
restricted to): 
 
a) Congestive heart failure or angina pectoris except if medically controlled.  
Previous history of myocardial infarction within 1 year from study entry, 
uncontrolled hypertension or arrhythmias. b) Existence of significant neurologic or 


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psychiatric disorders impairing the ability to obtain consent. c) Uncontrolled 
infection; d) known HIV positivity. 
12. Concurrent treatment with other experimental therapies or participation in another clinical 
trial within 30 days prior to first study treatment administration, or 5 half-lives of 
previously administered drugs, whichever is longer. 
13. Concurrent treatment with any other anticancer therapy, except hydroxyurea to reduced 
hyperleukocytosis. 
14.  Concomitant treatment with corticosteroids except chronic treatment with ≤ 30 mg of 
methylprednisolone daily or equivalent dose of other corticosteroids. 
15. Patients taking concomitant strong CYP3A4 interacting drugs (see appendix XI) 
16. Patients with prior irradiation on more than 30% of bone marrow reserves (including Total 
Body Irradiation), regardless of washout period, and patients having received high dose 
chemotherapy followed by autologous stem cell transplantation less than 90 days prior to 
first OTX015/MK-8628 dosing. 
Any waiver of these inclusion and exclusion criteria should be exceptional and justified and must 
be approved by the investigator and the sponsor on a case-by-case basis prior to enrolling the 
subject.  This must be documented by both the sponsor and the investigator. 
No subject will be allowed to be enrolled in this study more than once. 
No subjects who have previously been treated with OTX015/MK-8628 will be enrolled in this 
study. 
4.4 
SUBJECTS OF REPRODUCTIVE POTENTIAL 
Female patients must not be pregnant or breast-feeding at inclusion in the study (mentioned as 
exclusion criteria in Section 4.3).  Absence of pregnancy must be demonstrated by serum or urine 
testing unless there is a proven menopause (age > 50 years and last menarche > 3 years, or 
documented menopausal sex hormone profile, or surgical castration) prior to exposure to the 
investigational product or any study procedure with potential risk to the fetus. 
The patient must not become pregnant during the study.  
Female patients of childbearing potential (i.e. without proven menopause, see above), as well as 
male patients with a sexual partner of childbearing potential, must use a medically effective 
contraception during study and within 6 months after the last study medication intake. 


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ONCOETHIX                                                             CONFIDENTIAL 
Clinical Study Protocol  OTX015_104                       Date: 18 December 2015 
   Document Status: Version J 
 
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information contained therein may be reproduced or disclosed outside OncoEthix without their written consent 
 
 
Page 48 
with AL and 3 with other malignancies) will be hospitalized at least 24 hours for complete 
PK sampling (see section 7.3.3.1) All other patients enrolled in the same DL will have 
limited PK sampling and will stay at least 8 hours at the hospital on day 1. For the BID 
schedule, all patients will be hospitalized for 24 hours for PK sampling. 
• Route:  Oral capsules will be swallowed with water in a fasted state before lunch, at least 3 
hours after breakfast end), except the first dose (C1D1) that will be taken at the hospital 
before breakfast.  
• Capsules must not be open or chewed. 
• Schedule: The schedule of administration will initially depend on the indication: 
- 
patients with acute leukemia will initially take OTX015/MK-8628, over 14 
consecutive days followed by a 7-day rest period. Upon SMC decision, patients with acute 
leukemia will take OTX015/MK-8628 continuously without planned rest period, like 
patients with other haematological malignancies. 
- 
patients with other malignancies will take OTX015/MK-8628 continuously without 
planned rest period 
- 
In all cases, one cycle = 21 days by convention and day 22= day 1 of next cycle. 
 
ACUTE LEUKEMIA (initial schedule before amendment # 4) 
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 etc.. 
 
OTHER HEMATOLOGICAL MALIGNANCIES and ACUTE LEUKEMIA after 
amendment # 4 
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 etc.. 
 
• Interruptions are planned in case of toxicity according to specific guide lines (see section 0). 
If study medication interruptions due to toxicity are regularly observed, the SMC may 
decide to modify the schedule and to assess new cohorts of patients with this modified 
schedule. 
• Based upon human PK in the healthy volunteers study with repeated dose and especially 
long plasma half-life (t1/2), the first patients entered will take study medication once a day, 
According to PK data observed in these patients, and/or PD data the schedule of 
administration could be modified in further patients, upon SMC decision (e.g. b.i.). For the 
BID schedule, patients will take their medication in a fasted state around 8 a.m. (+ 2 hours) 
and 8 p.m (+ 2 hours). 
• Omitted doses will not be replaced. Dosing not performed at the same time (+ 2 hours) as 
the other days will be omitted 
• Vomited doses will not be replaced. 
 
 
 
 


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Clinical Study Protocol  OTX015_104                       Date: 18 December 2015 
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Page 49 
5.2.4 Dose 
5.2.4.1 Dose escalation  
• Starting dose: the starting dose will be 10 mg/day (once a day, flat dose, without 
adaptation for body weight or surface area), See justification in section 0. 
• DLTs will be collected during the first cycle (the first 21 days after study treatment 
initiation). 
• The dose escalation scheme is provided on Table 3. Dose escalation will proceed 
independently for each subset (acute leukemias and other hematological malignancies). 
The magnitude of dose escalation between two consecutive dose levels will depend upon 
the occurrence or not of DLT at the current DL: In the absence of any DLT (see definition 
section 3.2), the dose will be doubled between two successive DLs. In case of at least one 
DLT, dose escalation will proceed according to a modified Fibonacci model. 
• If and when the decision of exploring a BID schedule is taken by the SMC after the 
assessment of dose level Xmg once-a-day, the first BID dose level explored will be X/2 
mg twice-a-day (e.g. if the last once-a day dose level explored = 80mg → the first BID 
dose level explored = 40mg x 2/day). Then, further dose escalation with the BID schedule 
will proceed as described in the table (e.g. if the first BID dose level explored= 40mg x 
2/day, then the next dose level explored will be 80mg x 2/day if no DLT was observed at 
40mg x 2/day, or 60mg x 2 if one DLT was observed). 
 
• When the decision of delivering OTX015/MK-8628 continuously to AL patients is taken by 
the SMC, ongoing AL patients having received at least one intermittent cycle (14 days 
ON/7 days OFF) without DLT will be proposed to receive further cycles without planned 
interruption (21days ON) at the same daily dose.  When sufficient safety data will have 
been collected with the continuous schedule both in AL patients and in patients with other 
haematological malignancies, the SMC may allow further cohorts of AL patients to 
receive continuous OTX015/MK-8628 treatment from cycle 1. 
• RD will be defined either by the MTD, or, in the absence of DLT, based upon PK and/or 
PD considerations or other unforeseen condition (see Study Design).  
 
 


ONCOETHIX                                                             CONFIDENTIAL 
Clinical Study Protocol  OTX015_104                       Date: 18 December 2015 
   Document Status: Version J 
 
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information contained therein may be reproduced or disclosed outside OncoEthix without their written consent 
 
 
Page 50 
Table 3 : Dose escalation scheme 
Dose Level 
 
 
 
1 (starting dose) (mg) 
10 
 
 
2 
20 
 
 
3 
30 
40 
 
4 
40 
60 
80 
5 
50 
80 
120 
Dose escalation schedule: 
Doubling the dose in the absence of DLT (grey boxes). 
Fibonacci-like model once at least one  DLT occurs (white boxes) 
• Dose escalation guidelines are detailed in section 3.1.1. The dose escalation will proceed 
following the same rule in two separate subsets of patients (i.e. AL or  other hematological 
malignancies) 
• Enrolled patients will take OTX015/MK-8628 at the DL they were assigned at study entry 
throughout the study, or at reduced dose according to toxicity encountered (see 0).  
• Intrapatient dose escalation: In exceptional circumstances, intra-patient dose escalation 
could be allowed, provided all the following conditions are met: 1) The patient did not 
experienced toxicity of grade > 1 while treated at the initial dose for at least 2 cycles; 2) 
The dose immediately above has already been tested and is considered safe (i.e. at least 3 
patients were treated over 3 weeks and no DLT was observed, or at least 6 were treated 
over 3 weeks and no more than one of them has experienced a DLT); 3) the patient has 
experienced stable disease so far (no response and no progression); 4) the investigator 
considers the patient could benefit from dose increment and 5) the SMC agrees. 
 
The recommended dose (RD) for expansion cohorts for both acute leukemia and other 
hematologic malignancies is 80mg QD days 1 to 14 of 21-day cycles (2 weeks ON/one week 
OFF). 
5.2.4.2 Dose adaptation 
Study product dosing (OTX015/MK-8628) will be interrupted in the event of AEs corresponding 
to the definition of a DLT (see section 3.2), but regardless of the cycle in which they occur: 
Non hematological toxicity 
• Any grade 3 or 4 non-hematological event (regardless of duration), unless it was not optimally 
treated with supportive care (e.g. grade 3 vomiting not adequately treated according to 
antiemetic standard of care). 
• Grade 3-4 asymptomatic laboratory abnormal values lasting > 7 days. This definition applies 
for patients with lab values grade < 1 at baseline. For patients with grade 2 values at baseline, 
only grade 4 lasting > 7 days will be considered DLT, unless the SMC considers the event 
clinically significant. See below for liver function tests*. 


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Page 51 
• Any prolonged grade 2 toxicity (lasting more than 2 weeks) leading to treatment interruption 
and/or dose reduction. 
 
* Any of the following liver test abnormalities** (see Appendix 16.12) 
- 
ALT or AST > 8 x ULN  
- 
ALT or AST > 5 x ULN for > 2 weeks 
- 
ALT or AST > 3 x ULN AND (total bilirubin > 2 x ULN OR INR > 1.5) 
- 
ALT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%), unless the investigator 
assesses the rash or fatigue to be related to OTX015 and not related to liver impairment 
with sponsor’s agreement. 
**Note: All patients with these liver test abnormalities should be monitored weekly until all 
abnormalities return to normal or to the baseline state. For patients with isolated total bilirubin 
increases >2 x ULN or 2 x baseline (if elevated at baseline), except if associated with direct 
bilirubin ≤ ULN, monitoring should be every 2 weeks until bilirubin returns to normal or to the 
baseline state. Drug induced liver injury (DILI) may develop or progress even after the causative 
drug has been stopped. Results should be recorded on the CRF and in the database. See guidelines 
on the handling of these events (potential Hy’s law cases).  
Hematological toxicity 
Patients with AL 
• Pancytopenia with a hypocellular bone marrow and no marrow blasts lasting for ≥ 6 weeks 
after the start of a cycle.   
Patients with other hematological malignancies 
• Any grade 3  neutropenia, with fever or infection 
• Any grade 3 thrombocytopenia with bleeding,  
• Any grade 4 neutropenia or thrombocytopenia, regardless of symptoms and lasting > 3 days.  
 
OTX015/MK-8628 dosing will be resumed when all toxic events have resolved to grade < 2 (or 
baseline value). 
• At reduced dose : 
- During the dose escalation, at the DL immediately below.  
- During expansion cohorts, patients treated at 80mg QD (2 weeks ON/ 1 week OFF) will 
have their dose first reduced to 60mg QD (2 weeks ON/ 1 week OFF), then to 40mg QD (2 
weeks ON/ 1 week OFF), should the same toxicity recurs.  
 
• Dosing interruption for > 2 weeks due to toxicity will lead to definitive study treatment 
discontinuation, unless the investigator thinks the patient’s best interest is to pursue study 
treatment. 
 


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Clinical Study Protocol  OTX015_104                       Date: 18 December 2015 
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Page 52 
• If the same DLT is observed again after dose reduction, the study treatment should be 
definitely discontinued, unless the investigator thinks the patient’s best interest is to pursue 
study treatment with further dose reduction, with sponsor’s agreement. 
 
5.2.5 Supportive care guidelines in case of study treatment toxicity 
Toxicity will be managed by the investigators according to local standard of care. 
Supportive treatment of toxicities should be reported in the concomitant medication section of the 
case report form (CRF). 
Handling of hepatotoxicity for potential DILI will be managed according to the treatment 
guidelines outlined in Appendix 16.12. 
5.3 
TREATMENT DURATION 
Treatment will be continued until: 
• Disease progression 
• Intolerable toxicity 
• Treatment interruption for > 2 weeks due to toxicity (except in case of suspicion 
hematological DLT in acute leukemia, where treatment interruption for 3 weeks is 
allowed to confirm DLT) 
• Recurrence of DLT despite dose reduction. 
• Any of the following liver test abnormalities (see Appendix 16.12) 
- 
ALT or AST > 8 x ULN  
- 
ALT or AST > 5 x ULN for > 2 weeks 
- 
ALT or AST > 3 x ULN and (total bilirubin > 2 x ULN OR INR > 1.5) 
- 
ALT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%), unless 
the investigator assesses the rash or fatigue to be related to OTX015 and not 
related to liver impairment with sponsor’s agreement 
• Patient’s request (consent withdrawal). 
5.4 
TREATMENT ASSIGNMENT 
The investigational product will be administered only to subjects included in this study following 
the screening procedures set out in the clinical study protocol. 


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ONCOETHIX                                                             CONFIDENTIAL 
Clinical Study Protocol  OTX015_104                       Date: 18 December 2015 
   Document Status: Version J 
 
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information contained therein may be reproduced or disclosed outside OncoEthix without their written consent 
 
 
Page 54 
After validation and signature by the Sponsor’s Medical Monitor, the registration form will be 
returned to the investigators, with or without inclusion agreement. Any inclusion refusal will 
be motivated on the inclusion form. In case of inclusion, a unique patient number (UPN) will 
be assigned to the patient and reported on the inclusion form. 
The UPN will consist of 3 to 5 digits (1 or 2 for the center and 2 or 3 for the patient, by 
increasing order of inclusion) and will be recorded in the case report form (CRF). 
The dose level allocated, and the schedule of administration will be specified on the form. 
A patient should be included and therefore will receive a UPN only when the patient is about to 
start the treatment.  Anyway, the treatment must begin within 7 days after registration. 
Subjects withdrawn from the study retain their UPN.  New subjects must always be allotted a new 
UPN. 
 
5.5 
PACKAGING AND LABELING 
The investigational product is supplied as size 3 gelatin capsules containing 10 mg or 20 mg of 
OTX015/MK-8628 or size 0 gelatin capsules containing 40 mg of OTX015/MK-8628. 
OTX015/MK-8628 will be supplied in bottles of 21 capsules. Clinical supplies will be affixed 
with a clinical label in accordance with regulatory requirements. 
5.6 
CAPSULE STRENGTHS 
OTX015/MK-8628 will be provided as capsules with strengths of 10 mg, 20 mg and 40 mg of 
active compound. 
5.7 
SUPPLIES AND ACCOUNTABILITY 
The pharmacist of the investigational center will inventory and acknowledge receipt of all 
shipments of the investigational medicinal product.  The investigational product must be kept in a 
locked area with restricted access.  The investigational product must be stored and handled in 
accordance with the manufacturer’s instructions. Traceability of the temperature will be required.  
The pharmacist will also keep accurate records of the quantities of the investigational product 
dispensed, used, and returned by each subject.  The study monitor will periodically check the 
supplies of investigational product held by the pharmacist to verify accountability of all 
investigational product used.  The sponsor will verify that a final report of drug accountability to 
the unit dose level is prepared and maintained in the Pharmacy study file. At the conclusion of the 
study, all unused investigational product will be destroyed by the pharmacist or returned to the 
Sponsor after final accountability by the study monitor and agreement of the Sponsor.  A 
certificate of destruction will be provided by the pharmacist to the Sponsor. 


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Clinical Study Protocol  OTX015_104                       Date: 18 December 2015 
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Page 55 
At each study visit, the hospital pharmacist will provide the patients with the adequate number of 
capsules to ensure continuous study treatment until the next visit. 
5.8 
COMPLIANCE 
Administration of the investigational product will be supervised by the investigator.  Any 
delegation of this responsibility must follow Section 12.2. 
In practice, during study visit days, study nurses will supervise the intake of the appropriate dose 
of OTX015/MK-8628, explaining to patients the exact number of capsules. They will document 
the administration, the dose, the time of administration, as well as immediate reaction, if any. 
For non-visit days, OTX015/MK-8628  will be taken at home. The patient will notice the number 
of taken capsules, the time of administration, as well as reaction, if any, including occurrence and 
time of vomiting, on a specific patient’s diary (see Appendix VII; section 16.7). 
When a patient will attend a study visit, he/she will bring back to the pharmacist the unused 
capsules and their diary. According to the center procedures, the diary could be used to fill in the 
CRF treatment administration part, either directly as Source Document, or as a help for filing in 
nurse’s notes, which will be used as Source Document. 


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Clinical Study Protocol  OTX015_104                       Date: 18 December 2015 
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Page 56 
6 
PRIOR AND CONCOMITANT ILLNESSES AND TREATMENTS 
6.2 
PRIOR AND CONCOMITANT MEDICAL CONDITIONS 
Additional illnesses, independent of the treated condition, present at the time informed consent is 
given or within 30 days prior to first study treatment administration must be documented in the 
section “prior and concomitant conditions” of the CRF.  Relevant past illnesses (including other 
cancers) must also be documented in this section. 
Medical conditions first occurring or detected during the study, or worsening of a concomitant 
illness during the study, are to be regarded as treatment emergent adverse events (TEAEs) and 
must be documented as such in the section “Adverse Events” of the CRF (see Section 8.1 of the 
protocol). 
6.3 
PRIOR AND CONCOMITANT MEDICATIONS 
All treatments being taken by the subjects at study entry, or within 30 days prior to first study 
treatment administration, or at any time during the study in addition to the investigational product 
are regarded as concomitant medications and must be documented on the appropriate pages of the 
CRF. 
6.3.1 Forbidden concomitant medications / treatments 
• Concurrent treatment (or within 30 days, or 5 half-lives, whichever is longer) with other 
investigational drugs. 
• Concurrent treatment (or within 21 days) with any anticancer therapy including chemotherapy, 
immunotherapy, hormone therapy, or biological therapies, other than those specified in the 
protocol. The only exception is hydroxyurea given to control hyperleukocytosis that can be 
continued until 48 hours before OTX015/MK-8628 treatment initiation, but must be stopped at 
that time; Furthermore, should rapidly increasing white blood cell count occur during the first 
cycle of OTX015/MK-8628, hydroxyurea could be given not earlier than day 3 and not beyond 
day 43 for the shortest period as clinically indicated to control hyperleukocytosis and keep the 
patient on study. At day 43 the decision to start OTX015/MK-8628 cycle 3 will be taken by the 
investigator according to patient’s anticipated benefit but without hydroxyurea. If, nonetheless, 
hydroxyurea has to be resumed during cycle 3, this would be considered as OTX015/MK-8628 
treatment failure and the patient would be withdrawn from the study. 
• Prophylactic anti-emetic drugs or other drugs given with a prophylactic intent at the first cycle, 
unless the SMC decides to deliver systematic premedication. 
• Corticosteroid, except chronic treatment with < 30 mg/day of methymprednisolone or 
equivalent. 
• Concurrent treatment with drugs with potential interaction: No drug interaction study has been 
undertaken with OTX015/MK-8628 so far. However, OTX015/MK-8628 has been shown to 
inhibit CYP3A4 and CYP2A6. Thus, patients using concomitant drugs or other substances 


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Clinical Study Protocol  OTX015_104                       Date: 18 December 2015 
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Page 57 
interfering with these CYP450 species (see Appendix XI, section 16.11) should be followed-up 
carefully for possible potentialization/inhibition of effects of OTX015/MK-8628 and/or 
concomitant substance. In addition, concomitant treatment with strong (see Appendix XI, 
section 16.11) CYP3A4 interacting drugs is prohibited. Note that as these lists are not 
comprehensive, the investigator should use his/her medical judgment when a patient presents 
with a medication not on the list or call the Sponsor Medical Expert for clarification. 
 
6.3.2 Allowed concomitant medications / treatments 
• Supportive treatment of symptoms/adverse events or standard treatment of concomitant 
conditions, especially transfusion support and antibiotics, bisphosphonates will be given as 
medically indicated and reported in the CRF. 
7 
Patients on anticoagulant or antiaggregant (including low-dose aspirin) therapy at 
screening for concomitant medical conditions should be evaluated in coordination with 
their cardiologist for the benefit/risk ratio of continuing their anticoagulant or 
antiaggregant therapy during study due to the potential increased risk of bleeding in case 
of occurrence of severe thrombocytopenia. Blood cell count should be more frequently 
performed in such patients, at least weekly during the whole study, and more in case of 
grade 2 to 3 thrombocytopenia. Study procedures and schedule. 
7.2 
DESCRIPTION OF STUDY DAYS 
7.2.1 Pre-study screening 
Each potential subject will be examined before the start of the study to determine their eligibility 
for participation.  These tests are to be conducted within 7 days prior to the first study treatment 
administration, except tumor imaging, bone marrow biopsy and LVEF measurement that can be 
performed within 30 days and informed consent, and fresh tumor cell sampling that should be 
obtain within 14 days prior to the first study treatment administration.  


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symptoms
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intracellular PK
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TIMING
1. Clinical Examination
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malignancies
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and/or BJ proteinuria
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INVESTIGATIONS
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1. Clinical 
Examination
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ONCOETHIX                                                             CONFIDENTIAL 
Clinical Study Protocol  OTX015_104                       Date: 18 December 2015 
   Document Status: Version J 
 
The information in this document is the property of OncoEthix and is confidential. Neither the document nor the 
information contained therein may be reproduced or disclosed outside OncoEthix without their written consent 
 
 
Page 62 
7.3.1.2 Tumor assessment criteria 
The lesions will be assessed throughout the study according to standard criteria, for lymphomas 
[Cheson 2007], and multiple myeloma [Durie 2006]. Patients with acute leukemia will be 
assessed based on the recommendations from the European LeukemiaNet  [Döhner 2010] 
For details, see section 16.10; Appendix X. 
Nonetheless, in the context of a phase I study, any tumor shrinkage will be quantified and 
recorded, even though it does not meet admitted criteria for response, as clue of clinical activity. 
 
7.3.1.3 Overall survival (OS) 
Survival is defined as the duration between the date of first OTX015/MK-8628 intake and the date 
of death whatever the cause, or censored at the date of last contact if there is no documentation of 
death before the cut-off date. 
 
7.3.2 Safety data 
All the tests and laboratory measurements that will be performed prior and/or on specific days 
during and following therapy are described in section 7.2. 
7.3.2.1 Clinical Safety 
Clinical and physical examinations, as well as vital signs evaluation, will be performed.  Patient 
data will be analyzed for evidence of cumulative toxicity with repeated cycles of therapy. 
TEAEs / signs and symptoms of disease observed by the investigator (preferably by the same 
physician for a same subject) or reported by the subjects to the study nurses will be recorded and 
graded 
according 
to 
NCI-CTCAE 
version 
4.02, 
accessible 
via 
internet 
[http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.02_2009-09-15_QuickReference_8.5x11.pdf]. It is 
crucial that all events, even if not related to the study drug are reported in the CRF. 
7.3.2.2 Laboratory measurements 
All clinically significant laboratory values require to be reported as TEAEs in the CRF. Clinically 
significant laboratory results are those, which have clinical consequences (i.e. need for treatment 
or corrective measures, study drug dose reduction or interruption or discontinuation, 
hospitalization, prolongation of hospitalization, death, or are life-threatening, or are reported as 
SAE whatever the reason). The seriousness, the action taken regarding study medication and 
patient participation in the study, relation to study medication and the most likely cause, should 
then be recorded. 
Other laboratory changes, even severe in intensity (i.e. NCI-CTCAE grade 3-4), but without the 
aforementioned clinical consequences, are not clinically significant. They will be only reported in 
the laboratory results part of the CRF and should not be reported in the TEAE part of the CRF. 


ONCOETHIX                                                             CONFIDENTIAL 
Clinical Study Protocol  OTX015_104                       Date: 18 December 2015 
   Document Status: Version J 
 
The information in this document is the property of OncoEthix and is confidential. Neither the document nor the 
information contained therein may be reproduced or disclosed outside OncoEthix without their written consent 
 
 
Page 63 
7.3.3 Pharmacokinetics (PK) 
7.3.3.1 PK sampling schedule 
7.3.3.1.1 Blood collection schedule 
 
1. Once-a-day schedule 
• At each dose level (DL) 3 patients will have complete PK sampling. Other patients will 
have limited PK sampling. All patients enrolled at the same DL across both subsets 
(AL/other hematological malignancies) will be considered for the selection of the 3 
patients with complete PK sampling. Patients hospitalized due to medical reasons will be 
first considered for complete PK sampling. 
• Patients with complete PK sampling: 
Seven blood samples will be collected for PK analysis on days 1-2: T0,(before dosing), then T1h, 
T4h, T8h, T12h, T24h + either T10h or T16h (one of these points mandatory)  (Table 4).  
• Patients with limited PK sampling 
Five blood samples will be collected on day 1: T0,(before dosing), then T1h, T4h, T6h, T8h. 
2.  Twice-a-day (BID) schedule 
• All patients will have complete PK sampling during a 24-hour inpatient hospitalization. 
Height blood samples will be collected on days 1-2: T0 (before dosing), then 
T20min+5min, T1h+10min, T2h15min+15min, T3h15min+15min, T9h+1h, T12h+15min 
(just before the second intake), T24h (before drug dosing) 
In all patients residual plasma concentration (Cmin) will be assessed just before drug intake,  at 
days 8, 15 and 22 
 
• Three mL of blood will be collected in a peripheral vein for each sample, corresponding to 
a total of 21 mL of blood drawn on day 1-2 for patients with complete PK sampling and 15 
mL of blood drawn on day 1 for patients with limited PK sampling.  In addition, a total of 
9 mL of blood will be collected on days 8, 15 and 22. In total, 30 mL of blood will 
collected for PK for patients with complete PK sampling and 24 mL for patients with 
limited PK sampling.   
• 
Collected blood samples will be centrifuged immediately. Late samples (T10-16h) can be 
left vertically into refrigerator and centrifuged early in the morning the day after.  Plasma 
will be harvested, then stored at -20°C until centralized collection. See Appendix IV, 
section 16.4 for sample centrifugation, storage and shipment  
 
 


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ONCOETHIX                                                             CONFIDENTIAL 
Clinical Study Protocol  OTX015_104                       Date: 18 December 2015 
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The following parameters will be determined: Trough (Cmin) and peak (Cmax) concentrations, 
Tmax, AUC [0-∞], Vdss, t1/2, steady state, total Clearance (CL). 
7.2.4.7 Pharmacokinetic analysis:  
Pharmacokinetic analysis will be carried out using the nonlinear mixed effect modelling software 
program Monolix version 412. (http://wfn.software.monolix.org). 
7.3.4 Pharmacodynamic assessment 
PD biomarkers in tumor cells will be explored in tumor cells. Based on current knowledge, c-
MYC and BRD2, 3 and 4 expression will be measured. Other biomarkers could be explored 
according to increasing scientific knowledge. 
7.3.4.1 Fresh tumor cells 
Fresh leukemic cells will be collected from peripheral blood and bone marrow  at baseline 
(between day -7 and day 1) and on day 8. The total blood and marrow volume for PD will be 15 
and 3 mL, respectively, each day. 
 
For patients with other malignancies, fresh tumor cells may be optionally obtained in selected 
patients at baseline (between day -14 and day +1) and at day 15 + 7 days from superficial lymph 
nodes core biopsy, or any other easily accessible tumor without invasive procedure.  
Of note, fresh cells collected on day 8-22 will be also used for assessment of intracellular PK (see 
section 7.3.3.1.2) and that collected at baseline will be assessed for predictive biomarkers (see 
section 7.3.6.1).  
See Appendix V, section 16.5 for sampling technique, storage and shipment. 
 
7.3.5 Pharmacokinetic / pharmacodynamic relationship 
PK/safety correlations: The incidence and severity of AEs will be compared to Cmax, CL and 
AUC of OTX015/MK-8628. 
PD/safety correlations: The incidence and severity of AEs will be compared to the most pertinent 
biomarkers, if any.  
PK/PD correlations: Cmax, CL and AUC of OTX015/MK-8628 will be compared to the most 
pertinent biomarkers, if any. 
7.3.6 Tumor phenotype/Predictive factors of clinical activity 
7.3.6.1 Archived tumor material 
Available archived tumor material will be collected. The availability of a paraffin-embedded 
block is a pre-requisite for inclusion of patients with lymphoma into the study if no fresh tumor 
tissue is available.  
At least one H&E colored slide and 6 to 7 blank slides will be requested from the most recent 
biopsy. 


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Albeit not mandatory, archived bone marrow biopsy, if available, will also be requested in 
patients with multiple myeloma for analysis of predictive biomarkers. 
7.3.6.2 Fresh tumor cells 
Fresh leukemic cells will be collected from peripheral blood and bone marrow at baseline (day -
14 to day +1). 
For patients with other malignancies, mainly lymphoma, fresh tumor cells may be obtained in 
selected patients (optional and under specific consent) at screening from superficial lymph nodes 
core biopsy, or any other easily accessible tumor without invasive procedure.  
Of note, fresh cells collected at baseline will be also used for assessment of PD biomarkers (see 
section 7.3.4.1).  
 
 
8 ASSESSMENT OF SAFETY 
Patients will be monitored for signs and symptoms of adverse events (AEs) throughout the study 
by a qualified oncologist/hematologist, with experience in clinical research. All AEs will be 
reported in the case report form (CRF), including seriousness, NCI-CTCAE grade severity, causal 
relationship to the study medication, and action taken.  If AEs occur, the first concern will be the 
safety of the study participant.  
8.1  ADVERSE EVENT DEFINITIONS (21 CFR§312.32) 
● 
Adverse event (AE) means any untoward medical occurrence associated with use of a 
drug in humans, whether or not considered drug related. (The term treatment emergent adverse 
event [TEAE] covers any unfavorable and unintended sign, symptom, syndrome, or illness that 
develops or worsens during the period of observation in the clinical study).  Surgical or other 
procedures themselves are not TEAEs. The condition for which the surgery/other procedure is 
required is a TEAE, if it occurs or is detected during the study period. Planned surgical or other 
procedures planned/permitted by the study protocol and the condition(s) leading to these measures 
are not TEAEs, if the condition(s) was (were) known before the start of study treatment.  In the 
latter case the condition should be reported as medical history. 
 
● Suspected adverse reaction (SAR) means any AE for which there is a reasonable possibility 
that the drug caused the AE.  A “reasonable possibility” means there is evidence to suggest a 
causal relationship between the drug and the adverse event, such as: 
-   A single occurrence of an event that is uncommon and known to be strongly associated 
with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome); 
-  One or more occurrences of an event that is not commonly associated with drug exposure, 
but is otherwise uncommon in the population exposed to the drug (e.g., tendon rupture); 
- An aggregate analysis of specific events observed in a clinical trial (such as known 
consequences of the underlying disease or condition under investigation or other events that 
commonly occur in the study population independent of drug therapy) that indicates those 


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Page 67 
events occur more frequently in the drug treatment group than in a concurrent or historical 
control group. 
 
SAR implies a lesser degree of certainty about causality than adverse reaction, which means 
any AE caused by a drug. 
● Adverse reaction (AR) means an AE caused by the drug. 
● Serious adverse event (SAE) or serious suspected adverse reaction (SSAR) is an event 
that, in the view of either the investigator or sponsor, results in any of the following outcomes: 
- 
Death occurring within 4 weeks after the last administration study drug, irrespective of 
cause, or within any interval if related to the study drug  
[Although death may occur as a result of the basic disease process, all deaths occurring 
within 30 days of the last administration of study drug must be managed as SAEs and 
reported as such.  Additionally, all deaths that may be considered as related to the study 
drug, regardless of the interval, must be treated as SAEs and reported as such.]; 
- 
A life-threatening adverse event; 
- 
Inpatient hospitalization or prolongation of existing hospitalization; 
- 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions; or 
- 
A congenital anomaly/birth defect. 
In addition, medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in situations where none of the outcomes listed above occurred.  
Important medical events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the patient or may require intervention to prevent one of the 
other outcomes listed in the definition above should also usually be considered serious.  Examples 
of such events include overdose even not complicated, or AE requiring intensive treatment 
without hospitalization. A diagnosis of a new cancer type during the course of a treatment should 
be considered as medically important. In addition, any pregnancy diagnosed in a female subject 
on treatment with the investigational product or in the partner of a male subject on treatment with 
the investigational product must be reported to the sponsor immediately.  The List of Critical 
Terms (1998 adaptation of WHO Adverse Reaction Terminology Critical Terms List, provided in 
the “Instructions for completing the ‘Serious Adverse Event/Expedited Report from a Clinical 
Trial’ form”) should be used as guidance for adverse events that may be considered serious 
because they are medically important. 
Finally, for the purpose of this phase I study, any suspected DLT will be considered as medically 
important and reported as SAE, even if it does not meet other criteria for seriousness. In the latter 
case, the reason for seriousness will be “other important medical event”. The specific  SAE report 
form for this study includes a box “DLT: Yes/No” 
 
● Life-threatening adverse event or life-threatening suspected adverse reaction is an AE 
that, in the view of either the investigator or sponsor, places the patient or subject at 
immediate risk of death.  It does not include an AE or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death. 


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● Unexpected adverse event or unexpected suspected adverse reaction is an AE or suspected 
adverse reaction that is not listed in the investigator brochure or is not listed at the specificity 
or severity that has been observed. For example, under this definition, hepatic necrosis would 
be unexpected (by virtue of greater severity) if the investigator brochure referred only to 
elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral 
vasculitis would be unexpected (by virtue of greater specificity) if the investigator brochure 
listed only cerebral vascular accidents.  “Unexpected”, as used in this definition, also refers to 
AEs or suspected adverse reactions that are mentioned in the investigator brochure as 
occurring with a class of drugs or as anticipated from the pharmacological properties of the 
drug, but are not specifically mentioned as occurring with the particular drug under 
investigation. 
8.2 
DOCUMENTATION OF ADVERSE EVENTS 
 
Each and every TEAE occurring during the course of the study, whether or not considered related 
to the study drug or to underlying disease, must be individually recorded in the CRF, including the 
nature of the event, date and time of onset (where appropriate), duration of effect, action taken, 
seriousness, severity, and relationship to study medication.  Any consequent change to the dosage 
schedule or any corrective therapy should be recorded.   
Every attempt should be made to describe the TEAE in terms of a diagnosis.  If a clear diagnosis 
has been made, individual signs and symptoms will not be recorded. If a clear diagnosis cannot be 
established, each sign and symptom must be recorded individually. 
All subjects who experience a TEAE, regardless of the relationship to study treatment, must be 
monitored to determine the outcome.  The clinical course of the adverse event will be followed up 
even after the end of the period of observation, until a satisfactory explanation is found or the 
investigator considers it medically justifiable to terminate follow-up.  Should the adverse event 
result in death, post-mortem examination should be considered as far as possible. 
After last study treatment administration, patient will be observed during at least 30 days to 
document any late side effect and until resolution in case of AE thought to be related to study 
treatment, and every month and a half for the first three months, then every three months until 
death. 
 
AEs already recorded and designated as “continuing” should be reviewed at each subsequent 
assessment.  If resolved, details are to be recorded in the CRF.  If an AE changes for the worse, in 
frequency of attacks/symptoms or in severity, a new record of the event must be started (i.e., 
distinct AE reports are required for differing frequencies and/or severity of the same event to 
enable comprehensive safety reports and later analysis).   
 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, must be 
reported under “concomitant procedures” in the CRF and not as an AE. The medical condition for 
which the procedure was performed must be reported. 
 


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A clinical laboratory abnormality should be reported as an AE only if the abnormality is 
“clinically significant”, i.e. the abnormality is serious, OR requires active management (e.g., 
specific treatment, change or delay of dose, discontinuation of study drug, more frequent follow-
ups, and diagnostic investigation) OR is considered as a toxicity of the study treatment. 
8.2.1 
AE Grade 
All AEs, whether or not they are considered related to the study drug, must be graded using the 
NCI 
Common 
Toxicity 
Criteria 
for 
Adverse 
Events 
(CTCAE) 
Version 
4.02 
[http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.02_2009-09-15_QuickReference_8.5x11.pdf]. The 
worst grade for that particular event is to be documented. 
AE grades usually reflect their severity, with grade 1 meaning “mild”, grade 2 meaning 
“moderate”, grade 3 meaning “severe”, grade 4 meaning “life-threatening” and grade 5 meaning 
“fatal”. 
8.2.2 
AE Severity  
The term “severity” is used to describe the intensity of an adverse event; the event itself, 
however, may be of relatively minor clinical significance (e.g., ‘severe’ headache).  This is not 
the same as “serious”.  Seriousness of AEs is based on the outcome/action of an AE and usually is 
associated with events that pose a threat to a patient’s life or functioning. 
 
Intensity of the adverse event will be evaluated using the following criteria: 
● Mild:  The patient is aware of the sign or symptom, but finds it easily tolerated.  The event is of 
little concern to the patient and of little clinical significance.  The event is not expected to have 
any effects on the patient’s overall health or well-being. 
● Moderate: The patient has discomfort enough to cause interference with or change in usual 
activities.  The event is of some concern to the patient’s health or well-being and may require 
medical intervention and/or close follow-up. 
● Severe:  The adverse event interferes considerably with the patient’s usual activities.  The event 
is of definite concern to the patient and/or poses substantial risk to the patient’s health or well-
being.  The event is likely to require medical intervention and/or close follow-up and may be 
incapacitating or life-threatening.  Hospitalization and treatment may be required. 
8.2.3 
Adverse event relationship to study treatment or procedure 
All TEAEs occurring during treatment with an investigational agent may be related to the 
investigational agent. All TEAEs, regardless of the supposed relationship to study treatment, must 
therefore be collected. However, the investigator often has arguments to think that a TEAE is or is 
not related to the study treatment. Albeit subjective, and susceptible to be challenged, the 
assessment of relationship to study treatment is an important role of the investigator. Thus, the 
investigators should decide, based on their knowledge and medical expertise, whether, in their 
opinion, an AE is “reasonably related” or “unlikely related” to the study treatment (or to study 
specific procedures).  


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8.3 
EVENTS OF CLINICAL INTEREST 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor. 
For the time period beginning when the consent form is signed until patient registration, any ECI, 
or follow up to an ECI, that occurs to any patient must be reported within 24 hours to the Sponsor 
if it causes the subject to be excluded from the trial, or is the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, or a 
procedure. 
For the time period beginning at patient registration through 30 days following cessation of 
treatment, any ECI, or follow up to an ECI, whether or not related to the Sponsor’s product, must 
be reported within 24 hours to the Sponsor, either by electronic media or paper.  Electronic 
reporting procedures can be found in the data entry guidelines.   
1. An elevated AST or ALT lab value that is ≥3X ULN and an elevated total bilirubin lab 
value that is ≥2X ULN and, at the same time, an alkaline phosphatase lab value that is < 
2X ULN, as determined by protocol-specified laboratory testing or unscheduled laboratory 
testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The purpose of 
the criteria is to specify a threshold of abnormal hepatic tests that may require an additional 
evaluation for an underlying etiology. The trial site guidance for assessment and follow up of 
these criteria can be found in Appendix 5 and the Investigator Brochure section on discussion and 
guidance for investigator. 
2. An elevated total bilirubin lab value that is > 2X ULN. 
3. Any of the following liver test abnormalities are observed (see also Appendix 3): 
- 
ALT or AST > 8X ULN  
- 
ALT or AST > 5X ULN for more than 2 weeks 
- 
ALT or AST > 3X ULN AND (total bilirubin > 2X ULN OR INR > 1.5) 
- 
ALT or AST > 3X ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%), unless 
the investigator assesses the rash or fatigue to be related to OTX015 and not related 
to liver impairment with sponsor’s agreement. 
**All patients with these liver test abnormalities should be followed weekly until all 
abnormalities return to normal or to the baseline state. DILI may develop or progress even after 
the causative drug has been stopped. Results should be recorded on the case report form and in the 
database. See Appendix 16.12 for guidelines on the handling of events of ALT or AST >3 x ULN 
AND total bilirubin >2 x ULN or INR>1.5 (potential Hy’s law cases).  


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8.4 
IMMEDIATE REPORTING BY INVESTIGATOR TO SPONSOR 
SAEs and other events that fulfill a reason for expedited reporting to Pharmacovigilance 
(overdose and pregnancy and DLT for the present study) must be documented on a “Serious 
Adverse Event Report Form” (SAERF) at the time the SAE is detected. This form must be 
completed and sent within 24 hours, or at the latest on the following working day to the sponsor’s 
Pharmacovigilance representative: 
 
 


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Oncology Therapeutic Development (OTD) 
 
Tel : 
   
Fax : 
  
E-mail: 
 
 
 
The SAERF and the guidelines for filling it in are provided in the investigator’s study file. 
The sponsor will ensure that all legal reporting requirements are met. 
The initial report must be as complete as possible, including details of the current illness and 
(serious) adverse event, and an assessment of the causal relationship between the event and the 
investigational product(s). 
Information not available at the time of the initial report (e.g., an end date for the AE or laboratory 
values received after the report) must be documented on a follow-up SAERF. 
8.5 
PERIOD OF OBSERVATION 
For the purposes of this study, the period of observation for collection of AEs extends from the 
start of treatment with investigational product until the end of study treatment (i.e. 30 days after 
the last study drug administration), except for adverse events related to study drug, which must be 
reported during follow-up period until resolution or change of causality from related to non-
related or initiation of further antitumor therapy. 
If the investigator detects a SAE in a study subject after the end of the period of observation, and 
considers the event possibly related to prior study treatment, he or she should contact the sponsor 
to determine how the adverse event should be documented and reported. 
 
PPD
PPD
PPD


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9 STUDY TREATMENT DISCONTINUATION 
Study treatment will be definitely discontinued for the following reasons:  
• Patient’s request (consent withdrawal) at any time without need for any justification 
• If, in the investigator's opinion, the benefit/risk ratio is no longer favorable and 
continuation in the study could be detrimental to the subject. This includes: 
1. Progressive disease  
2. Intolerable toxicity 
3. Treatment interruption > 2 weeks due to TEAEs (except in cases of suspicion of 
hematologic DLT in acute leukemia, where treatment interruption for 3 weeks is allowed 
to confirm DLT) related to the study medication, unless the investigator thinks resuming 
study treatment is the best patient’s interest 
4. Recurrence of the same toxicity, with the same severity after one dose reduction, unless 
the investigator thinks pursuing study treatment at lower dose is the best patient’s interest, 
with sponsor’s agreement 
5. Lack of patient compliance 
6. Major protocol deviation 
7. Any of the following liver test abnormalities (see Appendix 5) 
- 
ALT or AST > 8 x ULN  
- 
ALT or AST > 5 x ULN for > 2 weeks 
- 
ALT or AST > 3 x ULN and (total bilirubin > 2 x ULN OR INR > 1.5) 
- 
ALT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%), unless the 
investigator assesses the rash or fatigue to be related to OTX015 and not related to 
liver impairment with sponsor’s agreement. 
• Upon specific request of the sponsor 
In all cases, the reason for and date of study treatment discontinuation must be recorded in the 
CRF at the “End of Study Treatment” page and source documented in the patient's medical 
records.  As far as possible, there should be only one reason for study treatment discontinuation. If 
there are several reasons (e.g.; concomitant progressive disease and toxicity), efforts will be made 
to select the most important one (i.e. the reason that would have been sufficient, should it occur 
alone). The subject must be followed up to establish whether the reason was a TEAE, and, if so, 
this must be reported as such (see Section 8.2). 
As far as possible, all examinations scheduled for the final study day must be performed on all 
subjects who receive the investigational product but do not complete the study according to 
protocol. 


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The investigator must make every effort to contact subjects lost to follow-up.  Especially, when a 
patient is treated in another, non-study, center, the investigator is responsible for collecting 
follow-up data from this center. 
Subjects early withdrawn from study (i.e. those receiving less than 18 days of treatment for the 
continuous, 21-day schedule or less than 12 days of treatment for the intermittent, 14 days ON/ 7 
days OFF schedule), or those having received < 85% of the intended cumulative dose during the 
first 21 days and who do not experience a DLT; (i.e. patients not evaluable for DLT, the primary 
study endpoint) will be replaced. 
After study withdrawal, patients’ care will be managed in their best interest, by the investigator 
and/or the referring physician 


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10  EMERGENCY PROCEDURES 
10.1 EMERGENCY SPONSOR CONTACT 
In emergency situations, the investigator should immediately contact a sponsor representative at 
the telephone number or email address given on the title page of the protocol. 
10.2 EMERGENCY IDENTIFICATION OF INVESTIGATIONAL PRODUCTS 
This section is not applicable as this is an open-label study. 
11  STATISTICAL PROCEDURES 
11.1 ANALYSIS VARIABLES/ STUDY ENDPOINTS 
 
Primary: DLT is the endpoint for the determination of the RD in each subset. 
Secondary: treatment-emergent adverse events (TEAEs), vital signs, laboratory results, ECG and 
LVEF changes, PK and PD parameters, disease specific tumor response assessment, quantitative 
tumor shrinkage, tumor-related symptoms, PS. 
Exploratory: Predictive factors of clinical activity:  clinical features / tumor phenotype/ 
cytogenetics / molecular biology markers / gene expression profile,   
11.2 ANALYSIS POPULATIONS 
• Intent-to-treat population: all enrolled patients 
• Per protocol population.: all enrolled patients with no violation of inclusion/exclusion 
criteria 
• Evaluable for safety population: all patients having received at least one dose of 
OTX015 
• Evaluable for DLT population: all treated patients having received at least 85% of the 
intended dose during the first cycle (i.e. > 12 days at full dose for AL and  > 18 days  at 
full dose for other hematological malignancies)* of OTX015/MK-8628 treatment, as well 
as patients not fulfilling these conditions, but having experienced a DLT. 
*e.g. for DL1 (10 mg/day), patients with AL having received > 120 mg over the first 21 days 
(10 mg x 12), or patients with other hematological malignancies having received > 180 mg   
over the first 21 days (10 mg x 18). 


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11.3 STATISTICAL METHODS 
 
This is an exploratory Phase Ib study aimed to assess the pharmacological effects of 
OTX015/MK-8628 in patients with hematological malignancies. The small subject sample size by 
cohorts does not allow for statistical hypotheses. The decisions will be taken by the SMC, 
composed of experts. The recommended dose will be validated in further phase II studies. 
11.4 INTERIM ANALYSIS 
No interim analysis is planned. Regular assessment by the SMC of the data of the last cohort of 3 
evaluable patients will be performed. 
11.5 SAMPLE SIZE JUSTIFICATION 
There is no justification of the sample size. 
Approximately 50 to 75 evaluable patients, depending on the number of DL in the dose escalation 
part and number of patients at each DL, are planned. 
 


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12 ETHICAL AND LEGAL ASPECTS 
12.1 GOOD CLINICAL PRACTICE 
This Phase 1 trial will be conducted in compliance with the protocol, Good Clinical Practice 
(GCP), as defined in ICH Guidance E6: Good Clinical Practice: Consolidated Guidance, in 
agreement with the Declaration of Helsinki and applicable federal and local regulatory 
requirements 
12.2 DELEGATION OF INVESTIGATOR DUTIES 
The investigator should ensure that all persons assisting with the trial are adequately qualified, 
informed about the protocol, any amendments to the protocol, the study treatments, and their trial-
related duties and functions. 
The investigator should maintain a list of subinvestigators and other appropriately qualified 
persons to whom he or she has delegated significant trial-related duties. 
12.3 SUBJECT INFORMATION AND INFORMED CONSENT 
Before being enrolled in the clinical study, subjects must give a written informed consent to 
participate into the study.  
A Patient Information Leaflet (PIL), including an Informed Consent Form (ICF) (see Appendix 
VI; section 16.6) will be given to each patient screened in the study.  This document contains all 
the information required by the ICH E6 Guideline for Good Clinical Practice and any additional 
elements required by local regulations.  The master document in Appendix VI is also translated 
into the national language(s) and in terms that are understandable to any subject. In addition to the 
document, the investigator should provide oral information and answer to patient’s questions. 
Patients should have a minimal time for thought and for asking questions and should not sign the 
ICF while first given to them.  
The patient's consent must be confirmed by their dated signature and by the name and dated 
signature of the principal investigator or subinvestigator conducting the informed consent 
discussions. 
A copy of the signed consent document must be given to the subject.  The original signed consent 
document will be retained in the investigator study file. 
The investigator will not undertake any measure specifically required for the clinical study until 
valid consent has been obtained. 


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12.4 CONFIDENTIALITY 
Subject names will not be supplied to the sponsor.  Only the unique patient number and subject 
initials will be recorded in the case report form, and if the subject name appears on any other 
document (e.g., laboratory report), it must be obliterated on the copy of the document to be 
supplied to the sponsor.  Study findings stored on a computer will be stored in accordance with 
local data protection laws.  The subjects will be informed that representatives of the sponsor, 
independent ethics committee (IEC)/ institutional review board (IRB), or regulatory authorities 
may inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws. 
The investigator will maintain a patients’ identification list (subject numbers with the 
corresponding subject names) to enable records to be identified. 
12.5 APPROVAL OF THE CLINICAL STUDY PROTOCOL AND AMENDMENTS 
Before the start of the study, the clinical study protocol, PIL/ICF, and any other appropriate 
documents will be submitted to the IEC/IRB and to the national Health Authorities, in accordance 
with local legal requirements. 
Before the first subject is enrolled in the study, all ethical and legal requirements must be met. 
The IEC/IRB and the authorities must be informed of all administrative changes and any 
important finding that could modify the risk of exposed patients. They also must be informed or 
their authorization obtained for all subsequent protocol, in accordance with local legal 
requirements.   
The investigator must keep a record of all communication with the IEC/IRB and the Health 
Authorities. 
12.6 ONGOING INFORMATION FOR INDEPENDENT ETHICS COMMITTEE/ 
INSTITUTIONAL REVIEW BOARD AND HEALTH AUTHORITIES 
The sponsor must submit to all investigators of OTX015/MK-8628 studies, the IEC/IRB and 
health Authorities: 
• Information on serious or unexpected adverse events from the investigator’s site, as soon as 
possible 
• Expedited safety reports according to regulations 
• Periodic reports on the progress of the study 


ONCOETHIX                                                             CONFIDENTIAL 
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Page 79 
12.7 CLOSURE OF THE STUDY 
The study must be closed at the site on completion.  Furthermore, the sponsor or the investigator 
has the right to close this study site at any time.   
Study materials must be returned, disposed of or retained as directed by the sponsor. 
12.8 RECORD RETENTION 
Study documents should be retained by the investigator for at least 15 years. Beyond this period, 
the investigator still must obtain approval in writing from the sponsor before destruction of any 
records. 
The documents to be retained include: 
• Original signed ICFs for all subjects 
• Subject identification code list*, screening log and enrollment log 
• Record of all communications between the investigator and the IEC/IRB 
• Composition of the IEC/IRB  
• Record of all communications between the investigator and sponsor (or CRO) 
• List of subinvestigators and other appropriately qualified persons to whom the investigator 
has delegated significant trial-related duties, together with their roles in the study and their 
signatures 
• Copies of CRFs and of documentation of corrections (DCF) for all subjects 
• Investigational product accountability records 
• Record of any body fluids or tissue samples retained 
• All other source documents (subject medical records, hospital records, laboratory records, 
etc.) 
• All other documents as listed in section 8 of the ICH E6 Guideline for Good Clinical 
Practice (Essential Documents for the Conduct of a Clinical Trial) 
12.9 LIABILITY AND INSURANCE 
Liability and insurance provisions for this study are given in separate agreements. Patient’s travel 
expenses made within the scope of the study will be reimbursed by the Sponsor to the patient, 
upon presentation of justification.  
The Sponsor has subscribed an insurance covering their civil responsibility.  
The Sponsor, OncoEthix, is a company established outside the European Union. As such, they 
have empowered the following Contract Research Organization (CRO) for representing them in 
the European Union: 


ONCOETHIX                                                             CONFIDENTIAL 
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Page 80 
 
OTD (Oncology Therapeutic Development) SARL, 
100 rue Martre  
92110 Clichy, 
France. 
12.10 FINANCIAL DISCLOSURE 
Before the start of the study, the investigator will disclose to the sponsor any proprietary or 
financial interests he or she might hold in the investigational products or the sponsor company as 
outlined in the financial disclosure form provided by the sponsor.  The investigator agrees to 
update this information in case of significant changes during the study or within one year of its 
completion.  The investigator also agrees that, where required by law or regulation, the sponsor 
may submit this financial information to domestic or foreign regulatory authorities in applications 
for marketing authorizations. 
Similar information will be provided by each subinvestigator to whom the investigator delegates 
significant study related responsibilities. 


ONCOETHIX                                                             CONFIDENTIAL 
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Page 81 
13 STUDY MONITORING AND AUDITING 
Monitoring and auditing procedures developed or endorsed by the sponsor will be followed, in 
order to comply with GCP guidelines.  Direct access to the on-site study documentation and 
medical records must be ensured. 
13.1 STUDY MONITORING AND SOURCE DATA VERIFICATION 
Monitoring will be done by personal visits from representatives of the sponsor (study clinical 
research assistant and medical monitor) who will check the CRFs for completeness and clarity, 
and crosscheck them with source documents.  In addition to the monitoring visits, frequent 
communications (letter, telephone, e-mail and fax), by the study monitors will ensure that the 
investigation is conducted according to protocol design and regulatory requirements. 
Study close-out will be performed by the study monitor upon closure of the study. 
13.2 ON-SITE AUDITS/INSPECTIONS 
An external auditor, appointed by the study sponsor, or the EC/IRBs, as well as inspectors, 
appointed by domestic and foreign regulatory authorities, may request access to all source 
documents, case report forms, and other study documentation for on-site audit or inspection.  
Direct access to these documents must be guaranteed by the investigator, who must provide 
support at all times for these activities.  Medical records and other study documents may be 
copied during audit or inspection provided that subject names are obliterated on the copies to 
ensure confidentiality. 
14 DOCUMENTATION AND USE OF STUDY FINDINGS 
14.1 DOCUMENTATION OF STUDY FINDINGS 
A case report form (CRF) will be provided for each subject. 
All protocol-required information collected during the study must be entered by the investigator, 
or designated representative, in the CRF.  Details of CRF completion and correction will be 
explained to the investigator.  If the investigator authorizes other persons to make entries in the 
CRFs, the names, positions, signatures, and initials of these persons must be supplied to the 
sponsor. 
The investigator, or designated representative, should complete the CRF pages as soon as possible 
after information is collected, preferably on the same day that a study subject is seen for an 
examination, treatment, or any other study procedure and at the latest before the next monitoring 
visit.  An explanation should be given for all missing data. 


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Page 82 
A source data location list will be prepared prior to study start.  This list will be filed in both the 
trial master file and the investigator study file and updated as necessary. 
The completed CRFs must be reviewed and signed by the investigator named in the clinical study 
protocol or by a designated co-investigator. 
All errors detected after the monitoring visit will be queried using data correction forms (DCFs). 
The Sponsor will answer the question and/or correct errors in the DCF duly signed and dated. 
Original DCFs will be taken by the sponsor’s study monitor, while a copy will be kept by the 
investigator and recorded in the investigator study file with the corresponding CRFs. 
The sponsor will retain the originals of all CRFs and DCFs.  The investigator will retain a copy of 
all completed CRF pages and DCFs. 
14.2 CONFIDENTIALITY/USE OF STUDY FINDINGS 
All information concerning the product as well as any matter concerning the operation of the 
sponsor, such as clinical indications for the drug, its formula, methods of manufacture and other 
scientific data relating to it, that have been provided by the sponsor and are unpublished, are 
confidential and must remain the sole property of the sponsor.  The investigator will agree to use 
the information only for the purposes of carrying out this study and for no other purpose unless 
prior written permission from the sponsor is obtained. 
The sponsor has full ownership of the original CRFs completed as part of the study. 
By signing the clinical study protocol, the investigator agrees that the results of the study may be 
used for the purposes of national and international registration, publication, and information for 
medical and pharmaceutical professionals.  The authorities will be notified of the investigator's 
name, address, qualifications, and extent of involvement. 
The sponsor will ensure that a final report on the study is prepared. 
All materials, documents and information supplied by the sponsor to the investigator, and all 
materials, documents and information prepared or developed in the course of the study to be 
performed under this protocol, shall be the sole and exclusive property of the sponsor.  Subject to 
obligations of confidentiality, the investigator reserves the right to publish only the results of the 
work performed pursuant to this protocol, provided, however, that the investigator provides an 
authorized representative of the sponsor with a copy of any proposed publication for review and 
comment at least 60 days in advance of its submission for publication.  In addition, if requested, 
the investigator will withhold publication an additional 90 days to allow for filing a patent 
application or taking such other measures as sponsor deems appropriate to establish and preserve 
its proprietary rights. 
It is agreed that, consistent with scientific standards, publication of the results of the study shall be 
made only as part of a publication of the results obtained by all sites performing the protocol. 


ONCOETHIX                                                             CONFIDENTIAL 
Clinical Study Protocol  OTX015_104                       Date: 18 December 2015 
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Page 83 
15  REFERENCES 
 
Belkina AC, Denis GV. BET domain co-regulators in obesity, inflammation and cancer. Nature 
reviews/cancer 2012; 12: 465-477. 
Blobel  GA, Kalota A, Sanchez PV, Carroll M. Short hairpin RNA screen reveals bromodomain 
proteins as novel targets in acute myeloid leukemia. Cancer Cell 2011; 20: 287-288. 
Boxer LM, Dang CV. Translocation involving c-Myc and c-Myc function. Oncogene 2001; 20: 
5595-5610. 
Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J 
Clin Oncol 2007; 25:579-586. 
Cuccuini W, Briere J, Mounier N, et al. MYC+ diffuse large B-cell lymphoma is not salvaged 
by classical R-ICE or R-DHAP followed by BEAM plus autologous stem cell transplantation. 
Blood. 2012;119:4619-4624. 
Dawson MA, et al. inhibition of BET recruitment to chromatin as an effective treatment for 
MLL-fusion leukemia. Nature 2011; 478: 529-533. 
Delmore JE, Issa GC, Lemieux ME, et al. BET bromodomain inhibition as a therapeutic 
strategy to target c-Myc. Cell 2011; 146: 1-14. 
Denis GV, Green MR: A novel, mitogen-activated nuclear kinase is related to a Drosophila 
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Denis GV, Vaziri G, Guo N, Faller D: RING3 kinase transactivates promoters of cell cycle 
regulatory genes through E2F. Cell Growth Diff 2000; 11:417-424  
Denis GV: Bromodomain coactivators in cancer, obesity, type 2 diabetes, and inflammation. Discov 
Med 2010; 10:489-499 
Dey A, Ellenberg J, Farina A, et al: A bromodomain protein, MCAP, associates with mitotic 
chromosomes and affects G2-to-M transition. Mol Cell Biol 2000; 20:6537-6549  
Dey A, Chitsaz F, Abbasi A, Misteli T, Osato K: The double bromodomain protein Brd4 binds to 
acetylated chromatin during interphase and mitosis. Proc Natl Acad Sci USA 2003; 100:8758-8763 
Dey A, Nishiyama A, Karpova T, McNally J, Ozato K: Brd4 marks select genes on mitotic 
chromatin and directs postmitotic transcription. Mol Cell Biol 2009; 20:4899-4909 
Döhner H, Estey EH, Amadori S, et al. Diagnosis and management of acute myeloid leukemia 
in adults: recommendations from an international expert panel, on behalf of the European 
LeukemiaNet. Blood. 2010;115:453-474.  
Durie BGM, Harousseau J-L, Miguel JL, et al. International uniform response criteria for 
multiple myeloma. Leukemia 2006; 20:1467-1473 
Huang B, Yang X-D, Zhou M-M, Ozata K, Chen L-F: Brd4 coactivates transcriptional activation of 
NF-κB vai specific binding to acetylated RelA. Mol Cell Biol 2009; 29:1375-1387 


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Clinical Study Protocol  OTX015_104                       Date: 18 December 2015 
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Page 84 
Kanno T, Kanno Y, Siegel RM, et al: Selective recognition of acetylated histones by bromodomain 
proteins visualized in living cells. Mol Cell 2004; 13:33-43 
Mertz JA, et al. Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc 
Natl Acad Sci USA 2011; 108: 16669-16674. 
Nakamura Y, Umehara T, Nakano K, et al: Crystal structure of the human BRD2 bromodomain: 
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Rachie NA, Seger R, Valentine MA, Ostrowski J, BomsztykK: Identification of an inducible 85-
kDa nuclear protein kinase. J Biol Chem 1993; 268:22143-22149 
Redner RL, Wang J, Liu JM. Chromatin remodelling and leukemia: new therapeutic paradigms. 
Blood 1999; 94: 417-428. 
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Cancer Biol 2006; 16:318-330 
Wu SY, Chiang CM: The double bromodomain-containing chromatin adaptor Brd4 and 
transcriptional regulation. J Biol Chem 2007; 282:13141-13145 
Yang XJ: Multisite protein modification and intramolecular signaling. Oncogene 2005; 24;1653-1662  
Yang Z, Yik JH, Chen R, et al: Recrutiment of P-TEFb for stimulation of transcriptional elongation 
by the bromodomain protein Brd4. Mol Cell 2005; 19:535-545 
Yang Z, He N, Zhou Q: Brd4 recruits P-TEFb to chromosomes at late mitosis to promote G1 gene 
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Zuber J, et al. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukemia. 
Nature 2011; 478: 524-528. 
 
 


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Page 85 
16 APPENDICES 
16.1  APPENDIX I:  ECOG PERFORMANCE STATUS 
PERFORMANCE STATUS: 
 
ECOG 
Characteristics 
0 
Normal Activity 
1 
Symptoms of disease, but ambulatory and able to carry out activities of 
daily living 
2 
Out of bed more than 50% of the time, occasionally needs assistance 
3 
In bed more than 50% of the time, needs nursing care 
4 
Bed ridden, may need hospitalization  
 
16.2  APPENDIX II: CALCULATION OF THE RENAL CLEARANCE 
• In patients aged < 65 years: Cockroft &Gault formula 
 
Male = 1.25 x weight (kg) x (140-age) / serum creatinine (µmol/L)   
Female = 1.04 x weight (kg) x (140-age) / serum creatinine (µmol/L) 
 
• In patients aged > 65 years: MDRD (Modification of Diet in Renal Disease) formula 
 
Male = 186 x (serum creatinine (µmol/L) x 0,0113)-1,154 x age- 0,203 
        x 1,21 in subjects with black skin  
        x 0.742 in female 
Automatic calculation on the web, e.g. http://filfola.fr/medecine/cockroft_MDRD.html, or 
http://mdrd.com/ 


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16.3 APPENDIX III:  PATIENT REGISTRATION FORM 
The patient registration form is provided as a separate document 
 


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Page 88 
• IMPORTANT: All PK points described in Table above are mandatory to explore PK of 
OTX015/MK-8628. For samples to be collected late in the evening or early in the morning 
(i.e, T10h, T12h, T16h), in the absence of research nurse or technician, the tubes of blood 
mixed with anticoagulant can be left in vertical position into the refrigerator and be 
centrifuged/aliquoted ASAP during research nurses’/technicians’ working hours. 
• All samples will be labeled with Sponsor and study identification, Unique patient number 
and initials, sample number, and actual date and time the sample was collected.  
 
TUMOR SAMPLE COLLECTION  
OTX015/MK-8628 concentration will be measured in tumor cells, as far as possible,  
• For AL patients: Approximately 7 mL of blood or 3 mL of bone marrow (whichever is 
more appropriate for blasts concentration) will be collected on specific Ficoll ready to use 
tubes (BD Vacutainer® CPTTM), on day 8. Upon collection, the samples will be 
centrifuged at room temperature in a horizontal rotor (swing-out head) for a minimum of 
20 minutes at 1500 to 1800 RCF; After centrigugation, the ring of mononuclear cells at the 
interface of plasma and density gradient fluid will then be resuspended into the plasma by 
inverting the unopened BD Vacutainer® CPTTM tube gently 5 to 10 times. The unopened 
will be labelled (date, time, patient number and initials) then sent to the pharmacology 
department at ambient temperature immediately after. Complete guidelines for sample 
processing and shipment will be provided in a separate document. 
ATTENTION: PD procedure is different and is detailed in Appendix .5 
• For patients with other hematological malignancies: If a patient has easily accessible 
tumor without invasive procedure (e.g. superficial lymph nodes or skin), an optional fresh 
core biopsy could be performed, conditional to a specific express informed consent) for 
intra-tumor OTX015/MK-8628 concentration measurement on day 15 + 7 days. A tumor 
sample of 30mg* approximately should be divided in two aliquots immediately put into 
liquid nitrogen containing isopentane, then stored at -70 to -80°C until shipment. Complete 
guidelines for sample processing and shipment will be provided in a separate document. 
*Warning: a tumor sample should be kept from the same biopsy for PD analysis, so the ideal total 
tissue sample amount should be around 60mg. 
SHIPMENT 
Blood samples on days 1-2 from a given patient must be sent as soon as possible to the laboratory 
below, to allow for results availability at the SMC meeting. If two patients in the same center are 
treated at the same time or a few days apart, the samples of the two patients should be sent 
together. 
Day 22 sampling and optionally, tumor specimens should be stored until further shipments with 
samples from other patients 


ONCOETHIX                                                             CONFIDENTIAL 
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Page 89 
Blood samples shipment should be performed at -20°C and tumor samples at -70 to -80°C. 
The central pharmacokinetics laboratory will be: 
Laboratoire de Pharmacology 
 
Institut Curie (Hôpital René Huguenin) 
35, rue Dailly 
92210 Saint-Cloud 
  tel: 
       e-mail: 
 
  tel:
       e-mail: 
 
     
fax : 
                                          
 
TRANSPORTER CONTACTS 
World Courier France 
e-mail: 
 ; 
Tel : 
 
fax : 
 
Adresse : Rue Montgolfier – 38090 Villefontaine 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
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PPD


ONCOETHIX                                                             CONFIDENTIAL 
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Page 90 
16.5  APPENDIX V: ARCHIVED TUMOR TISSUE AND COLLECTION OF FRESH 
TUMOR BIOPSY/CELLS FOR PHARMACODYNAMIC BIOMARKERS, 
PREDICTIVE BIOMARKER AND INTRACELLULAR PHARMACOKINETICS. 
Archived tumor tissue 
The availability of archived material should be checked at screening prior to inclusion procedures. 
This availability is mandatory for lymphoma patients only. 
Bone marrow biopsy will be requested, if available for MM patients. 
Archived paraffin-embedded block (formaldehyde-fixed) of histological material from lymphoma 
will be packed in plastic/carton boxes. At least one hematoxyn/eosin (H&E) colored slide and 6 to 
7 blank slides from the most recent biopsy will be required. 
Samples will be forwarded from the laboratory where they are stored to: 
 


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Page 91 
ANATOMIA PATOLOGICA GENERALE E ONCOGENETICA MOLECOLARE - U 
Ospedale Molinette: 
C.so Bramante, 88/90 
10126 Torino 
ITALY 
1.1.1 To : 
 
e-mail : 
 
Phone: 
  
Fax 
 
 
PPD
PPD
PPD
PPD


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Page 92 
Fresh leukemic cells (peripheral blood or bone marrow aspiration) 
• For AL patients: Approximately 3 tubes of 5 mL of blood and 3 mL of bone marrow will 
be collected on K2 EDTA tubes (lavender top), at baseline (day -14 to day +1) during the 
same bone marrow aspiration/blood collection as for diagnosis procedures, then on day 8. 
Upon collection, the samples will be inverted a few times to mix the anticoagulant and 
then processed within 24 hours. The tubes should arrive to the central laboratory the day 
after early in the morning. Mononuclear cells will then be separated using Ficoll gradient 
at their arrival at the central laboratory (no manipulation in the clinical department). 
Complete guidelines for sample processing and shipment will be provided in a separate 
document. 
 
 
 
Laboratoire d'hématologie A, Analyse spécialisée Biologie moléculaire 
 
Centre de biologie pathologie Pierre-Marie Degand, 
CHRU de Lille 
bd du professeur Leclercq 
59037 Lille cedex 
France 
Email : 
 
Phone : 
 
Fax : 
 
 
Warning: Day 8 mononuclear cells will also be used for Tumor PK. Attention : the procedure for 
PK sampling is different (see Appendix IV)   
 
 
PPD
PPD
PPD
PPD


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Page 93 
Fresh tumor biopsies (lymphoma)  
• For patients with other hematological malignancies: If a patient has easily accessible 
tumor without invasive procedure (e.g. superficial lymph nodes or skin), an optional fresh 
core biopsy could be performed, conditional to a specific express informed consent) for 
Pharmacodynamic and predictive factors exploration at baseline (day -14 to day +1) and 
on day 15 + 7 days. A tumor sample of 30mg* approximately should be divided in two 
aliquots immediately put into liquid nitrogen containing isopentane, then stored at -70 to -
80°C until shipment to: . 
IOR Institute of Oncology Research 
Fondazione per la Ricerca e la Cura dei Linfomi nel Ticino, 
via Vela 6, CH-6500 Bellinzona 
SWITZERLAND 
TO: 
 
e-mail/ichat: 
 
Phone: 
 (lab); 
Fax: 
 
 *Warning:  a tumor sample should be kept from the same biopsy for PK analysis, so the ideal 
total tissue sample amount should be around 60mg 
Alternatively, a few micrograms of extracted RNA and one microgram of extracted DNA will be 
sent directly to the same laboratory. In this case, no intratumor PK will be performed 
All tumor tissue/cell material (archived and fresh) will be identified by the pathology or 
hematology lab department of the investigational center, by study code, patient UPN and 
initials, origin of tumor tissue and date of biopsy. Complete guidelines for sample 
processing and shipment will be provided in a separate document. 
TRANSPORTER COORDINATES 
World Courier France 
e-mail: 
 ; 
Tel : 
 
fax : 
 
Adresse : Rue Montgolfier – 38090 Villefontaine 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD


ONCOETHIX                                                             CONFIDENTIAL 
Clinical Study Protocol  OTX015_104                       Date: 18 December 2015 
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16.6  APPENDIX VI: PATIENT INFORMATION LEAFLET (PIL) AND INFORMED CONSENT 
FORM (ICF)  
The Patient Information Leaflet/ Informed Consent Form is provided as a separate document in 
English (Master document) and in legally required local languages (French and Italian) 


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16.7 APPENDIX VII: PATIENT’S DIARY 
The Patient’s Diary is provided as a separate document. 


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Page 96 
16.8 APPENDIX VIII: SAFETY MONITORING COMMITTEE COMPOSITION AND CHART 
The study will be driven by a Safety Monitoring Committee (SMC), composed of the principal 
clinical investigators (PIs) (or subinvestigator delegated by the PI), the PK investigator,  two 
Sponsor representatives and one independent medical expert in oncology/hematology drug 
development (Table below) 
 
Name 
Institution/company 
Position 
Sponsor 
Representative 
Principal 
Investigator 
NO 
Principal 
Investigator 
NO 
Principal 
Investigator 
NO 
Principal 
Investigator 
NO 
Principal 
Investigator 
NO 
Principal 
Investigator 
NO 
Principal 
Investigator 
NO 
Principal 
Investigator 
NO 
Principal 
Investigator 
NO 
Principal 
Investigator 
NO 
Pharmacokineticist 
NO 
OTD, Clichy, France 
Medical Monitor 
YES 
Merck, USA 
Medical Monitor 
YES 
Merck, USA 
Drug Safety 
YES 
Independent Expert 
NO 
Curriculum Vitae provided in Appendix X 
 
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Page 97 
Safety Monitoring Committee Chart 
• The SMC will meet on a regular basis (physically or through teleconference), every 6 to 8 
weeks, as soon as possible after the full clinical data sets of a cohort of 3 patients 
independently in each subset (AL or other haematological malignancies) over their first 
cycle (i.e. 21 days following study treatment initiation) have been collected. PK data from 
at least day 1 of these 3 patients will be available for the meeting 
• After examination of the clinical and PK data and discussion, the SMC will take any 
decision to ensure/improve patients’ safety, and particularly the followings: 
1. Validate dose limiting toxicities (DLTs) 
2. Proceed to the dose level (DL) immediately above 
3. Add patients at the same DL 
4. Stop dose escalation and expand a DL 
5. Modify treatment schedule according to new safety, pharmacokinetic and/or 
pharmacodynamic  data 
6. Add intermediate unplanned DLs 
7. Recommend systematic premedications/supportive care for common toxicities 
8. Establish the recommended dose (RD) 
9. Discuss the relevance of the RD for further studies, based on PK and PD results. 
10. Recommend initiation of expansion cohorts 
• The minutes of the meetings will be written by the designed secretary (the sponsor’s safety 
officer by default) within a week, approved and signed by all attendees. The minutes of all 
meetings will be archived in the Trial Master File and put as appendices in the Clinical 
Study Report. 
• In addition, the SMC could be met in case of exceptional circumstance, justifying 
immediate decision to ensure patients’ safety. If it is not possible to hold a meeting or 
teleconference of the whole SMC, at least the Independent Expert will met with the 
Sponsor’s representatives. 
• In addition, the Independent Expert will review all CIOMs forms released by the Safety 
Officer before they are sent to the Health Authorities, EC/IRB and investigators. 
 


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Page 98 
16.9 APPENDIX IX: CURICULUM VITAE OF INVESTIGATORS AND SAFETY 
MONITORING COMMITTEE MEMBERS 
CVs are provided as separate documents 
 


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Page 99 
16.10  APPENDIX X: SUMMARY OF STANDARD RESPONSE CRITERIA FOR ACUTE 
LEUKEMIA, MALIGNANT LYMPHOMA, AND MULTIPLE MYELOMA 
1) Acute Leukemia (after Döhner, 2010) 
Response criteria in AML 
Category 
Definition 
Complete 
remission (CR)* 
Bone marrow blasts < 5%; absence of blasts with Auer rods; absence of 
extramedullary disease; absolute neutrophil count > 1.0 × 109/L (1000/μL); platelet 
count > 100 × 109/L (100 000/μL); independence of red cell transfusions  
CR with incomplete 
recovery (CRi)† 
All CR criteria except for residual neutropenia (< 1.0 × 109/L [1000/μL]) or 
thrombocytopenia (< 100 × 109/L [100 000/μL])  
Morphologic 
leukemia-free 
state‡ 
Bone marrow blasts < 5%; absence of blasts with Auer rods; absence of 
extramedullary disease; no hematologic recovery required 
Partial remission 
(PR) 
Relevant in the setting of phase 1 and 2 clinical trials only; all hematologic criteria of 
CR; decrease of bone marrow blast percentage to 5% to 25%; and decrease of 
pretreatment bone marrow blast percentage by at least 50%  
Cytogenetic CR 
(CRc)§ 
Reversion to a normal karyotype at the time of morphologic CR (or CRi) in cases with 
an abnormal karyotype at the time of diagnosis; based on the evaluation of 20 
metaphase cells from bone marrow  
Molecular CR 
(CRm)‖ 
No standard definition; depends on molecular target 
Treatment failure 
Resistant disease 
(RD)     
Failure to achieve CR or CRi (general practice; phase 2/3 trials), or failure to achieve 
CR, CRi, or PR (phase 1 trials); only includes patients surviving ≥ 7 days following 
completion of initial treatment, with evidence of persistent leukemia by blood and/or 
bone marrow examination  
Death in aplasia  
Deaths occurring ≥ 7 days following completion of initial treatment while cytopenic; with 
an aplastic or hypoplastic bone marrow obtained within 7 days of death, without 
evidence of persistent leukemia  
Death from 
indeterminate 
cause     
Deaths occurring before completion of therapy, or < 7 days following its completion; or 
deaths occurring ≥ 7 days following completion of initial therapy with no blasts in the 
blood, but no bone marrow examination available  
Relapse¶ 
Bone marrow blasts ≥ 5%; or reappearance of blasts in the blood; or development of 
extramedullary disease 
↵* All criteria need to be fulfilled; marrow evaluation should be based on a count of 200 nucleated cells in an aspirate with spicules; if 
ambiguous, consider repeat exam after 5 to 7 days; flow cytometric evaluation may help to distinguish between persistent leukemia and 
regenerating normal marrow; a marrow biopsy should be performed in cases of dry tap, or if no spicules are obtained; no minimum duration of 
response required.  


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↵† The criterion of CRi is of value in protocols using intensified induction or double induction strategies, in which hematologic recovery is not 
awaited, but intensive therapy will be continued. In such protocols, CR may even not be achieved in the course of the entire treatment plan. In 
these instances, the overall remission rate should include CR and CRi patients. Some patients may not achieve complete hematologic recovery 
upon longer observation times.  
↵‡ This category may be useful in the clinical development of novel agents within phase 1 clinical trials, in which a transient morphologic 
leukemia-free state may be achieved at the time of early response assessment.  
↵¶ In cases with low blast percentages (5-10%), a repeat marrow should be performed to confirm relapse. Appearance of new dysplastic 
changes should be closely monitored for emerging relapse. In a patient who has been recently treated, dysplasia or a transient increase in blasts 
may reflect a chemotherapy effect and recovery of hematopoiesis. Cytogenetics should be tested to distinguish true relapse from therapy-related 
MDS/AML. 
 
2) Revised Response Criteria for Malignant Lymphoma (after Cheson, 2007) 
Response Definitions for Clinical Trials 
Response Definition 
Nodal Masses 
Spleen, Liver 
Bone Marrow 
CR 
Disappearance of 
all evidence of 
disease 
(a) FDG-avid or PET 
positive prior to therapy; 
mass of any size permitted 
if PET negative (b) Variably 
FDG-avid or PET negative; 
regression to normal size 
on CT  
Not palpable, nodules 
disappeared 
Infiltrate cleared on 
repeat biopsy; if 
indeterminate by 
morphology, 
immunohistochemistry 
should be negative 
PR 
Regression of 
measuable 
disease and no 
new sites 
≥ 50% decrease in SPD of 
up to 6 largest dominant 
masses; no increase in size 
of other nodes (a) FDG-avid 
or PET positive prior to 
therapy; one or more PET 
positive at previously 
involved site (b) Variably 
FDG-avid or PET negative; 
regression on CT  
≥ 50% decrease in 
SPD of nodules (for 
single nodule in 
greatest transverse 
diameter); no increase 
in size of liver or 
spleen 
Irrelevant if positive prior 
to therapy; cell type 
should be specified 
SD 
Failure to attain 
CR/PR or PD 
(a) FDG-avid or PET 
positive prior to therapy; 
PET positive at prior sites of 
disease and no new sites 
on CT or PET 
(b) Variably FDG-avid or 
PET negative; no change in 
size of previous lesions on 
CT 
Relapsed 
disease or 
PD 
Any new lesion or 
increase by ≥ 50% 
of previously 
involved sites from 
nadir 
Appearance of a new 
lesion(s) > 1.5 cm in any 
axis, ≥ 50% increase in 
SPD of more than one 
node, or ≥ 50% increase in 
longest diameter of a 
previously identifed node > 
1 cm in short axis  
> 50% increase from 
nadir in the SPD of 
any previous lesions 
New or recurrent 
involvement 
Lesions PET positive if 
FDG-avid lymphoma or 
PET positive prior to 
therapy 


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Abbreviations: CR, complete response; FLC, free light chain; PR, partial response; SD, stable disease; sCR, stringent complete response; 
VGPR, very good partial response. 
a All response categories require two consecutive assessments made at anytime before the institution of any new therapy; complete and PR and 
SD categories also require no known evidence of progressive or new bone lesions if radiographic studies were performed. Radiographic studies 
are not required to satisfy these response requirements. 
b Confirmation with repeat bone marrow biopsy not needed. 
c Presence/absence of clonal cells is based upon thek/  ratio. An abnormalk/  ratio by immunohistochemistry and/or immunofluorescence 
requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting presence of an abnormal clone isk/  of >4:1 or <1;2. 
Alternatively, the absence of clonal plasma cells can be defined based on the investigation of phenotypically aberrant PC. The sensitivity level is 
10-3(less than one phenotypically aberrant PC within a total of 1000 Pc). Examples of aberrant phenotypes include (1) CD38 +dim and CD56+ strong 
and CD19- and CD45-; (2) CD38+dim and CD138+and CD56++ and CD28+; (3) CD138+, CD19- CD56++, CD117+. 
Relapse subcategory 
Relapse criteria 
Progressive diseaseaTo be used for calculation 
of time to progression and progression-free 
survival end points for all patients including 
those in CR (includes primary progressive 
disease and disease progression on or off 
therapy) 
Laboratory or Biochemical Relapse or Progressive 
Disease: requires any one or more of the following: 
Increase of 
25% from baseline in Serum M-
component and/or (the absolute increase must be
0.5 
g/dl)b 
Urine M-component and/or (the absolute increase 
must be
200 mg/24 h 
Only in patients without measurable serum and urine 
M-protein levels: the difference between involved and 
uninvolved FLC levels. The absolute increase must be 
>10 mg/dl. 
Bone marrow plasma cell percentage: the absolute % 
must be 
10%c 
Definite development of new bone lesions or soft 
tissue plasmacytomas or definite increase in the size 
of existing bone lesions or soft tissue plasmacytomas 
Development of hypercalcemia (corrected serum 
calcium> 11.5 mg/dl or 2.65 mmol/l) that can be 
attributed solely to the plasma cell proliferative disorder 
 
Clinical relapse (i.e., progressive disease 
requiring re-treatment or alternate treatment)a 
Clinical relapse or progressive disease requires one or 
more of: 
Direct indicators of increasing disease and/or end 
organ dysfunction (CRAB features)b It is not used in 
calculation of time to progression or progression-free 


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Relapse subcategory 
Relapse criteria 
survival but is listed here as something that can be 
reported optionally or for use in clinical practice 
 
1. Development of new soft tissue plasmacytomas or 
bone lesions 
 
2. Definite increase in the size of existing 
plasmacytomas or bone lesions. A definite increase is 
defined as a 50% (and at least 1 cm) increase as 
measured serially by the sum of the products of the 
cross-diameters of the measurable lesion 
 
3. Hypercalcemia (>11.5 mg/dl) [2.65 mmol/l] 
 
4. Decrease in hemoglobin of 
2 g/dl [1.25 mmol/l] 
(see Table 3 for further details) 
 
5. Rise in serum creatinine by 2 mg/dl or more [177 
mol/l or more] 
 
 
Relapse from CRa(To be used only if the end 
point studied is DFS)d 
Any one or more of the following: 
Reappearance of serum or urine M-protein by 
immunofixation or electrophoresis 
 
Development of 
5% plasma cells in the bone 
marrowc 
 
Appearance of any other sign of progression (i.e., new 
plasmacytoma, lytic bone lesion, or hypercalcemia see 
below) 
Abbreviations: CR, complete response; DFS, disease-free survival. 
a All relapse categories require two consecutive assessments made at anytime before classification as relapse or disease progression and/or the 
institution of any new therapy. 
b For progressive disease, serum M-component increases of
1 gm/dl are sufficient to define relapse if starting M-component is 
5 g/dl. 
c Relapse from CR has the 5% cutoff versus 10% for other categories of relapse. 
d For purposes of calculating time to progression and progression-free survival, CR patients should also be evaluated using criteria listed above 
for progressive disease. 


ONCOETHIX                                                             CONFIDENTIAL 
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   Document Status: Version J 
 
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Page 104 
16.11 
APPENDIX XI: LIST (NON EXHAUSTIVE) OF DRUGS AND OTHER 
SUBSTANCES INTERFERING WITH CYTOCHROME P450 3A4 AND 2A6 (CYP3A4 
AND CYP2A6) 
Strong CYP3A4 interfering agents are prohibited (in bold and underlined). A strong 
inhibitor increases the AUC of a substrate for a given CYP by ≥5-fold or > 80% decrease in 
clearance. A strong inducer decreases the AUC of a substrate for a given CYP by ≥ 80%. 
CYP3A4 inducers 
CYP3A4 inhibitors 
avasimibe 
carbamazepine 
phenytoin 
rifampicin 
St John’s wort1 
amobarbital 
dexamethasone 
efavirenz 
felbamate 
nevirapine 
omeprazole 
phenobarbital 
pioglitazone 
primidone 
rifabutin 
tamoxifen 
troglitazone 
boceprevir 
clarithromycin 
conivaptan 
grapefruit juice1 
indinavir 
itraconazole 
ketoconazole 
lopinavir 
mibefradil  
nefazodone 
nelfinavir 
posaconazole 
ritonavir  
saquinavir 
telaprevir 
telithromycin 
tipranavir 
voriconazole 
atazanavir  
amiodarone 
amprenavir 
aprepitant 
cimetidine 
cyclosporine 
darunavir 
delavirdine 
diltiazem  
erythromycin 
fluconazole 
fosamprenavir 
imatinib 
miconazole  
suboxone  
verapamil 
 
 
CYP2A6 inducers 
CYP2A6 inhibitors 
Other CYP2A6 substrates 
phenobarbital  
rifampicin  
 
grapefruit juice  
ketoconazole  
methoxsalen  
pilocarpine  
tranylcypromine  
coumarin 
halothane  
losigamone  
methoxyflurane  
nicotine  
quinoline 
SM-12502  
valproic acid 
1. Preparation-dependent 
 
 


ONCOETHIX                                                             CONFIDENTIAL 
Clinical Study Protocol  OTX015_104                       Date: 18 December 2015 
   Document Status: Version J 
 
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Page 105 
16.12 
APPENDIX XII: GUIDANCE FOR POTENTIAL DRUG-INDUCED LIVER INJURY 
(DILI)I 
 
1.1.1 Purpose 
The purpose of this document is to provide guidance to enable the investigator/study coordinator 
to provide clinical follow-up and systematically gather and report data on potential DILI.  The 
data collected will be used by the Sponsor to create narratives for regulatory agency reporting. 
1.1.2 Introduction 
Hepatotoxicity is injury or damage to the liver that may be associated with impaired liver function 
(Navarro and Senior 2006). Drug-induced hepatotoxicity is one of the most common causes of 
termination of drug development, a major reason for refusal of market authorization and for 
restricted use, and the single most important cause of the withdrawal of market authorization for 
products (Björnsson and Olsson 2005).  Thus, drug-induced hepatotoxicity is a major concern 
during the discovery, development to post-authorization phases of the product life cycle 
(excerpted from Draft Guidance Document, Hepatotoxicity of Health Products, Ministry of Public 
Health, Canada, December 2010). 
As stated in the United States Food and Drug Administration (FDA) “Guidance for Industry - 
Drug-Induced Liver Injury: Premarketing Clinical Evaluation”; hepatocellular injury (usually 
detected by serum aminotransferase elevations [AT]) can be caused by drugs that rarely, if ever, 
cause severe DILI (e.g., aspirin, tacrine, statins, and heparin), as well as by drugs that do cause 
such injury. The frequency of serum AT elevations also is not a good indicator of a potential for 
severe DILI because drugs such as tacrine (not a cause of severe DILI) can cause AT elevations in 
as many as 50 percent of patients. Very high levels of observed ATs may be a somewhat better 
indicator of potential for severe DILI, but the most specific indicator is evidence of altered liver 
function accompanying or promptly following evidence of hepatocellular injury. 
The single clearest (most specific) predictor found to date of a drug’s potential for severe 
hepatotoxicity, is the occurrence of hepatocellular injury (AT elevation) accompanied by 
increased serum total bilirubin (TBL) not explained by any other cause, such as viral hepatitis or 
exposure to other hepatotoxins, and without evidence of cholestasis, together with an increased 
incidence of AT elevations in the overall trial population compared to control.  Increased plasma 
prothrombin time, or its international normalized ratio (INR), a consequence of reduced hepatic 
production of Vitamin K-dependent clotting factors, is another potentially useful measure of liver 
function that might suggest the potential for severe liver injury. 
Recognition of the importance of altered liver function, in addition to liver injury, began with 
Hyman Zimmerman’s observation that drug-induced hepatocellular injury (i.e., AT elevation) 
accompanied by jaundice (i.e., TBL elevation) had a poor prognosis, with a 10 to 50 percent 
mortality from acute liver failure (in pretransplantation days) (Zimmerman 1978, 1999).  This 
became known as "Hy's Law".  This document describes the recommended process for monitoring 
and evaluation of patients meeting the laboratory criteria for potential DILI defined as: 
• an elevated alanine transaminase (ALT) or aspartate transaminase (AST) lab value that is greater 
than or equal to three times (3X) the upper limit of normal (ULN) and  


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Page 106 
• an elevated TBL lab value that is greater than or equal to two times (2X) ULN and 
• at the same time, an alkaline phosphatase (ALP) lab value that is less than 2X ULN,  
as a result of within-protocol-specific testing or unscheduled testing.  
The protocol identifies these laboratory criteria for potential DILI as ECIs.  ECIs are selected 
adverse experiences that must be reported to the Sponsor within 24 hours. The Principal 
Investigator should record these ECIs on the Adverse Experience CRFs and complete pertinent 
adverse experience fields as outlined in the Data Entry Guidelines (DEGs). 
1.1.3 Close Observation Recommendations 
The following steps should be taken when a patient is observed to have an elevated AST or ALT 
lab value that is greater than or equal to 3X ULN and an elevated TBL lab value that is greater 
than or equal to 2X ULN and, at the same time, an ALP lab value that is less than 2X ULN, as a 
result of within-protocol-specific testing or unscheduled testing. In addition, close monitoring of 
isolated bilirubin increases greater than 2X ULN will be required. 
Initiate close observation, defined below, and continue performing follow-up to resolution.  
Close observation is defined as follows:  
• Repeat liver enzyme and serum bilirubin tests two (2) or three (3) times weekly.  Frequency of 
retesting can decrease to once a week or less if abnormalities stabilize or study drug has been 
discontinued and the patient is asymptomatic. 
o For patients with isolated bilirubin elevations greater than 2X ULN, repeat serum bilirubin 
tests every 2 weeks until the bilirubin returns to normal or baseline. 
• Obtain a more detailed history of symptoms and prior or concurrent diseases. (See Section 16.5). 
• Obtain a history of concomitant medication use (including prescription and nonprescription 
medications, herbal and other dietary supplements), alcohol use, recreational drug use and special 
diets. (See Section 16.5 for details.) 
• Obtain a history of exposure to chemical agents or other environmental toxins.  
• Obtain additional history and complete Stage 1 work-up to attempt to rule out other potential 
causes of the transaminase elevation, including but not limited to the following:  acute viral 
hepatitis types A, B, C, D, and E; autoimmune or alcoholic hepatitis; non-alcoholic steatohepatitis 
(NASH); hypoxic/ischemic hepatopathy; and biliary tract disease. (See Section 16.5.5 for details.) 
• Consider gastroenterology or hepatology consultation.   
In general, treatment with study therapy should be stopped if the laboratory criteria for potential 
DILI are met.  Please refer to the specific discontinuation criteria in the protocol as appropriate. 
 


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Page 107 
1.1.4 Hepatic Assessment Flow Chart 
Hepatic Assessment Flow Chart 
 
1.1.5 Factors to Consider in Assessing Potential DILI 
When there is a potential DILI, it is important to thoroughly assess the patient’s history, hepatic 
risk factors, clinical condition and hepatic function until resolution (normal or baseline levels).  
Answers to the following questions should be recorded in source documents and in appropriate CRFs as 
outlined in the DEGs. 
1.1.5.1 Study Medication 
Considerations should include the following: What was the time interval between administration of study 
medication and the laboratory abnormality(ies)? What is the status of study medication use: Continuing? 
Interrupted? Discontinued?  Was the patient re-challenged with study medication? 
1.1.5.2 Treatment 
Record any concomitant treatments. 
1.1.5.3 Signs and Symptoms (associated with the potential DILI event) 
Does the patient have a concomitant illness?  Does the patient currently exhibit signs or symptoms of 
hepatitis/DILI?  What are the patient’s signs and symptoms (see examples below)?  What are the pertinent 
findings from medical history, physical/laboratory examination (e.g., fatigue, nausea, vomiting, right upper 
Triggering Event 
ALT or AST > 
3X ULN with 
TBL>2x ULN 
and ALP <2X 
ULN 
Within 48-72 hours, 
perform stage 1 testing. 
Initiate Close 
Observation (as defined 
in Section 3) and follow-
up to resolution. 
Investigator: investigate 
potential etiology, gather 
history, more 
information  
Follow-up 
Enter/update in CRF 
Dialogue with Sponsor staff 
Sponsor staff, if appropriate, will prepare 
narrative for report 
Enter data into CRF 
and report within 24 
hours of learning the 
event to the sponsor 
If results of Stage 
1 evaluation are 
negative, perform 
Stage 2 work-up 
within one (1) 
week of receiving 
Stage 1 result)  
(see Section 5.5) 


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Page 108 
quadrant pain or tenderness, fever, rash, and/or eosinophilia > 5%, hepatomegaly, splenomegaly, etc.) that 
could suggest DILI? 
Category 
Examples of Signs and Symptoms 
Blood/lymphatic 
Eosinophilia, coagulopathy, susceptibility to 
bleeding/bruising 
Circulatory 
Varicose veins, edema 
Constitutional 
Fever, fatigue, malaise, weight gain, other (identify). 
Digestive/hepatic 
Anorexia, diarrhea, bloody or black stool, light-colored 
stools, nausea, vomiting, hematemesis, upper quadrant 
abdominal pain, upper quadrant tenderness, hepatomegaly, 
jaundice, splenomegaly, ascites, cholestasis 
Endocrine/reproductive 
Loss of libido 
Integumentary 
Rash, pruritus 
Muscular 
Myalgia 
Nervous 
Changes in mental status or level of consciousness 
Urinary 
Dark urine 
 
1.1.5.4 Confounding Variables 
What are the relevant medical history and findings?  What is the differential diagnosis? What risk factors 
does the patient have for hepatic injury? (See examples below.) Provide onset of risk factor and duration. 
Category 
Examples of Confounding Variables 
Subject medical history 
Autoimmune disorder, cancer, Gilbert’s syndrome, obesity, Wilson’s 
disease 
Substance use/abuse 
Alcohol, illegal drugs, illegal intravenous (IV) drugs  
Prior & Concomitant Medications:  
Review all non-study medications 
and therapies, including: over-the-
counter (OTC), as well as 
prescription. Ask the patient to bring 
products/packaging to site and 
review contents. 
History of recent concomitant acetaminophen (APAP)/paracetamol 
use, excessive nonsteroidal anti-inflammatory drug (NSAID) intake, 
use of non-study drug or therapy that can cause liver damage or 
idiosyncratic adverse drug reactions 
Herbal and nutritional supplements 
Herbal, complementary therapies, and nutritional supplements 
Adulteration of products 
History of previous exposure to the product or a similar product, and 
information on potential contamination or adulteration of products 
Chemical exposure 
Occupational or in other situations 
Potential exposure to infectious 
agents  
Infectious hepatitis, transfusion, travel, tattoos, sexually transmitted 
diseases, new sexual partner, shared needles 
Special Diet 
Special diet started since randomization 
Other 
Recent physical trauma, excessive exercise, or other prolonged 
physical exertion 
Family history  
Autoimmune disorder, cancer, Gilbert’s syndrome, Wilson’s disease 
 
 
 


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Page 109 
1.1.5.5 Evaluation algorithm for potential DILI if there are no other clinical reasons 
Note: If clear etiology for the laboratory abnormalities has been confirmed, Stage 1 and 2 testing may not 
be required.  In this case, consultation with the Sponsor is recommended. 
Stage 1 work-up should be performed within 48-72 hours:  
• ALT 
• AST 
• Bilirubin: total, direct, indirect 
• Alkaline phosphatase (ALP)  
• Prothrombin Time (PT)/international normalized ratio (INR)  
• Creatine phosphokinase (CPK) 
• Manual eosinophil count (if automated count was elevated)  
• Toxicology screen for drugs of abuse (including ethanol) and for acetaminophen/paracetamol 
level should also be sent.  Investigators may order additional toxicology tests as clinically 
indicated. 
• Evaluate patient for the following signs and symptoms: fatigue, nausea, vomiting, right upper 
quadrant abdominal pain or tenderness, fever, rash. 
• Obtain the following additional history and assessment for associated risk/confounding factors: 
- 
More detailed history of symptoms and prior or concurrent illness 
- 
Aminotransferase values obtained prior to the study or administration of study medication 
- 
Alcohol consumption (recent and historical) 
- 
Acetaminophen (APAP)/paracetamol use  
- 
New prescription, concomitant, or non-prescription (including herbal and other dietary 
supplements) medications 
- 
Unusual foods (e.g. mushrooms) or special diets. Consumption of seasonal foods. 
- 
Recreational drug use 
- 
Prior history of liver injury or disease, including but not limited to Gilbert's syndrome, 
autoimmune disorders, cancer, Wilson's disease, NASH, alcoholic or infectious hepatitis, 
biliary tract disease, hypoxic/ischemic hepatopathy 
- 
Obesity/abdominal adiposity (record weight, height, and waist circumference) 
- 
Occupational history and history of exposure to chemical agents or other environmental 
toxins 
- 
Recent travel (last three [3] years) 
- 
Transfusion history 
• Perform the following required laboratory tests:  
- 
Albumin 
- 
Eosinophils (percentage and absolute; obtain manual count if automated count is elevated) 
- 
Viral hepatitis serologies (obtain appropriate consent prior to testing, if required locally) 
 A (IgG, IgM) 
 B (HepBs Ag, Hep Bs Ab, Hep Bc Ab, Hep Be Ag) 
 C (RNA) 
 D (requires concomitant hepatitis B infection) 


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Page 110 
- 
Human Immunodeficiency Virus (HIV) testing (obtain appropriate consent prior to testing, 
if required locally) 
- 
Evaluation for autoimmune hepatitis:  
 Serum gamma globulin levels/ serum protein electrophoresis   
 Antinuclear antibody (ANA)  
 Anti-mitochondrial antibody (if ALP or TBL >ULN) 
- 
If AST/ALT ratio is greater than one (1) with suspicions of increased alcohol intake, 
perform the following: 
 Gamma-glutamyl transferase (GGT) 
• Obtain a right upper quadrant ultrasound 
Stage 2 work-up tests should be drawn within one (1) week of receiving the Stage 1 work-up 
results and the results of Stage 1 evaluation are negative. 
Note: A specific test may be performed earlier if the investigator determines that the clinical 
presentation leads to a certain diagnosis. 
Stage 2 work-up: 
• Perform the following laboratory tests: 
- 
Genetic test for Gilbert's disease if there is a suspicious history. Ensure appropriate patient 
consent is obtained for this test. 
- 
Viral hepatitis E (IgG and IgM, obtain appropriate consent prior to testing, if required 
locally)  
- 
Anti-smooth muscle antibody  
- 
Anti-liver-kidney microsomal antibody  
- 
Anti-soluble liver antigen 
- 
Serologies for the following: 
 Cytomegalovirus (CMV) (IgG, IgM) 
 Epstein-Barr Virus (EBV) (IgG, IgM) 
 Herpes simplex 
 Toxoplasmosis 
 Varicella 
 Parvovirus 
- 
Ceruloplasmin 
- 
Serum alpha-1 anti-trypsin 
- 
Genetic test for hemochromatosis. Ensure appropriate patient consent is obtained for this 
test  
- 
Iron Studies:  
 serum ferritin,  
 serum iron,   
 total iron binding capacity 
• Consider referral to hepatologist/gastroenterologist 
• Consider screen for celiac disease and cystic fibrosis if clinically indicated  


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Page 111 
• If laboratory tests or ultrasound evidence of biliary tract obstruction, consider obtaining 
Endoscopic Retrograde Cholangiopancreatography (ERCP) or Magnetic Resonance 
Cholangiopancreatography (MRCP) 
If applicable, request copies of hospital discharge summaries, consultation reports, pathology 
reports, special studies (e.g. imaging or biopsy), etc. 
1.1.5.6 Potential diagnosis 
What diagnosis do the history, clinical course, and laboratory tests suggest? 
1.1.5.7 Overall clinical impression 
What are the investigator’s overall clinical impressions (e.g., differential diagnosis, potential alternative 
causes)? 
1.1.5.8 Treatment plan 
What is the plan for treatment and follow-up? 
1.1.6 Contacts 
If you have any questions, please refer to your Sponsor contact list for the following personnel: 
- 
 (OTD)  
- 
 (Merck) 
 
1.1.7 References 
• Navarro, VJ and JR Senior, 2006, Drug-Related Hepatotoxicity, N Eng J Med, 354(7):731-9. 
• Björnsson, E and R Olsson, 2005, Outcome and Prognostic Markers in Severe Drug-Induced 
Liver Disease, Hepatology, 42(2):481-9. 
• Zimmerman, HJ, 1978, Drug-Induced Liver Disease, in: Hepatotoxicity, The Adverse Effects 
of Drugs and Other Chemicals on the Liver, 1st ed., pp. 351-3, Appleton-Century-Crofts, New 
York. 
• Zimmerman, HJ, 1999, Drug-Induced Liver Disease, in: Hepatotoxicity, The Adverse Effects 
of Drugs and Other Chemicals on the Liver, 2nd ed., pp. 428-33, Lippincott Williams & 
Wilkins, Philadelphia. 
• Draft Guidance Document, Hepatotoxicity of Health Products, Ministry of Public Health, 
Canada, December 2010 
http://www.hc-sc.gc.ca/dhp-mps/alt_formats/pdf/consultation/drug-
medic/draft_ebauche_hepatotox_guide_ld-eng.pdf  
• FDA Guidance for Industry - Drug-Induced Liver Injury: Premarketing Clinical Evaluation, 
July 2009 
www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UC
M174090.pdf 
PPD
PPD

SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Official Protocol Title: A phase I, dose-finding study of the bromodomain (Brd) inhibitor 
OTX015/MK- 8628 in haematological malignancies 
 
NCT number: 
NCT01713582
Document Date: 
10-Mar-2017


Protocol OTX015_104/PN001; Version H, Amendment 7, 30 September 2014 
Statistical Analysis Plan, v2.0, 10March2017 
 
- 1 - 
 
 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
 
A phase I, dose-finding study of the bromodomain (Brd) inhibitor OTX015/MK-
8628 in haematological malignancies 
 
 
 
 
Protocol OTX015_104/PN001, Version  H, Amendment 7, 30 September 2014 
 
 
SAP v2.0 10 March, 2017 
 
 
 
 
 
 
  
Investigational Product: 
Bromodomain (Brd) inhibitor OTX015/MK-8628 
 
Sponsor: 
ONCOETHIX GmbH, a wholly owned subsidiary of Merck, Sharp & 
Dohme Corp, 32 Avenue de l’Elysée, 1006 Lausanne, Switzerland 
 
Sponsor Medical Expert: 
 
 
Merck Research Laboratories, Rahway, US 
 
Tel: 
 
 
E-mail: 
 
CRO Medical Monitor: 
 
 
OTD, Clichy, France 
 
Tel: 
 
 
E-mail: 
 
 
Coordinating Investigator: 
 
 
 France 
 
Tel: 
 
 
E-mail: 
 
 
Statistician: 
 
 
eXYSTAT, Malakoff, France 
 
Tel: 
 
 
E-mail: 
 
 
 
 
 
04MQLN
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PPD
PPD
PPD
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PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


 
 
04MQLN
PPD


Protocol OTX015_104/PN001; Version H, Amendment 7, 30 September 2014 
Statistical Analysis Plan, v2.0, 10March2017 
 
- 3 - 
 
 
2. TABLE OF CONTENTS  
1. 
SIGNATURE PAGE ................................................................................................................................................ 2 
2. 
TABLE OF CONTENTS ......................................................................................................................................... 3 
3. 
PROTOCOL SYNOPSIS ........................................................................................................................................ 5 
4. 
ABBREVIATIONS ................................................................................................................................................ 13 
5. 
STUDY CONDUCT ............................................................................................................................................... 15 
6. 
STATISTICAL METHODOLOGY ..................................................................................................................... 15 
6.1 
GENERAL CONSIDERATIONS ............................................................................................................................ 15 
6.2 
HANDLING OF MISSING DATA ........................................................................................................................... 16 
7. 
NUMBER OF PATIENTS .................................................................................................................................... 17 
8. 
POPULATIONS ..................................................................................................................................................... 17 
8.1 
DATA SETS ANALYZED .................................................................................................................................... 17 
9. 
PATIENT DISPOSITION AND PROTOCOL DEVIATIONS ......................................................................... 18 
9.1 
PROTOCOL DISPOSITION ................................................................................................................................... 18 
9.2 
PROTOCOL DEVIATIONS ................................................................................................................................... 18 
10. 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ...................................................... 18 
10.1 
DEMOGRAPHICS ............................................................................................................................................... 18 
10.2 
DISEASE CHARACTERISTICS ............................................................................................................................. 18 
10.3 
SIGNS AND SYMPTOMS ..................................................................................................................................... 19 
10.4 
CONCOMITANT MEDICATIONS .......................................................................................................................... 19 
10.5 
MEASUREMENTS OF COMPLIANCE .................................................................................................................... 19 
11. 
EFFICACY ANALYSES .................................................................................................................................. 20 
12. 
SAFETY EVALUATION ................................................................................................................................. 20 
12.1 
SAFETY VARIABLES.......................................................................................................................................... 20 
12.2 
TREATMENT EXPOSURE ................................................................................................................................... 20 
12.3 
PRIMARY CRITERION: DOSE LIMITING TOXICITY ............................................................................................. 21 
12.4 
ADVERSE EVENTS ............................................................................................................................................ 21 
12.4.1 
Listing of Adverse Events by Patient ...................................................................................................... 22 
12.5 
DEATHS, OTHER SERIOUS ADVERSE EVENTS, AND OTHER SIGNIFICANT ADVERSE EVENTS ........................... 22 
12.6 
CLINICAL LABORATORY EVALUATION ............................................................................................................. 22 
12.6.1 
Laboratory values over time ................................................................................................................... 22 
12.6.2 
Individual patient changes...................................................................................................................... 22 
12.6.3 
Individual clinically significant abnormalities ....................................................................................... 22 
12.7 
VITAL SIGNS, PHYSICAL FINDINGS AND OTHER OBSERVATIONS RELATED TO SAFETY....................................... 22 
12.7.1 
Vital Signs ............................................................................................................................................... 22 
12.7.2 
ECG and LVEF evaluations ................................................................................................................... 23 
12.7.3 
Physical examination .............................................................................................................................. 23 
13. 
PK ANALYSES ................................................................................................................................................. 23 
14. 
CHANGES FROM PROTOCOL .................................................................................................................... 23 
15. 
INDIVIDUAL LISTINGS ................................................................................................................................. 23 
16. 
APPENDIX ........................................................................................................................................................ 24 
16.1 
PROPOSED STATISTICAL OUTPUT TABLES ....................................................................................................... 24 
A) 
PATIENTS ............................................................................................................................................................. 25 
I. 
PATIENT DISPOSITION .......................................................................................................................................... 25 
II. 
PROTOCOL DEVIATIONS ....................................................................................................................................... 27 
III. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ................................................................................... 28 
B) 
SAFETY EVALUATION ...................................................................................................................................... 41 
 
 
04MQLN


Protocol OTX015_104/PN001; Version H, Amendment 7, 30 September 2014 
Statistical Analysis Plan, v2.0, 10March2017 
 
- 4 - 
 
 
I. 
EVALUATION OF DLT AND DETERMINATION OF RD ............................................................................................. 41 
II. 
EXPOSURE ............................................................................................................................................................ 42 
III. 
ADVERSE EVENTS ................................................................................................................................................ 44 
IV. 
SAES AND OTHER SIGNIFICANT AES ................................................................................................................... 47 
V. 
ECG AND LVEF EVALUATIONS ........................................................................................................................... 48 
VI. 
CLINICAL LABORATORY EVALUATIONS ............................................................................................................... 51 
C) 
PHARMACOKINETICS EVALUATION .......................................................................................................... 57 
D) 
PHARMACODYNAMICS EVALUATIONS ...................................................................................................... 57 
E) 
EFFICACY EVALUATIONS ............................................................................................................................... 57 
 
 
 
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Protocol OTX015_104/PN001; Version H, Amendment 7, 30 September 2014 
Statistical Analysis Plan, v2.0, 10March2017 
 
- 5 - 
 
 
3.  PROTOCOL SYNOPSIS  
 
Title: 
A phase I, dose-finding study of the bromodomain (Brd) inhibitor OTX015/MK-8628 in haematological 
malignancies 
Study code: OTX015_104/PN001 
Investigator(s), study site(s): 
 
 France 
 
 France 
 
 Italy 
  
 
 Switzerland 
 
 France 
 
 France 
 
 France 
 
 France 
 
 France 
 
 United Kingdom 
 
 Canada 
Objectives 
 
Primary: 
To determine the recommended dose (RD) of OTX015/MK-8628 for further phase II studies, in patients with 
acute leukemia and in patients with other hematologic malignancies 
Secondary: 
 To assess the safety profile of OTX015/MK-8628 as a single agent in patients with hematologic 
malignancies  
 To assess pharmacokinetics (PK) of OTX015/MK-8628 in patients with hematologic malignancies 
and PK/safety relationship 
 To assess pharmacodynamics (PD) of OTX015/MK-8628 in patients with hematologic malignancies, 
PD/safety and PK/PD relationships  
 To detect clues of clinical antitumor activity 
Exploratory: 
 To detect predictive factors of clinical activity 
Study design: Multicenter, dose finding, open label, phase I b study in successive cohorts of 3 patients with 
cohort expansion. 
Dose escalation part:  
 
Two dose escalation subsets will be assessed independently in parallel: patients with acute leukemia 
(AL) and patients with other hematologic malignancies (OHM).   
 
In each subset, patients will be enrolled by successive cohorts of 3 patients. 
 
Three patients will be initially treated at the starting dose level (DL) in each subset. If no dose limiting 
toxicity (DLT) is observed among these 3 patients during the first cycle of treatment (i.e. the first 21 
days following study treatment initiation, regardless of the treatment schedule), the next 3 patients will 
be treated at the DL immediately above, according to the dose escalation schedule defined below. In the 
absence of DLT observed at the current DL, the dose will be doubled. 
 
At each DL in each subset, the second patient enrolled will not start the study treatment before the first 
treated patient of the cohort has completed at least 2 weeks of treatment (i.e. 14 consecutive daily 
administrations). The first patient enrolled into a higher DL cohort will not start the study treatment 
 
 
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before the last treated patient in the DL immediately below has completed one cycle of study treatment 
(21 days following study treatment initiation, regardless of the treatment schedule). 
 
If one 1 of 3 patients of a cohort experiences a DLT during the first cycle (i.e. the first 21 days 
following study treatment initiation, regardless of the treatment schedule), 3 additional patients will be 
entered at this DL. If no more than 1/6 treated and evaluable patient experience a DLT, the dose 
escalation will proceed to the DL immediately above. As soon as a DLT is observed, the magnitude of 
dose escalation will follow a Fibonacci-like model (see below). If more than 1 patient out of 6 (or more 
than 1 out of 3) experiences a DLT, the DL will be considered exceeding the maximum tolerated dose 
(MTD) for this subset.  
 
Patients not evaluable for DLT (i.e. those having received less than 85% of the intended cumulative 
dose during the first 21 days) and who have not experienced a DLT, will be replaced. 
 
The dose escalation will be stopped independently in each subset upon a decision of the Safety 
Monitoring Committee (SMC). This decision can be taken if one of the following conditions is met: 
o 
A DL exceeding the MTD has been reached 
o 
Biological activity (PD) or sustained biologically active concentrations (PK) of OTX015/MK-
8628 have been achieved 
o 
Or any other unforeseen condition, which, in the judgment of the SMC, would prevent, or would 
not deserve, further dose escalation. 
 
In the absence of other data (PD or PK) suggesting a lower RD, the MTD will be considered the RD. At 
least 6 evaluable patients will be enrolled at the supposed RD (one DL below the dose exceeding the 
MTD) in each subset. The RD will be confirmed for each subset if no more than 1/6 patient experiences 
a DLT. Otherwise the DL immediately below will be explored with a minimum of 6 evaluable patients. 
Expansion part   
 
Once the RD will be established with at least 3 patients having received at least 2 cycles of study 
treatment for each subset, the study will be prolonged with expansion cohorts in selected patients to 
confirm feasibility, safety, PK and PD at the RD. At least 12 evaluable patients with acute leukemia 
will be treated at the RD established for patients with acute leukemia. At least 12 evaluable patients 
with diffuse large B-cell lymphoma (DLBCL) or multiple myeloma (MM) will be treated at the RD 
established for patients with other hematologic malignancies. Additional expansion cohorts may be 
decided by the SMC, based upon the data collected during the dose escalation phase. 
 
The RD for expansion cohorts for both acute leukemia and other hematologic malignancies was 
established at 80 mg QD days 1 to 14 of 21-day cycles (2 weeks ON/one week OFF). 
Inclusion criteria 
1. Signed informed consent prior to beginning protocol specific procedures.  Patients registered for this trial 
must be treated and followed at the participating centers.   
2. Histologically or cytologically proven hematologic malignancy, or confirmed multiple myeloma using 
standard diagnosis criteria. For the dose finding part, any refractory/relapsing hematologic malignancy will 
be accepted. For the expansion cohorts, only patients with selected hematologic malignancies will be 
enrolled: acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), DLBCL and MM) and/or 
other diseases, as decided by the SMC after closure of the dose finding part. 
3. Patient having failed all standard therapies or for whom standard treatment are contra-indicated: 
 For acute leukemia: patients < 60 years old in second or further relapse or relapsing after allogeneic 
stem cell transplantation (aSCT) regardless of number of relapses;  patients > 60 years old in first 
relapse with a disease-free interval (DFI) < 12 months, or further relapse ; irrespective of age, in 
patients relapsing after aSCT, the time elapsed since aSCT should be > 90 days. Patients with 
Philadelphia chromosome positive (Ph+) and/or bcr-abl+ B-cell ALL must have received at least two 
lines of therapy, including 2 bcr-abl tyrosine-kinase (TK) inhibitors (among imatinib, nilotinib and 
dasatinib), or only one line including one TK inhibitor, if the relapse/refractoriness is associated with 
the detection of a resistance mutation to these inhibitors. 
 For MM: patients adequately exposed to at least one alkylating agent, one corticosteroid, one 
immunomodulatory drug (IMiD) and bortezomib,  
 For lymphomas: Patients having failed 2 standard lines of therapy (at least one containing an anti-CD20 
antibody if B-cell lymphoma), or for whom such treatment is contra-indicated. 
4. Patients with evaluable disease 
 
AL patients must have > 5% bone marrow blasts at study entry, without alternative causality (e.g. bone 
marrow regeneration)  
 
 
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 
Lymphoma patients must have at least one non-irradiated tumor mass > 15 mm (long axis of lymph 
node) or > 10 mm (short axis of lymph node or extranodal lesions) on spiral CT-scan.  
 
Patients with MM must have at least one of the following: serum monoclonal component > 1g/dL 
(IgG), or > 0.5g/dL (IgA), or Bence-Jones (BJ) proteinuria > 200mg/24h, or measurable plasmacytoma 
(not previously irradiated). 
5. Patients > 18 years old. 
6. Life expectancy of at least 3 months   
7. ECOG performance status of 0 to 2  
8. Off previous therapy for at least 3 weeks, or 5 half-lives of previously administered drug, whichever is 
longer, prior to first study treatment administration, except 1) hydroxyurea given to control 
hyperleukocytosis that should be stopped 48 hours prior to start study medication and 2) rituximab, which 
should be stopped for at least 3 weeks, regardless of half-life 
9. Recovery from the non-hematologic toxic effects of prior treatment to grade ≤1, or baseline value, 
according to NCI-CTC classification, except alopecia. 
10. Bone marrow function:  
 
For patients with acute leukemia: No limitation 
 
For patients with other hematologic malignancies: Neutrophils  1.0 x 109 /L and platelets  150 x 
109 /L (without transfusion)  
11. Calculated creatinine clearance  30 mL/min (Cockroft & Gault formula, or MDRD formula for patients 
aged > 65 years).  
12. Adequate LFTs: Total bilirubin < the institutional upper normal limits (UNL); ALAT/ASAT  3 x UNL (or 
 5 x UNL in case of liver involvement). 
13. Serum albumin > 28g/L 
14. Complete baseline disease assessment workup prior to first study treatment administration. 
Exclusion criteria 
1. History of prior malignancy other than those previously treated with a curative intent more than 5 years ago 
and without relapse (any tumor) or basal cell skin cancer, in situ cervical cancer, superficial bladder cancer, 
or high grade intestinal polyps treated adequately, regardless of the disease-free interval. 
2. Pregnant or lactating women or women of childbearing potential not using adequate contraception. Male 
patients not using adequate contraception. 
3. Patients with peripheral cytopenias (i.e. auto-immune hemolytic anemia or thrombocytopenia) 
4. Patients with acute promyelocytic leukemia or with clinically uncontrolled (i.e. with bleeding) disseminated 
intravascular coagulation (DIC) 
5. MM patients with POEMS syndrome or plasma cell leukemia. 
6. Patient with chronic graft versus host disease (GVHD) or on immunosuppressive therapy for the control of 
GVHD 
7. Uncontrolled leptomeningeal disease. 
8. Other tumor location necessitating an urgent therapeutic intervention (palliative care, surgery or radiation 
therapy), such as spinal cord compression, other compressive mass, uncontrolled painful lesion, bone 
fracture, etc..) 
9. Uncontrolled disease-related metabolic disorder (e.g. hypercalcemia) 
10. Patients unable to swallow oral medications, or patients with gastrointestinal condition (e.g. malabsorption, 
resection…) deemed to jeopardize intestinal absorption. 
11. Other serious illness or medical conditions, which, in the investigator’s opinion could hamper understanding 
of the study by the patient, patient’s compliance to study treatment, patient’s safety or interpretation of study 
results. These conditions include (but are not restricted to): 
a) 
Congestive heart failure or angina pectoris except if medically controlled.  Previous history of 
myocardial infarction within 1 year from study entry, uncontrolled hypertension or arrhythmias. 
b) 
Existence of significant neurologic or psychiatric disorders impairing the ability to obtain consent. 
c) 
Uncontrolled infection.  
d) 
Known HIV positivity 
12. Concurrent treatment with other experimental therapies or participation in another clinical trial within 21 
days prior to first study treatment administration, or 5 half-lives of previously administered drugs, 
whichever is longer. 
 
 
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13. Concurrent treatment or within 21 days prior to first study treatment administration with any other 
anticancer therapy, except hydroxyurea to reduced hyperleukocytosis. 
14. Concomitant treatment with corticosteroids except if chronic treatment with corticosteroids  30 mg of 
methylprednisolone daily or equivalent. 
15. Patients taking concomitant strong CYP3A4 interacting drugs. 
16. Patients with prior irradiation on more than 30% of bone marrow reserves (including Total Body 
Irradiation), regardless of washout period, and patients having received high dose chemotherapy followed 
by autologous stem cell transplantation less than 90 days prior to first OTX015/MK-8628 dosing. 
Treatment 
 
Patients should receive the study treatment within 7 days after registration. 
 
All patients will be hospitalized for at least 8 hours after the first study drug administration to check 
vital signs and ECG and collect PK blood samples around the anticipated Tmax.  
 
Patients will take OTX015/MK-8628 orally, daily in a fasted state just before lunch, at least 3 hours 
after breakfast end (except outpatient who must take the study medication before breakfast at the 
hospital on day 1). The schedule of administration will initially depend on the indication: 
- 
AL patients will initially take OTX015/MK-8628, over 14 consecutive days followed by a 7-
day rest period. Upon SMC decision, AL patients may take OTX015/MK-8628 continuously without 
planned rest period (as for OHM patients). 
- 
OHM patients will take OTX015/MK-8628 continuously without planned rest period 
- 
a cycle = 21 days by convention. 
 
The initial daily schedule of administration will be once a day (QD) at the first DL. Based upon PK and 
PD results, this schedule could be modified (e.g. to twice daily [BID] by SMC decision) for further 
patients.  For the BID schedule, patients will take their medication in a fasted state around 8 a.m. (+ 2 
hours) and 8 p.m. (+ 2 hours). 
 
Treatment will be interrupted in cases of toxicity according to specific guidelines (see dose and 
schedule adaptation). 
 
Enrolled patients will receive OTX015/MK-8628 at the DL they were assigned at study entry 
throughout the study, or at reduced dose according to toxicity encountered.  
 
However, in exceptional circumstances, intra-patient dose escalation could be allowed, provided all the 
following conditions are met: 1) The patient did not experience toxicity of grade > 1 while treated at 
the initial dose for at least 2 cycles; 2) The dose immediately above has already been tested and is 
considered safe (i.e. at least 3 patients were treated over 3 weeks and no DLT was observed, or at least 
6 were treated over 3 weeks and no more than one of them has experienced a DLT); 3) the patient has 
experienced stable disease so far (no response and no progression); 4) the investigator considers that 
the patient could benefit from dose increment and 5) the SMC agrees. 
 
Treatment will be definitively discontinued upon patient’s request, or in cases of disease progression, 
intolerable toxicity, treatment interruption > 2 weeks due to toxicity (except in cases of suspicion of 
hematologic DLT in acute leukemia, where treatment interruption for 3 weeks is allowed to confirm 
DLT), recurrence of the same toxicity despite dose reduction, lack of compliance, or major protocol 
deviation. 
 
Dosing not performed at the same time (+ 2 hours) as the other days will be omitted. 
 
Omitted or vomited doses will not be replaced. 
 
Dose & schedule adaptation  
Study product dosing (OTX015/MK-8628) will be interrupted in case of: 
Non-hematologic toxicities: 
 
any grade 3-4 non hematologic toxicity despite adequate medication, regardless of duration;  
 
grade 3-4 asymptomatic non hematologic laboratory abnormal values, deemed related to study 
medication,  lasting > 7 days. This definition applies for patients with LFTs/creatinine clearance grade 
< 1 at baseline. For patients with grade 2 values at baseline, only grade 4 lasting > 7 days will be 
considered DLT, unless the SMC considers the event clinically significant.  
 
Any prolonged grade 2 toxicity (lasting more than 2 weeks), leading to treatment interruption and/or 
dose reduction. 
 
 
 
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Hematologic toxicities: 
-- Patients with acute leukemia: 
 
pancytopenia with a hypocellular bone marrow and no marrow blasts lasting for ≥ 6 weeks after the 
start of a cycle.   
- Patients with other hematologic malignancies: 
 
any grade 3  neutropenia, with fever or infection; any grade 3 thrombocytopenia with bleeding,  
 
any grade 4 neutropenia or thrombocytopenia, lasting > 3 days. 
OTX015/MK-8628 dosing will be resumed when all toxic events have resolved to grade < 1 (or to the baseline 
value) at reduced dose at the DL immediately below during the dose escalation phase.  
During the cohort expansion phase, patients initially treated at 80 mg will have their dose reduced to 60 mg QD 
(2 weeks ON/1 week OFF) at the first occurrence of toxicity, then to 40 mg QD (2 weeks ON/1 week OFF) if 
the same toxicity recurs. 
In all cases: 
Dosing interruption for > 2 weeks due to toxicity or recurrence of the same toxicity with the 
same severity despite one dose reduction will lead to definite study treatment discontinuation, 
unless the investigator thinks the patient’s best interest is to pursue study treatment, with 
sponsor’s agreement. 
Premedication 
No premedication is planned at the first cycle, in the first 3 patients. Decisions of further systematic 
premedication will be made by the SMC. 
Dose escalation scheme  
 
The starting dose will be 10 mg/day (once a day, flat dose, without adaptation for body weight or 
surface area) 
 
DLTs will be collected during the first cycle (21 days after the first OTX015/MK-8628 administration) 
The dose escalation scheme will be as followed for each patient subset (AL and OHM). The magnitude of dose 
escalation between two consecutive dose levels will depend upon the occurrence or not of DLT at the current 
DL. 
Dose Level 
 
 
 
1 (starting dose) (mg) 
10 
 
 
2 
20 
 
 
3 
30 
40 
 
4 
40 
60 
80 
5 
50 
80 
120 
Dose escalation schedule: 
Doubling the dose in the absence of DLT (grey boxes). 
Fibonacci-like model once at least one  DLT occurs (white boxes) 
 
 
Dose escalation will be stopped by SMC decision separately and independently for the two patient 
subsets when the RD is deemed to be reached or exceeded.  
 
If and when the decision of exploring a BID schedule is taken by the SMC after the assessment of dose 
level X mg once-a-day, the first BID dose level explored will be X/2 mg twice-a-day (e.g. if the last 
once-a day dose level explored = 80 mg → the first BID dose level explored = 40 mg x 2/day).Further 
dose escalation with the BID schedule will proceed as described in the table above (e.g. if the first BID 
dose level explored= 40 mg x 2/day, then the next dose level explored will be 80 mg x 2/day if no DLT 
was observed at 40 mg x 2/day, or 60 mg x 2 if one DLT was observed).  
If a decision to deliver OTX015/MK-8628 continuously to AL patients is taken by the SMC, ongoing 
AL patients having received at least one intermittent cycle (14 days ON/7 days OFF) without DLT will 
be proposed to receive further cycles without planned interruption (21days ON) at the same daily dose. 
When sufficient safety data have been collected with the continuous schedule both in AL and OHM 
patients, the SMC may allow further cohorts of AL patients to receive continuous OTX015/MK-8628 
treatment from cycle 1. 
 
The RD will be defined either by the MTD, or, in the absence of DLT, based upon PK and/or PD 
 
 
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considerations or other unforeseen condition (see Study Design). 
The final decision of further escalating the dose and of stopping dose escalation, determining the RD and 
starting expansion cohorts enrollment will be left to the discretion of the SMC. According to the nature, 
suspected relationship to study drug, or other clinical considerations, the SMC will make ad-hoc decisions, such 
as replacing non-evaluable patients, adding more patients at the same DL, adding intermediate DLs, not 
considering a given DLT as clinically relevant for the determination of the RD. Serial assessments of PK/PD 
results will be forwarded to the SMC and taken into account for the determination of the RD, especially if no 
DLT occurs.  
Safety Monitoring Committee (SMC) 
The SMC will be composed of the principal investigators of each participating center, the pharmacokinetics 
(PK) specialist, the medical and safety representatives of the Sponsor and an independent expert in 
oncology/hematology phase I development. All decisions taken by the SMC and their rationale will be recorded 
in meeting minutes that will be integrated in the final clinical study report. 
Definition of dose limiting toxicities (DLTs) 
The DLTs are identical to the events leading to treatment interruption and dose adjustment (see dose & schedule 
adaptation), as well as any other unforeseen drug-related AE resulting in study drug discontinuation or 
interruption with/without dose reduction. But only such AEs occurring during cycle 1 (or the first 21 days 
following the first dosing of OTX015/MK-8628) are considered DLT, except for the hematologic DLT for 
patient with acute leukemia that must be confirmed after 6 weeks of treatment, 
Treatment compliance 
Patients will record daily in a specific diary, the number of capsules swallowed, time of intake, as well as 
possible reactions, including vomiting, and their time of occurrence. At each study visit the hospital pharmacist 
of the study center will provide the patient with the needed number of capsules for the visit interval and retrieve 
the unused capsules that will be kept until study end for accountability by the study monitor. 
Number of subjects 
 
The total number of patients enrolled will depend on the number of DLs explored and of DLT encountered. 
Approximately 80 evaluable patients will be enrolled in the dose escalation part  (40 by subset AL/OHM) 
At least 12 evaluable patients by expansion cohorts will be enrolled in at least 3 expansion cohorts 
Pharmacokinetics (PK) 
Blood collection: 
 
Once-a-day schedule 
Three patients by DL will have complete PK sampling, consisting of 7 blood draws of 3 mL each at days 1 and 
2 (T0, T1h, T4h, T8h, T12h and T24h, plus one sampling ay either T10h or T16h). Complete PK sampling will 
preferably be performed in patients hospitalized due to medical reasons. All other patients enrolled at this DL 
will have limited PK sampling, consisting of 5 blood draws on day 1 (T0, T1h, T4h, T6h and T8h). Patients 
enrolled into the same DL across both dose escalation subsets (AL/OHM) will be considered for the selection of 
the 3 patients with complete PK sampling. 
In addition, all patients will have blood sampling at T0 (just before drug intake) on days 8, 15 and 22. 
 
Twice-a-day (BID) schedule 
All patients will have complete PK consisting of 8 blood draws of 3 mL each on days 1 and 2 (T0, 
T20min±5min, T1h±10min, T2h15min±10min, T3h15min±10min, T9h+1h, T12h±15min (before drug intake) 
and T24h (before drug intake)). Patients will be hospitalized for 24 hours for PK sampling.  
In addition, all patients will have blood sampling at T0 (just before drug intake) on days 8, 15 and 22.  
Fresh tumor collection: 
OTX015/MK-8628 concentration will be measured in tumor cells. 
 
Patients with AL will have one bone marrow (3 mL) or one blood (7 mL)  sample of at day 8.  
 
Patients with OHM* (optional): If a tumor is easily accessible to tumor cell collection using non-
invasive method (i.e., skin or superficial lymph node deposits), optional tumor core biopsy will be 
strongly encouraged, with patient’s express additional consent at baseline, and on D15 + 7 days. 
Assay method: Ultra Performance Liquid Chromatography with tandem Mass Spectrometry detection (UPLC-
MS/MS). 
Pharmacokinetic/safety correlations: The incidence and severity of AEs will be compared to Cmax, CL and 
AUC of OTX015/MK-8628. 
 
 
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Pharmacodynamics (PD) 
Potential biomarkers will be explored in tumor cells, including c-MYC and BRD2, 3 and 4. 
 
Patients with AL will have 2 bone marrow (3 mL each) and blood (15 mL each) samples  at screening 
and at day 8.  
 
Patients with other hematologic malignancies* (optional): If a tumor is easily accessible to tumor cell 
collection using non-invasive method (i.e., skin or superficial lymph node deposits), optional tumor 
core biopsy will be strongly encouraged, with patient’s express additional consent, for intra tumor PK 
at baseline, and on D15 + 7 days. 
PD/safety correlation: The incidence and severity of AEs will be compared to the most pertinent biomarker(s), 
if any.  
PK/PD correlation: Cmax, CL and AUC of OTX015/MK-8628 will be compared to the most pertinent 
biomarker(s), if any. 
As far as possible the same cytology/tissue samples will be used for intratumor PK and PD 
Predictive biomarkers   
 
Available archived tumor material (lymphoma) will be collected, as well as fresh tumor material at 
baseline (leukemic blasts or optional biopsy for other hematologic malignancies) for preliminary detection 
of predictive factors of OTX015/MK-8628 clinical antitumor activity. The availability of a paraffin-
embedded block is a pre-requisite for inclusion of patients with lymphoma into the study if no fresh tumor 
cells/tissue are available.  
Study endpoints 
 
Primary: the primary endpoint for the determination of the RD will be DLT 
 
Secondary: treatment-emergent adverse events (TEAEs), PK and PD parameters, laboratory results, tumor 
response assessment (according to most recently published standard criteria) (see details by disease in the 
core protocol), tumor-related symptoms, performance status (PS). 
 
Exploratory: tumor phenotype, karyotype, molecular biology, etc. 
Safety parameters 
Safety will be assessed on every patient having received the study treatment. It will be evaluated on: 
 
Vital signs (temperature, breath rate, blood pressure and heart rate), physical examination, within 1 week 
prior to the first study drug administration and then weekly for 3 weeks, and then every 21 days.  
 
In addition, vital signs will be collected immediately before, then, 1 and 2 hours  (around the Tmax) after 
the first study drug administration on day 1 
 
ECG will be performed within one week prior to the first study drug administration, immediately before, 
then, 1 and 2 hours (around Tmax) after study drug administration at days 1. 
 
Echocardiography, with measurement of LVEF will be performed at baseline and at the end of treatment. 
 
AEs will be recorded and graded according to the NCI-CTC (v4.03). 
Laboratory tests 
 Hematology: 
Complete blood cell counts (CBC): platelets, WBC and differential and hemoglobin, INR, will be performed 
within 7 days prior to the first study drug administration, then at day 1, then weekly during the first 3 weeks 
and then every 3 weeks thereafter. In cases of grade >2 hematologic toxicity CBC will be performed twice a 
week until recovery to grade < 2. In case of neutropenia/thrombocytopenia grade 4, CBC will be performed 
at least every other day until recovery to grade < 3. In addition, in cases of thrombocytopenia grade 4 lasting 
> 3 days, a bone marrow aspiration is to be performed. In cases of fever  38°C, infection, purpura or 
bleeding, additional CBC should be done as clinically indicated. 
 
Biochemistry: 
LDL, HDL, β2-microglobulin (only for patients with myeloma), serum creatinine, glucose, ionogram 
(sodium, potassium, chloride, HCO3- (bicarbonate)), calcium, phosphorus, magnesium, total protein, 
albumin, AP, ASAT, ALAT, total bilirubin, LDH, CPK and CRP will be performed within 7 days prior to 
the first OTX015/MK-8628 intake, then at day 1, then weekly during the first 3 weeks, and then every 3 
weeks thereafter. In addition, apolipoprotein A-1 (Apo A1) will be assessed within 7 days prior to first 
OTX015/MK-8628 intake and at day 22 only. 
 Urinalysis: 
Dipsticks for protein, glucose and blood at day 1, 2, 8, 15, 22, then every 3 weeks. 
 
 
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Efficacy parameters 
 
Tumor response will be evaluated using standard criteria for lymphoma, acute leukemia and multiple 
myeloma.  
 
Any hints of anti-tumor activity will be quantified and recorded, even if they do not meet criteria for 
response 
 
Overall survival (OS) 
Statistical considerations: 
This is an exploratory Phase I study aimed to assess the pharmacological effects of OTX015/MK-8628 in 
humans with hematologic malignancies. The small subject sample size by cohort does not allow for statistical 
hypotheses. The decisions will be taken by a board of experts (SMC) and the recommended dose will be 
validated in further studies. 
Study duration and dates 
Enrolment: 24-26 months according to the number of DLs explored. 
First-patient in: January 2013 
Last patient in: December 2015- January 2016 
End of study follow-up: December 2016 
 
 
 
 
 
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4. ABBREVIATIONS  
AE 
Adverse Event 
AL 
Acute Leukemia 
ALL 
Acute Lymphoblastic Leukemia 
AML 
Acute Myeloid Leukemia 
ALAT 
Serum Alanine Aminotransferase 
AP 
Alkaline Phosphatase 
Apo A1 
Apolipoprotein A-1 
ASAT 
Serum Aspartate Aminotransferase 
aSCT 
Allogenic Stem Cell Transplant 
ASCT 
Autologous Stem Cell Transplant 
BID 
Twice Daily 
BJ 
Bence Jones Protein 
BMI 
Body Mass Index 
BP 
Blood Pressure 
BRD 
Bromodomain 
BSA 
Body Surface Area 
CBC 
Complete Blood Count 
CHOP 
Cyclophosphamide, Adriamycin, Vincristine, Prednisone 
CI 
Confidence Interval 
CPK 
Creatine PhosphoKinase 
CR 
Complete Response 
CRi 
CR With Incomplete Blast Clearance 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
CRP 
C-Reactive Protein 
CSC 
Clinically Significant Change 
CYP 
Cytochrome P 
DIC 
Disseminated Intravascular Coagulation 
DL 
Dose Level 
DLT 
Dose Limiting Toxicity 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
GCB 
Germinal Center B-Cell-Like 
GVHD 
Graft Versus Host Disease 
IMid 
Immunomodulatory Drug 
INR 
International Normalized Ratio 
ITT 
Intent To Treat 
 
 
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LDH 
Lactate Dehydrogenase 
LFTs 
Liver Function Tests 
LVEF 
Left Ventricle Ejection Fraction 
MDRD 
Modification Of Diet In Renal Disease 
MLFS 
Morphologic Leukemia-Free State 
MM 
Multiple Myeloma 
MTD 
Maximum Tolerated Dose 
NA 
Not Applicable 
NCI-CTCAE 
National Cancer Institute -Common Toxicity Criteria For Adverse Events 
OHM 
Other Hematologic Malignancies 
PC 
Predefined Change 
PD 
Progressive Disease 
PP 
Per Protocol 
PK 
Pharmacokinetics 
POEMS 
Polyneuropathy, Organomegaly, Endocrinopathy, M-Component, Skin Changes 
PR 
Partial Remission 
PS 
Performance Status 
PT 
Preferred Term 
QD 
Daily 
RD 
Recommended Dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SMC 
Safety Monitoring Committee 
SCO 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
Tmax 
Time To Peak Concentration 
UNL 
Upper Normal Limit 
UPN 
Unique Patient Number 
WHO 
World Health Organization 
 
 
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5. STUDY CONDUCT 
The study has been completed and the current SAP applies to all the patients included in the study (dose 
escalation and cohort expansion). 
All statistical programs employed in the analysis, data reporting and statistical outputs will be validated by 
the statistician in charge of the study. In addition, primary criteria (DLT) will be validated by a second 
eXYSTAT statistician. 
 
6. STATISTICAL METHODOLOGY 
6.1 GENERAL CONSIDERATIONS 
The statistical analysis will be performed by eXYSTAT, under the responsibility of the Sponsor OncoEthix 
GmbH and the study CRO, OTD, on the basis of the present document. 
The statistical analysis will be performed using SAS software, version 9.4 in a Windows XP operating 
system environment.  
The baseline value is defined as the last available value prior to administration of the investigational product.  
The study treatment phase is defined as the period between the date of first administration of investigational 
product and the date of last administration of investigational product + 30 days. 
No replacement of missing values is planned, other than those noted in Section 6.2. Thus the number of 
patients included in the analyses may vary depending on availability of the parameter considered. 
Descriptive statistics will be provided by dose level (DL1 to DL5 or DL6 then expansion cohort, depending 
on the disease cohort) and overall for each of the two patient cohorts (AL and OHM), and by time point 
when appropriate, according to the nature of the variable. 
- For quantitative variables, descriptive statistics will include: number of missing values, number of observed 
values, minimum, maximum and median or mean and standard deviation.  
- For qualitative variables, descriptive statistics will include: number and percentage of missing values, 
number of observed values, frequencies and percentages (only for the overall column) per modality.  
Calculated statistics and percentages will be displayed with one decimal, unless otherwise specified.  
No statistical tests will be performed due to the descriptive nature of this analysis. 
 
 
 
 
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In terms of terminology, the mention of "by dose level and overall" will always correspond to the following, 
according to the cohort:  
Acute Leukemia Patients 
DL1  (10mg 
QD)  14-21 
(N=3) 
DL2  (20mg 
QD)   14-21 
(N=3) 
DL3A  
(40mg QD)   
14-21 
(N=4) 
DL3B  
(20mg BID)  
21-21 
(N=3) 
DL4A  
(80mg QD)   
14-21 
(N=4) 
DL4B  
(40mg BID)  
14-21 
(N=8) 
DL5A  
(120mg 
QD)   14-21 
(N=7) 
DL5B  
(120mg 
QD)   21-21 
(N=6) 
DL6   
(160mg 
QD)   14-21 
(N=7) 
Exp. (80mg 
QD)  14-21 
– AML/de 
novo 
(N=19) 
Exp. (80mg 
QD)   14-21 
– 
AML/MDS 
(N=16) 
Total 
(N=80) 
 
Other Hematologic Malignancies Patients 
DL1  (10mg 
QD)  21-21 
(N=5) 
DL2  (20mg 
QD)   21-21 
(N=3) 
DL3  (40mg 
QD)   21-21 
(N=4) 
DL4A  
(80mg QD)   
21-21 
(N=7) 
DL4B  
(40mg BID)   
21-21 
(N=6) 
DL5A  
(120mg QD)   
21-21 
(N=7) 
DL5B  
(120mg QD)   
14-21 
(N=3) 
DL5C  
(120mg QD)   
5-7 
(N=5) 
DL5D  
(120mg QD)   
7-21 
(N=5) 
Exp. (80mg 
QD)   14-21 - 
DLBCL 
(N=16) 
Total 
(N=61) 
All analyses will be repeated in the two populations, AL patients and OHM patients, unless otherwise 
specified. 
6.2 HANDLING OF MISSING DATA 
In the event of a missing date, replacement will be applied so as to be in the worst case scenario, as follows: 
For the concomitant medication start date:  
Completely missing dates will be estimated as the first treatment administration date. 
If the day and the month are missing: 
 
If the year is the same as the year of the first treatment administration date, the date will be estimated as 
the first treatment administration date. 
 
If the year is different to the year of the first treatment administration date, the date will be estimated as 
the 1st January. 
If only the day is missing: 
 
If the month/year are the same as the month/year of the first treatment administration date, the date will 
be estimated as the first treatment administration date. 
 
If the month/year are different from the month/year of the first treatment administration date, the date 
will be estimated as the first day of the month. 
For the concomitant medication end date (if ongoing is not ticked at the end of the study):  
Completely missing dates will be estimated by the End of Study date. 
If the day and the month are missing: 
 
If the year is the same as the year of the End of Study date, the date will be estimated as the End of Study 
date. 
 
If the year is prior to the year of End of Study date, the date will be estimated as the 31 December. 
If only the day is missing: 
 
If the month/year are the same as the month/year of End of Study date, the date will be estimated as the 
End of Study date. 
 
If the year or month is different to the year or month of End of Study date, the date will be estimated as 
the last day of the month. 
If after imputation, the end date is before the estimation start date, the estimation start date will be replaced 
by the end date. 
For the start date of an adverse event:  
Completely missing dates will be estimated as the first treatment administration date. 
 
 
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7. NUMBER OF PATIENTS 
A total number of 141 patients were enrolled according to the number of observed DLs and expansion 
groups selected. 
 
8. POPULATIONS 
Enrolled Population: all patients who signed an Informed Consent Form. 
Treated/Safety Population: all included patients receiving at least one dose of the investigational drug.  
Evaluable for Efficacy Population: All treated patients with at least one available tumor assessment (BM 
aspiration for AL patients or imaging for OHM patients) by the end of cycle 2 or later, OR with earlier 
evidence (i.e. cycle 1) of response or progression. 
Evaluable for DLT Population: all treated patients receiving at least 85% of the intended OTX015/MK-
8628 dose during the first cycle (i.e. ≥ 12 days at full dose for AL and ≥ 18 days at full dose for other 
hematologic malignancies)*, as well as patients not fulfilling these conditions, but who experienced DLT. 
*e.g. for DL1 (10 mg/day), AL patients receiving ≥ 120 mg over the first 21 days (10 mg x 12), or other 
hematologic malignancy patients receiving ≥ 180 mg over the first 21 days (10 mg x 18). 
 
8.1 DATA SETS ANALYZED 
Statistical analyses will be carried out as described below. The number of patients per analysis set will be 
tabulated by DL and overall according to the population evaluated.  
A listing will also be provided (for CSR appendices). 
The following table describes use of the above-defined patients populations in the different analyses 
conducted.  
Analyses Sets 
Enrolled 
Safety 
Evaluable for 
efficacy 
population 
Evaluable for 
DLT 
Disposition 
 
 
 
 
Population characteristics 
 
 
 
 
Compliance and exposure 
 
 
 
 
Efficacy assessments 
 
 
 
 
DLT 
 
 
 
 
Safety assessment 
 
 
 
 
 
 
 
 
 
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9. PATIENT DISPOSITION AND PROTOCOL DEVIATIONS 
9.1 PROTOCOL DISPOSITION 
The number of patients per center will be tabulated for enrolled, treated, evaluable for DLT and evaluable for 
safety patients will be detailed by DL and overall. 
Reasons for discontinuation will be tabulated by DL and overall, and detailed in a patient listing for the CSR 
appendices. Patients classified by the investigator as reason=”Other” but with evidence of clinical or tumoral 
progression will be reclassified as progression in the table. 
Overview of treated conditions will be tabulated by AL (AML/ALL) or OHM (lymphoma, multiple 
myeloma, other). 
 
9.2 PROTOCOL DEVIATIONS 
Totals of major/minor protocol deviations, the number of patients with at least one major/minor protocol 
deviation and type of major/minor deviation will be tabulated for the enrolled population. 
A listing of patients with protocol deviations for relevant items will be presented in the CSR Appendices. 
Protocol deviations will be examined prior to database lock relative to inclusion and exclusion criteria and to 
protocol compliance with regard to administration of treatment and prohibited medication. 
Major protocol deviations are defined as deviations liable to prevent or change the interpretation of the 
results of the study.  
 
10. DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
Demographic and other baseline characteristics recorded at the baseline visit (Day 0) before the first product 
administration will be described by DL and overall for the safety population. 
10.1 DEMOGRAPHICS 
 Age (years; by category) and gender. 
 ECOG performance status at the screening visit by score (0, 1, 2, 3, 4) 
 Height (cm), weight (kg), BMI (kg/m2) = weight in kg/(height in m)² and BSA (m2) = (W 0.425 x H 
0.725) x 0.007184. 
 Pregnancy test (positive, negative, NA) 
10.2 DISEASE CHARACTERISTICS 
 Acute leukemia: Disease duration (months; = [screening year - diagnosis year] *12 + [screening month - 
diagnosis month]), number of lines (in total=number of lines + number of NA in CRF page 17), number 
of lines prior therapy (from CRF page 17), type of systemic therapy (standard, AZA, aSCT, other: coded 
from CRF), leukemia WHO 2008 Classification, FAB classification, genetic group, bone marrow (from 
CRF page 401) (absolute value and 5-20%/>20%), presence peripheral blasts, hyperleukocytis (absolute 
value and >15*109/l, hydroxyurea requirement (coded from prior medication), type (de 
novo/secondary/therapy related/ALL), cellularity (poor, intermediate, rich), extramedullary disease, 
cytogenetics and molecular genetics (from CRF page 15). 
 For lymphoma: disease duration (months), number of lines in total (=number of lines + number of NA in 
CRF page 17), number of lines prior therapy (from CRF page 17), prior therapy (systemic, surgery, 
radiotherapy), type of systemic therapy (CHOP/R-CHOP, ASCT, other; coded from CRF), lymphoma 
 
 
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WHO 2008 classification, number of tumor sites (from CRF page 21), number of nodal sites, number of 
extranodal sites, BM involved (CRF pages 19 and 301).  
 Multiple myeloma: disease duration (months), M-component (IgG, IgA, Bence Jones, Other), Kappa or 
Lambda light chain (max of the two values from CRF page 201), bone lesions, extramedullary disease, 
bone marrow plasma cells, cellularity (poor, intermediate, rich), prior therapy (systemic, surgery, 
radiotherapy), type of systemic therapy (alkylating, steroid, bortezomib, IMiD, ASCT, other; coded from 
CRF), number of lines prior therapy (from CRF page 17) 
Listings of disease characteristics and cancer treatments will be provided for the CSR Appendices.  
10.3 SIGNS AND SYMPTOMS 
Summary tables (number and % patients) grouped by System Organ Class (SOC) will be presented by DL 
and overall for Signs and Symptoms present at baseline (i.e., concomitant diseases "Ongoing" at the 
screening visit) and for Medical History (i.e., events "Not Ongoing" at the inclusion visit). 
The totals of each Signs and Symptoms and the number of patients with at least one Sign and/or Symptom 
will be tabulated for the safety population for baseline Signs and Symptoms and for Medical History. 
10.4 CONCOMITANT MEDICATIONS 
Summary tables (number and % of patients) grouped by the first and the last level of ATC code will be 
presented by DL and overall. Concomitant medications are those ongoing at or started after the first 
treatment. 
Presence at baseline of selected concomitant medications classes (e.g. cardiac antiarrhythmics, 
antihypertensive drugs, neurologic and/or psychiatric drugs) will be described by DL and overall.   
 
10.5 MEASUREMENTS OF COMPLIANCE  
Compliance to the study treatment will be derived only for patients with no missing data (collected in the 
CRF) using the following definition:  
 
Compliance (%) =[nb dose not equal to 0 in the CRF  / ( (nb completed lines in the CRF  + 1 )] * 100 
 
Compliance over the whole study treatment period (from first visit to last visit) and over cycle 1 only will be 
calculated. 
 
 
 
 
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11. EFFICACY ANALYSES 
Response: tumor response will be assessed throughout the study according to standard criteria; acute 
leukemia patients will be assessed based on the recommendations from the European LeukemiaNet [Döhner 
2010], lymphoma patients according to [Cheson 2007], and MM patients according to [Durie 2006]. 
Tumor response will be tabulated per DL and overall, according to disease indication (AL/lymphoma/MM) 
in evaluable patients. 
Waterfall plots showing disease response according to DL will be prepared for lymphoma patients according 
to tumor dimensions, and for AL patients in terms of percent peripheral blood blasts decrease, percent BM 
blasts decrease and percent neutrophil increase (with different colors per dose level). 
A listing of all responders will be provided including response, disease indication, duration of response. 
Duration of response is defined as the time from the date of response to the date of documented progression 
or death. If progression or death is not observed during the study, data will be censored at the last date of 
documented response.  
Event 
Censoring decision 
Event or censored date 
PD during the study 
Not censored 
Date of last assessment 
Lost to follow-up 
Censored 
Date of last assessment 
Study ended without PD or death  
Censored  
Date of last assessment  
Death during the study 
Not censored 
Date of death 
Patients with any possible evidence of antitumor activity will be reported and described with narratives: 
standard responses (all patients), minor tumor shrinkages (lymphomas), neutrophil increase, platelets 
increase, transfusion requirement decrease, no further requirement of hydroxyurea, partial blasts clearance 
(AL patients),  unexpected long stabilization (all patients). 
 
12. SAFETY EVALUATION 
12.1 SAFETY VARIABLES 
Safety analyses will be performed in the Safety Population other than for DLT which will be presented in the 
evaluable for DLT population. All safety data from the study treatment phase will be presented.  
Safety data are obtained from clinical and physical examinations, as well as vital signs evaluation.  
TEAEs / signs and symptoms of disease observed by the investigator (preferably by the same physician for 
the same patient) or reported by patients to the study nurses will be recorded and graded according to NCI-
CTCAE version 4.03. 
Clinically significant laboratory results are those which have clinical consequences. The seriousness, the 
action taken regarding study medication and patient participation in the study, relation to study medication 
and the most likely cause, should then be recorded. 
 
12.2 TREATMENT EXPOSURE 
OTX015/MK-8628 treatment will be described by DL and overall. 
The intended dose (mg, mg/kg, mg/m²), study duration (days), treatment duration (days), number cycles 
initiated, cumulative dose (mg), absolute dose intensity (mg/week), the relative dose intensity (%).  
In addition, treatment modifications will be described including, the number (%) of patients having at least 
one dose reduction (compared to the initial DL), intra-cycle interruption (dose 0 between two non 0 doses), 
 
 
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delay (definition), or dose increase (compared to the initial DL). The number of modifications per patient 
and per modification type will be reported and listings will be provided. 
 
Intended dose (mg, mg/m2, mg/kg) = nb of planned courses * planned dose by course 
 
Study duration =[(last cycle dose date - first cycle dose date)/7 + 1] 
 
N days treatment intake (observed) =  
 
Actual cumulative dose (mg) = sum of all doses received from first cycle 1 day 1 to actual last day of 
treatment during the last cycle  
 
Absolute dose intensity (mg/week) = Actual cumulative dose / Actual duration 
 
Relative dose intensity (%)=[Actual dose intensity / Planned dose intensity]*100 
 
Cumulative dose during the cycle 1 (mg/m2)= sum of all doses received during cycle 1 with 
 
Planned period of administration = 21 days 
12.3 PRIMARY CRITERION: DOSE LIMITING TOXICITY 
DLTs are defined as any treatment-emergent adverse events (TEAEs) occurring during the first cycle (i.e., 
the first 21 days following study treatment initiation; note that hypocellular bone marrow and no marrow 
blasts in AL patients had to be confirmed at day 43), leading to treatment interruption or dose adjustment, or 
any unforeseen drug-related AE leading to study treatment interruption or discontinuation, unless a 
relationship to study medication can be definitively ruled out. 
The number of patients evaluable for DLT/with DLT in cycle 1 will be tabulated per dose level and overall 
for safety population. 
Type of DLT will be tabulated for patients evaluable for DLT by DL and overall. 
Non-hematologic DLTs 
 
Any grade 3 or 4 non-hematologic event (regardless of duration), unless it was not optimally treated 
with supportive care (e.g. grade 3 vomiting not adequately treated according to antiemetic standard 
of care). 
 
Grade 3-4 asymptomatic laboratory abnormal values lasting > 7 days. This definition applies for 
patients with lab values grade < 1 at baseline. For patients with grade 2 values (liver function test 
(LFTs) or creatinine clearance) at baseline, only grade 4 lasting > 7 days will be accounted as DLT, 
unless the SMC considers the event clinically significant. 
 
Any other AE (such as prolonged and intolerable grade 2 event) resulting in study drug 
discontinuation or interruption with or without dose reduction 
Hematologic DLTs 
Acute leukemia 
 
Pancytopenia with a hypocellular bone marrow and no marrow blasts lasting for ≥ 6 weeks after the 
start of a cycle. DLT will be suspected in case of pancytopenia with a hypocellular bone marrow and 
no marrow blast on bone marrow aspiration on day 22, but confirmed on bone marrow aspiration on 
day 43. Decision of adding or not patients in the cohort will be based on day 22 findings.   
Other hematologic malignancies 
 
Any grade 3 neutropenia, with fever or infection 
 
Any grade 3 thrombocytopenia with bleeding 
 
Any grade 4 neutropenia or thrombocytopenia, regardless of symptoms and lasting > 3 days. 
12.4 ADVERSE EVENTS 
Adverse events occurring or worsening after the treatment start date and before the last study treatment 
administration date +30 days were considered treatment-emergent adverse events (TEAEs).  
Summary AEs (number and % of patients) will be tabulated by DL and overall for patients with: 
 
 
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 
at least one treatment-emergent grade 1-5 adverse event (TEAE) 
 
at least one related treatment-emergent grade 1-5 adverse event (TEAE) 
 
at least one treatment-emergent grade 3-5 adverse event (TEAE) 
 
at least one related treatment-emergent grade 3-5 adverse event (TEAE) 
 
at least one serious TEAE 
 
at least one serious TEAE related to the study treatment 
 
a TEAE leading to treatment discontinuation 
 
a related TEAE leading to treatment discontinuation 
 
a TEAE leading to death 
Tables of individual TEAEs (number and % of patients) grouped by primary System Organ Class (SOC) and 
Preferred Term (PT; for MedDRA) will be presented by DL and overall. Patients will be counted only once 
per primary SOC and PT.  
These tables will be presented for all cycles as well as for cycle 1 only. 
12.4.1 Listing of Adverse Events by Patient 
AEs will be individually described per subject number, presenting: first/last application, treatment phase 
(Initial or Follow-up), emergence, description, SOC, preferred term, start and end date, duration, the toxicity 
grade, the relationship to study drug, the action taken and the seriousness. 
12.5 DEATHS, OTHER SERIOUS ADVERSE EVENTS, AND OTHER SIGNIFICANT ADVERSE EVENTS 
All deaths and all SAEs experienced during the treatment period related to the study drug will be separately 
listed per subject number, presenting: first/last application, treatment phase (initial or follow-up), emergence, 
description, SOC, preferred term, start and end date, duration, the toxicity grade, the relationship to study 
drug, the action taken and the seriousness. 
12.6 CLINICAL LABORATORY EVALUATION 
All laboratory values recorded during the study (plus the calculated creatinine clearance) will be individually 
listed and flagged for values outside reference ranges.  
12.6.1 Laboratory values over time 
Each hematology and chemistry parameter will be described for each visit and by DL.  
12.6.2 Individual patient changes 
A listing of patients with worsening hematology or biochemistry parameters on study will be provided 
(baseline grade, worst grade, % decrease). 
For thrombocytopenia, description of nadir (duration) and recovery (time to recovery) will be provided. A 
listing of patients experiencing thrombocytopenia during the study will be provided. 
12.6.3 Individual clinically significant abnormalities 
For each hematology and chemistry parameter, number and percentage of patients with at least one clinically 
significant value (according to the investigator) during the study as well as number and percentage of 
patients with at least one NCI-CTCAE worst grade of 3 to 5 during the study will be presented by DL. 
12.7 VITAL SIGNS, PHYSICAL FINDINGS AND OTHER OBSERVATIONS RELATED TO SAFETY 
12.7.1 Vital Signs  
Raw values and changes from baseline of systolic/diastolic blood pressure (mmHg), Heart rate (beats/min) 
and respiratory rate (/min) will be described for each visit and for the last value during the study treatment 
phase by DL. 
 
 
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For weight (kg), systolic/diastolic blood pressure (mmHg) and heart rate (beats/min), number and percentage 
of patients with at least one predefined change (PC)/clinically significant change (CSC) during the study 
treatment phase will be presented by DL.  
Predefined changes and clinically significant changes are defined below: 
Parameter 
Predefined change (from 
baseline) 
Clinically significant change 
Weight 
Increase ≥ 5%   
Decrease ≥ 5%  
 
Systolic blood pressure 
Increase ≥ 20 mmHg 
Decrease ≥ 20 mmHg 
≥180 mmHg and PC Increase 
≤ 90 mmHg and PC Decrease 
Diastolic blood pressure 
Increase ≥ 15 mmHg 
Decrease ≥ 15 mmHg 
≥105 mmHg and PC Increase 
≤ 50 mmHg and PC Decrease 
Heart rate 
Increase ≥ 15 bpm 
Decrease ≥ 15 bpm 
≥120 bpm and PC Increase  
≤ 50 bpm and PC Decrease 
12.7.2 ECG and LVEF evaluations 
Absolute and relative differences between max post dosing Day 1 and pre-dosing will be presented by DL 
and overall. Absolute and relative difference between end of study value and pre-dosing will be presented by 
DL and overall. 
12.7.3 Physical examination 
Physical examination will be individually listed.  
 
13. PK ANALYSES 
The PK analyses will performed by the Laboratoire de Pharmacology 
 Institut Curie 
(Hôpital René Huguenin), 35 rue Dailly, 92210 Saint Cloud, France. 
A separate PK report will be provided.  
 
14. CHANGES FROM PROTOCOL 
The protocol allowed for analysis in a per protocol population (section 11.2). This analysis was not 
performed as it is not appropriate for a phase 1 study with small expansion cohorts. 
Overall survival analysis planned in the protocol (section 7.2.2.7) were not performed.  
The secondary objectives allowing for assessment of PK/safety, PD/safety and PK/PD relationships were not 
performed due to insufficient PD data, while PK analyses were not considered pertinent.    
 
15. INDIVIDUAL LISTINGS 
All relevant CRF data will be provided using individual data listings. 
All listings will include center number, cohort, patient number, dose level. 
 
 
 
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16. APPENDIX 
16.1 PROPOSED STATISTICAL OUTPUT TABLES 
 
Templates of the planned tables and listings for the Clinical Study Report are provided as presented for two 
dry runs performed on 18 December 2016 & 11 February 2017 and validated by the Sponsor/Sponsor 
Representative. 
Changes to the data presented or format may be made during the programing on the basis of the output 
results in agreement with the Sponsor Representative and the Statistician. 
Each table will be presented for each of the two patient cohorts - the AL population and Other Hematologic 
Malignancies population - independently (a single table is shown per analysis with AL header); exceptions 
are noted when distinct tables are required for the two cohorts (disease characteristics, hematology 
examinations, efficacy). A representative table for each population is shown.  For quantitative variables, % 
patients will only be reported in the total column, with N patients for individual dose levels.  
 
 
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Tables will be prepared according to the headers in Section 6.1 
 
A) 
PATIENTS 
i. 
PATIENT DISPOSITION  
Table i-1 Patients enrolled by center and dose level, AL patients 
Center Center name 
 
 
 
 
 
 
 
 
 
 
 
 
1 
 
 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total  
 
 
 
 
 
 
 
 
 
 
 
 
Data source: Statistical Output, Section  
 
Table i-2 Patients enrolled by center and dose level, OHM patients 
Center Center name 
 
 
 
 
 
 
 
 
 
 
 
1 
 
 
 
 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
 
 
 
 
…..  
 
 
 
 
 
 
 
 
 
 
 
Total  
 
 
 
 
 
 
 
 
 
 
 
Data source: Statistical Output, Section  
 
Listing i-1 Patient inclusion per site, AL / OHM enrolled patients 
Dose level / schedule 
(initial) 
Day 1, Cycle 1 
Center Name 
Cohort  
(AL/ OHM) 
Patient # 
 
 
 
 
 
 
 
 
 
 
Data source: Statistical Output, Section  
 
 
 
 
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Table i-3 Patient disposition, AL / OHM patients 
Patients 
 
 
 
 
 
 
 
 
 
 
 
 
Enrolled 
 
 
 
 
 
 
 
 
 
 
 
 
Treated 
 
 
 
 
 
 
 
 
 
 
 
 
Evaluable for DLT 
 
 
 
 
 
 
 
 
 
 
 
 
Evaluable for safety 
 
 
 
 
 
 
 
 
 
 
 
 
Data source: Statistical Output, Section  
 
Listing i-2 Patients not evaluable or NA for DLT or safety evaluation, AL / OHM enrolled patients 
Dose Level 
Center name 
Cohort 
Patient 
ID 
Treated 
Evaluable for DLT 
Evaluable for safety Reason for non evaluability 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
Data source: Statistical Output, Section  
 
Table i-4 Main reason for treatment discontinuation, AL / OHM enrolled patients 
Reason 
 
 
 
 
 
 
 
 
 
Disease progression 
 
 
 
 
 
 
 
 
 
Death, unrelated 
 
 
 
 
 
 
 
 
 
Death, related 
 
 
 
 
 
 
 
 
 
AE, related 
 
 
 
 
 
 
 
 
 
AE, non-related 
 
 
 
 
 
 
 
 
 
Non-compliance 
 
 
 
 
 
 
 
 
 
Withdrawal of consent 
 
 
 
 
 
 
 
 
 
Recurrence of toxicity* 
 
 
 
 
 
 
 
 
 
Treatment delay >2 weeks 
for toxicity 
 
 
 
 
 
 
 
 
 
Still on treatment 
 
 
 
 
 
 
 
 
 
Other** 
 
 
 
 
 
 
 
 
 
Data source: Statistical Output, Section  
 
 
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* Despite dose reduction; **Detail 
 
Listing i-3 Discontinuation for progressive disease with date of death, AL / OHM enrolled patients 
Center name 
Patient 
ID 
Dose Level 
Disease 
Progression 
Disease 
progression 
date 
Patient 
status 
Date of 
Death 
 
 
 
  
  
 
 
 
  
  
 
Listing i-4 AEs leading to discontinuation, AL / OHM enrolled patients 
Center name 
Patient 
ID 
Dose Level 
Adverse Event 
AE 
start 
date 
AE 
stop 
date 
Grade 
Relation 
to study 
drug SAE 
Action taken 
for patient 
Dose Adjustment 
Dose 
modification: 
specify 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
ii. 
PROTOCOL DEVIATIONS 
Inclusion/Exclusion criteria deviations 
Table ii-1 Protocol deviations at inclusion, AL / OHM enrolled patients 
Reason 
 
 
 
 
 
 
 
 
 
N patients with ≥1 major 
deviation 
 
 
 
 
 
 
 
 
 
Xxx  (specify criterion) 
 
 
 
 
 
 
 
 
 
Xxx   
 
 
 
 
 
 
 
 
 
N patients with ≥1 minor 
deviation 
 
 
 
 
 
 
 
 
 
xxx 
 
 
 
 
 
 
 
 
 
xxx 
 
 
 
 
 
 
 
 
 
Data source: Statistical Output, Section  
 
 
 
 
 
 
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iii. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Table iii-1 Patient characteristics at baseline, AL / OHM safety population 
Characteristic 
 
 
 
 
 
 
 
 
 
Gender, N  
 
 
 
 
 
 
 
 
 
Male 
 
 
 
 
 
 
 
 
 
Female 
 
 
 
 
 
 
 
 
 
Age (years) 
 
 
 
 
 
 
 
 
 
Median (range) 
 
 
 
 
 
 
 
 
 
< 60 years, N  
 
 
 
 
 
 
 
 
 
60 to < 70 years, N  
 
 
 
 
 
 
 
 
 
70 to < 80 years, N  
 
 
 
 
 
 
 
 
 
≥ 80 years, N 
 
 
 
 
 
 
 
 
 
BMI (kg/m²), median 
(range) 
 
 
 
 
 
 
 
 
 
BSA (m²), median (range) 
 
 
 
 
 
 
 
 
 
ECOG PS, N 
 
 
 
 
 
 
 
 
 
0 
 
 
 
 
 
 
 
 
 
1 
 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
 
Data source: Statistical Output, Section  
 
 
 
 
 
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Table iii-2 Overview of treated conditions, AL / OHM safety population 
 
 
 
 
 
 
 
 
 
 
AL, N  
 
 
 
 
 
 
 
 
 
AML 
 
 
 
 
 
 
 
 
 
ALL 
 
 
 
 
 
 
 
 
 
MDS  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
OHM, N  
 
 
 
 
 
 
 
 
 
Lymphoma 
 
 
 
 
 
 
 
 
 
Multiple myeloma 
 
 
 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
 
 
 
Data source: Statistical Output, Section  
*Detail: Provide listing with pt # and type  
 
 
 
 
 
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Table iii-3 Disease pathology, AL safety population 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow aspiration / 
Blasts (%) 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
Range 
 
 
 
 
 
 
 
 
 
Bone marrow blasts 
category 
 
 
 
 
 
 
 
 
 
<5% 
 
 
 
 
 
 
 
 
 
[5-20%] 
 
 
 
 
 
 
 
 
 
>20% 
 
 
 
 
 
 
 
 
 
Bone marrow aspiration / 
Cellularity 
 
 
 
 
 
 
 
 
 
Poor 
 
 
 
 
 
 
 
 
 
Intermediate 
 
 
 
 
 
 
 
 
 
Rich 
 
 
 
 
 
 
 
 
 
Missing data 
 
 
 
 
 
 
 
 
 
Hyperleukocytosis > 
15*10E9/L 
 
 
 
 
 
 
 
 
 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table iii-4 Disease characteristics (1), AML safety population 
 
 
 
 
 
 
 
 
 
 
AML / Type (recoded) 
 
 
 
 
 
 
 
 
 
De Novo 
 
 
 
 
 
 
 
 
 
Therapy-related 
 
 
 
 
 
 
 
 
 
Secondary to MDS 
 
 
 
 
 
 
 
 
 
Secondary to MPD 
 
 
 
 
 
 
 
 
 
AML / FAB Classification 
 
 
 
 
 
 
 
 
 
M0 
 
 
 
 
 
 
 
 
 
M1 
 
 
 
 
 
 
 
 
 
M2 
 
 
 
 
 
 
 
 
 
M5 
 
 
 
 
 
 
 
 
 
M6 
 
 
 
 
 
 
 
 
 
Missing data 
 
 
 
 
 
 
 
 
 
AML / Cytogenetic-
molecular genetic group 
 
 
 
 
 
 
 
 
 
Favorable 
 
 
 
 
 
 
 
 
 
Intermediate I 
 
 
 
 
 
 
 
 
 
Intermediate II 
 
 
 
 
 
 
 
 
 
Adverse 
 
 
 
 
 
 
 
 
 
Missing data 
 
 
 
 
 
 
 
 
 
Cytogenetics karyotype 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
Missing data 
 
 
 
 
 
 
 
 
 
Molecular genetics 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
Missing data 
 
 
 
 
 
 
 
 
 
 
 
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Listing iii-1 Cytogenetics: abnormal karyotype, AML patients 
Center name 
Cohort 
Patient 
ID 
Cytogentics abnormalities 
 
 
 
 
 
 
 
 
 
Listing iii-2 Molecular genetics: abnormal karyotype, AML patients 
Center name 
Cohort 
Patient 
ID 
Molecular genetics abnormalities 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table iii-5 Disease characteristics (2), AML safety population 
Characteristic 
 
 
 
 
 
 
 
 
 
Time since diagnosis (months)  
 
 
 
 
 
 
 
 
 
Median (range) 
 
 
 
 
 
 
 
 
 
Systemic therapy  
 
 
 
 
 
 
 
 
 
Median (range) 
 
 
 
 
 
 
 
 
 
N lines prior therapy (in total)*, N  
 
 
 
 
 
 
 
 
 
Median (range) 
 
 
 
 
 
 
 
 
 
1 
 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
 
≥4 
 
 
 
 
 
 
 
 
 
N lines prior therapy current AML, 
N  
 
 
 
 
 
 
 
 
 
Median (range) 
 
 
 
 
 
 
 
 
 
1 
 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
 
≥4 
 
 
 
 
 
 
 
 
 
Systemic therapy for AML, N  
 
 
 
 
 
 
 
 
 
Standard intensive therapy (3+7) 
 
 
 
 
 
 
 
 
 
Azacitidine 
 
 
 
 
 
 
 
 
 
aSCT 
 
 
 
 
 
 
 
 
 
Other** 
 
 
 
 
 
 
 
 
 
Data source: Statistical Output, Section  
aSCT: allogeneic stem cell transplantation 
* Incudes therapies for previous conditions 
 
Listing iii-3 Other systemic therapies, AML patients 
Center name 
Cohort 
Patient 
ID 
Molecular genetics abnormalities 
 
 
 
 
 
 
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Note that in light of the small patient numbers, a descriptive presentation of disease characteristics for the non-AML patients in the AL cohort will be provided 
from data listings. 
Table iii-6 Disease characteristics (1), lymphoma safety population 
 
 
 
 
 
 
 
 
 
 
 
Lymphoma / Classification 
 
 
 
 
 
 
 
 
 
 
B-cell neoplasms 
 
 
 
 
 
 
 
 
 
 
T-cell neoplasms 
 
 
 
 
 
 
 
 
 
 
Hodgkin lymphoma 
 
 
 
 
 
 
 
 
 
 
B-cell neoplasms 
 
 
 
 
 
 
 
 
 
 
Diffuse large B-cell 
lymphoma (DLBCL) 
 
 
 
 
 
 
 
 
 
 
Follicular lymphoma 
 
 
 
 
 
 
 
 
 
 
Mantle cell lymphoma 
 
 
 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
 
 
B-cell neoplasms/DLBCL 
 
 
 
 
 
 
 
 
 
 
ABC 
 
 
 
 
 
 
 
 
 
 
CGB 
 
 
 
 
 
 
 
 
 
 
Missing data 
 
 
 
 
 
 
 
 
 
 
Hodgkin Lymphoma 
 
 
 
 
 
 
 
 
 
 
Classical Hodgkin 
lymphoma 
 
 
 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
 
 
Nodal status 
 
 
 
 
 
 
 
 
 
 
Nodal only 
 
 
 
 
 
 
 
 
 
 
Extra nodal only 
 
 
 
 
 
 
 
 
 
 
Extranodal and nodal 
 
 
 
 
 
 
 
 
 
 
Missing data 
 
 
 
 
 
 
 
 
 
 
BM involved, N 
 
 
 
 
 
 
 
 
 
 
Data source: Statistical Output, Section  
ABC, Activated B-Cell-Like; BM, bone marrow; GCB, Germinal Center B-Cell-Like 
 
 
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* Detail: Provide listing with pt # and type 
 
Table iii-7 Disease characteristics (2), lymphoma safety population 
 
 
 
 
 
 
 
 
 
 
 
Time since diagnosis (months)  
 
 
 
 
 
 
 
 
 
 
Median (range) 
 
 
 
 
 
 
 
 
 
 
Systemic therapy, N 
 
 
 
 
 
 
 
 
 
 
N lines prior therapy (in total)* 
 
 
 
 
 
 
 
 
 
 
Median (range) 
 
 
 
 
 
 
 
 
 
 
1 
 
 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
 
 
≥4 
 
 
 
 
 
 
 
 
 
 
N lines prior therapy for 
lymphoma, N  
 
 
 
 
 
 
 
 
 
 
Median (range) 
 
 
 
 
 
 
 
 
 
 
1 
 
 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
 
 
≥4 
 
 
 
 
 
 
 
 
 
 
Prior therapy for lymphoma, N 
 
 
 
 
 
 
 
 
 
 
Systemic 
 
 
 
 
 
 
 
 
 
 
CHOP/R-CHOP 
 
 
 
 
 
 
 
 
 
 
ASCT 
 
 
 
 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
 
 
 
 
Surgery 
 
 
 
 
 
 
 
 
 
 
Radiotherapy 
 
 
 
 
 
 
 
 
 
 
Data source: Statistical Output, Section  
ASCT: autologous stem cell transplantation;  
* Incudes therapies for previous conditions 
 
 
 
 
 
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Table iii-8 Disease characteristics (1), MM safety population 
 
 
 
 
 
 
 
 
 
 
 
Multiple myeloma, N  
 
 
 
 
 
 
 
 
 
 
M-component 
 
 
 
 
 
 
 
 
 
 
IgG 
 
 
 
 
 
 
 
 
 
 
IgA 
 
 
 
 
 
 
 
 
 
 
Bence-Jones 
 
 
 
 
 
 
 
 
 
 
Kappa light chain 
 
 
 
 
 
 
 
 
 
 
Lambda light chain 
 
 
 
 
 
 
 
 
 
 
Other* 
 
 
 
 
 
 
 
 
 
 
Bone lesions, N 
 
 
 
 
 
 
 
 
 
 
Extramedullary disease, N  
 
 
 
 
 
 
 
 
 
 
Bone marrow plasma cells, N  
 
 
 
 
 
 
 
 
 
 
Cellularity, N  
 
 
 
 
 
 
 
 
 
 
Poor  
 
 
 
 
 
 
 
 
 
 
Intermediate 
 
 
 
 
 
 
 
 
 
 
Rich 
 
 
 
 
 
 
 
 
 
 
Data source: Statistical Output, Section  
* Detail: Provide listings with pt # and type 
 
 
 
 
 
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Table iii-9 Disease characteristics (2), MM safety population 
 
 
 
 
 
 
 
 
 
 
 
Time since diagnosis (months)  
 
 
 
 
 
 
 
 
 
 
Median (range) 
 
 
 
 
 
 
 
 
 
 
N lines prior therapy, N 
 
 
 
 
 
 
 
 
 
 
Median (range) 
 
 
 
 
 
 
 
 
 
 
1 
 
 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
 
 
≥4 
 
 
 
 
 
 
 
 
 
 
Systemic therapy, N 
 
 
 
 
 
 
 
 
 
 
Systemic 
 
 
 
 
 
 
 
 
 
 
Alkylating 
 
 
 
 
 
 
 
 
 
 
Steroid 
 
 
 
 
 
 
 
 
 
 
Proteosome inhibitor 
 
 
 
 
 
 
 
 
 
 
IMiD 
 
 
 
 
 
 
 
 
 
 
ASCT 
 
 
 
 
 
 
 
 
 
 
Surgery 
 
 
 
 
 
 
 
 
 
 
Radiotherapy 
 
 
 
 
 
 
 
 
 
 
Data source: Statistical Output, Section  
ASCT: autologous stem cell transplantation ; IMiD, immunomodulatory drug 
 
 
 
 
 
 
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Table iii-10 Signs and symptoms at baseline according to SOC and PT per patient, AL / OHM safety population 
 
 
 
 
 
 
 
 
 
 
Overall 
 
 
 
 
 
 
 
 
 
≥1 sign or symptom, N   
 
 
 
 
 
 
 
 
 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data source: Statistical Output, Section  
 
 
Table iii-11 Medical history according to SOC and PT per patient, AL / OHM safety population 
 
 
 
 
 
 
 
 
 
 
Overall 
 
 
 
 
 
 
 
 
 
≥1 sign or symptom, N   
 
 
 
 
 
 
 
 
 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data source: Statistical Output, Section  
 
 
 
 
 
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Table iii-12 Abnormal biologic values at baseline (grade ≥1 NCI-CTCAE), AL / OHM safety population 
 
 
 
 
 
 
 
 
 
 
Biochemistry, N 
 
 
 
 
 
 
 
 
 
ASAT 
 
 
 
 
 
 
 
 
 
ALAT 
 
 
 
 
 
 
 
 
 
Alkaline phosphatase 
 
 
 
 
 
 
 
 
 
LDH 
 
 
 
 
 
 
 
 
 
CPK 
 
 
 
 
 
 
 
 
 
Total bilirubin 
 
 
 
 
 
 
 
 
 
Albumin 
 
 
 
 
 
 
 
 
 
Creatinine 
 
 
 
 
 
 
 
 
 
CRP 
 
 
 
 
 
 
 
 
 
Calcium 
 
 
 
 
 
 
 
 
 
Mg 
 
 
 
 
 
 
 
 
 
Glucose 
 
 
 
 
 
 
 
 
 
INR 
 
 
 
 
 
 
 
 
 
Factor VII 
 
 
 
 
 
 
 
 
 
β2-microglobulin* 
 
 
 
 
 
 
 
 
 
Apo A1 
 
 
 
 
 
 
 
 
 
Data source: Statistical Output, Section  
* Patients with myeloma  
 
 
 
 
 
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Table iii-13 Abnormal hematologic values at baseline (grade ≥1 NCI-CTCAE), AL / OHM safety population 
 
 
 
 
 
 
 
 
 
 
Hematology, N  
 
 
 
 
 
 
 
 
 
Hemoglobin 
 
 
 
 
 
 
 
 
 
Lymphocytes 
 
 
 
 
 
 
 
 
 
Platelets 
 
 
 
 
 
 
 
 
 
Neutrophils 
 
 
 
 
 
 
 
 
 
Leucocytes 
 
 
 
 
 
 
 
 
 
Data source: Statistical Output, Section  
 
Table iii-14 Prior medications at baseline, by  ATC classification, AL / OHM safety population 
 
 
 
 
 
 
 
 
 
 
xx,  N  
 
 
 
 
 
 
 
 
 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data source: Statistical Output, Section  
 
 
 
Table iii-15 Concomitant medications at baseline, ATC classification, AL / OHM safety population 
 
 
 
 
 
 
 
 
 
 
N patients  
 
 
 
 
 
 
 
 
 
xx,  N 
 
 
 
 
 
 
 
 
 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data source: Statistical Output, Section  
 
 
 
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B) 
SAFETY EVALUATION 
i. 
EVALUATION OF DLT AND DETERMINATION OF RD 
 
Table i-1 Determination of RD, AL / OHM safety population 
 
 
 
 
 
 
 
 
 
 
N patients evaluable for DLT 
 
 
 
 
 
 
 
 
 
N patients with DLT in cycle 1 
 
 
 
 
 
 
 
 
 
N DLTs  
 
 
 
 
 
 
 
 
 
Description of DLT 
 
 
 
 
 
 
 
 
 
xxx 
 
 
 
 
 
 
 
 
 
Data source: Statistical Output, Section  
* including grade 
 
Listing i-1 Patients with DLT during cycle 1, AL / OHM safety population 
Cohort  
(AL/ OHM) 
Dose level /  
schedule 
Patient # 
DLT 
(PT) 
Date of  
Day 1 Cycle 1 
Date of  
AE onset 
Date of  
AE stop 
Grade 
Relation 
SAE 
Action/ 
Outcome 
Comment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data source: Statistical Output, Section  
 
 
 
 
 
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ii. 
EXPOSURE 
Table ii-1 Extent of exposure, AL / OHM safety population 
 
 
 
 
 
 
 
 
 
 
Intended dose* 
 
 
 
 
 
 
 
 
 
Median (range) (mg/kg) 
 
 
 
 
 
 
 
 
 
Median (range) (mg/m²) 
 
 
 
 
 
 
 
 
 
Study duration (treatment 
start to last dose last cycle 
in days) 
 
 
 
 
 
 
 
 
 
Median/patient (range) 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
N days treatment intake 
(observed) 
 
 
 
 
 
 
 
 
 
Median/patient (range) 
 
 
 
 
 
 
 
 
 
Total 
 
 
 
 
 
 
 
 
 
N cycles started  
 
 
 
 
 
 
 
 
 
Median/patient (range) 
 
 
 
 
 
 
 
 
 
1 
 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
 
3…. 
 
 
 
 
 
 
 
 
 
Cumulative dose 
(observed) 
 
 
 
 
 
 
 
 
 
Median (range) (mg/kg) 
 
 
 
 
 
 
 
 
 
Median (range) (mg/m²) 
 
 
 
 
 
 
 
 
 
Absolute dose intensity 
(mg/week)  
 
 
 
 
 
 
 
 
 
Median (range) 
 
 
 
 
 
 
 
 
 
Relative dose intensity (%) 
 
 
 
 
 
 
 
 
 
Median (range) 
 
 
 
 
 
 
 
 
 
Data source: Statistical Output, Section  
* From Day 1 until last treatment intake + 30 days ;  Intended dose  = nb of planned courses * planned dose by course 
 
 
 
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Table ii-2 Dose reductions, delays and interruptions, AL / OHM safety population 
 
 
 
 
 
 
 
 
 
 
N patients with ≥1 dose 
reduction 
 
 
 
 
 
 
 
 
 
N reductions/patient 
 
 
 
 
 
 
 
 
 
1 
 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
 
N patients with ≥ 1 dose 
interruption 
 
 
 
 
 
 
 
 
 
N interruptions/patient 
 
 
 
 
 
 
 
 
 
1 
 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
 
N patients with ≥1 dose delay 
 
 
 
 
 
 
 
 
 
N delay/patient 
 
 
 
 
 
 
 
 
 
1 
 
 
 
 
 
 
 
 
 
N patients with ≥1 dose increase 
 
 
 
 
 
 
 
 
 
Data source: Statistical Output, Section  
 
 
Listing ii-1 Reason for reduction/intracycle interruption/delay, AL / OHM enrolled patients 
Cohort  
(AL/ OHM) 
Patient # 
Dose level / schedule 
(initial) 
Reason for reduction 
Other 
 
 
 
 
 
 
 
 
 
 
 
Listing ii-2 Patients with dose reduction/delay for AE, AL / OHM enrolled patients 
Patient 
ID 
Dose Level 
Visit 
Adverse Event 
AE start 
date 
AE stop date Grade 
Relation 
to study 
drug 
SAE 
Action taken 
for patient 
Dose 
Adjustment 
Dose modification: 
specify 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
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iii. 
ADVERSE EVENTS 
 
Table iii-1 Summary of all AEs, AL / OHM safety population 
 
 
 
 
 
 
 
 
 
 
N patients with ≥1 : 
 
 
 
 
 
 
 
 
 
Grade 1-4 AE 
 
 
 
 
 
 
 
 
 
Grade 3-4 AE 
 
 
 
 
 
 
 
 
 
Related AE 
 
 
 
 
 
 
 
 
 
Related grade 3-4 AE 
 
 
 
 
 
 
 
 
 
DLT in cycle 1 
 
 
 
 
 
 
 
 
 
SAE 
 
 
 
 
 
 
 
 
 
Related SAE 
 
 
 
 
 
 
 
 
 
AE leading to treatment 
discontinuation 
 
 
 
 
 
 
 
 
 
Related AE leading to 
treatment discontinuation 
 
 
 
 
 
 
 
 
 
Data source: Statistical Output, Section  
 
 
 
 
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AE TABLES FOR ALL CYCLES AND CYCLE 1 ONLY 
 
Table iii-2 NCI-CTCAE grade 1-4 AEs regardless of relationship to treatment, worst grade per patient, AL / OHM/ ALL PATIENTS safety population 
Adverse event 
 
 
 
 
 
 
 
 
 
N patients with ≥1 AE / N AE 
 
 
 
 
 
 
 
 
 
SOC 
 
 
 
 
 
 
 
 
 
PT 
 
 
 
 
 
 
 
 
 
PT 
 
 
 
 
 
 
 
 
 
Data source: Statistical Output, Section  
 
Table iii-3 NCI-CTCAE grade 1-4 related AEs, worst grade per patient, AL / OHM/ ALL PATIENTS safety population 
Adverse event 
 
 
 
 
 
 
 
 
 
N patients with ≥1 AE / N AE 
 
 
 
 
 
 
 
 
 
SOC 
 
 
 
 
 
 
 
 
 
PT 
 
 
 
 
 
 
 
 
 
PT 
 
 
 
 
 
 
 
 
 
Data source: Statistical Output, Section  
 
 
 
 
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Table iii-4 NCI-CTCAE grade 3-4 AEs regardless of relationship to treatment, worst grade per patient, AL / OHM/ ALL PATIENTS safety population 
Adverse event 
 
 
 
 
 
 
 
 
 
N patients with ≥1 AE / N AE 
 
 
 
 
 
 
 
 
 
SOC 
 
 
 
 
 
 
 
 
 
PT 
 
 
 
 
 
 
 
 
 
PT 
 
 
 
 
 
 
 
 
 
Data source: Statistical Output, Section  
 
Table iii-5 NCI-CTCAE grade 3-4 related AEs, worst grade per patient,  AL / OHM/ ALL PATIENTS safety population 
Adverse event 
 
 
 
 
 
 
 
 
 
N patients with ≥1 AE / N AE 
 
 
 
 
 
 
 
 
 
SOC 
 
 
 
 
 
 
 
 
 
PT 
 
 
 
 
 
 
 
 
 
PT 
 
 
 
 
 
 
 
 
 
Data source: Statistical Output, Section  
 
 
 
 
 
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iv. 
SAES AND OTHER SIGNIFICANT AES 
 
Table iv-1 Summary of SAEs, related / non-related, AL / OHM safety population 
Adverse event 
 
 
 
 
 
 
 
 
 
N patients with ≥1 SAE / N AE 
 
 
 
 
 
 
 
 
 
SOC 
 
 
 
 
 
 
 
 
 
PT 
 
 
 
 
 
 
 
 
 
Type SAE 
 
 
 
 
 
 
 
 
 
Death (related) 
 
 
 
 
 
 
 
 
 
Death (non-related) 
 
 
 
 
 
 
 
 
 
Hospitalization 
 
 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
 
Data source: Statistical Output, Section  
 
Table iv-2 Summary of AEs resulting in discontinuation, related / non-related, AL / OHM safety population 
Adverse event 
 
 
 
 
 
 
 
 
 
N patients with ≥1 AE for 
discontinuation / N AE 
 
 
 
 
 
 
 
 
 
SOC 
 
 
 
 
 
 
 
 
 
PT 
 
 
 
 
 
 
 
 
 
 
Listing iv-1 SAEs/ AEs resulting in treatment discontinuation, AL / OHM safety population 
Center name 
Patient 
ID 
Dose 
Level 
Visit Adverse Event 
AE 
start 
date 
AE 
stop 
date 
Grade 
Relation 
to study 
drug SAE 
Action taken 
for patient 
Dose 
Adjustment 
Dose 
modification: 
specify 
 
 
 
  
 
 
 
 
 
 
  
Data source: Statistical Output, Section  
 
 
 
 
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v. 
ECG AND LVEF EVALUATIONS 
Table v-1 QT variations on study, AL / OHM safety population 
QTc difference (msec) 
 
 
 
 
 
 
 
 
 
QTc (msec)  
 
 
 
 
 
 
 
 
 
Median (range) 
 
 
 
 
 
 
 
 
 
<=450 msec 
 
 
 
 
 
 
 
 
 
>450 to <=480 msec 
 
 
 
 
 
 
 
 
 
>480 to <=500 msec 
 
 
 
 
 
 
 
 
 
QTc (msec), absolute 
variation 
 
 
 
 
 
 
 
 
 
Median (range) 
 
 
 
 
 
 
 
 
 
<=30 msec 
 
 
 
 
 
 
 
 
 
>30 to <=60 msec 
 
 
 
 
 
 
 
 
 
QTc (msec), relative variation 
 
 
 
 
 
 
 
 
 
Median (range) 
 
 
 
 
 
 
 
 
 
QTc (msec) maximal post-
dose value 
 
 
 
 
 
 
 
 
 
Median (range) 
 
 
 
 
 
 
 
 
 
<=450 msec 
 
 
 
 
 
 
 
 
 
>450 to <=480 msec 
 
 
 
 
 
 
 
 
 
>480 to <=500 msec 
 
 
 
 
 
 
 
 
 
QTc (msec), maximal absolute 
variation 
 
 
 
 
 
 
 
 
 
Median (range) 
 
 
 
 
 
 
 
 
 
<=30 msec 
 
 
 
 
 
 
 
 
 
30< to <=60 msec 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data source: Statistical Output, Section  
 
 
 
 
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Table v-2 QT variations on study, AL / OHM safety population 
QTc difference (msec) 
 
 
 
 
 
 
 
 
 
LVEF Baseline (%) 
 
 
 
 
 
 
 
 
 
Median (range) 
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
Notsignificant 
abnormalities 
 
 
 
 
 
 
 
 
 
Clinically significant 
abnormalities 
 
 
 
 
 
 
 
 
 
LVEF EOS (%) 
 
 
 
 
 
 
 
 
 
 Median (range)  
 
 
 
 
 
 
 
 
 
Normal 
 
 
 
 
 
 
 
 
 
No significant 
abnormalities 
 
 
 
 
 
 
 
 
 
LVEF absolute change (%) 
 
 
 
 
 
 
 
 
 
Median (range) 
 
 
 
 
 
 
 
 
 
LVEF relative change (%) 
 
 
 
 
 
 
 
 
 
Median (range) 
 
 
 
 
 
 
 
 
 
Data source: Statistical Output, Section 
 
 
 
 
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Listing v-1 Patients QTc prolongation on study, AL / OHM safety population 
Cohort  
(AL/ OHM) 
Dose level / schedule 
Patient # 
Visit 
Date 
Time 
CS 
NCS 
QTc (msec) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data source: Statistical Output, Section  
 
 
Listing v-2 Patients with LVEF decrease on study, AL / OHM safety population 
Cohort  
(AL/ OHM) 
Dose level / schedule 
Patient # 
Visit 
Date 
LVEF Value (%) 
Normal/CS/NCS 
 
 
 
Baseline 
 
 
 
 
 
 
Visit…. 
 
 
 
Data source: Statistical Output, Section  
 
 
 
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vi. 
CLINICAL LABORATORY EVALUATIONS 
Table vi-1 Summary of hematologic abnormalities (NCI-CTCAE), worst grade per patient, AL / OHM safety population 
 
 
 
 
 
 
 
 
 
 
Hemoglobin 
 
 
 
 
 
 
 
 
 
Grade 1-4 
 
 
 
 
 
 
 
 
 
Grade 3-4 
 
 
 
 
 
 
 
 
 
Platelets 
 
 
 
 
 
 
 
 
 
Grade 1-4 
 
 
 
 
 
 
 
 
 
Grade 3-4 
 
 
 
 
 
 
 
 
 
Neutrophils 
 
 
 
 
 
 
 
 
 
Grade 1-4 
 
 
 
 
 
 
 
 
 
Grade 3-4 
 
 
 
 
 
 
 
 
 
Lymphocytes 
 
 
 
 
 
 
 
 
 
Grade 1-4 
 
 
 
 
 
 
 
 
 
Grade 3-4 
 
 
 
 
 
 
 
 
 
Leukocytes 
 
 
 
 
 
 
 
 
 
Grade 1-4 
 
 
 
 
 
 
 
 
 
Grade 3-4 
 
 
 
 
 
 
 
 
 
Data source: Statistical Output, Section  
 
 
 
 
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Table vi-2 Hematologic abnormalities (NCI-CTCAE) worst grade per patient, AL / OHM safety population 
 
 
 
 
 
 
 
 
 
 
Hemoglobin 
 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
 
Grade 2 
 
 
 
 
 
 
 
 
 
Grade 3 
 
 
 
 
 
 
 
 
 
Grade 4 
 
 
 
 
 
 
 
 
 
Platelets etc… 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Listing vi-1 Patients with worsening hematology parameters, OHM safety population 
Parameter 
Dose level 
/schedule 
Patient # 
Baseline grade 
Worst   grade 
Baseline absolute 
value 
% decrease 
Hemoglobin 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neutrophils 
 
 
 
 
 
 
 
 
 
 
 
 
 
Platelets 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lymphocytes 
 
 
 
 
 
 
 
 
 
 
 
 
 
Leukocytes 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data source: Statistical Output, Section  
 
Table vi-3 Nadir and recovery for patients with grade 3 or 4 thrombocytopenia, OHM safety population 
 
 
 
 
 
 
 
 
 
 
Thrombocytopenia grade 3-4 
 
 
 
 
 
 
 
 
 
Time to nadir, median (range) 
 
 
 
 
 
 
 
 
 
Time to first G3 or 4, median 
(range) 
 
 
 
 
 
 
 
 
 
Time to first G3, median (range) 
 
 
 
 
 
 
 
 
 
Time to first G4, median (range) 
 
 
 
 
 
 
 
 
 
Duration of G3 or G4 
 
 
 
 
 
 
 
 
 
Data source: Statistical Output, Section  
 
Listing vi-2 Patients with grade 3-4 thrombocytopenia, AL / OHM safety population 
Dose Level 
Pt ID 
Start date 
Stop date 
Grade 
Relation to 
study drug SAE 
Action taken for 
patient 
Dose adjustment 
 
 
 
 
 
 
 
 
 
 
 
 
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Biochemistry 
 
Table vi-4 Grade 1-4 biochemistry toxicity (NCI-CTCAE) worst grade per patient, AL / OHM safety population 
NCI grade 
 
 
 
 
 
 
 
 
 
ASAT 
 
 
 
 
 
 
 
 
 
Grade 1-4 
 
 
 
 
 
 
 
 
 
Grade 3-4 
 
 
 
 
 
 
 
 
 
ALAT 
 
 
 
 
 
 
 
 
 
Alkaline phosphatase 
 
 
 
 
 
 
 
 
 
LDH 
 
 
 
 
 
 
 
 
 
CPK 
 
 
 
 
 
 
 
 
 
Total bilirubin 
 
 
 
 
 
 
 
 
 
Albumin 
 
 
 
 
 
 
 
 
 
Creatinine 
 
 
 
 
 
 
 
 
 
CRP 
 
 
 
 
 
 
 
 
 
Calcium 
 
 
 
 
 
 
 
 
 
Mg 
 
 
 
 
 
 
 
 
 
Glucose 
 
 
 
 
 
 
 
 
 
INR 
 
 
 
 
 
 
 
 
 
Factor VII 
 
 
 
 
 
 
 
 
 
β2-microglobulin* 
 
 
 
 
 
 
 
 
 
Apo A1 
 
 
 
 
 
 
 
 
 
Data source: Statistical Output, Section  
 
 
 
 
 
 
 
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Table vi-5 Hematologic abnormalities (NCI-CTCAE) per patient, worst grade per patient, cycle 1 only AL / OHM safety population 
 
 
 
 
 
 
 
 
 
 
ASAT 
 
 
 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
 
 
 
Grade 2 
 
 
 
 
 
 
 
 
 
Grade 3 
 
 
 
 
 
 
 
 
 
Grade 4 
 
 
 
 
 
 
 
 
 
ALAT etc… 
 
 
 
 
 
 
 
 
 
 
Listing vi-3 Patients with worsening biochemistry parameters, AL / OHM safety population 
Parameter 
Dose level 
/schedule 
Patient # 
Baseline grade 
Worst   grade 
Absolute value at 
baseline 
 Absolute value at 
max change 
% decrease 
ASAT 
 
 
 
 
 
 
 
ALAT 
 
 
 
 
 
 
 
Alkaline phosphatase 
 
 
 
 
 
 
 
LDH 
 
 
 
 
 
 
 
CPK 
 
 
 
 
 
 
 
Total bilirubin 
 
 
 
 
 
 
 
Albumin 
 
 
 
 
 
 
 
Creatinine 
 
 
 
 
 
 
 
CRP 
 
 
 
 
 
 
 
Calcium 
 
 
 
 
 
 
 
Mg 
 
 
 
 
 
 
 
Glucose 
 
 
 
 
 
 
 
INR 
 
 
 
 
 
 
 
Factor VII 
 
 
 
 
 
 
 
β2-microglobulin* 
 
 
 
 
 
 
 
Apo A1 
 
 
 
 
 
 
 
Data source: Statistical Output, Section  
 
 
 
 
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Table vi-6 Change in hemato/bioch values on study, all patients combined,  AL / OHM safety population 
 
Not done 
 
Grade 0 
 
Grade 1 
 
Grade 2 
 
Total 
 
Worst grade post baseline 
- lowest value 
 
 
 
 
 
Grade 0 
 
 
 
 
 
Grade 1 
 
 
 
 
 
Grade 2 
 
 
 
 
 
Grade 3 
 
 
 
 
 
Grade 4 
 
 
 
 
 
 
 
 
 
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C) 
PHARMACOKINETICS EVALUATION 
 
REPORTED SEPARATELY AND WITH EXTENSION COHORT CLINICAL STUDY REPORT 
 
 
D) 
PHARMACODYNAMICS EVALUATIONS 
 
REPORTED SEPARATELY AND WITH EXTENSION COHORT CLINICAL STUDY REPORT 
 
 
E) 
EFFICACY EVALUATIONS 
Table vi-1 Tumor response, AL efficacy population  
Best overall response 
 
 
 
 
 
 
 
 
 
CR 
 
 
 
 
 
 
 
 
 
CRi  
 
 
 
 
 
 
 
 
 
MLFS 
 
 
 
 
 
 
 
 
 
PR 
 
 
 
 
 
 
 
 
 
CRc 
 
 
 
 
 
 
 
 
 
CRm 
 
 
 
 
 
 
 
 
 
RD 
 
 
 
 
 
 
 
 
 
Death in aplasia 
 
 
 
 
 
 
 
 
 
Death other 
 
 
 
 
 
 
 
 
 
Overall response rate 
 
 
 
 
 
 
 
 
 
Data source: Statistical Output, Section  
CR, complete remission; Cri, CR with incomplete hematologic recovery; MLFS: Morphologic leukemia-free state; PR = Partial remission, CRc, cytogenetic CR, CRm, molecular 
CR, RD, resistant disease 
 
 
 
 
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Table vi-2 Tumor response, lymphoma efficacy population  
Best overall response 
 
 
 
 
 
 
 
 
 
 
CR 
 
 
 
 
 
 
 
 
 
 
PR 
 
 
 
 
 
 
 
 
 
 
SD 
 
 
 
 
 
 
 
 
 
 
PD 
 
 
 
 
 
 
 
 
 
 
Not evaluable 
 
 
 
 
 
 
 
 
 
 
Overall response rate 
 
 
 
 
 
 
 
 
 
 
Data source: Statistical Output, Section  
 
 
Table vi-3 Tumor response, myeloma efficacy population  
Best overall response 
 
 
 
 
 
 
 
 
 
 
sCR 
 
 
 
 
 
 
 
 
 
 
CR 
 
 
 
 
 
 
 
 
 
 
VGPR 
 
 
 
 
 
 
 
 
 
 
PR 
 
 
 
 
 
 
 
 
 
 
SD 
 
 
 
 
 
 
 
 
 
 
PD 
 
 
 
 
 
 
 
 
 
 
Not evaluable 
 
 
 
 
 
 
 
 
 
 
Overall response rate 
 
 
 
 
 
 
 
 
 
 
Data source: Statistical Output, Section  
 
 
 
 
 
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Listing vi-1 Response, CR/CRi/PR, AL / OHM efficacy populations 
Dose level 
/schedule 
Patient # 
Diagnosis 
Response 
Date of 
Response 
Date of 
Progression/Last 
News 
Duration of 
response 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data source: Statistical Output, Section  
 
 
Figure: Waterfall plot of response, absolute maximal BM blasts value (109/L) relative to baseline per patient (AL patients)* 
Figure: Waterfall plot of response, absolute minimal BM blasts value (109/L) relative to baseline per patient (AL patients)* 
Figure: Waterfall plot of response, relative maximal BM blasts value (%) relative to baseline per patient (AL patients)* 
Figure: Waterfall plot of response, relative minimal BM blasts value (%) relative to baseline per patient (AL patients)* 
Figure: Waterfall plot of response, absolute maximal neutrophil value (109/L) relative to baseline per patient (AL patients)* 
Figure: Waterfall plot of response, relative maximal BM blasts value (%) relative to baseline per patient (AL patients)* 
Figure: Waterfall plot of response, absolute change in tumor dimension (mm²) (lymphoma patients)* 
Figure: Waterfall plot of response, relative change in tumor dimension (%) (lymphoma patients)* 
 
* Different colors for different dose levels 
 
 
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