A Phase IB Trial With MK-8628, a Small Molecule Inhibitor of the Bromodomain and Extra-Terminal (BET) Proteins, in Subjects With Selected Hematologic Malignancies
Phase: PHASE1
Conditions: AML Including AML de Novo and AML Secondary to MDS, DLBCL
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT02698189 
Document Date: 
29-Sep-2017
A Phase IB Trial with MK-8628, a Small Molecule 
Inhibitor of the Bromodomain and Extra-Terminal 
(BET) Proteins, in Subjects with Selected Hematologic 
Malignancies

Product:  MK-8628 
1
Protocol/Amendment No.: 005-02 
MK-8628-005-02 Final Protocol
29-Sep-2017
Confidential
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK &
CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A.
This protocol amendment is only applicable to the United Kingdom.
SPONSOR:
Oncoethix GmbH, a wholly owned subsidiary of Merck Sharp & Dohme Corp. 
(hereafter referred to as the Sponsor or Merck)
Weystrasse 20
6000 Lucerne
Switzerland
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent).
TITLE:
A Phase IB Trial with MK-8628, a Small Molecule Inhibitor of the Bromodomain and Extra-
Terminal (BET) Proteins, in Subjects with Selected Hematologic Malignancies
IND NUMBER:  116,806
EudraCT NUMBER:  2015-005487-42
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TABLE OF CONTENTS
SUMMARY OF CHANGES................................................................................................ 11
1.0
TRIAL SUMMARY.................................................................................................. 14
2.0
TRIAL DESIGN........................................................................................................ 15
Trial Design ........................................................................................................... 15
2.1
Trial Diagram........................................................................................................ 16
2.2
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 16
Primary Objective(s) & Hypothesis(es) .............................................................. 16
3.1
Secondary Objective(s) & Hypothesis(es)........................................................... 16
3.2
Exploratory Objectives......................................................................................... 17
3.3
4.0
BACKGROUND & RATIONALE.......................................................................... 17
Background ........................................................................................................... 17
4.1
Pharmaceutical and Therapeutic Background .................................................... 17
4.1.1
Justification of Selecting Subjects with Hematologic Malignancies ........... 18
4.1.1.1
MK-8628 Metabolism – CYP Interactions.................................................. 18
4.1.1.2
MK-8628 – Ongoing Clinical Trials in Hematologic Malignancies ........... 19
4.1.1.3
Rationale................................................................................................................ 20
4.2
Rationale for the Trial and Selected Subject Population .................................... 20
4.2.1
Rationale for Dose Selection/Regimen/Modification ......................................... 21
4.2.2
Starting Dose for This Trial ......................................................................... 21
4.2.2.1
Maximum Dose/Exposure for This Trial..................................................... 23
4.2.2.2
Rationale for Dose Interval and Trial Design .............................................. 23
4.2.2.3
Rationale for Endpoints ...................................................................................... 24
4.2.3
Safety Endpoints .......................................................................................... 24
4.2.3.1
4.2.3.1.1
Primary Safety Endpoint:...................................................................... 24
Pharmacokinetic Endpoints ......................................................................... 24
4.2.3.2
Efficacy Endpoints....................................................................................... 25
4.2.3.3
4.2.3.3.1
Secondary Efficacy Endpoints.............................................................. 25
4.2.3.3.2
Exploratory Efficacy Endpoints............................................................ 26
Planned Exploratory Biomarker Research................................................... 26
4.2.3.4
Future Biomedical Research........................................................................ 26
4.2.3.5
 
 
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Benefit/Risk ........................................................................................................... 26
4.3
5.0
METHODOLOGY ................................................................................................... 27
Entry Criteria........................................................................................................ 27
5.1
Diagnosis/Condition for Entry into the Trial ...................................................... 27
5.1.1
Subject Inclusion Criteria.................................................................................... 27
5.1.2
Subject Exclusion Criteria .................................................................................. 29
5.1.3
Trial Treatment(s) ................................................................................................ 31
5.2
Dose Selection/Modification .............................................................................. 31
5.2.1
Dose Selection (Preparation) ....................................................................... 31
5.2.1.1
Dose Escalation............................................................................................ 31
5.2.1.2
Definition of Dose Limiting Toxicity.......................................................... 33
5.2.1.3
Recommended Phase 2 Dose (RP2D).......................................................... 35
5.2.1.4
Dose Adaptation........................................................................................... 35
5.2.1.5
Timing of Dose Administration.......................................................................... 38
5.2.2
Premedication .............................................................................................. 38
5.2.2.1
Trial Blinding...................................................................................................... 38
5.2.3
Randomization or Treatment Allocation............................................................ 38
5.3
Stratification.......................................................................................................... 38
5.4
Concomitant Medications/Vaccinations (Allowed and Prohibited)................. 39
5.5
Medications......................................................................................................... 39
5.5.1
Rescue Medications & Supportive Care............................................................. 40
5.6
Supportive Care Guidelines ................................................................................ 40
5.6.1
General Guidelines for Clinically Significant Toxicities............................. 40
5.6.1.1
Hepatic Laboratory Abnormalities .............................................................. 41
5.6.1.2
Diet/Activity/Other Considerations..................................................................... 41
5.7
Diet...................................................................................................................... 41
5.7.1
Potential Phototoxicity........................................................................................ 41
5.7.2
Contraception...................................................................................................... 41
5.7.3
Pregnancy............................................................................................................ 44
5.7.4
Nursing Women .................................................................................................. 44
5.7.5
Subject Withdrawal/Discontinuation Criteria................................................... 44
5.8
Subject Replacement Strategy............................................................................. 45
5.9
 
 
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Beginning and End of the Trial ........................................................................... 45
5.10
Clinical Criteria for Early Trial Termination ................................................... 46
5.11
6.0
TRIAL FLOW CHART ........................................................................................... 47
7.0
TRIAL PROCEDURES ........................................................................................... 51
Trial Procedures ................................................................................................... 51
7.1
Administrative Procedures.................................................................................. 51
7.1.1
Informed Consent......................................................................................... 51
7.1.1.1
7.1.1.1.1
General Informed Consent.................................................................... 51
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 52
Inclusion/Exclusion Criteria ........................................................................ 52
7.1.1.2
Subject Identification Card .......................................................................... 52
7.1.1.3
Medical History ........................................................................................... 52
7.1.1.4
Prior and Concomitant Medications Review ............................................... 52
7.1.1.5
7.1.1.5.1
Prior Medications.................................................................................. 52
7.1.1.5.2
Concomitant Medications..................................................................... 52
Assignment of Screening Number............................................................... 53
7.1.1.6
Assignment of Treatment/Randomization Number ..................................... 53
7.1.1.7
Trial Compliance ......................................................................................... 53
7.1.1.8
Clinical Procedures/Assessments........................................................................ 54
7.1.2
Adverse Event (AE) Monitoring.................................................................. 54
7.1.2.1
Full Physical Exam ...................................................................................... 54
7.1.2.2
Directed Physical Exam............................................................................... 54
7.1.2.3
Eastern Cooperative Oncology Group (ECOG) Performance Scale ........... 54
7.1.2.4
Vital Signs.................................................................................................... 54
7.1.2.5
12 Lead Electrocardiogram (ECG) .............................................................. 54
7.1.2.6
Tumor Assessment / Response Evaluation .................................................. 55
7.1.2.7
7.1.2.7.1
Bone Marrow Aspiration / Biopsy & Criteria for Response 
Assessment - AML ............................................................................... 55
7.1.2.7.2
Positron Emission Tomography (PET), Computed Tomography 
(CT), & Criteria for Response Assessment - DLBCL.......................... 56
Tumor Sample Submission.......................................................................... 57
7.1.2.8
7.1.2.8.1
Bone Marrow Aspiration (AML Subjects) ........................................... 57
 
 
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7.1.2.8.2
Lymph Node Biopsy (DLBCL Subjects).............................................. 57
Laboratory Procedures/Assessments .................................................................. 57
7.1.3
Laboratory Safety and Other Evaluations (Hematology, Chemistry, 
7.1.3.1
Urinalysis, and Other).................................................................................. 58
7.1.3.1.1
Complete Blood Count ......................................................................... 58
7.1.3.1.2
Serum Chemistry .................................................................................. 59
7.1.3.1.3
Urine or Serum β-hCG.......................................................................... 59
Pharmacokinetic/Pharmacodynamic Evaluations ........................................ 59
7.1.3.2
7.1.3.2.1
PK Sample Collection (Plasma) ........................................................... 59
7.1.3.2.2
PK Assay Method and Parameters Analyzed ....................................... 60
7.1.3.2.3
PD Sample Collection........................................................................... 60
Planned Genetic Analysis Sample Collection.............................................. 60
7.1.3.3
Future Biomedical Research Sample Collection ......................................... 61
7.1.3.4
Other Procedures................................................................................................. 61
7.1.4
Withdrawal/Discontinuation........................................................................ 61
7.1.4.1
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 61
Blinding/Unblinding .................................................................................... 61
7.1.4.2
Domiciling ................................................................................................... 62
7.1.4.3
Calibration of Critical Equipment................................................................ 62
7.1.4.4
Visit Requirements.............................................................................................. 62
7.1.5
Screening...................................................................................................... 62
7.1.5.1
Treatment Period.......................................................................................... 63
7.1.5.2
End of Treatment ......................................................................................... 63
7.1.5.3
Post-Treatment............................................................................................. 63
7.1.5.4
7.1.5.4.1
30 Day Safety Follow-up...................................................................... 63
7.1.5.4.2
Additional Follow-up............................................................................ 63
Assessing and Recording Adverse Events .......................................................... 63
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 64
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 65
7.2.2
Immediate Reporting of Adverse Events to the Sponsor.................................... 66
7.2.3
Serious Adverse Events ............................................................................... 66
7.2.3.1
Events of Clinical Interest............................................................................ 67
7.2.3.2
 
 
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Protocol-Specific Exceptions to Serious Adverse Event Reporting ............ 68
7.2.3.3
Evaluating Adverse Events ................................................................................. 68
7.2.4
Sponsor Responsibility for Reporting Adverse Events ...................................... 71
7.2.5
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 71
Statistical Analysis Plan Summary ..................................................................... 71
8.1
Responsibility for Analyses/In-House Blinding ................................................. 72
8.2
Hypotheses/Estimation ......................................................................................... 72
8.3
Analysis Endpoints ............................................................................................... 72
8.4
Safety Endpoints ................................................................................................. 72
8.4.1
Efficacy/Pharmacokinetics/Pharmacodynamics Endpoints ................................ 72
8.4.2
Analysis Populations............................................................................................. 73
8.5
Safety Analysis Populations ............................................................................... 73
8.5.1
Efficacy Analysis Populations ............................................................................ 73
8.5.2
Statistical Methods................................................................................................ 73
8.6
Statistical Methods for Safety Analyses ............................................................. 73
8.6.1
Statistical Methods for Efficacy Analyses .......................................................... 73
8.6.2
Summaries of Baseline Characteristics, Demographics, and Other Analyses.... 73
8.6.3
Interim Analyses ................................................................................................... 74
8.7
Multiplicity ............................................................................................................ 74
8.8
Sample Size and Power Calculations .................................................................. 74
8.9
Subgroup Analyses and Effect of Baseline Factors ........................................... 75
8.10
Compliance (Medication Adherence).................................................................. 75
8.11
Extent of Exposure................................................................................................ 75
8.12
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 75
Investigational Product ........................................................................................ 75
9.1
Packaging and Labeling Information ................................................................. 76
9.2
Clinical Supplies Disclosure................................................................................. 76
9.3
Storage and Handling Requirements.................................................................. 76
9.4
Discard/Destruction/Returns and Reconciliation .............................................. 76
9.5
Standard Policies................................................................................................... 76
9.6
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 77
 
 
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Confidentiality....................................................................................................... 77
10.1
Confidentiality of Data ....................................................................................... 77
10.1.1
Confidentiality of Subject Records ..................................................................... 77
10.1.2
Confidentiality of Investigator Information........................................................ 77
10.1.3
Confidentiality of IRB/IEC Information............................................................. 78
10.1.4
Compliance with Financial Disclosure Requirements....................................... 78
10.2
Compliance with Law, Audit and Debarment ................................................... 78
10.3
Compliance with Trial Registration and Results Posting Requirements ........ 80
10.4
Quality Management System............................................................................... 80
10.5
Data Management................................................................................................. 80
10.6
Publications ........................................................................................................... 81
10.7
11.0
LIST OF REFERENCES......................................................................................... 82
12.0
APPENDICES........................................................................................................... 86
Merck Code of Conduct for Clinical Trials........................................................ 86
12.1
Collection and Management of Specimens for Future Biomedical 
12.2
Research................................................................................................................. 88
Understanding the Intent, Scope and Public
Health Benefits of 
12.3
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff ...................................................................................... 92
Response Assessment of AML ........................................................................... 103
12.4
Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: the 
12.5
Lugano Classification ......................................................................................... 104
ECOG Performance Status................................................................................ 107
12.6
Calculation of Renal Clearance ......................................................................... 108
12.7
Guidance for Potential Drug-Induced Liver Injury (DILI)............................ 109
12.8
Purpose.............................................................................................................. 109
12.8.1
Introduction....................................................................................................... 109
12.8.2
Close Observation Recommendations .............................................................. 110
12.8.3
Hepatic Assessment Flow Chart ....................................................................... 111
12.8.4
Study Medication....................................................................................... 111
12.8.4.1
Treatment ................................................................................................... 112
12.8.4.2
Signs and Symptoms (associated with the potential DILI event) .............. 112
12.8.4.3
Confounding Variables .............................................................................. 112
12.8.4.4
 
 
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Evaluation Algorithm for Potential DILI if there are No Other Clinical 
12.8.4.5
Reasons...................................................................................................... 113
Potential Diagnosis .................................................................................... 115
12.8.4.6
Overall Clinical Impression ....................................................................... 115
12.8.4.7
Treatment Plan........................................................................................... 115
12.8.4.8
Contacts............................................................................................................. 116
12.8.5
References......................................................................................................... 116
12.8.6
Non-Exhaustive List of Drugs and Substances with the Potential to 
12.9
Interfere with CYP3A4 and CYP2A6............................................................... 117
List of Abbreviations .......................................................................................... 118
12.10
13.0
SIGNATURES......................................................................................................... 120
Sponsor's Representative ................................................................................... 120
13.1
Investigator.......................................................................................................... 120
13.2
 
 
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LIST OF TABLES
    
Table 1
Adequate Organ Function Laboratory Values........................................................ 28
Table 2
Trial Treatment ....................................................................................................... 31
Table 3
Dose Escalation Scheme......................................................................................... 32
Table 4
Modified Toxicity Probability Interval (mTPI) Design.......................................... 32
Table 5
Dose Modification Guidelines for Drug-Related Adverse Events ......................... 36
Table 6
MK-8628 Dose and Schedule Modifications.......................................................... 38
Table 7
Laboratory Tests ..................................................................................................... 58
Table 8
PK Sample Collection Timing................................................................................ 59
Table 9
PD Sample Collection Timing................................................................................ 60
Table 10 Evaluating Adverse Events .................................................................................... 69
Table 11 Bayes credible interval for DLT rate estimate and confidence interval for ORR 
estimate for different sample sizes and number of events .......................................... 75
Table 12 Product Descriptions .............................................................................................. 76
Table 13 Response Assessment of AML [45]..................................................................... 103
Table 14 Response Assessment of Hodgkin and Non Hodgkin Lymphoma: the Lugano 
Classification [46]..................................................................................................... 104
 
 
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LIST OF FIGURES
          
Figure 1
Dose Escalation Scheme..................................................................................... 16
Figure 2
PK comparison of QD versus BID...................................................................... 23
Figure 3
Dose-Dependent Changes in BET Protein Target Gene Expression in 
Human Whole Blood Ex Vivo.................................................................................... 25
Figure 4
Hepatic Assessment Flow Chart ....................................................................... 111
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section 
Number (s)
Section Title(s)
Description of Change (s)
Rationale
All
All
Enrollment in this protocol was prematurely 
discontinued due to the Sponsor’s
decision to 
terminate the MK-8628 program based on very 
limited efficacy signals and evaluation of the 
risk/benefit profile given limited efficacy.  It is 
important to note that this program was not being 
discontinued due to a safety concern with MK-8628.
Previous procedures are not deleted from this 
amendment but are superseded by this amendment.  
This is outlined in the Summary of Changes.  
Upon approval of this amendment by the site’s 
Institutional Review Board (IRB) or Independent 
Ethics Committee (IEC), data entry in the data entry 
system eCRF will no longer be required, the database 
will be closed, and procedures and the outcome of 
procedures should be documented in the medical 
record.  
The IVRS was closed after the last subject was 
enrolled, and trial site personnel will contact the 
Sponsor 3 weeks before additional clinical supplies 
are required to treat the remaining subject.
Continued treatment is subject to availability of study 
medications.
Procedures as detailed in MK-8628-005-02 will be 
performed as standard of care.
To allow the remaining subject enrolled 
in the trial to continue to receive 
treatment with MK-8628.
 
 
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Section 
Number (s)
Section Title(s)
Description of Change (s)
Rationale
No efficacy measures will be recorded.  Imaging 
studies will be conducted only to determine the 
subject’s response to treatment.
All serious adverse events will be reported to the 
Sponsor’s central safety reporting system using the 
paper reporting method as outlined in the Investigator 
trial file.
1.0 
Trial Summary
Added statements at the beginning of the section.
Enrollment in this protocol was prematurely 
discontinued due to the Sponsor’s
decision to 
terminate the MK-8628 program based on very 
limited efficacy signals and evaluation of the 
risk/benefit profile given limited efficacy.  It is 
important to note that this program was not being 
discontinued due to a safety concern with MK-8628.
Previous procedures are not deleted from this 
amendment but are superseded by this amendment.  
This is outlined in the Summary of Changes.  
Upon approval of this amendment by the site’s 
Institutional Review Board (IRB) or Independent 
Ethics Committee (IEC), data entry in the data entry 
system eCRF will no longer be required, the database 
will be closed, and procedures and the outcome of 
procedures should be documented in the medical 
record.  
The IVRS was closed after the last subject was 
enrolled, and trial site personnel will contact the 
To allow the remaining subject enrolled
in the trial to continue to receive 
treatment with MK-8628.
 
 
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Section 
Number (s)
Section Title(s)
Description of Change (s)
Rationale
Sponsor 3 weeks before additional clinical supplies 
are required to treat the remaining subject.
Continued treatment is subject to availability of study 
medications.
Procedures as detailed in MK-8628-005-02 will be 
performed as standard of care.
No efficacy measures will be recorded.  Imaging 
studies will be conducted only to determine the 
subject’s response to trial treatment.
All serious adverse events will be reported to the 
Sponsor’s central safety reporting system using the 
paper reporting method as outlined in the Investigator 
trial file.
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
No additional changes.
 
 
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1.0 TRIAL SUMMARY
Enrollment in this protocol was prematurely discontinued due to the Sponsor’s decision to 
terminate the MK-8628 program based on very limited efficacy signals and evaluation of the 
risk/benefit profile given limited efficacy. It is important to note that this program was not 
being discontinued due to a safety concern with MK-8628.
Previous procedures are not deleted from this amendment but are superseded by this 
amendment. This is outlined in the Summary of Changes. 
Upon approval of this amendment by the site’s Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC), data entry in the data entry system eCRF will no 
longer be required, the database will be closed, and procedures and the outcome of 
procedures should be documented in the medical record. The IVRS was closed after the last 
subject was enrolled, and trial site personnel will contact the Sponsor 3 weeks before 
additional clinical supplies are required to treat the remaining subject. 
Continued treatment is subject to availability of study medications.
Procedures as detailed in MK-8628-005-02 will be performed as standard of care.
No efficacy measures will be recorded. Imaging studies will be conducted only to determine 
the subject’s response to trial treatment.
All serious adverse events will be reported to the Sponsor’s central safety reporting system 
using the paper reporting method as outlined in the Investigator trial file.
Abbreviated Title
A phase Ib trial with MK-8628, a small molecule inhibitor of the 
bromodomain and extra-terminal (BET) proteins, in subjects with 
selected hematologic malignancies.  
Sponsor Product Identifiers
MK-8628
Trial Phase
Phase Ib
Clinical Indication
The treatment of subjects with one of the following hematologic 
malignancies:

Acute myeloid leukemia (AML) - AML de Novo and post-
MDS

Diffuse large B cell lymphoma (DLBCL)
Trial Type
Interventional
Type of control
No treatment control 
Route of administration
Oral 
Trial Blinding
Unblinded Open-label
Treatment Groups
MK-8628 20 mg, twice a day, continuous for 21 consecutive days per 
cycle;
MK-8628 30 mg, twice a day, continuous for 21 consecutive days per 
cycle
Number of trial subjects
Approximately a maximum of 56 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 20 
months from the time the first subject signs the informed consent until 
the last subject’s last study-related phone call or visit.
 
 
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Duration of Participation
Each subject will participate in the trial from the time the subject signs 
the Informed Consent Form (ICF) through the final contact.    After a 
screening phase of up to 2 weeks, eligible subjects will receive
treatment according to their assigned regimen and dose level in 3-
week dosing cycles.  Treatment with MK-8628 will continue until 
documented disease progression, unacceptable toxicity, subject 
withdrawal of consent, subject non-compliance with trial treatment or 
procedure requirements, treatment interruption > 2 weeks for any 
reason (except in the event of perceived benefit, with Sponsor 
agreement), recurrence of dose limiting toxicity (DLT) despite dose 
reduction (except in the event of perceived benefit, with Sponsor 
agreement), or by the investigators decision to withdraw the subject. 
After the end of treatment, subjects are to be followed up for safety for 
at least 30 days following the last MK-8628 dosing and until recovery 
or stabilization of all related toxicities.
A list of abbreviations used in this document can be found in Section 12.9.
2.0 TRIAL DESIGN
Trial Design
2.1
This is an open-label, multicenter, international, non-randomized phase Ib trial with dose 
exploration of single-agent MK-8628 (formally known as OTX015) administered orally in 
subjects with selected hematologic malignancies (AML and DLBCL), to be conducted in 
conformance with Good Clinical Practices.
This dose escalation study will evaluate a twice-daily (BID) dosing regimen to establish the 
recommended phase 2 dose (RP2D).
Dose administration will be continuous for 21 consecutive days per cycle (21-day cycles) at a 
starting dose of 20 mg BID.
A 6+8 two-stage design is used, offering a fast approach with continuous dose-limiting 
toxicity (DLT) rate monitoring via a modified toxicity probability index (mTPI)(Ji design) 
[1]. Two dose levels will be evaluated: 20 and 30 mg BID, continuous, 21-day cycles. 
Between 6 and 14 subjects will be enrolled per dose level and per cohort, depending on the 
occurrence of a DLT (see Sections 5.2.1.2 and 5.2.1.3) during the first 21 days of treatment. 
Thus a maximum of up to 56 subjects (28 subjects per cohort) evaluable for DLT will be 
enrolled.  All AML subjects participating in the 20 mg BID regimen of the MK-8628-001 
protocol (approximately up to 3 subjects) will count toward the initial 6 AML subjects 
needed for the 20 mg BID dose level in this study.
Subjects will undergo a dose and/or schedule modification in the event of toxicity (see 
Section 5.2.1).
Each cohort (AML and DLBCL) will be evaluated independently in regards to enrollment 
and dose level escalation/de-escalation. 
The RP2D will be selected based on a multi-faceted decision taking into account safety, 
tolerability, early efficacy signal, PK exposure and PD markers. The primary endpoint 
driving dose selection is the DLT rate, with weight given to the highest DL tolerated (< 25% 
DLT rate).
 
 
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Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.
Trial Diagram
2.2
The trial design is depicted in Figure 1.
Figure 1
Dose Escalation Scheme
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
3.1
Objectives for this trial are to be evaluated for single agent MK-8628 administered orally to 
subjects with selected hematologic malignancies as follows:
1) Objective:  To determine the recommended phase II dose (RP2D) respectively in 
subjects with AML and DLBCL.  
Secondary Objective(s) & Hypothesis(es)
3.2
Objectives for this trial are to be evaluated for single agent MK-8628 administered orally to 
subjects with selected hematologic malignancies as follows:
1) Objective:   To assess the safety and tolerability.
2) Objective:
To characterize pharmacokinetic
(4.2.3.2) and pharmacodynamic
(4.2.3.3) parameters.
3) Objective: To evaluate antitumor activity using objective response rate (ORR), 
duration of response (DOR) and disease control rate (DCR) by Response Evaluation 
Criteria in AML or DLBCL (see Section 7.1.2.7.1 and 7.1.2.7.2) as assessed by 
investigator review
 
 
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Exploratory Objectives
3.3
1) Objective:   Evaluate antitumor activity using progression-free survival (PFS) by 
Response Evaluation Criteria in AML or DLBCL (see Section 7.1.2.7.1 and 
7.1.2.7.2) as assessed by investigator review, and overall survival (OS).
2) Objective: To explore the relationship between genomic variation and response to the 
treatment(s) administered. Variation across the human genome (germline and tumor) 
will be analyzed for association with clinical data collected in this study.
4.0 BACKGROUND & RATIONALE
Background
4.1
Refer to the Investigator’s Brochure (IB) for detailed background information on MK-8628.
Pharmaceutical and Therapeutic Background
4.1.1
MK-8628 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 extraterminal) proteins.
In cancer, pathologic activation of c-MYC plays a central role in disease pathogenesis, by the 
coordinated upregulation of a transcriptional program influencing cell division, metastatic 
adaptation and survival [2][3]. Amplification of MYC is one of the most common genetic 
alterations observed in cancer genomes [4], and the validation of c-MYC as therapeutic target 
is supported by numerous lines of experimental evidence [5][6][7][8][9][10]. Nevertheless, 
despite the central importance of MYC in cancer pathogenesis, conventional approaches 
toward its direct inhibition have not proven successful. The absence of a clear ligand-binding 
domain is a formidable obstacle to direct inhibition, a challenging feature shared by many 
compelling transcriptional targets in cancer [11]. Considering chromatin as a platform for 
signal transduction [12], the inhibition of MYC transcription and function has been achieved 
through displacement of chromatin-binding, co-activator proteins, the bromodomains (BRD), 
using competitive small molecules [13].
BRDs are protein interaction modules that specifically recognize Ɛ-N-acetylated lysine
residues [14][15]. BRDs are common in nuclear proteins that regulate gene transcription and 
chromatin organization and play a key function of recruiting these protein complexes to 
acetylated chromatin. Dysfunction of BRD-containing proteins has been linked to the 
development of diverse diseases, and in particular to the development of cancer [16]. BRDs 
are highly sequence diverse but share a conserved fold comprised of a left-handed bundle of 
four alpha helices (αZ, αA, αB, αC) [17]. The acetyl-lysine side chain is typically anchored 
by a hydrogen bond to a conserved asparagine residue and has water-mediated interactions 
with a conserved tyrosine [15][18]. Crystal structures of BET complexes with di-acetylated 
histone 4-tail peptides showed that the first BRDs of BRD4 and BRDT may accommodate 
two acetyl-lysines in a single site [15][19]. 
The BET family of BRD proteins, which includes BRD2, BRD3, BRD4, and BRD testis-
specific protein (BRDT), are epigenetic reader proteins that bind acetylated lysine residues 
on histones playing critical roles in cellular proliferation and cell-cycle progression [20]. 
 
 
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BRD4 binds to the positive transcription elongation factor b (P-TEFb), a cyclin-dependent 
kinase, and stimulates RNA polymerase II-dependent elongation [21][22]. BRD4 is critical 
for survival of several diverse tumors due to its function promoting transcription of growth-
promoting and anti-apoptotic genes [23], which has prompted the development of potent and 
selective protein interaction inhibitors targeting BET BRDs.
The biological action of BET proteins occurs through a protein-protein interaction (BET 
protein binding to an acetylated histone protein) and, as such, this biochemical activity has 
historically possessed poor tractability for small molecule drug discovery identification. The 
identification by Chung and colleagues [24] of potent, selective BET inhibitors was not the 
result an oncology drug discovery effort to “drug” the BRD4 protein to target NMC, but 
rather was fortuitous, being the result a high-throughput screen to identify molecules for 
potential use in atherosclerosis (apolipoprotein A1 upregulation). In independent studies 
during the same time period, Mitsubishi Tanabe scientists reported the discovery and 
development of thienotriazolodiazepine as a BET inhibitor (including MK-8628) [Mitsubishi 
Tanabe Pharma Corporation. Antitumor agent. WO 2009084693; 2009]. Building on these 
findings, Bradner and colleagues synthesized a thienotriazolodiazepine, JQ1[23]. The initial 
presumption of low tractability of the BET proteins has proven not to be the case, as multiple 
researchers have identified other potent, selective BET inhibitors with substantially different 
chemical structures [23][25][26][27]. The crystal structures of these small molecule 
inhibitors bound to BRD4 illustrate that the binding pocket, which also binds acetyl-lysine, is 
small, deep, and hydrophobic.
Justification of Selecting Subjects with Hematologic Malignancies
4.1.1.1
Hematologic malignancies are heterogeneous diseases. There is increasing evidence in 
preclinical models that BRD inhibition can result in antitumor activity against various 
illnesses, including acute leukemia (AL) [28][29][26][30] to lymphoma [31][32][33] and 
myeloma [13][34][35]. It is known that in many hematologic malignancies, the oncogenesis 
is driven by the oncogene c-Myc [13][36][37][38][39]. It has been shown that BRD 
inhibition was frequently associated with c-Myc, and downstream targets down regulation 
[38].
Though a significant proportion of subjects with AL and lymphoma can be cured or can 
benefit of prolonged overall survival with current therapies, the majority of subjects with 
hematologic malignancies will die from their disease. The level of unmet medical need is 
therefore very high and innovative new drugs are eagerly expected.
MK-8628 Metabolism – CYP Interactions
4.1.1.2
Results from MK-8628 incubations either with individual recombinant CYPs or with human 
microsomes and chemical inhibitors to individual CYPs show MK-8628 was metabolized to 
the mono-hydroxylated metabolite mainly by CYP3A4 and to a lesser extent by CYP2C9 and 
potentially by CYP2C19, which will need to be confirmed.  Results from incubations with 
individual UDP glucuronosyltransferase(s) (UGT) showed that MK-8628 can be 
glucuronidated mainly by UGT1A7 and, to a lesser extent, by UGT1A1, 1A10, 1A3, 1A8, 
and 1A9.  MK-8628 inhibits CYP2A6 and 3A4 turnover of probe substrates in microsomes 
with IC50 values that were >10 µM.  At 10 µM MK-8628, the inhibition of CYP2A6 and 
CYP3A4 were 30% and 39%, respectively.  MK-8628 has a high apparent permeability (Papp
 
 
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21 x 10-6 cm/s apical-to-basal) across cell monolayers and is a P-gp substrate.  The 
involvement of several enzymes in the metabolism of MK-8628 reduces concerns for victim 
drug-drug interaction (DDI).  The inhibition of CYP2A6 and particularly CYP3A4 raises 
concerns that MK-8628 could be a perpetrator in a DDI with co-administered drugs whose 
clearance is primarily mediated by these enzymes.
MK-8628 – Ongoing Clinical Trials in Hematologic Malignancies
4.1.1.3
Study MK-8628-001 (previously known as OTX015_104), a Phase Ib study in subjects
with AL or other hematologic malignancies was started (first subject enrolled) in January 
2013.  The study is composed of a dose escalation part evaluating MK-8628/OTX015 doses 
from 10 mg to 160 mg QD in subjects with AL or other hematologic malignancies using a 
classic 3+3 design, followed by evaluation of dose expansion cohorts in three selected 
hematologic indications with the QD dosing. The preliminary RD and schedule for the Phase
2 study in hematologic malignancies was 80 mg/day with 14 days on/7 days off schedule,
with dose interruptions in the event of grade 4 thrombocytopenia.  This preliminary RD will 
be further explored looking at 20 mg and 30 mg BID continuous dosing.  Phase 1 expansion 
cohorts in AML de novo, AML post-MDS, and DLBCL at 80 mg (14 days on/7 days off) are
ongoing.   Consideration for further enrollment will be based on findings at additional BID 
continuous dosing.  As of 04-Sep-2015, a total of 135 subjects have been enrolled.
Efficacy data is available for 135 subjects with advanced hematologic malignancies as of 04-
Sep-2015.  Of 75 subjects with AL, complete responses were observed for 2 subjects (1 
subject in the 40 mg QD cohort and 1 subject in the 160 mg QD cohort) and a complete 
response with incomplete marrow recovery was observed for 1 subject.  Of 48 subjects with 
lymphoma, a complete response was observed for 2 subjects (at 120 mg QD on 14-day and 
21- day regimens) and a partial response was observed for 2 subjects (at 80 mg QD on 14-
day and 21- day regimens); stable disease was observed for 18 subjects.  Of 12 subjects with 
multiple myeloma, no responses were observed; stable disease was reported for 5 subjects.  
The duration of response among all responders ranged from 1.4 to 9.2 months.
All 75 subjects with AL had at least 1 AE and 57 (76%) had at least 1 AE considered by the 
investigator to be drug related.  At least 1 AE graded 3 to 5 was observed for 68 (90.7%) 
subjects and at least 1 drug-related AE was observed for 23 (30.7%) subjects.  Drug-limiting 
toxicity during cycle 1 was reported for 3 (4%) subjects.  Serious events were reported for 57 
(76%) subjects and serious events that were drug related were reported for 11 (14.7%) 
subjects.  Adverse events led to discontinuation of 22 (29.3%) subjects and AEs considered 
to be drug related led to discontinuation of 1 (1.3%) subject.  
All 60 subjects with other hematologic malignancies (OHM) had at least 1 AE and 49 
(81.7%) had at least 1 AE considered by the investigator to be drug related.  At least 1 AE 
graded 3 to 5 was observed for 45 (75%) subjects and at least 1 drug-related AE was 
observed for 33 (55%) subjects.  Drug-limiting toxicity during cycle 1 was reported for 18 
(30%) subjects.  Serious events were reported for 30 (50%) subjects and serious events that 
were drug related were reported for 20 (33%) subjects.  Adverse events led to discontinuation 
of 7 (11.7%) subjects and AEs considered to be drug related led to discontinuation of 2 (3%) 
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The most common AEs in all subjects pooled (AL and OHM) were hematologic (n=99, 
73.3%): anemia (n=60, 44.4%), leukocytosis (n=26, 19.3%), and thrombocytopenia (n=59, 
43.7%) (see also Section 7.1); gastrointestinal disorders (n=118, 87.4%): diarrhea (n=88, 
65.2%), nausea (n=62, 45.9%), vomiting (n=32, 23.7%), abdominal pain (n=28, 20.7%), and 
constipation (n=25, 18.5%); general disorders (n=113, 83.7%): asthenia (n=74, 54.8%), 
pyrexia (n=55, 40.7%), weight decreased (n=30, 22.2%); metabolic (n=83, 61.5%): 
decreased appetite (n=45, 33.3%), hypokalemia (n=29, 21.5%); musculoskeletal and 
connective tissue disorders (n=50, 37.0%); nervous system disorders (n=56, 41.5%); 
psychiatric disorders (n=30, 22.2%); renal (n=29, 21.5%); respiratory: cough (n=37, 27.4%), 
dyspnea (n=36, 26.7%), and epistaxis (n=29, 21.5%); skin and subcutaneous tissue disorders 
(n=60, 44.4%); and vascular disorders (n=30, 22.2%).
Notable were investigations: hyperbilirubinaemia (n=10, 7.4%). It’s plausible that the 
mechanism to explain clinical hyperbilirubinemia could be the competitive inhibition of 
enzymes and transporters involved in the disposition of bilirubin and its conjugates. The 
competitive inhibition could be mediated by parent MK-8628 and/or its metabolites. 
Experiments are ongoing to attempt to elucidate this mechanism.
Additional details can be found in the Investigator’s Brochure (IB).
Rationale
4.2
Rationale for the Trial and Selected Subject Population
4.2.1
In the present study, adult subjects with selected hematologic malignancies with the potential 
to respond to BET inhibition (AML De Novo and Post MDS, and DLBCL) will receive MK-
8628/OTX015 orally to determine the RD for phase II studies. QD evaluations were 
previously evaluated in study MK-8628-P001/OTX015_104. This study will focus on the 
evaluation of a BID regimen.
MK-8628, a pan-BET bromodomain inhibitor, shows activity in several preclinical 
hematologic and somatic cancer models. Meaningful antitumor activity has also been 
reported in subjects with heavily pretreated hematological malignancies in the ongoing phase 
I clinical study treated with MK-8628. Accumulating studies reveal the critical roles of BET 
bromodomains in cancer development.
Several experimental cancer models have demonstrated the functional consequences of BET 
protein overexpression and translocation:
• B-cell restricted constitutive expression of BRD2 in mice inappropriately transactivates 
the cyclin A gene in pre-malignant B cells [31] to cause a malignancy that is highly 
similar to DLBCL [32].  The BRD2-driven DLBCL in mice can be cured with the 
standard regimen of cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) 
chemotherapy used to treat human DLBCL [33].
• The MLL (mixed lineage leukemia) gene is one of the most frequently involved genes in 
both lymphoblastic and myeloid leukemias. A global proteomic strategy found that MLL 
fusions, as part of super elongation complex (SEC) and the polymerase-associated factor 
complex (PAFc), are associated with the BET family of proteins [26].  Treatment with 
 
 
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BET inhibitors was shown to provide a survival advantage in three MLL leukemia models 
[26][29].
Taken together, preclinical data and results from the ongoing phase Ib hematologic study 
(MK-8628-001) provide the rationale for further investigating MK-8628 in subjects with 
selected hematologic malignancies.
Rationale for Dose Selection/Regimen/Modification
4.2.2
In the previous hematologic phase I study (OTX015_104 / MK-8628-001), a dose escalation
was completed and preliminary results of the cohort expansion are available. As of J une 
2015, a total of 87 subjects had been included in the dose escalation part in the two cohorts 
(AL and OHM), and a further 49 subjects had been included in three dose expansion cohorts. 
A QD schedule was evaluated at all levels (up to 160 mg) and a 40 mg BID schedule was 
also evaluated.
The preliminary RD for the QD schedule was 80 mg QD, with a 14 days ON/7 days OFF 
schedule for both the OHM and the AL cohorts. DLT of thrombocytopenia was the 
prevalently observed AE in the OHM cohort, occurring above 40 mg QD. At DL4, 
thrombocytopenia was more frequent at 40 mg BID with a higher incidence of 
thrombocytopenia compared to the equivalent total dose per day given as QD, i.e., 5/6 
subjects vs. 2/7 subjects, respectively - making the dose of 40 mg BID unacceptable with 
>33% of DLT in this cohort. The main limiting toxicities reported are thrombocytopenia, 
fatigue, gastrointestinal toxicities, as well as asymptomatic bilirubin increases and Factor VII 
decreases.
Preliminary clinical activity has been observed at a range of dose levels, including objective 
responses at 40 mg QD (1 CR), 80 mg (CRi) and 160 mg (CR) in the AL cohort and at 80 mg 
QD (1 PR) and 120 mg (2 CR) in DLBCL subjects.
A total of 49 subjects had been treated in the expansion cohorts with non-continuous dosing 
at 80 mg QD, 14 days ON/7 days OFF: 16 AML post-MDS subjects, 18 AML non-MDS 
related (i.e. de novo, secondary to chemotherapy or MPD) subjects, and 15 DLBCL subjects. 
The expansion cohort demonstrated that at 80 mg QD, 14 days ON/7 days OFF was 
reasonably well tolerated with no DLTs reported.  However, one subject with AML had 
grade 3 asthenia, deemed not related by the investigator after clarification (related to 
aspergillosis), and one subject with AML had a dose reduction due to poor tolerance 
(asthenia, anorexia, dysgeusia G2).
In the dose expansion cohort, one PR has been reported to date in a DLBCL subject along 
with evidence of clinical activity not yet meeting standard response criteria in some ongoing 
subjects (decrease in bone marrow blasts in five AML subjects and decreased lymph node 
lesions in two DLBCL subjects).
Starting Dose for This Trial
4.2.2.1
Data is now emerging on how to better dose epigenetic therapies, including more frequent 
dosing that avoids undesirable effects mediated by higher concentrations and resultant 
enhanced broad inhibition of the targeted genes. The limited number objective responses in 
 
 
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the dose expansion cohorts in the hematologic malignancies study where MK-8628 was 
given in a discontinuous manner (i.e. 14 days ON/7 days OFF) raises the question of whether 
there is a need for continuous and sustained target inhibition. On the basis of several 
translational and clinical studies, low, prolonged drug exposure is becoming the hallmark of 
successful epigenetic modulation [40]. Notable epigenetic agents where this phenomenon is 
observed include FDA-approved DNMT inhibitors such as 5-azacitidine and decitabine [41]. 
Clinical development of these agents was initially hindered because early trials used higher, 
infrequent doses that proved to be substantially toxic to subjects (likely because of off-target 
epigenetic modulation). Lower, continuous dosing was found to markedly decrease 
treatment-related AEs and enhance targeted effects on DNA methyltransferases because the 
concentrations are maintained at a level where cytotoxic effects are not the prevailing mode 
of action. The available data support the notion that maintaining concentrations that avoid 
immediate cytotoxic effects but engage the target in a continuous fashion allows for 
reprogramming of the tumor cells that can alter disease biology in a durable, clinically 
meaningful manner [40].
Therefore, to maintain or sustain target inhibition with MK-8628 and mitigate daily 
fluctuations in systemic concentrations, a more frequent dosing schedule will be evaluated in 
this protocol using BID dosing. The hypothesis underlying this approach is that a higher 
Ctrough achieved with lower, more frequent dosing may be needed to disrupt  super-
enhancer driven oncogene expression (e.g., Myc, Bcl-2) over longer periods of time in order 
to induce antitumor activity [38]. Enhanced preclinical efficacy seen with the BET inhibitor 
JQ1 and MK-8628 with more frequent dosing (BID versus QD) seen in preclinical 
evaluations [26][38][42] is likely attributable to the ability of these powerful gene expression 
enhancers to quickly restore oncogene expression once the compound exposure wanes. 
Considering the short half-life for MK-8628 of ~5-6 hours, BID dosing has the potential to 
maintain sustained target engagement at a lower dose (i.e. lower Cmax could help avoid off-
target toxicities). 
Based on available PK data and results suggesting MK-8628 exhibits dose proportional 
exposure and a half-life much shorter than either a 12-hour or 24-hour dosing interval, a 
Ctrough 12 hours after BID dosing will more than likely result in significantly higher 
concentrations than a Ctrough of double the same dose at 24 hours (~4 cumulative half-
lives). For example, the MK-8628 PK results from both cohorts combined shown in Figure 1 
demonstrate that a 40 mg BID dose attains significantly higher Ctrough than a similar daily 
dose of 80 mg QD. In the absence of a clear understanding of target engagement at different 
doses and an appropriate efficacious dose, total daily doses up to 60 mg administered as BID 
(i.e., max of 30 mg BID) or additional dose schedules will be evaluated with the hypothesis 
that more frequent dosing may improve efficacy.
Because epigenetic reprogramming can take longer to become apparent than the actions of 
traditional chemotherapies, a continuous prolonged course of treatment may be required for 
efficacy evaluation. Balancing this against risk (thrombocytopenia) and tolerability issues (as 
seen in the initial dose escalation), a lower, more frequent BID dosing schedule will be 
explored primarily for Proof of Concept (POC). 
In Figure 2 below, PK comparison of QD versus BID in the combined dose escalation 
cohorts suggests that Ctrough or time above threshold could underlie hematologic toxicity and 
potentially efficacy of MK-8628. PK data suggest no difference in total exposure (top graph). 
 
 
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Median daily AUC of 40 mg BID is similar to 80 mg QD. However, there is a large 
difference in median trough concentration (bottom graph). 
Figure 2
PK comparison of QD versus BID
Maximum Dose/Exposure for This Trial
4.2.2.2
The maximum dose for the BID regimen in this study will be the highest dose level tolerated 
(< 25% DLT rate).
Rationale for Dose Interval and Trial Design
4.2.2.3
The purpose of this trial is to determine the recommended phase 2 dose (RP2D) of MK-8628 
for further phase II trials in subjects with selected hematologic malignancies that might 
benefit from BET inhibition. The RP2D of BID administration regimens will be explored 
using a 6+8 two-stage design which offers a fast approach with continuous DLT rate 
monitoring via a modified toxicity probability index (mTPI)(Ji design)[1].
 
 
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Rationale for Endpoints
4.2.3
Safety Endpoints
4.2.3.1
4.2.3.1.1 Primary Safety Endpoint: 
A primary objective of this trial is to determine the recommended phase II dose (RP2D) of 
MK-8628. Selecting the RP2D will involve a multi-faceted decision taking into account 
safety, tolerability, early efficacy signal, PK exposure and PD markers. The primary endpoint 
driving dose selection is the DLT rate, with weight given to the highest DL tolerated (< 25% 
DLT rate). All other facets will be considered supportive. It is important to note that dose 
selection in this study aims to assess a recommended phase 2 dose range, with other factors 
aside from those mentioned above, such as target engagement, contributing to refining the 
dose selection for phase 2. This will be further evaluated in subsequent clinical investigations 
in either monotherapy or combination trials.
Secondary Safety Endpoints
The secondary safety endpoint will be to evaluate the safety and tolerability of MK-8628 
across subjects with AML (de Novo and post-MDS) and DLBCL included in this trial. Safety 
will be assessed in subjects who have received MK-8628 by determining the RP2D and 
quantifying and grading reported AEs using CTCAE, Version 4.0. Attribution to drug, time-
of-onset, duration of the event, resolution, and any concomitant medications administered 
will be recorded.  AEs to be analyzed include but are not limited to all AEs, ECIs, SAEs, 
fatal SAEs, and laboratory changes.
Pharmacokinetic Endpoints
4.2.3.2
Plasma parameters of MK-8628 as appropriate and according to analyses performed (non-
compartmental or nonlinear mixed effect modelling) will be determined and may include 
trough (Cmin) and peak (Cmax) concentrations, Tmax, AUC[0-∞], Vdss, t1/2, steady state, 
total clearance (CL). PK data for MK-8628 will be interpreted in terms of safety findings and 
compared with historical data. Incidence and severity of AEs along with PK parameters will 
be analyzed in relation to the most pertinent biomarker(s), if any.
Pharmacodynamic Endpoints
Inhibition of BET proteins by MK-8628 leads to alterations in the transcription of mRNA at 
loci most sensitive to disruption of BET activity. These are considered target genes. Changes 
in expression, measured via mRNA, of prespecified target genes* will be used as PD 
biomarkers to assess target engagement of BET proteins by MK-8628. (*Note: the following 
non-exhaustive list of target genes may be considered for testing: Bcl2, IL7R, and MYC as 
down-regulated target genes; CSRNP2, HEXIM1, and HIST1H2BK as up-regulated target 
genes.) A range of PD biomarkers will be explored in surrogate samples from all subjects
treated, using appropriate assays to establish target engagement. Rather than rely on gene 
expression changes in cancer cells, these PD biomarkers will be based on current PD 
knowledge from translational studies of mouse and human whole blood (e.g. Figure 3
below). Using RNA extracted from whole blood samples collected both prior to and 
following administration of MK-8628, messenger RNA transcript profiling may be 
performed to assess gene expression and evaluate whether changes in specific genes or sets 
 
 
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of genes may represent a PD biomarker of response. Potential limitations of this assay 
include subject-to-subject variability and a small effect size of induction or repression upon 
treatment with MK-8628. Due to these limitations, the PD endpoint is considered to be 
qualitative given the assay may not be able to differentiate target engagement between the 
MK-8628 doses examined in this study.    
See Figure 3.  Whole blood from 6 normal healthy volunteers was treated with either vehicle 
(0.1% DMSO) or increasing concentrations of MK-8628. After 4 hours, whole blood was 
lysed (PAXgene tube) and mRNA extracted for qPCR analysis of candidate BET target 
genes. Data were normalized (∆Ct) by PPIB and plotted for all six individuals as change in 
ΔCt.
Figure 3
Dose-Dependent Changes in BET Protein Target Gene Expression in Human 
Whole Blood Ex Vivo
Efficacy Endpoints
4.2.3.3
4.2.3.3.1 Secondary Efficacy Endpoints
The secondary efficacy objectives for this trial are to evaluate the anti-tumor activity of MK-
8628 in subjects with AML (de Novo and post-MDS) and DLBCL biomarker unselected.  
Secondary efficacy endpoints include (1) ORR, defined per standard response criteria for 
acute leukemia (Section 12.4) and malignant lymphoma (Sections 12.5), as assessed by 
investigator, (2) DOR, defined as the time from first documented evidence of CR or PR until 
disease progression or death due to any cause, whichever occurs first, (3) disease control rate 
defined as the percentage of subjects with advanced or metastatic cancer who have achieved 
CR, PR and stable disease. 
 
 
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4.2.3.3.2 Exploratory Efficacy Endpoints
Exploratory efficacy endpoints include PFS, defined as the time from allocation to the first 
documented disease progression according to
Response Evaluation Criteria in AML or 
DLBCL (see Section 7.1.2.7.1 and 7.1.2.7.2), or death due to any cause, whichever occurs 
first, and OS.  
Planned Exploratory Biomarker Research
4.2.3.4
Planned Genetic Analysis 
Understanding genetic determinants of drug response is an important endeavor during medical 
research. This research will evaluate whether genetic variation within a clinical trial population 
correlates with response to the treatment(s) under evaluation. If genetic variation is found to 
predict efficacy or adverse events, the data might inform optimal use of therapies in the patient 
population. This research contributes to understanding genetic determinants of efficacy and 
safety associated with the treatments in this study.
Future Biomedical Research
4.2.3.5
The Sponsor will conduct Future Biomedical Research on specimens collected for future 
biomedical research during this clinical trial.  This research may include genetic analyses 
(DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or 
the measurement of other analytes.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
subjects receive the correct dose of the correct drug/vaccine at the correct time.  The details 
of this Future Biomedical Research sub-trial are presented in Section 12.2 - Collection and 
Management of Specimens for Future Biomedical Research.  Additional informational 
material for institutional review boards/ethics committees (IRBs/ERCs) and investigational 
site staff is provided in Section 12.3.
Benefit/Risk
4.3
Subjects in clinical trials generally cannot expect to receive direct benefit from 
treatment/vaccination during participation, as clinical trials are designed to provide 
information about the safety and effectiveness of an investigational medicine.
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying Investigators Brochure (IB) and Informed 
Consent documents.
 
 
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5.0 METHODOLOGY
Entry Criteria
5.1
Diagnosis/Condition for Entry into the Trial
5.1.1
Male and female subjects with either AML (de Novo and post-MDS) or DLBCL ≥18 years 
of age will be enrolled in this trial.
Subject Inclusion Criteria
5.1.2
In order to be eligible for participation in this trial, the subject must:
1.
Be willing and able to provide written informed consent for the trial. Study entry is 
defined as the date that subject provides written informed consent.  The subject may 
also provide consent for Future Biomedical Research. However, the subject may 
participate in the main trial without participating in Future Biomedical research.
2.
Be ≥18 years of age on the day of providing written informed consent.
3.
Have an ECOG performance status score of ≤1.  
4.
Have an interval of ≥ 3 weeks since chemotherapy (≥ 6 weeks for nitrosoureas or 
mitomycin C), immunotherapy, hormone therapy or any other anticancer therapy 
(including investigational) or surgical intervention resection, or ≥3 half-lives for 
monoclonal antibodies, or ≥5 half-lives for other non-cytotoxic agents (whichever is 
longer).
5.
Female subjects of childbearing potential must have a negative urine or serum 
pregnancy test within 72 hours prior to receiving the first dose of study medication. If 
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required.
6.
Female subjects of childbearing potential should be willing to use an adequate 
method of contraception as outlined in section 5.7.3 - Contraception, for the course of 
the study through 90 days after the last dose of study medication. Note: Abstinence is 
acceptable if this is the usual lifestyle and preferred contraception for the subject.
7.
Male subjects of childbearing potential 5.7.3 – Contraception, starting with the first 
dose of trial treatment through 90 days after the last dose of study medication. Note: 
Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject
8.
Demonstrate adequate organ function as defined in Table 1 below. All screening labs 
should be performed within 7 days of treatment initiation.
 
 
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Table 1
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
AML Subjects = No Limit
DLBCL Subjects = ≥1.0 x 109/L
Platelets
AML Subjects = No Limit
DLBCL Subjects = ≥150 x 109/L (4 weeks without 
transfusion)
Hemoglobin
AML Subjects = No Limit
DLBCL Subjects = ≥ 8.0 g/dL (4 weeks without 
transfusion)
Renal
Creatinine clearance 
≥ 30 mL/min calculated according to the Cockroft 
and Gault formula or MDRD formula for  subjects 
aged > 65 years (see Section 12.7)
Hepatic
Serum total bilirubin
≤1.25 X ULN 
OR
In case of liver involvement, ≤ 2 X ULN will be 
allowed
AST (SGOT) and ALT (SGPT)
≤3 X ULN  
Alkaline Phosphatase
If > 2.5 X ULN, then liver fraction should be ≤2.5 
X ULN 
Chemistry 
Serum albumin
≥ 2.8 g/dL
Coagulation
International Normalized Ratio (INR) or 
Prothrombin Time (PT)
Activated Partial Thromboplastin Time 
(aPTT)
≤1.5 X ULN
≤1.5 X ULN
9.
Have a histologically or cytologically proven malignancy (AML or DLBCL)
according to the WHO 2008 classifications [43][44]. AML includes AML de novo 
and AML secondary to a pre-existing myelodysplastic syndrome.
The subject must also display the following specific malignancy criteria:
a) AML (de Novo and post-MDS): 

Subjects must have measurable and evaluable disease per tumor response 
criteria (see Section 7.1.2.7.1).

Subjects must have ≥ 5% bone marrow blasts at study entry, without 
alternative causality (e.g. bone marrow regeneration).

Subjects < 60 years old in second or further relapse or relapsing after 
allogeneic stem cell transplantation regardless of number of relapses.  
 
 
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
Subjects ≥60 years old in first relapse* with a disease-free interval (DFI) < 12 
months, or further relapse. If locally approved therapies exclude patients in 
this age group, with no prior lines of therapy, these patients will be considered 
eligible per local requirements.
*Note: First relapse is also applicable to AML post-MDS patients who have 
received prior treatment for MDS, but have not received prior treatment for 
AML.

Irrespective of age, in subjects relapsing after allogeneic stem cell transplant, 
the time elapsed since allogeneic stem cell transplant should be > 90 days. 

Subjects with Philadelphia chromosome positive (Ph+) 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.
b) DLBCL: 

Subjects must have measurable and evaluable disease per tumor response
criteria (see Section 7.1.2.7.2).  

Subjects 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 a spiral CT-scan.

Subjects having failed 2 standard lines of therapy (at least one containing an 
anti-CD20 monoclonal antibody), or for whom such treatment is 
contraindicated.
Subject Exclusion Criteria
5.1.3
The subject must be excluded from participating in the trial if the subject:
1. Has participated in another clinical trial or treatment with any investigational drug
(excluding anticancer treatments) within 30 days prior to study entry.
2. Has other concomitant anticancer treatment.
3. Has persistent grade >1 clinically significant toxicities related to prior antineoplastic 
therapies (except for alopecia); stable sensory neuropathy ≤grade 2 NCI-CTCAE v. 
4.0 is accepted.
4. Has a known additional malignancy that is progressing or requires active 
treatment.
Exceptions include basal cell carcinoma of the skin, squamous cell 
carcinoma of the skin, or in situ cervical cancer that has undergone potentially 
curative therapy.
5. Has taken a similar class of therapy previously (BET inhibitor).
6. Has inability to swallow oral medications or presence of a gastrointestinal disorder 
(e.g. malabsorption) deemed to jeopardize intestinal absorption of MK-8628.
 
 
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7. Has known primary CNS malignancy or symptomatic or untreated CNS metastases.
8. Has other serious illness or medical condition, such as active infection, unresolved 
bowel obstruction, psychiatric disorders, or cerebrovascular accident (within 1 year of 
study entry).
9. Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).  
HIV 1/2 antibodies testing is only required when the investigator has reason to 
suspect the patient has Human Immunodeficiency Virus infection.
10. Has known active Hepatitis B (e.g. HBsAg reactive) or Hepatitis C (e.g. HCV RNA 
[qualitative] is detected). Hepatitis B surface Antigen reactive testing and HCV RNA 
[qualitative] testing is only required when the investigator has reason to suspect the 
patient has Hepatitis B infection or Hepatitis C infection.
11. Has received high dose chemotherapy followed by autologous stem cell 
transplantation less than 90 days prior to first dose of MK-8628.
12. Has concomitant (and cannot discontinue) therapy with strong CYP3A4 or CYP2A6
interfering drugs, or any other medication / therapy prohibited by the protocol.  Please 
see Section 5.5 .
13. Has peripheral cytopenia (i.e. auto-immune hemolytic anemia or thrombocytopenia).
14. Has acute promyelocytic leukemia or clinically uncontrolled (i.e. with bleeding) 
disseminated intravascular coagulation (DIC).
15. Has chronic graft versus host disease (GVHD) or on immunosuppressive therapy for 
the control of GVHD.
16. Has uncontrolled disease-related metabolic disorder (e.g. hypercalcemia).
17. Is pregnant or breast-feeding.
18. Has any of the following cardiac related conditions:
a) Congestive heart failure (except if medically controlled)
b) Angina pectoris (except if medically controlled)
c) Previous history of myocardial infarction (within 1 year of study entry)
d) Uncontrolled hypertension (defined as systolic blood pressure (SBP) ≥ 140 
mm Hg and/or diastolic blood pressure (DBP) > 90 mm Hg and not 
adequately managed by anti-hypertensive medication)
e) Uncontrolled arrhythmias
 
 
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Trial Treatment(s)
5.2
The treatment to be used in this trial is outlined below in 
Table 2
Trial Treatment
Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/Treatment 
Period
Use 
MK-8628
20 mg
BID
Oral 
Continuous / 
21 
days per cycle
Experimental
MK-8628
30 mg
BID
Oral
Continuous / 
21 
days per cycle
Experimental
The first dose of trial treatment will be administered at the trial site in the morning of the 
Cycle 1 Day 1 Visit, and then again in the evening.  Subsequent dosing will be performed 
twice daily either at the trial site on scheduled visit days, or by the subject (i.e., unsupervised 
at his/her home), at approximately the same times each day.
All supplies indicated in Table 2 above will be provided centrally by the Sponsor or locally 
by the trial site, subsidiary or designee, depending on local country operational or regulatory 
requirements.
For any commercially available product that is provided by the trial site, subsidiary or 
designee every attempt will be made to source these supplies from a single lot/batch number. 
The trial site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product as per local guidelines unless otherwise instructed by the 
Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection/Modification
5.2.1
Dose Selection (Preparation)
5.2.1.1
The rationale for selection of doses to be used in this trial is provided in Section 4.0 –
Background & Rationale.  There are no specific calculations or evaluations required to be 
performed in order to administer the proper dose to each subject.
Dose Escalation 
5.2.1.2
A twice daily (BID) dose escalation will be performed using a 6+8 two-stage design with 
continuous DLT rate monitoring via a modified toxicity probability index (mTPI) (Ji design), 
targeting a maximum 25% DLT rate [1].
Two planned dose levels will be evaluated sequentially: 20 mg BID and 30 mg BID (all 
continuous daily).  See Table 3 and Table 4 for the dose escalation scheme.
 
 
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Table 3
Dose Escalation Scheme
Dose Level
(DL)
MK-8628 (mg/dose)
Outcome (#DLT/#Subjects)* / Actions to be taken
BID Regimen
(continuous)
DL 1
20
At each DL:
- Escalate/de-escalate per DLT rate observed using mTPI (Table 4)
DL 2
30
* Evaluated during the first 21 days of treatment
Table 4
Modified Toxicity Probability Interval (mTPI) Design
Number of subjects treated at current dose
Number of toxicities
6
7
8
9
10
11
12
13
14
0
E
E
E
E
E
E
E
E
E
1
S
E
E
E
E
E
E
E
E
2
S
S
S
S
S
S
S
S
E
3
D
S
S
S
S
S
S
S
S
4
DU
DU
DU
D
S
S
S
S
S
5
DU
DU
DU
DU
DU
D
S
S
S
6
DU
DU
DU
DU
DU
DU
DU
DU
D
7
DU
DU
DU
DU
DU
DU
DU
DU
8
DU
DU
DU
DU
DU
DU
DU
9
DU
DU
DU
DU
DU
DU
10
DU
DU
DU
DU
DU
11
DU
DU
DU
DU
12
DU
DU
DU
13
DU
DU
14
DU
E = Escalate to the next higher dose
S = Stay at the current dose
D = De-escalate to the next lower dose
DU = The current dose is unacceptably toxic
Target toxicity rate = 25%
E = Escalate; S = Stay; D = De-escalate; DU = Unacceptable
Note: 

De-escalation at lowest dose level indicates stopping of trial

Escalation at highest dose level indicates staying at that level
Each cohort (AML and DLBCL) will be evaluated independently in regards to enrollment 
and dose level escalation/de-escalation. 
 
 
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Subjects may be enrolled continuously (i.e., without waiting for Cycle 1 completion of 
subjects who have received the first dose) unless a DLT is observed at the particular dose.  If 
0 out of the first 6 subjects in a given dose level develop a DLT, then the dose can escalate to 
the next level without further expansion. If 3 patients out of the first 6 patients develop a 
DLT, the dose will be de-escalated to the next lowest dose level. If ≥ 4 out of the first 6 
patients develop a DLT, this indicates an unacceptable toxicity. If 1 to 2 out of the first 6 
subjects of a given dose level develop a DLT, expand the current dose level according to 
Table 4 by continuing enrollment as follows. The number of subjects who are enrolled at that 
dose but are not yet fully evaluable for DLT assessment may not exceed the number of 
remaining subjects who are at risk of developing a DLT before the dose would be considered 
unacceptably toxic (denoted as DU in Table 4).  For example, if 2/7 subjects have 
experienced a DLT at a given dose level, no more than an additional 3 subjects should be 
enrolled at this dose level until additional DLT data are available. This is because this dose 
level would be considered unacceptably toxic if all 3 of the additional subjects experience a 
DLT (i.e., 5/10 subjects with DLT in Table 4). To find out how many more subjects can be 
enrolled, one can count steps in diagonal direction (down and to the right) from the cell (7 
subjects, 2 toxicities) to the first cell marked DU.
De-escalation (D) or unacceptable (DU) at the lowest dose level (DL1) indicates stopping of 
the trial. Escalation (E) at the highest dose level (DL2) indicates staying at that level. Note 
that while 25% has been the target toxicity rate used to generate the guidelines in Table 4, the 
observed rate of subjects with DLT at the RP2D may be slightly above or below 25%.
Subjects not evaluable for DLT (i.e. receiving less than 85% of the intended cumulative dose 
in Cycle 1 for any reason other than toxicity; < 18 days of treatment) and who do not 
experience DLT will be replaced.
Subjects will receive MK-8628 at the DL they were assigned at treatment allocation 
throughout the study, or at a reduced dose according to toxicity encountered.
A Safety Review Committee will meet on a regular basis to make decisions related to current 
dose level duration, escalation, de-escalation, and stopping of the trial.  Decisions will be 
based on available safety and toxicity data.  The Safety Review Committee will be composed 
of an independent medical expert in oncology drug development, the principal investigators 
(or sub-investigator delegated by the PI) from each of the participating sites, the PK 
investigator, and Sponsor representatives. 
Definition of Dose Limiting Toxicity 
5.2.1.3
DLT is defined as any of the following toxicities occurring during the first cycle of treatment 
(21 days) for each dose level. See Section 5.9 for rules on replacement of subjects in the DLT 
period.
 
 
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The occurrence of any of the following toxicities during Cycle 1, if assessed by the 
investigator to be possibly, probably or definitely related to MK-8628, will be considered 
a DLT:
Hematologic Toxicity:
AML
1. Pancytopenia with a hypocellular bone marrow and no marrow blasts lasting for ≥6 
weeks after the start of a cycle.  For subjects with AML who have a suspected DLT in 
case of pancytopenia with a hypocellular bone marrow and no marrow blast on Day 
22 bone marrow aspiration, the DLT window will be extended to the first 2 cycles or 
Day 42 for repeat bone marrow confirmation. However, enrollment of additional 
patients at this dose level should not be delayed during the extended window for DLT 
in this situation assuming a confirmed DLT for such a subject would not affect a dose 
escalation or de-escalation decision.
DLBCL
1. Grade 4 hematologic toxicity lasting ≥7 days, except thrombocytopenia
Grade 4 thrombocytopenia of any duration
Grade 3 thrombocytopenia is a DLT if associated with bleeding
2. Febrile or infection related neutropenia, Grade 3 or Grade 4
Non-Hematologic Toxicity:
1. Grade 4 non-hematologic toxicity (not laboratory)
2. Grade 3 non-hematologic toxicity (not laboratory) lasting > 3 days despite optimal 
supportive care. Grade 3 nausea, vomiting or diarrhea will be considered a DLT if 
lasting more than 3 days despite optimal supportive care.
3. Any Grade 3 or Grade 4 non-hematologic laboratory abnormality, if

medical intervention is required, or

the abnormality leads to hospitalization, or

the abnormality persists for > 1 week
4. Any of the following liver test abnormalities** are observed (see also Section 12.8):

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 MK-
8628 and not related to liver impairment with sponsor’s agreement.
 
 
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Other Toxicity:
1. Any drug-related AE which caused subject to discontinue treatment during Cycle 1
2. Any study drug-related toxicity resulting in a subject missing ≥20% of planned doses 
during Cycle 1.
3. Any treatment-related toxicity which causes a greater than 2 week delay in initiation 
of Cycle 2.
4. Grade 5 toxicity
DLTs must be reported within 24 hours to the Sponsor as Events of Clinical Interest (see 
Section 7.2.3.2). If the event also meets the criteria for seriousness, follow the reporting 
guidelines for Serious Adverse Events (SAEs) outlined in Section 7.2.3.1.
Recommended Phase 2 Dose (RP2D)
5.2.1.4
Selecting the RP2D will involve a multi-faceted decision taking into account safety,
tolerability, early efficacy signal, PK exposure and PD markers. The primary endpoint 
driving dose selection is the DLT rate, with weight given to the highest DL tolerated (< 25% 
DLT rate). All other facets will be considered supportive. It is important to note that dose 
selection in this study aims to assess a recommended phase 2 dose range, with other factors 
aside from those mentioned above, such as target engagement, contributing to refining the 
dose selection for phase 2. This will be further evaluated in subsequent clinical investigations 
in either monotherapy or combination trials.
Dose Adaptation 
5.2.1.5
The Common Terminology Criteria for Adverse Events version 4.0 (CTCAE 4.0) must be
used to grade the severity of adverse events. For AEs not specifically addressed in Section 
5.6, MK-8628 will be withheld for drug related Grade 4 hematologic toxicities, non-
hematological toxicity ≥Grade 3 including laboratory abnormalities, and severe or life-
threatening AEs as per Table 5 below. If a dose of MK-8628 is withheld for toxicity, then 
subjects may resume dosing with MK-8628 if that is appropriate at their next scheduled 
appointment or when toxicity has improved as described below or in Section 5.6.
 
 
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Table 5
Dose Modification Guidelines for Drug-Related Adverse Events
Toxicity
Grade
Hold 
Treatment 
(Y/N)
Timing 
for 
restarting 
treatment
Dose/Schedule 
for restarting 
treatment
Criteria for 
discontinuation 
after 
consultation 
with Sponsor
Hematologic 
toxicity
DLBCL
1, 2, 3
No 
N/A
N/A
N/A
3
associated 
neutropenia 
with 
infection;
or 
Thrombocytopenia 
with bleeding or 
lasting > 7 days
Yes
Toxicity 
resolves to 
Grade 0-1, 
or 
to 
baseline
Resume 
treatment at next 
lowest 
dose 
level (Table 6)
Toxicity does not 
resolve within 2 
weeks 
of 
last 
dose.
Permanent 
discontinuation 
should 
be 
considered 
for 
any severe or life-
threatening event
4
or
Febrile 
neutropenia
Yes
Toxicity 
resolves to 
Grade 0-1, 
or 
to 
baseline
Resume 
treatment at next 
lowest 
dose 
level (Table 6)
Toxicity does not 
resolve within 2 
weeks 
of 
last 
dose.
Permanent 
discontinuation 
should 
be 
considered 
for 
any severe or life-
threatening event
Hematologic 
toxicity
AML
1, 2, 3
No 
N/A
N/A
N/A
4
or
Pancytopenia 
with a hypocellular 
bone marrow and 
no marrow blasts 
lasting ≥ 6 weeks 
after the start of a 
cycle.
Yes
Toxicity 
resolves to 
Grade 0-1, 
or 
to 
baseline
Resume 
treatment at next 
lowest 
dose 
level (Table 6)
Toxicity does not 
resolve within 2 
weeks 
of 
last 
dose.
Permanent 
discontinuation 
should 
be 
considered 
for 
any severe or life-
threatening event
 
 
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Toxicity
Grade
Hold 
Treatment 
(Y/N)
Timing 
for 
restarting 
treatment
Dose/Schedule 
for restarting 
treatment
Criteria for 
discontinuation 
after 
consultation 
with Sponsor
Non-Hematologic 
Laboratory 
Abnormalities
1, 2
No 
N/A
N/A
N/A
3, 4
with 
or 
without 
symptoms lasting > 
48 hours
Consider 
holding;  
Hold 
treatment 
for 
total 
bilirubin 
increases 
>2X 
ULN 
or 
2X 
baseline (if 
elevated at 
baseline) 
and/or AST 
or ALT ≥
5X ULN 
Toxicity 
resolves to 
Grade 0-1, 
or 
to 
baseline
Laboratory 
abnormalities 
resolves within 
1 week: treat at 
same dose and 
schedule
Laboratory 
abnormalities 
does not resolve 
within 1 week: 
may 
consider 
resuming 
treatment at next 
lowest 
dose 
level (Table 6)
Toxicity does not 
resolve within 2 
weeks 
of 
last 
dose.
Permanent 
discontinuation 
should 
be 
considered 
for 
any severe or life-
threatening event
Non-Hematologic 
toxicity
Note: Exception to 
be treated similar to 
Grade 1 toxicity

Grade 2 
alopecia

Grade 2 
fatigue
1
No 
N/A
N/A
N/A
2
Any intolerable G2 
non-hematologic 
toxicity lasting >7 
days 
with 
or 
without 
dose 
reduction
Consider 
holding for 
persistent 
symptoms 
Toxicity 
resolves to 
Grade 0-1 
or baseline
Clinical 
AE 
resolves within 
2 weeks: treat at 
same dose and 
schedule
Clinical 
AE 
does not resolve 
within 2 weeks: 
may 
consider 
resuming 
treatment at next 
lowest 
dose 
level (Table 6)
Dose 
is 
interrupted for > 
2 weeks.
3, 4
unless 
not 
optimally 
treated 
with 
supportive 
care (e.g., Grade 3 
vomiting 
not 
adequately treated 
according to anti-
emetic standard of 
care)
Yes
Toxicity 
resolves to 
Grade 0-1 
or baseline
Resume 
treatment at next 
lowest 
dose 
level (Table 6)
Toxicity does not 
resolve within 2 
weeks 
of 
last 
dose. 
Permanent 
discontinuation 
should 
be 
considered 
for 
any severe or life-
threatening event
After recovery from toxicity, treatment will be resumed at the next lowest dose level (Table 
6). For subjects treated at DL1 (20 mg BID), treatment will be resumed at a level of 10 mg 
BID.
 
 
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Table 6
MK-8628 Dose and Schedule Modifications
Dose Level (DL)
Initial Dose
1st Modification
DL 1
20 mg BID continuous
10 mg BID continuous
DL 2
30 mg BID continuous
20 mg BID continuous
No more than one dose reduction should be implemented unless the investigator thinks it in 
the subject’s best interests to pursue study treatment with further dose reduction (additional 
dose reduction by one dose level), with the Sponsor’s agreement. 
Dosing interruption for > 2 weeks due to toxicity will lead to definitive study treatment 
discontinuation, unless the investigator thinks it in the subject’s best interests to pursue study 
treatment, with the Sponsor’s agreement.
Timing of Dose Administration
5.2.2
MK-8628 is to be administered orally with water in a fasted state, and as part of a BID 
regimen (twice daily, approximately 12 hours apart).   Subjects should not have food for 1 
hour before or 3 hours after study drug administration.  
Dosing not performed at the same time (±2h) as on other days should be skipped. Subjects
are to be instructed that if they vomit or omit their dose in that time frame, it is not to be 
replaced. Capsules must not be opened or chewed.
A treatment cycle is 21 days (3 weeks). The subsequent cycle will begin on day 22 or after 
recovery from any AEs to baseline or Grade < 2 associated with the previous cycle.
Subjects should receive study treatment within 3 days following treatment allocation.
Details of the exact dose and time of administration will be documented in a validated 
subject diary and reported in the electronic case report form (eCRF).
Premedication
5.2.2.1
No systematic premedication will be given at least during the first cycle. See section 5.5 for a 
list of allowed and prohibited medications.
Trial Blinding 
5.2.3
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
Randomization or Treatment Allocation
5.3
Cohort management and treatment allocation will occur centrally using an interactive web 
response system (IWRS). Subjects will be allocated to treatment by non-random assignment 
based on the open dosing cohort and number of available slots.
Stratification
5.4
No stratification based on age, sex or other characteristics will be used in this trial.
 
 
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Concomitant Medications/Vaccinations (Allowed and Prohibited)
5.5
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required.  The investigator should discuss any questions regarding this with the Sponsor 
Clinical Director.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician.  However, the decision to continue the 
subject on trial therapy or vaccination schedule requires the mutual agreement of the 
investigator, the Sponsor and the subject.
Medications
5.5.1
All treatments taken by subjects at study entry or within 4 weeks or 5 half-lives prior to 
initiating treatment (whichever is longer) or at any time during the study, in addition to the 
investigational product are considered concomitant medications and must be documented in 
the eCRF.
No premedication is planned.
Allowed
Listed below are allowed concomitant medications / therapy during the course of the trial:
1. Supportive treatment of symptoms/adverse events or standard treatment of concomitant 
conditions, notably transfusion support and antibiotics or bisphosphonates will be given 
as medically indicated and reported in the eCRF.
2. Chemotherapy, hormone therapy or any other anticancer therapy or surgical intervention 
resection performed ≥ 3 weeks prior to study start (≥ 6 weeks for nitrosoureas or 
mitomycin C) or ≥3 half-lives for monoclonal antibodies or ≥5 half-lives for other non-
cytotoxic agents (whichever is longer). 
3.
Subjects 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 the study due to the potential increased risk of bleeding in 
the event of occurrence of severe thrombocytopenia. Blood cell count should be 
performed more frequently in such subjects, at least weekly throughout study, and more 
often in cases of grade 2 to 3 thrombocytopenia. 
 
 
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Prohibited
Listed below are specific restrictions for concomitant medications / therapy during the course 
of the trial:
1. Concurrent treatment with any investigational drug or anticancer (antineoplastic) therapy, 
including the following: chemotherapy, immunotherapy, hormone therapy, or biological 
therapies. 
(The only exception is hydroxyurea given to control hyperleukocytosis that can be 
continued until 48 hours before MK-8268 treatment initiation, but must be stopped at that 
time. Furthermore, should a rapidly increasing white blood cell count occur during the 
first cycle of MK-8268 treatment, hydroxyurea should not be given earlier than day cycle 
1 / day 3, nor beyond day 43 (cycle 3 / day 1), and for the shortest period possible as 
clinically indicated to control hyperleukocytosis and maintain the subject on study. On 
day 43 (cycle 3 / day 1), the decision to start MK-8268 for cycle 3 will be made by the 
investigator according to the subject’s anticipated benefit. If hydroxyurea has to be 
resumed during cycle 3, this will be considered as MK-8268 treatment failure, and the 
subject will be withdrawn from the study)
2. Corticosteroids (except chronic treatment with ≤ 4.0 to 6.0 mg / day of 
methylprednisolone or equivalent dose of other corticosteroids). 
3. Prophylactic antiemetic drugs or other drugs given with a prophylactic intent in the first 
cycle (unless the Early Phase Safety Teleconferences Meeting decides to deliver 
systematic premedication).
4. Strong inducers, strong inhibitors, and sensitive / narrow therapeutic range substrates of 
the P450 cytochrome enzymes CYP3A4 and CYP2A6 (see Section 12.9) are prohibited.   
Moderate inducers and moderate inhibitors of these cytochrome enzymes should be used 
with caution. Since this list is not comprehensive, the investigator should use his/her 
medical judgment when a subject presents with a medication not on the list or call the 
Sponsor Clinical Director for clarification.
Rescue Medications & Supportive Care
5.6
No rescue or supportive medications are specified to be used in this trial.
Supportive Care Guidelines
5.6.1
Toxicities will be managed by the investigator according to the local standard of care, except 
where noted in this protocol. Supportive treatment must be reported in the concomitant 
medication section of the eCRF.
General Guidelines for Clinically Significant Toxicities
5.6.1.1
General guidelines regarding management and dose reduction for adverse events that are 
considered by the investigator to be related to study treatment are provided in Section 5.2.1.5.  
All adverse events should be monitored closely, with supportive care provided according to 
institutional standards.
 
 
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Hepatic Laboratory Abnormalities
5.6.1.2
All trial subjects with liver test abnormalities should be followed weekly until all 
abnormalities return to normal or to the baseline state. For subjects with isolated total 
bilirubin increases > 2X ULN or 2X baseline (if elevated at baseline), monitoring should be 
every 2 weeks until bilirubin returns 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 Section 12.8 for guidelines on the handling of 
these events (potential Hy’s law cases).
Diet/Activity/Other Considerations
5.7
Diet
5.7.1
Subjects must avoid drinking grapefruit juice while on study, as this is a CYP3A4 inhibitor 
and is therefore not permitted. Subjects should otherwise maintain a normal diet, except 
when required to fast prior to MK-8628 administration (Section 5.2.2), or
unless 
modifications are required to manage an AE such as diarrhea, nausea or vomiting. 
Potential Phototoxicity
5.7.2
No phototoxicity studies have been performed in humans to date.  However, as MK-8628 
absorbs light in the range of 290 and 400 mm with a molar extinction coefficient (MEC) of > 
1,000 L/mol.cm, it is recommended that subjects avoid the sun and UV exposure until the 
results of phototoxicity studies are available.
Contraception
5.7.3
MK-8628 may have adverse effects on a fetus in utero.  Furthermore, it is not known if MK-
8628 has transient adverse effects on the composition of sperm.  
For this trial, male subjects will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).  
Female subjects will be considered of non-reproductive potential if they are either: 
1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle-stimulating hormone (FSH) 
level in the postmenopausal range may be used to confirm a post-menopausal state in 
women not using hormonal contraception or hormonal replacement therapy.  In the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.); 
OR
2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy, or 
bilateral tubal ligation/occlusion at least 6 weeks prior to screening; 
OR
 
 
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3) has a congenital or acquired condition that prevents childbearing.
Female and male subjects of reproductive potential must agree to avoid becoming pregnant 
or impregnating a partner, respectively, while receiving study drug MK-8628 and for 90 days 
after the last dose of study drug.  Subjects must comply with one of the following:  
1) practice abstinence† from heterosexual activity; 
OR
2) use (or have their partner use) acceptable contraception during heterosexual activity.  
Acceptable methods of contraception are‡:
Single method (one of the following is acceptable):
•
intrauterine device (IUD)
•
vasectomy of a female subject’s sole male partner 
•
contraceptive rod implanted into the skin
Combination method (requires use of two of the following):
•
diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide)
•
cervical cap with spermicide (nulliparous women only)  
•
contraceptive sponge (nulliparous women only)
•
male condom or female condom (cannot be used together)
•
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-only 
pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous contraceptive 
injection
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual lifestyle and 
if considered acceptable by local regulatory agencies and ERCs/IRBs.  Periodic abstinence 
(e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are 
not acceptable methods of contraception. 
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it 
does not qualify as an acceptable method of contraception for subjects participating at sites in 
this country/region.
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate 
in the study, subjects of childbearing potential must adhere to the contraception requirement 
 
 
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(described above) from the day of study medication initiation (or 14 days prior to the 
initiation of study medication treatment [Day 1] for oral contraception) throughout the study 
period up to 90 days after the last dose of trial therapy.  If there is any question that a subject 
of childbearing potential will not reliably comply with the requirements for contraception, 
that subject should not be entered into the study.  
Monthly pregnancy testing is recommended per local standards if applicable.
For countries (e.g., Sweden and Norway) or sites that follow the Clinical Trial 
Facilitation Group (CTFG) guidance, please use the following:
MK-8628 may have adverse effects on a fetus in utero.  Furthermore, it is not known if it 
may have transient adverse effects on the composition of sperm.  Therefore, non-pregnant, 
non-breastfeeding women may only be enrolled if they are willing to follow the CTFG 
Guidance (Final Version 2014-09-15, Sections 4.1 and 4.2) for highly effective birth control 
as outlined below, or are considered to be highly unlikely to conceive.  Highly unlikely to 
conceive is defined as 1) surgically sterilized, or 2) postmenopausal (a woman who is ≥45 
years of age and has not had menses for greater than 1 year will be considered 
postmenopausal), or 3) not heterosexually active for the duration of the study.  Subjects 
should use birth control methods that can achieve a failure rate of less than 1% per year when 
used consistently and correctly and are considered as highly effective birth control methods. 
Such methods include:
•
Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation:
o
Oral
o
Intravaginal
o
Transdermal
•
Progestogen-only hormonal contraception associated with inhibition of ovulation:
o
Oral
o
Injectable
o
Implantable
•
Intrauterine device (IUD)
•
Intrauterine hormone-releasing system (IUS)
•
Bilateral tubal occlusion
•
Vasectomised partner
 
 
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•
Sexual abstinence
Subjects should start using birth control from study Visit 1 throughout the study period up to 
90 days after the last dose of study therapy. 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate 
in the study they must adhere to the contraception requirement (described above) for the 
duration of the study and during the follow-up period defined in Section 7.2.2 – Reporting of 
Pregnancy and Lactation to the Sponsor.  If there is any question that a subject will not 
reliably comply with the requirements for contraception, that subject should not be entered 
into the study. 
Pregnancy 
5.7.4
If a subject inadvertently becomes pregnant while on treatment with MK-8628, the subject 
will immediately be discontinued from trial treatment.  The site will contact the subject at 
least monthly and document the subject’s status until the pregnancy has been completed or 
terminated.  The outcome of the pregnancy will be reported to the SPONSOR without delay 
and within 24 hours if the outcome is a serious adverse experience (e.g., death, abortion, 
congenital anomaly, or other disabling or life-threatening complication to the mother or 
newborn).  The study investigator will make every effort to obtain permission to follow the 
outcome of the pregnancy and report the condition of the fetus or newborn to the SPONSOR. 
If a male subject impregnates his female partner the study personnel at the site must be 
informed immediately and the pregnancy reported to the SPONSOR and followed as 
described above and in Section 7.2.2.
Nursing Women
5.7.5
It is unknown whether MK-8628 is excreted in human milk.  Since many drugs are excreted 
in human milk, and because of the potential for serious adverse reactions in the nursing 
infant, subjects who are breast-feeding are not eligible for enrollment.
Subject Withdrawal/Discontinuation Criteria
5.8
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal procedures; including specific details regarding 
withdrawal from Future Biomedical Research, are provided in Section 7.1.4 – Other 
Procedures.
Subjects will continue study treatment until any of the following events at which point it will 
be definitively discontinued: 

Disease progression

Unacceptable toxicity
 
 
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
Subject withdrawal of consent

Subject non-compliance

Treatment interruption for > 2 weeks for any reason (except in the event of perceived 
benefit, with Sponsor agreement)

Recurrence of DLT despite dose reduction (except in the event of perceived benefit, with 
Sponsor agreement)
However, in case of investigator’s perceived benefit for the subject, treatment continuation 
can be considered with dose reduction despite delay/interruption > 2 weeks or reoccurrence 
of a DLT with the same intensity after one dose reduction. The perceived benefit of the 
investigator is defined by 1) any objective tumor response, or 2) any tumor regression not 
meeting standard response criteria, but which could improve with additional treatment, or 3) 
any symptomatic improvement, which, in the investigator’s opinion, could not be achieved 
by other means. If, in the cases described above, DLT recurs with the same intensity despite 
one dose reduction, a second dose reduction may be considered. The decision should be 
discussed with the Sponsor, but the final decision must be made by the investigator.  The 
reason for and date of dose reduction must be recorded in the eCRF and source documented 
in the subject's medical records.
In all cases, the reason for and date of study treatment discontinuation must be recorded in 
the eCRF and source documented in the subject's medical records. As far as possible, there 
should be only one reason for treatment discontinuation. If there are several (e.g. concomitant 
progressive disease and toxicity), the primary one must be reported. The subject must be 
followed up to establish whether the reason was an AE, and if so, this must be reported as 
such.
As far as possible, all examinations scheduled for the final study day must be performed for 
all  subjects who receive the investigational product but who do not complete the study 
according to protocol.
The investigator must make every effort to contact subjects lost to follow-up, especially 
when a subject is treated in another non-study center.
Subject Replacement Strategy
5.9
Subjects not evaluable for DLT (i.e. receiving less than 85% of the intended cumulative dose 
in Cycle 1 for any reason other than toxicity; < 18 days of treatment) and who do not 
experience DLT will be replaced.
A subject who discontinues from the trial for any other reason will not be replaced.
Beginning and End of the Trial
5.10
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last study-related phone-call or visit,
discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by 
the investigator).
 
 
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Clinical Criteria for Early Trial Termination
5.11
Early trial termination will be the result of the criteria specified below:
1. Incidence or severity of adverse drug reactions in this or other trials suggest a potential 
health hazard to subjects
2. Quality or quantity of data recording is inaccurate or incomplete
3. Poor adherence to protocol and regulatory requirements
4. Plans to modify or discontinue the development of the study drug
In the event of Sponsor decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made
 
 
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6.0 TRIAL FLOW CHART
Screening 
Phase
Treatment Phase
Cycle = 21 days
End of 
Treatment
Post Treatment Phase
Treatment Cycle/Title:
Pre-study / 
Screening
(Visit 1)
Cycle 1
Cycle 2
Cycle 3
Cycle 4 
Cycle 5 
and 
beyond
Treatment 
Discontinuation 
Visit
30 Day Post 
Treatment 
Safety Follow-
up Visit
Follow-up Visits 
(AML)a
Follow-up Visits
(DLBCL)a
Cycle Day:
1
8
15
1
1
1
1
At the time of 
discontinuation
30 days post 
discontinuation
Every 6 weeks 
post 
discontinuation
Every 12 weeks 
post 
discontinuation
Scheduling Window Days:
-14 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±7
Administrative Procedures
Informed Consent
X
Informed Consent for Future 
Biomedical Research
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics, Medical History
X
Concomitant Medication Review
X
X
X
X
X
X
X
X
X
X
Diagnosis & prior treatments for 
malignancy
X
Baseline symptoms & complaints
X
MK-8628 
Administration/Dispensing
MK-8628 
Administration/Dispensing
BID continuouslyb at assigned dose level; Study 
drug will be dispensed on or prior to day 1 of each 
cycle.
Clinical 
Procedures/Assessments
Full Physical Examination
X
X
X
Directed Physical Examination 
X
X
X
X
X
X
ECOG Performance Status (PS)
X
X
X
X
X
X
X
X
X
 
 
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Screening 
Phase
Treatment Phase
Cycle = 21 days
End of 
Treatment
Post Treatment Phase
Treatment Cycle/Title:
Pre-study / 
Screening
(Visit 1)
Cycle 1
Cycle 2
Cycle 3
Cycle 4 
Cycle 5 
and 
beyond
Treatment 
Discontinuation 
Visit
30 Day Post 
Treatment 
Safety Follow-
up Visit
Follow-up Visits 
(AML)a
Follow-up Visits
(DLBCL)a
Cycle Day:
1
8
15
1
1
1
1
At the time of 
discontinuation
30 days post 
discontinuation
Every 6 weeks 
post 
discontinuation
Every 12 weeks 
post 
discontinuation
Scheduling Window Days:
-14 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±7
Height
X
Weight
X
X
X
X
X
X
X
X
X
Vital Signs (heart rate, blood 
pressure, temperature)
X
Xc
Xd Xd
Xd
Xd
Xd
Xd
X
Xn
12 Lead Electrocardiogram (ECG)
X
Xc
Xd
Xe
X
Xn
Bone Marrow Aspiration / 
Biopsy: AMLf
X
X
X
Tumor Assessment & Response 
Evaluation: AMLf
X
X
X
X
X
Xa
PET & CT Imaging (Neck, Chest, 
Abdomen, Pelvis): DLBCLg
X
X
Xh
Xa
Tumor Assessment & Response 
Evaluation: DLBCLg and 
Assessment of  Lymphoma B 
Symptomsg
X
Xh
Xa
Adverse Events Monitoring
X
X
X
X
X
X
X
X
X
X i
X i
X i
Tumor Sample Submission j
X
Laboratory 
Procedures/Assessments
Complete Blood Count (CBC) k
Xm
X
X
X
X
X
X
X
X
Xn
Xa
PT-International Normalized 
Ratio (INR), aPTT, and Factor 
VII
Xm
X
X
X
X
X
X
X
X
Xn
Serum Chemistry l
Xm
X
X
X
X
X
X
X
X
Xn
Urinalysis
X
X
X
X
X
X
X
X
X
Xn
 
 
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Screening 
Phase
Treatment Phase
Cycle = 21 days
End of 
Treatment
Post Treatment Phase
Treatment Cycle/Title:
Pre-study / 
Screening
(Visit 1)
Cycle 1
Cycle 2
Cycle 3
Cycle 4 
Cycle 5 
and 
beyond
Treatment 
Discontinuation 
Visit
30 Day Post 
Treatment 
Safety Follow-
up Visit
Follow-up Visits 
(AML)a
Follow-up Visits
(DLBCL)a
Cycle Day:
1
8
15
1
1
1
1
At the time of 
discontinuation
30 days post 
discontinuation
Every 6 weeks 
post 
discontinuation
Every 12 weeks 
post 
discontinuation
Scheduling Window Days:
-14 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±7
Urine or Serum Pregnancy Test –
if applicableo
Xo
PK Blood Sampling 
Xp Xq Xq
Xq
PD Blood Sampling 
Xr
Xs
Blood for Genetic Analysis t
X
a.
In subjects who discontinue study therapy without documented disease progression, every effort should be made to continue monitoring their disease status 
every 6 weeks (± 3 days)  for AML subjects and every 12 weeks (± 7 days) for DLBCL subjects  until (1) the start of new anti-cancer treatment, (2) 
documented disease progression, (3) death, or (4) the end of the study, whichever occurs first. If subjects have stable disease, partial response, or complete 
response, they should continue on this assessment schedule. Tumor response assessments should occur at any time where there is clinical suspicion of 
progression or relapse.
b.
MK-8628 is to be administered orally with water in a fasted state, and as part of a BID regimen (twice daily, approximately 12 hours apart).   Subjects 
should not have food for 1 hour before or 3 hours after study drug administration.  Dosing not performed at the same time (±2h) as on other days should be 
skipped. Subjects are to be instructed that if they vomit or omit their dose in that time frame, it is not to be replaced.
c.
Collected at the following time points on day 1 of cycle 1: pre-dose, 1 hour post-dose, 2 hours post-dose.
d.
Collected prior to the subject dosing (pre-dose) on that day.
e.
Collected prior to the subject dosing (pre-dose) on day 1 of every odd treatment cycle (every 6 weeks) after cycle 3 day 1.
f.
AML tumor response assessments will be completed through the analysis of bone marrow aspiration samples and bone marrow biopsy samples (if 
necessary). See Section 7.1.2.7.1.  Bone marrow analysis is required at screening, cycle 2 day 1, and cycle 3 day.  Tumor response assessments will be 
conducted on day 1 of every cycle beyond cycle 3 through hematological analysis of peripheral blood. Evidence of response in peripheral blood may be 
confirmed by further bone marrow assessments as displayed in the tumor response criteria.  The timing of tumor response assessments should follow 
calendar days and should not be adjusted for delays in cycle starts.   
g.
DLBCL tumor response assessments will be completed through PET-CT and CT imaging analysis. See Section 7.1.2.7.2.  The timing of tumor response 
assessments should follow calendar days and should not be adjusted for delays in cycle starts. The same imaging technique should be used in a subject 
throughout the trial. Routine imaging assessments (or bone marrow biopsy) performed outside of the scope of this study will be acceptable to complete the 
response criteria for DLBCL at screening, if performed ≤ 4 weeks prior to study entry.  Assessment of lymphoma B symptoms should occur with each 
lymphoma disease response assessment.
 
 
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h.
In subjects with an unconfirmed PD assessment, a radiological assessment should be performed at the time of treatment discontinuation. If previous scan was 
obtained within 4 weeks prior to the date of discontinuation, then a repeat scan at treatment discontinuation isn’t mandatory. However, imaging should occur 
at any time where there is clinical suspicion of progression.
i.
Record all AEs occurring within 30 days after the last dose of trial treatment regardless when the Treatment Discontinuation Visit occurs. After 30 days, any 
drug related AE regardless of seriousness occurring outside of any reporting timeframes must be reported.
j.
Submission of tumor samples is applicable to subjects that sign the Future Biomedical Research consent form.  A fresh bone marrow aspiration sample is 
required for AML subjects, in addition to a bone marrow trephine sample (if available).  If a bone marrow trephine sample was not obtained (because not 
needed or unable to perform) or the bone marrow trephine sample is inadequate/poor quality, then only a bone marrow aspirate sample should be submitted. 
An archived or fresh lymph node biopsy sample without invasive procedure (e.g. superficial lymph node) is required for DLBCL subjects.   If an archived 
lymph node sample is not available, the subject must agree to undergo a fresh tumor biopsy.  All tumor biopsy samples will be sent to a central laboratory for 
further analysis.
k.
In cases of grade > 2 hematologic toxicity CBC will be performed twice a week until recovery to grade ≤ 2. In cases of neutropenia/thrombocytopenia grade
4, CBC will be performed at least every other day until recovery to grade ≤ 3. In cases of fever ≥ 38 °C, infection, purpura, or bleeding, additional CBC 
should be done as clinically indicated. In addition, bone marrow aspiration will be performed in all subjects with grade 4 thrombocytopenia lasting > 3 days.
l.
See Section 7.1.3, from cycle 3 on, in the absence of ≥ grade 2 abnormalities, these tests will be performed every cycle, otherwise they are to be done weekly 
until resolution to baseline levels or < grade 2.
m. Screening CBC, PT-International Normalized Ratio (INR), aPTT, Factor VII and serum chemistry measurements must be taken within 7 days of the first dose of 
study treatment.  
n.
Unresolved abnormal assessments that are drug related AEs should be followed until resolution. 
o.
For women of reproductive potential, urine pregnancy test must be confirmed negative within 72 hours prior to receiving the first dose of study medication. 
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. The subject must be excluded in the event of a 
positive or borderline-positive serum test result.
p.
PK blood samples will be collected at pre-dose (before drug intake), 20 minutes post-dose (±5 min), 1 hour post-dose (±10 min), 2 hours 15minutes post-
dose (±10 min), 3hours15minutes post-dose (±10 min), 8 hours post-dose (± 1 hour), and 12 hours post-dose (± 2 hours, before the second daily dose on day 
1).
q.
PK blood samples will be collected at pre-dose (before drug intake).
r.
PD blood samples will be collected at pre-dose (before drug intake), 3 hours 15 minutes post-dose (±10 min), 8 hours post-dose (± 1 hour), and 12 hours 
post-dose (± 2 hours, before the second daily dose on day 1).
s.
PD blood samples will be collected at pre-dose (before drug intake).
t.
Details for collection can be found in Section 7.1.3 Laboratory Procedures/Assessments.
 
 
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7.0 TRIAL PROCEDURES
Trial Procedures
7.1
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
7.1.1
Informed Consent
7.1.1.1
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative prior to participating in a clinical 
trial or Future Biomedical Research. If there are changes to the subject’s status during the 
trial (e.g., health or age of majority requirements), the investigator or qualified designee must 
ensure the appropriate consent is in place. 
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
 
 
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7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to the Future Biomedical Research sub-trial.  A copy of the 
informed consent will be given to the subject.
Inclusion/Exclusion Criteria
7.1.1.2
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
Subject Identification Card
7.1.1.3
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial. The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency. The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides written informed consent. At the time of treatment allocation/randomization, site 
personnel will add the treatment/randomization number to the Subject Identification Card.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
Medical History
7.1.1.4
A medical history will be obtained by the investigator or qualified designee. A detailed 
medical history must be documented, including:

non-cancer medical history

concurrent illnesses

demographics 

diagnosis and prior treatments for malignancies 
Prior and Concomitant Medications Review
7.1.1.5
7.1.1.5.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 4 weeks or 5 half-lives before first dose of trial medication.
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.
 
 
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Assignment of Screening Number
7.1.1.6
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or treatment allocation.  Each 
subject will be assigned only one screening number.  Screening numbers must not be re-used 
for different subjects.
Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 7.1.5.1.  
Assignment of Treatment/Randomization Number
7.1.1.7
All eligible subjects will be allocated, by non-random assignment, and will receive a 
treatment/randomization number.  The treatment/randomization number identifies the subject 
for all procedures occurring after treatment allocation/randomization.  The assigned 
screening number will become the subjects’ treatment allocation number. Once a 
treatment/randomization number is assigned to a subject, it can never be re-assigned to 
another subject.
A single subject cannot be assigned more than 1 treatment/randomization number.
Trial Compliance
7.1.1.8
Administration of the investigational product will be supervised by the investigator. Any 
delegation of this responsibility must be documented. 
In practice, on study visit days study nurses will supervise the intake of the appropriate MK-
8628 dose, explaining to subjects the exact number of capsules they should take. Nurses will 
document in the eCRF the administration, the dose, the time of administration, as well as any 
immediate reactions at the time of intake.
For non-visit days, MK-8628 will be taken at home. Subjects will record daily in a specific 
diary, the number of capsules swallowed, time of intake, as well as possible reactions, 
including vomiting, and their date/time of occurrence. 
When a subject attends a study visit, he/she will bring any unused capsules and their diary. 
According to the center procedures, the diary will be used to complete the eCRF treatment 
administration section, either directly as a Source Document or as an aid for completing the
nurse’s notes which will be used as a Source Document.
Interruptions from the protocol specified treatment > 2 weeks require consultation between 
the investigator and the Sponsor and written documentation of the collaborative decision on 
subject management.
 
 
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Clinical Procedures/Assessments
7.1.2
Adverse Event (AE) Monitoring
7.1.2.1
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated. Adverse experiences will be graded and recorded throughout the study and during 
the follow-up period according to NCI CTCAE Version 4.0. Toxicities will be characterized 
in terms including seriousness, causality, toxicity grading and action taken with regard to 
trial treatment.
Please refer to Section 7.2 for detailed information regarding the assessment and recording of 
AEs.
Full Physical Exam
7.1.2.2
The investigator or qualified designee will perform a complete physical exam during the 
screening period. Clinically significant findings should be recorded as medical history. After 
the first dose of trial treatment, new clinically significant abnormal findings should be 
recorded as AEs. A final full physical exam should be completed during the end of treatment 
visit.
Directed Physical Exam
7.1.2.3
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator 
or qualified designee will perform a directed physical exam as clinically indicated prior to 
trial treatment administration.  New clinically significant abnormal findings should be 
recorded as AEs.
Eastern Cooperative Oncology Group (ECOG) Performance Scale
7.1.2.4
The investigator or designee will assess the ECOG status (see Section) at screening, prior to 
trial administration on Day 1 of each cycle, and during the post-treatment follow-up period.
Vital Signs
7.1.2.5
The investigator or qualified designee will take vital signs at screening, prior to trial 
administration on day 1 of each cycle, and during the treatment discontinuation visit as 
specified in the Trial Flow Chart.   Vital signs include heart rate, blood pressure, body 
temperature, and weight.
12 Lead Electrocardiogram (ECG)
7.1.2.6
The investigator or qualified designee will take 12 lead ECGs as specified in the Trial Flow 
Chart.  ECGs collected on cycle 1 day 1 should be taken at the following time points: 

Pre-dose

1 hour post-dose

2 hours post-dose
 
 
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After cycle 1, ECGs should be collected on day 1 of every odd cycle (every 6 weeks) at the 
pre-dose (prior to dosing) time point.
Tumor Assessment / Response Evaluation
7.1.2.7
Tumor response should be assessed on the cycle days depicted in section 6.0, and based on 
the criteria displayed in Sections 7.1.2.7.1 and 7.1.2.7.2.  
7.1.2.7.1 Bone Marrow Aspiration / Biopsy & Criteria for Response Assessment - AML
The anti-tumor activity of MK-8628 will be evaluated as part of the efficacy endpoints using 
the following criteria:

Diagnosis and management of acute myeloid leukemia in adults: recommendations 
from an international expert panel, on behalf of the European LeukemiaNet (Döhner 
et al, Blood, 2010)] See Appendices 12.4.
These International Working Group criteria will be applied by the site as the primary 
measure for assessment of disease response and as a basis for all protocol guidelines related 
to disease status (e.g. discontinuation of study therapy).  The assessments will be completed 
through analysis of bone marrow aspiration samples, and bone marrow biopsy samples (if 
necessary).  The timing for tumor response assessments should follow calendar days and 
should not be adjusted for delays in cycle starts.
Tumor assessment and response evaluation should be completed at the following visits:

Screening

Cycle 2 day 1 (± 3 days)

Cycle 3 day 1 (± 3 days)

*Beyond Cycle 3

Treatment Discontinuation Visit
**Follow-up Visits (every 6 weeks post-treatment, ± 3 days)*Response assessments will be 
conducted on day 1 of every cycle (± 3 days) beyond cycle 3 through hematological analysis 
of peripheral blood. Evidence of response or progression in peripheral blood may be 
confirmed by further bone marrow assessments as displayed in Section 12.4.
**In subjects who discontinue study therapy without documented disease progression, every 
effort should be made to continue monitoring their disease status every 6 weeks (± 3 days) 
until (1) the start of new anti-cancer treatment, (2) documented disease progression, (3) 
death, or (4) the end of the study, whichever occurs first. If subjects have stable disease, 
partial response, or complete response, they should continue on this assessment schedule. 
Tumor response assessments should occur at any time where there is clinical suspicion of 
progression.
 
 
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7.1.2.7.2 Positron Emission Tomography (PET), Computed Tomography (CT), & Criteria 
for Response Assessment - DLBCL
The anti-tumor activity of MK-8628 will be evaluated as part of the efficacy endpoints using 
the following International Working Group criteria:

5 Point-Scale per the Lugano Classification (Cheson et al, J Clin Oncol, 2014) [46] 
See Appendices 12.5.
These International Working Group criteria will be applied by the site as the primary
measure for assessment of disease response and as a basis for all protocol guidelines related 
to disease status (e.g. discontinuation of study therapy).  The assessments will involve the
use of PET-CT and CT imaging (PET based response to analyze FDG-avid uptake using a 5 
point scale, and confirm residual vs. metabolically active tumor locations).  The timing of 
tumor response assessments should follow calendar days and should not be adjusted for 
delays in cycle starts.  The same imaging technique should be used in a subject throughout 
the trial. Local reading (investigator assessment with site radiology reading) will be used to 
determine eligibility and for subject management.  The sponsor may potentially collect 
radiologic assessments for retrospective analysis by a central vendor.  Assessment of 
lymphoma B symptoms should occur with each lymphoma disease response assessment.
The tumor response assessments should be completed at the following visits:

*Screening

Cycle 5 day 1 (Week 12, ± 3 days) and every 12 weeks thereafter (± 3 days)

** Treatment Discontinuation Visit

***Follow-up Visits (every 12 weeks post-treatment, ± 7 days)
*Routine imaging (or bone marrow biopsy) performed outside of the scope of this study will 
be acceptable to complete the criteria for response assessment at screening, if performed ≤   4 
weeks prior to study entry.  
**In subjects with an unconfirmed PD assessment, a radiological assessment should be 
performed at the time of treatment discontinuation. If previous scan was obtained within 4
weeks prior to the date of discontinuation, then a repeat scan at treatment discontinuation 
isn’t mandatory. However, imaging should occur at any time where there is clinical suspicion 
of progression.
***In subjects who discontinue study therapy without documented disease progression, 
every effort should be made to continue monitoring their disease status every  12 weeks (± 7
days) until (1) the start of new anti-cancer treatment, (2) documented disease progression, (3) 
death, or (4) the end of the study, whichever occurs first. If subjects have stable disease, 
partial response, or complete response, they should continue on this assessment schedule. 
Tumor response assessments should occur at any time where there is clinical suspicion of 
progression.
 
 
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Tumor Sample Submission 
7.1.2.8
A tumor biopsy sample must be collected for the purpose of predictive biomarker analysis, 
and submitted to the central laboratory within the 14 day screening window.  Additional 
details can be found in the trial specific laboratory manual.
7.1.2.8.1 Bone Marrow Aspiration (AML Subjects)
A fresh bone marrow aspiration sample is required for AML subjects, in addition to a bone 
marrow trephine sample (if available).  If a bone marrow trephine sample was not obtained 
(because not needed or unable to perform) or the bone marrow trephine sample is 
inadequate/poor quality, then only a bone marrow aspirate sample should be submitted.
This sample collection procedure should occur during the tumor response assessment 
required at screening (Section 7.1.2.7.1).  
7.1.2.8.2 Lymph Node Biopsy (DLBCL Subjects)
Archival or fresh superficial lymph node biopsy samples are required from subjects during
screening.  The sample should be a formalin-fixed paraffin embedded (FFPE) tumor biopsy 
sample or newly obtained core or excisional biopsy [fine needle aspiration (FNA) is not 
adequate] to be submitted for characterization at a central laboratory.  If an archived sample 
is not available, the subject must agree to undergo a fresh tumor biopsy.  Submission of 
FFPE tumor tissue sample blocks is preferred.  
Biopsy samples (archival or newly obtained) may be used for confirmation of diagnosis.
Biopsy of lesions on study should be limited to non-target lesions or new lesions if their 
pathologic etiology is ambiguous, and the tissue sample should have proper size to enable 
multiple planned biomarker analyses but not artificially decrease the longest diameter of the 
lesion.  If a tumor biopsy was of a target lesion during eligibility assessment, it is preferred to 
obtain a new baseline scan.
•
Newly Obtained Tumor Tissue
This sample should be sent to the central laboratory in formalin (strongly preferred) or as a 
formalin-fixed paraffin embedded (FFPE) block. 
If approved by the Sponsor, 
unstained/freshly cut slides cut from FFPE tissue block may be accepted.  
•
Archival Tumor Tissue (if available)
Archival tissue sample should be provided in the form of formalin-fixed paraffin embedded 
(FFPE) tissue block (preferred).  If approved by the Sponsor, unstained/freshly cut slides cut 
from FFPE tissue block may be accepted.  
Laboratory Procedures/Assessments
7.1.3
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
the trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject can be found in the Procedures 
Manual.  .  
 
 
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Laboratory Safety and Other Evaluations (Hematology, Chemistry, Urinalysis, and 
7.1.3.1
Other)
Laboratory tests for hematology, chemistry, urinalysis, and other are specified in Table 7.
Table 7
Laboratory Tests
Hematology
Chemistry
Urinalysisb
Other

Complete Blood Count (CBC): 

White Blood Cell (WBC) 
Count

WBC Differential

Red Blood Cell (RBC) 
Count

Hemoglobin 

Hematocrit

Platelet Count 

Mean Corpuscular Volume 
(MCV)

Mean 
Corpuscular 
Hemoglobin Concentration 
(MCHC)

Red 
Cell 
Distribution 
Width (RDW)

Reticulocyte Count 

Mean 
Platelet 
Volume 
(MPV)

Platelet Distribution Width 
(PDW)

Prothrombin 
Time 
(PT) 
/ 
International Normalized Ratio 
(INR)

Activated 
Partial 
Thromboplastin Time (aPTT)

Factor VII

Albumin

Alkaline 
phosphatase

Alanine 
aminotransferase 
(ALT)

Aspartate 
aminotransferase 
(AST)

Carbon 
dioxide 
(CO2 
or 
bicarbonate)b

Calcium

Chloride

Creatininec

Glucose

Lactate 
dehydrogenase 
(LDH)

Phosphorus

Potassium

Sodium

Total Bilirubin  

Direct Bilirubin, if 
total 
bilirubin 
is 
elevated above the 
upper 
limit 
of 
normal

Total protein

Blood 
Urea 
Nitrogen (BUN) or 
Urea

Blood

Glucose

Protein

Specific 
gravity

Microscop
ic exam, if 
abnormal 
results are 
noted

Serum 
β-human 
chorionic gonadotropin 
(β-hCG)a

Urine Pregnancy Testa
a
Perform on women of childbearing potential only.  Urine pregnancy test is preferred.  If the urine test is positive or cannot be confirmed 
as negative, a serum pregnancy test will be required.
b
If these tests are not done per local institutional standards as part of standard of care in a geographical region then these tests do not need 
to be performed. 
c. For subjects with a baseline calculated creatinine clearance below the normal institutional laboratory range, a baseline measured 
creatinine clearance should be performed.
7.1.3.1.1 Complete Blood Count
In cases of grade > 2 hematologic toxicity, CBC will be performed twice a week until 
recovery to grade ≤2. In cases 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.
 
 
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7.1.3.1.2 Serum Chemistry
From cycle 3 on, in the absence of ≥grade 2 abnormalities, these tests will be performed 
every cycle, otherwise they are to be done weekly until resolution to baseline levels or < 
grade 2.
7.1.3.1.3 Urine or Serum β-hCG
All women who are being considered for participation in the study, and who are not 
surgically sterilized or postmenopausal, will be tested for pregnancy via a urine test within 72 
hours prior to receiving the first dose of study medication. If the urine test is positive or 
cannot be confirmed as negative, a serum pregnancy test will be required. The subject must 
be excluded in the event of a positive or borderline-positive serum test result.
Pharmacokinetic/Pharmacodynamic Evaluations
7.1.3.2
7.1.3.2.1 PK Sample Collection (Plasma)
Samples will be collected on day 1 and three additional steady-state trough concentrations 
will be collected 1, 2 and 3 weeks after the first treatment intake. 
The timing of the PK sample collections is as follows (see also Table 8 below). Seven blood 
samples will be collected on Day 1 of Cycle 1: immediately prior to the first dose (T0) and 
20 min±5min, 1h±10min, 2h15min±10min, 3h15min±10min, 8h±1h, and 12h±2 hours
(immediately before the second daily dose on day 1). Subjects will either remain in the 
clinical research unit (CRU), or be hospitalized, for a minimum of 12±2hours hours for PK 
sampling on day 1. 
In addition, a single blood sample will be collected from all subject immediately before drug 
intake on days 8 (±1 days), 15 (±2 days), and 22 (±3 days) to evaluate steady-state trough 
concentrations. Note: On these three days, it is critical that the subject withhold the morning 
dose until after the PK sample is collected in the clinic. Every effort should be made to 
collect the sample approximately 12h after the previous evening dose. The timing of the 
previous dose should be recorded. See Table 8.
Table 8
PK Sample Collection Timing
PK Sample #
Visit
Time of collection
1
Cycle 1 Day 1
T0: Pre-morning dose
2
Cycle 1 Day 1
20 min ±5 min post-morning dose
3
Cycle 1 Day 1
1 hr ±10 min post-morning dose
4
Cycle 1 Day 1
2 hr 15 min ±10 min post-morning dose
5
Cycle 1 Day 1
3 hr 15 min ±10 min post-morning dose
6
Cycle 1 Day 1
8 hr ±1 hr post-morning dose
7
Cycle 1 Day 1
12 hr ± 2 hours post-morning dose
8
Cycle 1 Day 8
Pre-morning dose
9
Cycle 1 Day 15
Pre-morning dose
10
Cycle 1 Day 22
(Cycle 2 Day 1)
Pre-morning dose
 
 
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In total, ten blood samples of 3.0 mL each will be collected, i.e. approximately 30 mL of 
blood will be drawn per subject treated in the BID regimen from a peripheral venous access 
for PK analysis.
Sample collection, storage and shipment instructions for plasma samples will be provided in 
the Procedure Manual.
7.1.3.2.2 PK Assay Method and Parameters Analyzed
Plasma concentrations of MK-8628 will be measured using Ultra Performance Liquid 
Chromatography with tandem Mass Spectrometry detection (UPLC-MS/MS).
The following parameters will be determined as appropriate, and may include trough (C min) 
and peak (Cmax) concentrations, Tmax, AUC[0-∞], Vdss, t1/2, steady state, total clearance (CL) 
if non-compartmental analysis is performed.
PK data for MK-8628 will be interpreted in terms of safety findings and compared with 
historical data.
7.1.3.2.3 PD Sample Collection
A range of PD biomarkers (based on current PD knowledge) will be explored in all subjects
treated, using appropriate assays.
The timing of the PD sample collections is as follows (see also Table 9 below), and timing 
of collections should align with the collection of the PK samples at the same timepoints 
described in Table 9. PD biomarkers will be analyzed in peripheral blood. Four blood 
samples will be collected on Day 1 of Cycle 1: immediately prior to the first dose (T0) and 
3h15min±10min, 8h±1h, and 12h±2 hours (immediately before the second daily dose on day 
1). In addition, a single blood sample will be collected from all subjects immediately before 
drug intake on day 8 (±1 day)(same day as PK sample collection). See Table 9.
Table 9
PD Sample Collection Timing
PD Sample #
Visit
Time of collection
1
Cycle 1 Day 1
T0: Pre-morning dose
2
Cycle 1 Day 1
3 hr 15 min ±10 min post-morning dose
3
Cycle 1 Day 1
8 hr ±1 hr post-morning dose
4
Cycle 1 Day 1
12 hr ±2 hours post-morning dose
5
Cycle 1 Day 8
Pre-morning dose
Planned Genetic Analysis Sample Collection
7.1.3.3
This sample should be drawn for planned analysis of the association between genetic variants 
in DNA and drug response. If there is either a documented law or regulation prohibiting 
collection, or if the IRB/IEC does not approve the collection of the sample for these 
purposes, then this sample will not be collected at that site. If the sample is collected, leftover 
extracted DNA will be stored for future biomedical research if the subject signs the FBR 
consent. If the planned genetic analysis is not approved, but FBR is approved and consent is 
given, this sample will be collected for the purpose of FBR.
 
 
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Sample collection, storage and shipment instructions for plasma samples will be provided in 
the Procedure Manual.
Future Biomedical Research Sample Collection
7.1.3.4
The following specimens are to be obtained as part of Future Biomedical Research:
DNA for future research.

Leftover main study tumor (bone marrow samples) stored for future research (AML 
subjects)

Archived or fresh lymph node samples for future research (DLBCL subjects)
Other Procedures
7.1.4
Withdrawal/Discontinuation
7.1.4.1
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the Treatment Discontinuation Visit should be performed at the time of 
discontinuation. 
 
Any 
adverse 
events 
which 
are 
present 
at 
the 
time 
of 
discontinuation/withdrawal should be followed in accordance with the safety requirements 
outlined in Section 7.2 - Assessing and Recording Adverse Events.
7.1.4.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main trial 
are still available, the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@merck.com), and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed.  A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
trial data and results.   No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
Blinding/Unblinding
7.1.4.2
This is an open label trial; there is no blinding for this trial.
 
 
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Domiciling
7.1.4.3
Subjects will report to the clinical research unit (CRU) the morning of the scheduled day of 
trial drug administration in Cycle 1 and remain in the unit for a minimum of 12±2 hours post-
dose to collect PK blood samples and check vital signs, when appropriate.  It is 
recommended, but not required, that subjects be admitted overnight for this first treatment 
day (Cycle 1 Day 1), and at the discretion of the investigator, subjects may be requested to 
remain in the CRU longer.
Calibration of Critical Equipment
7.1.4.4
The investigator or qualified designee has the responsibility to ensure that any critical device
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
reproducible.  Documentation of equipment calibration must be retained as source 
documentation at the trial site.
Critical Equipment for this trial includes:

Laboratory equipment 

Imaging equipment 

Other equipment (exg: 12 Lead ECG Machines)

See protocol-specified guidance in the Administrative Binder, Procedures Manual,
and Site Imaging Manual.
Visit Requirements
7.1.5
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
Screening
7.1.5.1
Each candidate subject will be examined before starting the study to determine eligibility for 
participation as set forth in Section 5.1. This must be done within 2 weeks prior to the first 
study treatment administration (exceptions listed below).  Screening procedures may be 
repeated after consultation with the Sponsor.
Written consent must be obtained prior to performing any protocol specific procedure. 
Results of a test performed prior to the subject signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time 
frame. 
Screening procedures are to be performed within 2 weeks prior to the first dose of trial 
treatment except for the following:

For women of reproductive potential, a urine or serum pregnancy test will be
performed within 72 hours prior to the subject’s first dose of trial treatment on cycle 1 
/ day 1.
 
 
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
The following assessments need to be completed within a 7 day window (day -7 to 
day -1) prior to the subject’s first dose of trial treatment on cycle 1 / day 1:
o
Complete Blood Count (CBC)
o
PT-International Normalized Ratio (INR), aPTT, and Factor VII
o
Serum Chemistry

The following is applicable to DLBCL subjects only: routine imaging (or bone 
marrow biopsy) performed outside of the scope of this study will be acceptable to 
complete the Response Criteria for Malignant Lymphoma (Section7.1.2.7.2) at 
screening, if performed ≤ 4 weeks prior to study entry.
Treatment Period
7.1.5.2
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
End of Treatment
7.1.5.3
All subjects will complete a treatment discontinuation visit at the time of MK-8628 treatment 
withdrawal, or within 3 days of last dose.
Post-Treatment
7.1.5.4
7.1.5.4.1 30 Day Safety Follow-up
After the last treatment administration, subjects will be followed up for safety for 30 days 
and then until resolution of any AEs for which a relationship to MK-8628 cannot definitely 
be excluded (or categorized as sequelae). A safety follow-up visit will be performed 30 days 
(±5 days) after the last MK-8628 intake.
7.1.5.4.2 Additional Follow-up
In subjects who discontinue study therapy without documented disease progression, every 
effort should be made to continue monitoring their disease status every 6 weeks (± 3 days)
for AML subjects and every 12 weeks (± 7 days) for DLBCL subjects until (1) the start of 
new anti-cancer treatment, (2) documented disease progression, (3) death, or (4) the end of 
the study, whichever occurs first. If subjects have stable disease, partial response, or 
complete response, they should continue on this assessment schedule. Tumor response 
assessments should occur at any time where there is clinical suspicion of progression or 
relapse.
Assessing and Recording Adverse Events
7.2
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
 
 
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specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
Progression of the cancer under study is not considered an adverse event unless it is 
considered to be drug related by the investigator 
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. From the time of treatment allocation/randomization through 30 days following 
cessation of treatment, all adverse events must be reported by the investigator. Such events 
will be recorded at each examination on the Adverse Event case report forms/worksheets.  
The reporting timeframe for adverse events meeting any serious criteria is described in 
section 7.2.3.1. The investigator will make every attempt to follow all subjects with non-
serious adverse events for outcome.
Electronic reporting procedures can be found in the Electronic Data Capture (EDC) data 
entry guidelines. Paper reporting procedures can be found in the Investigator Trial File 
Binder (or equivalent).
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of archival tissue status) as long as that subject has not undergone any 
protocol-specified procedure or intervention.  If the subject requires a blood draw, fresh 
tumor biopsy etc., the subject is first required to provide consent to the main study and AEs 
will be captured according to guidelines for standard AE reporting.
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
7.2.1
Sponsor
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose for MK-8628 by 1 dose in a 24 hour time period (i.e. ≥ 3 total doses in 24 hrs). No 
specific information is available on the treatment of overdose of MK-8628. In the event of 
overdose, MK-8628 should be discontinued and the subject should be observed closely for 
signs of toxicity.  Appropriate supportive treatment should be provided if clinically indicated.
 
 
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If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
7.2.2
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.  Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 30 days following cessation of Sponsor’s product must be 
reported by the investigator. 
All reported pregnancies must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events). If 
the pregnancy continues to term, the outcome (health of infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them), including the pregnancy of a male subject's female partner 
that occurs during the trial.
Pregnancies and lactations of subjects and female partners of male subjects from the time the 
consent form is signed but before treatment allocation/randomization must be reported by the 
investigator if they cause the subject to be excluded from the trial, or are the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.  Pregnancies and lactations of subjects 
and female partners of male subjects that occur from the time of treatment 
allocation/randomization through 30 days following cessation of Sponsor’s product must be 
reported. All reported pregnancies must be followed to the completion/termination of the 
pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign 
 
 
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hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Immediate Reporting of Adverse Events to the Sponsor
7.2.3
Serious Adverse Events
7.2.3.1
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event.
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.
●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose.
Refer to Table 10 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause other than progression of the cancer under study (reference 
Section 7.2.3.3 for additional details), that occurs to any subject 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, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 30 days 
following cessation of treatment, any serious adverse event, or follow up to a serious adverse 
event, including death due to any cause other than progression of the cancer under study 
(reference Section 7.2.3.3 for additional details), 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 EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time following consent through the end of the specified safety follow-up 
 
 
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period specified in the paragraph above, or at any time outside of the time period specified in 
the previous paragraph also must be reported immediately to the Sponsor.  
All subjects with serious adverse events must be followed up for outcome.
Events of Clinical Interest
7.2.3.2
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 treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject 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, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization 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 EDC data entry 
guidelines.  Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Events of clinical interest for this trial include:

an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an 
Overdose for This Protocol and Reporting of Overdose to the Sponsor, that is not 
associated with clinical symptoms or abnormal laboratory results. 

an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X 
the upper limit of normal and, at the same time, an alkaline phosphatase lab value that 
is less than 2X the upper limit of normal, as determined by way of 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 the Investigator Trial File Binder (or 
equivalent).
1. an elevated total bilirubin lab value that is greater than or equal to 2X the upper limit 
of normal.
2. an elevated AST or ALT lab value that is greater than or equal to 5X the upper limit 
of normal.
*Note: For further guidance on the monitoring, treatment and follow-up of any ECI 
related to potential drug-induced liver injury (DILI), please see Section 12.8.
 
 
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3. For the purpose of this dose-finding study, any suspected DLT occurring during dose 
escalation will be considered as medically important and reported as an ECI. If the 
event also meets the criteria for seriousness, follow the reporting guidelines for 
Serious Adverse Events (SAEs) outlined in Section 7.2.3.1
Protocol-Specific Exceptions to Serious Adverse Event Reporting
7.2.3.3
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described
in Section 7.2.3 - Immediate Reporting of Adverse Events to the Sponsor.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the subjects in the trial. Any suspected endpoint which upon review is 
not progression of the cancer under study will be forwarded to global safety as a SAE within 
24 hours of determination that the event is not progression of the cancer under study.
Evaluating Adverse Events
7.2.4
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets.
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.
 
 
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Table 10
Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 CTCAE 
Grading
Grade 1
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL.
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of Sponsor’s product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in 
the patient’s medical history.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local 
requirements); or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor’s product to be discontinued?
Relationship to 
Sponsor’s 
Product
Did the Sponsor’s product cause the adverse event? The determination of the likelihood that the Sponsor’s product caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information.
The following components are to be used to assess the relationship between the Sponsor’s product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor’s product caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to the Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did 
the 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
the 
Sponsor’s
product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors
 
 
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Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor’s product discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge. If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of 
the Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor’s product in this study?
If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge. If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or 
(3) Sponsor’s product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE SPONSOR'S PRODUCT, OR IF REEXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 
CLINICAL DIRECTOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor’s product or drug class pharmacology 
or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor’s product relationship).
Yes, there is a reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's 
product is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause.
No, there is not a reasonable 
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without an 
associated AE.)
 
 
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Sponsor Responsibility for Reporting Adverse Events
7.2.5
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study.  If, after 
the study has begun, but prior to final database lock, changes made to primary and/or key 
secondary hypotheses, or the statistical methods related to those hypotheses, then the 
protocol will be amended (consistent with ICH Guideline E-9).  Changes to exploratory or 
other non-confirmatory analyses made after the protocol has been finalized, but prior to final 
database lock, will be documented in a supplemental SAP (sSAP) and referenced in the 
Clinical Study Report (CSR) for the study.  Post hoc exploratory analyses will be clearly 
identified in the CSR.  Separate analysis plans (i.e., separate documents from the sSAP) will 
be developed to detail other planned analyses (i.e., those specific to the analysis of PK data, 
and future biomedical research
Statistical Analysis Plan Summary
8.1
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in subsequent sections.
Study Design Overview
A Phase IB Dose Exploration Trial with MK-8628, a Small Molecule 
Inhibitor of the Bromodomain and Extra-Terminal (BET) Proteins, in  
Subjects with Selected Hematologic Malignancies
Treatment Assignment
This is an open label study with dose-level-specific cohorts.
Analysis Populations
Efficacy: Treatment Full Analysis Set (FAS), which is the same as ASaT
Safety: DLT evaluable, and All Subjects as Treated (ASaT)
Primary Endpoint(s)
Proportion of subjects experiencing at least one DLT in cycle 1 (day 1 to 
21) 
Secondary Endpoints
Proportion of 
subjects in different response categories per protocol 
specified response criteria for each tumor type (AML or DLBCL)
Statistical Methods for Key 
Efficacy/Immunogenicity/ 
Pharmacokinetic Analyses
Proportion of subjects in different response categories will be estimated 
using Exact method based on binomial distribution (Clopper-Pearson 
Interval) for each tumor type.
Statistical Methods for Key 
Safety Analyses
Count and percentage of DLT will be provided. The Bayes credible 
interval (80%) for DLT rate will be estimated based on a prior distribution 
of Beta (1,1).   
Interim Analyses
During the dose escalation phase, regular assessment of DLT from the 
most recent cohort will be performed.
Multiplicity
This is an estimated study and no multiplicity adjustment will be 
implemented
Sample Size and Power 
The study is designed to assess the safety of MK-8628 in subjects with 
selected hematologic malignancies. The small numbers per cohort are not 
intended for statistical hypotheses.
Up to 28 evaluable subjects (6-14 per two dose levels) will be included in 
each subject cohort (AML or DLBCL). This results in a study sample size 
of up to approximately 56 subjects.  The final sample size will depend on 
the number of patients experiencing DLTs at each DL, and may be 
increased if additional DLTs are required.
 
 
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Responsibility for Analyses/In-House Blinding
8.2
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the SPONSOR.
This trial is being conducted as an open-label study with dose level-specific cohorts.
Hypotheses/Estimation
8.3
Objectives of the study are stated in Section 3.0.
There are no statistical hypotheses for this study.
Analysis Endpoints
8.4
Safety Endpoints
8.4.1
The primary safety objective of this trial is to estimate proportion of subjects experiencing at 
least one DLT in cycle 1 (day 1 to 21) for each of the regimens and tumor type
independently.
Other safety endpoints include incidence, severity and relationship of AEs, laboratory 
abnormalities, SAEs, discontinuations due to AEs, dose adaptations due to AEs
Efficacy/Pharmacokinetics/Pharmacodynamics Endpoints
8.4.2
Secondary efficacy endpoints are presented below:
Objective Response Rate (ORR): is defined as the percentage of subjects who have 
achieved confirmed complete response (CR) or partial response (PR) according to specified 
response criteria for each tumor type (AML or DLBCL) by the investigator review.
Duration of Response (DOR): is defined as the time interval between the date of the first 
confirmed response (CR/PR) (the response prior to confirmation) and the date of first 
documented disease progression based upon specified response criteria for each tumor type 
(AML or DLBCL) by the investigator review.
Disease Control Rate (DCR): is defined as the percentage of subjects who have achieved 
stable disease or confirmed complete response (CR) or confirmed partial response (PR) 
according to Response  Evaluation  Criteria  in  AML  or  DLBCL  (see Section 7.1.2.7.1 and 
7.1.2.7.2) by the investigator review. Subjects with missing response will be considered not 
to have achieved disease control.
Pharmacokinetics
Plasma parameters of MK-8628 as appropriate and according to analyses performed (non-
compartmental or nonlinear mixed effect modelling).
Pharmacodynamics
Incidence and severity of AEs along with PK parameters will be analyzed in relation to the 
most pertinent biomarker(s), if any.
 
 
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Analysis Populations
8.5
Safety Analysis Populations
8.5.1
DLT Evaluable population:  subjects who receive at least 85% of the planned dose of study 
drug (18 days) or experience DLT during the first 21-day cycle.
The All Subjects as Treated (ASaT) population, also known as treated population, 
consisting of subjects who receive at least one dose of study drug, will be used for the 
analysis of all other safety data in this study.
Efficacy Analysis Populations
8.5.2
Treatment Full Analysis Set (FAS), also known as evaluable for efficacy: subjects who 
receive at least one dose of study drug 
Statistical Methods
8.6
This section describes the statistical methods to address the primary and secondary 
objectives.  Methods related to exploratory endpoints will be described in the supplemental 
SAP.  Data will be presented by dose level and where appropriate by indication. No 
imputations for missing data will be made.  
Pharmacokinetics and pharmacodynamics will be analyzed and reported separately.
Statistical Methods for Safety Analyses
8.6.1
Counts and percentage of DLT will be provided. Bayes credible interval (80%) for the DLT 
rate will be estimated based on a prior distribution of Beta (1,1) with other credible levels 
considered as clinically needed.
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences (AEs), laboratory tests, and vital signs. Counts and percentage of AE 
will be provided. Confidence intervals (95%, for rate of AE of clinical interest) will be 
estimated using an exact method based on binomial distribution (Clopper-Pearson interval).
Statistical Methods for Efficacy Analyses
8.6.2
ORR and DCR will be estimated using an exact method based on binomial distribution 
(Clopper-Pearson interval) for each tumor type (AML or DLBCL).
DOR will be estimated by Kaplan-Meier method.
Summaries of Baseline Characteristics, Demographics, and Other Analyses
8.6.3
The number and percentage of subjects screened, enrolled, the primary reasons for screening 
failure, and the primary reason for discontinuation will be displayed.  Demographic 
variables, baseline characteristics, primary and secondary diagnoses, and prior and 
concomitant therapies will be summarized by treatment either by descriptive statistics or 
categorical tables.
 
 
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Interim Analyses
8.7
During the dose escalation phase, regular assessment of data from the most recent cohort of 
subjects by cohort evaluable for DLT will be performed.
Multiplicity
8.8
This is an estimation study and no multiplicity adjustment will be implemented.
Sample Size and Power Calculations
8.9
The study is designed to assess the safety of MK-8628 in subjects with selected hematologic 
malignancies. The small numbers per cohort are not intended for statistical hypotheses. 
Up to 28 evaluable subjects will be included in each subject cohort (AML or DLBCL). This 
results in a study sample size of up to approximately 56 subjects.  There will be a maximum 
of 14 patients in each of the pre-specified dose levels for DLT evaluation.  All AML subjects 
participating in the 20 mg BID regimen of the MK-8628-001 protocol (approximately up to 3 
subjects) will count toward the initial 6 AML subjects needed for the 20 mg BID dose level 
in this study.  The sample size (in AML 20mg BID cohort) of PN005 will be reduced 
according to the number of AML 20mg BID patients treated in PN001. PN005 will be 
analyzed on its’ own but relevant results (limited to the AML 20mg BID cohort) in PN001 
will be described in the clinical study report of PN005. And the DLT information for the 
AML 20mg BID cohort in PN001 will be used together with the AML 20mg BID cohort in 
PN005 for dose escalation/de-escalation decisions and RP2D decisions.  The final sample 
size will depend on the number of patients experiencing DLTs at each dose level, and may be 
increased if additional dose levels are required.  For ORR, the sample size will be dependent 
on the number of subjects in each cohort.  Table 11 below provides Bayes credible interval 
and confidence interval with different number of events or responses for sample sizes of 6 
and 14 to characterize the precision of the estimates for DLT rate and ORR, respectively.
 
 
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Table 11
Bayes credible interval for DLT rate estimate and confidence interval for ORR 
estimate for different sample sizes and number of events
Sample 
Size
Number of 
Events or 
Responses
Observed 
Rate
80% Bayes 
credible interval
95% Bayes 
credible interval
95% confidence 
intervala
6
0
0
(0, 0.205)
(0, 0.348)
(0, 0.459)
6
1
0.167
(0.040, 0.391)
(0.013, 0.527)
(0.004, 0.641)
6
2
0.333
(0.146, 0.567)
(0.081, 0.685)
(0.043, 0.777)
6
3
0.500
(0.279, 0.721)
(0.184, 0.816)
(0.118, 0.882)
14
0
0
(0, 0.102)
(0, 0.181)
(0, 0.232)
14
1
0.071
(0.014, 0.194)
(0.004, 0.281)
(0.002, 0.339)
14
2
0.143
(0.053, 0.283)
(0.027, 0.373)
(0.018, 0.428)
14
3
0.214
(0.102, 0.367)
(0.062, 0.456)
(0.047, 0.508)
14
4
0.286
(0.156, 0.445)
(0.105, 0.533)
(0.084, 0.581)
14
5
0.357
(0.215, 0.519)
(0.154, 0.605)
(0.128, 0.649)
14
6
0.429
(0.276, 0.590)
(0.208, 0.672)
(0.177, 0.711)
a. Confidence intervals were calculated using Exact method based on binomial distribution (Clopper-Pearson 
interval).
Subgroup Analyses and Effect of Baseline Factors
8.10
Subgroup analyses and effect of baseline factors may be explored as appropriate.
Compliance (Medication Adherence)
8.11
Drug accountability data for trial treatment will be collected during the study. Any deviation 
from protocol-directed administration will be reported.
Extent of Exposure
8.12
Extent of Exposure for a subject is defined as number of cycles in which the subject receives 
the study medication. Summary statistics will be provided on Extent of Exposure for ASaT 
population.
9.0 LABELING, PACKAGING,
STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
9.1
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
 
 
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Clinical Supplies will be provided by the Sponsor as summarized in Table 12.
Clinical supplies will be packaged to support enrollment and replacement subjects as 
required.  When a replacement subject is required, the Sponsor or designee needs to be 
contacted prior to dosing the replacement supplies.
Table 12
Product Descriptions
Product Name & Potency
Dosage Form
Source/Additional Information
MK-8628 10 mg
Gelatin capsules 
(white, size 3)
Provided centrally by the Sponsor.
MK-8628 20 mg
Gelatin capsules 
(green, size 3)
Provided centrally by the Sponsor.
Packaging and Labeling Information
9.2
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Subjects will receive open label bottles.  No kitting is required.
Clinical Supplies Disclosure
9.3
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded. Treatment (name, strength or potency) is included in the label text; 
random code/disclosure envelopes or lists are not provided.
Section 5.8 outlines the criteria for allowing subjects who are discontinued from treatment to 
continue to be monitored in the trial.
Storage and Handling Requirements
9.4
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
Discard/Destruction/Returns and Reconciliation
9.5
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. For all trial sites, the local country Sponsor 
personnel or designee will provide appropriate documentation that must be completed for 
drug accountability and return, or local discard and destruction if appropriate.   Where local 
discard and destruction is appropriate, the investigator is responsible for ensuring that a local 
discard/destruction procedure is documented.
Standard Policies
9.6
Trial 
site 
personnel 
will 
have 
access 
to 
a 
central 
electronic 
treatment 
allocation/randomization system (IVRS/IWRS system) to allocate subjects, to assign 
 
 
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treatment to subjects and to manage the distribution of clinical supplies. Each person 
accessing the IVRS system must be assigned an individual unique PIN.  They must use only 
their assigned PIN to access the system, and they must not share their assigned PIN with 
anyone.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
10.1
Confidentiality of Data
10.1.1
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of Subject Records
10.1.2
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
Confidentiality of Investigator Information
10.1.3
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
 
 
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when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
10.1.4
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this trial.  The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Compliance with Financial Disclosure Requirements
10.2
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Compliance with Law, Audit and Debarment
10.3
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
 
 
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The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
 
 
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conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the 
anticipated review process, thorough understanding of clinical trial methods, appropriate 
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must 
be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
10.4
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Merck, as 
Sponsor of this trial, will review this protocol and submit the information necessary to fulfill 
these requirements.  Merck entries are not limited to FDAMA/FDAAA mandated trials. 
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.    
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAMA/FDAAA are that of the Sponsor and agrees not to submit any information about this 
trial or its results to the Clinical Trials Data Bank.
Quality Management System
10.5
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
Data Management
10.6
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
 
 
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electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
Publications
10.7
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
 
 
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contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
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acetylation marks on a histone tail by a single bromodomain. Nature 461, 664–668.
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Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain 
protein Brd4. Mol. Cell 19, 535–545.
22. Jang, M.K., Mochizuki, K., Zhou, M., Jeong, H.-S., Brady, J.N., and Ozato, K. (2005). 
The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and 
stimulates RNA polymerase II-dependent transcription. Mol. Cell 19, 523–534.
23. Filippakopoulos, P., Qi, J., Picaud, S., Shen, Y., Smith, W.B., Fedorov, O., Morse, E.M., 
Keates, T., Hickman, T.T., Felletar, I., et al. (2010). Selective inhibition of BET 
bromodomains. Nature 468, 1067–1073.
24. Chung, C.-W., Coste, H., White, J.H., Mirguet, O., Wilde, J., Gosmini, R.L., Delves, C., 
Magny, S.M., Woodward, R., Hughes, S.A., et al. (2011). Discovery and characterization 
of small molecule inhibitors of the BET family bromodomains. J. Med. Chem. 54, 3827–
3838.
 
 
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25. Nicodeme, E., Jeffrey, K.L., Schaefer, U., Beinke, S., Dewell, S., Chung, C.-W., 
Chandwani, R., Marazzi, I., Wilson, P., Coste, H., et al. (2010). Suppression of 
inflammation by a synthetic histone mimic. Nature 468, 1119–1123.
26. Dawson, M.A., Prinjha, R.K., Dittmann, A., Giotopoulos, G., Bantscheff, M., Chan, W.-
I., Robson, S.C., Chung, C., Hopf, C., Savitski, M.M., et al. (2011). Inhibition of BET 
recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature 
478, 529–533.
27. Picaud, S., Da Costa, D., Thanasopoulou, A., Filippakopoulos, P., Fish, P.V., Philpott, 
M., Fedorov, O., Brennan, P., Bunnage, M.E., Owen, D.R., et al. (2013). PFI-1, a highly 
selective protein interaction inhibitor, targeting BET Bromodomains. Cancer Res. 73, 
3336–3346.
28. Redner RL, Wang J, Liu JM. Chromatin remodelling and leukemia: new therapeutic 
paradigms. Blood 1999; 94: 417-428.
29. Zuber J, et al. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid 
leukemia. Nature 2011; 478: 524-528.
30. 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.
31. Greenwald RJ, Tumang JR, Sinha A, et al: Eµ-BRD2 transgenic mice develop B-cell
lymphoma and leukemia. Blood 2004; 103:1475-1484.
32. Lenburg M, Sinha A, Faller DV, Denis GV: Tumor-specific and proliferation-specific
gene expression typifies mrine transgenic B cell lymphomagenesis. J Biol Chem 2007;
282:4803-4811.
33. Longe HO, Romesser PB, Rankin AM, et al: Telomere homolog oligonucleotides induce
apoptosis in malignant but not in normal lymphoid cells: Mechanisms and therapeutic
potential. Int J Cancer 2009; 124:473-482.
34. Chng WJ, Huang GF, Chung TH, et al: Clinical and biological implications of MYC
activation: common difference between MGUS and newly diagnosed multiple myeloma.
Leukemia 2011; 25:1026-1035.
35. Chesi M, Matthews GM, Garbitt VM, et al: Drug response in a genetically engineered
mouse model of multiple myeloma is predictive of clinical efficacy.
Blood 2012;
120:376-385.
36. Boxer LM, Dang CV. Translocation involving c-Myc and c-Myc function. Oncogene
2001; 20: 5595-5610.
37. Vita M, Henriksson M.The Myc oncoprotein as a therapeutic target for human cancer. 
Semin Cancer Biol 2006; 16:318-330.
38. Mertz JA, et al. Targeting MYC dependence in cancer by inhibiting BET bromodomains. 
Proc Natl Acad Sci USA 2011; 108: 16669-16674.
 
 
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39. 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.
40. Azad, N., Zahnow, C., Rudin, C., Baylin, S. (2013). The future of epigenetic therapy in 
solid tumors – lessons from the past. Nature Rev Clin Onco 10, 256-266.
41. Issa, J., Kantarjian, H., Kirkpatrick, P. (2005). Azacitidine. Nature Rev Drug Disc 4, 275-
276.
42. Ouafik L, Berenguer C, Cayol M, et al. OTX015, a novel BET-bromodomain (BET-
BRD) inhibitor, is a promising anticancer agent for human glioblastoma. Eur J Cancer
2014; 50 (Supp 6): 153; Abstract 469.
43. Vardiman J, et al.  The 2008 revision of the World Health Organization (WHO) 
classification of myeloid neoplasms and acute leukemia: rationale and important changes.  
Blood. 2009 114: 937-951.
44. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of 
Haematopoietic and Lymphoid Tissues (ed 4th). Lyon, France: IARC Press; 2008.
45. 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. 
46. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, 
staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano 
classification, J Clin Oncol. 2014; Sep 20;32(27):3059-68.
 
 
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12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
12.1
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication of 
results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to 
defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
 
 
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III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a minimum, trial 
designs will take into account the local standard of care.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible.  Unless required by law, 
only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.   Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made 
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
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Collection and Management of Specimens for Future Biomedical Research
12.2
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease.  A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens collected in this trial as outlined in Section 7.1.3.3 – Future Biomedical 
Research Sample Collection will be used to study various causes for how subjects may 
respond to a drug/vaccine.  Future biomedical research specimen(s) will be stored to 
provide a resource for future trials conducted by the Sponsor focused on the study of 
biomarkers responsible for how a drug/vaccine enters and is removed by the body, how a 
drug/vaccine works, other pathways a drug/vaccine may interact with, or other aspects of 
disease. The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by the Sponsor or those working for 
or with the Sponsor.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in the 
Future Biomedical Research sub-trial.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on Visit 1.  If delayed, 
present consent at next possible Subject Visit. Informed consent must be obtained 
prior to collection of all Future Biomedical Research specimens.  Consent forms 
signed by the subject will be kept at the clinical trial site under secure storage for 
regulatory reasons.  
 
 
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A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository. Each consent will be assessed for appropriate 
specimen permissions.  
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of subject consent for Future Biomedical Research will be captured in 
the electronic Case Report Forms (eCRFs). Any specimens for which such an 
informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Collection of specimens for Future Biomedical Research will be performed as 
outlined in the trial flow chart. In general, if additional blood specimens are being 
collected for Future Biomedical Research, these will usually be obtained at a time 
when the subject is having blood drawn for other trial purposes.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens for transfer to the storage facility.  This first code is a random number which 
does not contain any personally identifying information embedded within it. The link (or 
key) between subject identifiers and this first unique code will be held at the trial site.  No 
personal identifiers will appear on the specimen tube.  
5. Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good 
scientific practices.  Analyses utilizing the Future Biomedical Research specimens may 
be performed by the Sponsor, or an additional third party (e.g., a university investigator) 
designated by the Sponsor. The investigator conducting the analysis will follow the 
Sponsor’s privacy and confidentiality requirements. Any contracted third party analyses 
will conform to the specific scope of analysis outlined in this sub-trial. Future Biomedical 
Research specimens remaining with the third party after specific analysis is performed 
will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial. If medical records for the main 
trial are still available, the investigator will contact the Sponsor using the designated 
 
 
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mailbox (clinical.specimen.management@merck.com) and a form will be provided to 
obtain appropriate information to complete specimen withdrawal. Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. 
Documentation will be sent to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for specimen destruction can not be processed. 
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
trial, the trial site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens.  Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated trial administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards (e.g., ISO17799) to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Subjects
No information obtained from exploratory laboratory studies will be reported to the 
subject, family, or physicians. Principle reasons not to inform or return results to the 
subject include: Lack of relevance to subject health, limitations of predictive capability, 
and concerns regarding misinterpretation.
If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information. 
After the clinical trial has completed, if any exploratory results are definitively associated 
with clinical significance, the Sponsor will endeavor to make such results available 
 
 
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through appropriate mechanisms (e.g., scientific publications and/or presentations). 
Subjects will not be identified by name in any published reports about this study or in any 
other scientific publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all subjects diagnosed and treated on Sponsor clinical 
trials for Future Biomedical Research.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. No additional 
risks to the subject have been identified as no additional specimens are being collected 
for Future Biomedical Research (i.e., only leftover samples are being retained).
The Sponsor has developed strict security, policies and procedures to address subject data 
privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
13. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
 
 
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Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
12.3
IRBs/IECs and Investigational Site Staff
 
 
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Response Assessment of AML
12.4
Table 13
Response Assessment of AML [45]
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)ǁ
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. 
↵† 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.
 
 
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Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: the Lugano 
12.5
Classification
Table 14
Response Assessment of Hodgkin and Non Hodgkin Lymphoma: the Lugano 
Classification [46]
Response and Site
PET-CT Based Response
CT-Based Response
Complete
Complete metabolic response
Complete radiologic response (all 
of the following)
     Lymph 
nodes 
and 
extralymphatic sites
Score 1, 2, or 3* with or without a 
residual mass on 5PS†
Target nodes/nodal masses must 
regress to ≤ 1.5 cm in LDi
It is recognized that in Waldeyer's 
ring or extranodal sites with high 
physiologic 
uptake 
or 
with 
activation within spleen or marrow 
(eg, with chemotherapy or myeloid 
colony-stimulating factors), uptake 
may 
be 
greater 
than 
normal 
mediastinum and/or liver. In this 
circumstance, complete metabolic 
response may be inferred if uptake 
at sites of initial involvement is no 
greater than surrounding normal 
tissue even if the tissue has high 
physiologic uptake.
No extralymphatic sites of disease
     Nonmeasured lesion
Not applicable
Absent
     Organ enlargement
Not applicable
Regress to normal
     New lesions
None
None
     Bone marrow
No evidence of FDG-avid disease 
in marrow
Normal 
by 
morphology; 
if 
indeterminate, IHC negative
Partial
Partial metabolic response
Partial 
remission 
(all 
of 
the 
following)
     Lymph 
nodes 
and 
extralymphatic sites
Score 4 or 5† with reduced uptake 
compared 
with 
baseline 
and 
residual mass(es) of any size
≥50% decrease in SPD of up to 6 
target 
measurable 
nodes 
and 
extranodal sites
At interim, these findings suggest 
responding disease
When a lesion is too small to 
measure on CT, assign 5 mm × 5 
mm as the default value
At end of treatment, these findings 
indicate residual disease
When no longer visible, 0 × 0 mm
For a node > 5 mm × 5 mm, but 
smaller than normal, use actual 
measurement for calculation
     Nonmeasured lesions
Not applicable
Absent/normal, regressed, but no 
increase
     Organ enlargement
Not applicable
Spleen must have regressed by 
> 50% in length beyond normal
     New lesions
None
None
 
 
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Response and Site
PET-CT Based Response
CT-Based Response
     Bone marrow
Residual uptake higher than uptake 
in normal marrow but reduced 
compared with baseline (diffuse 
uptake compatible with reactive 
changes 
from 
chemotherapy 
allowed). If there are persistent 
focal changes in the marrow in the 
context of a nodal response, 
consideration should be given to 
further evaluation with MRI or 
biopsy or an interval scan
Not applicable
No response or stable disease
No metabolic response
Stable disease
     Target 
nodes/nodal 
masses, 
extranodal lesions
Score 4 or 5 with no significant 
change in FDG uptake from 
baseline at interim or end of 
treatment
< 50% decrease from baseline in 
SPD 
of 
up 
to 
6 
dominant, 
measurable nodes and extranodal 
sites; no criteria for progressive 
disease are met
     Nonmeasured lesions
Not applicable
No 
increase 
consistent 
with 
progression
     Organ enlargement
Not applicable
No 
increase 
consistent 
with 
progression
     New lesions
None
None
     Bone marrow
No change from baseline
Not applicable
Progressive disease
Progressive metabolic disease
Progressive disease requires at 
least 1 of the following
     Individual target nodes/nodal 
masses
Score 4 or 5 with an increase in 
intensity of uptake from baseline 
and/or
PPD progression
     Extranodal lesions
New FDG-avid foci consistent 
with lymphoma at interim or end-
of-treatment assessment
An individual node/lesion must be 
abnormal with:
LDi > 1.5 cm and
Increase by ≥ 50% from PPD nadir 
and
An increase in LDi or SDi from 
nadir
0.5 cm for lesions ≤ 2 cm
1.0 cm for lesions > 2 cm
In the setting of splenomegaly, the 
splenic length must increase by 
> 50% of the extent of its prior 
increase beyond baseline (eg, a 
15-cm spleen must increase to 
> 16 cm). If no prior splenomegaly, 
must increase by at least 2 cm from 
baseline.
New or recurrent splenomegaly.
Nonmeasured lesions
None
New or clear progression of 
preexisting nonmeasured lesions
 
 
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Response and Site
PET-CT Based Response
CT-Based Response
     New lesions
New FDG-avid foci consistent 
with lymphoma rather than another 
etiology 
(eg, 
infection,
inflammation). 
If 
uncertain 
regarding etiology of new lesions, 
biopsy or interval scan may be 
considered.
Regrowth of previously resolved 
lesions
A new node > 1.5 cm in any axis
A new extranodal site > 1.0 cm in 
any axis; if < 1.0 cm in any axis, its 
presence must be unequivocal and 
must be attributable to lymphoma
Assessable disease of any size 
unequivocally 
attributable 
to 
lymphoma
     Bone marrow
New or recurrent FDG-avid foci
New or recurrent involvement
•Abbreviations: 5PS - 5-point scale; CT - computed tomography; FDG - fluorodeoxyglucose; IHC - immunohistochemistry; LDi - longest 
transverse diameter of a lesion; MRI - magnetic resonance imaging; PET - positron emission tomography; PPD - cross product of the LDi 
and perpendicular diameter; SDi - shortest axis perpendicular to the LDi; SPD - sum of the product of the perpendicular diameters for 
multiple lesions.
•↵* A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an interim scan. However,
in trials involving PET where de-escalation is investigated, it may be preferable to consider a score of 3 as inadequate response (to avoid 
undertreatment). Measured dominant lesions: Up to six of the largest dominant nodes, nodal masses, and extranodal lesions selected to be 
clearly measurable in two diameters. Nodes should preferably be from disparate regions of the body and should include, where applicable, 
mediastinal and retroperitoneal areas. Non-nodal lesions include those in solid organs (eg, liver, spleen, kidneys, lungs), GI involvement, 
cutaneous lesions, or those noted on palpation. Nonmeasured lesions: Any disease not selected as measured, dominant disease and truly 
assessable disease should be considered not measured. These sites include any nodes, nodal masses, and extranodal sites not selected as 
dominant or measurable or that do not meet the requirements for measurability but are still considered abnormal, as well as truly assessable 
disease, which is any site of suspected disease that would be difficult to follow quantitatively with measurement, including pleural 
effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot be confirmed and followed by 
imaging. In Waldeyer's ring or in extranodal sites (eg, GI tract, liver, bone marrow), FDG uptake may be greater than in the mediastinum 
with complete metabolic response, but should be no higher than surrounding normal physiologic uptake (eg, with marrow activation as a 
result of chemotherapy or myeloid growth factors).
•↵† PET 5PS: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum but ≤ liver; 4, uptake moderately > liver; 
5, uptake markedly higher than liver and/or new lesions; X, new areas of uptake unlikely to be related to lymphoma
 
 
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ECOG Performance Status
12.6
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 
 
 
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Calculation of Renal Clearance
12.7
Subjects 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)
Subjects 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
Clearance can be calculated using tools available via the internet, e.g. 
http://filfola.fr/medecine/cockroft_MDRD.html
or
http://mdrd.com
 
 
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Guidance for Potential Drug-Induced Liver Injury (DILI)
12.8
Purpose
12.8.1
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.
Introduction 
12.8.2
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 2006).  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 subjects.  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.
 
 
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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 subjects 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 

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 Case Report Forms (CRFs) 
and complete pertinent adverse experience fields as outlined in the Data Entry Guidelines 
(DEGs).
Close Observation Recommendations
12.8.3
The following steps should be taken when a subject 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 subject is asymptomatic.
o
For subjects 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
12.8.5).

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 12.8.5 for details).

Obtain a history of exposure to chemical agents or other environmental toxins. 
 
 
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
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 12.8.5 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.
Hepatic Assessment Flow Chart
12.8.4
Figure 4
Hepatic Assessment Flow Chart
Factors to Consider in Assessing Potential DILI
When there is a potential DILI, it is important to thoroughly assess the subject’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.
Study Medication
12.8.4.1
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 subject re-
challenged with study medication?
 
 
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Treatment
12.8.4.2
Record any concomitant treatments.
Signs and Symptoms (associated with the potential DILI event)
12.8.4.3
Does the subject have a concomitant illness?  Does the subject currently exhibit signs or 
symptoms of hepatitis/DILI?  What are the subject’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 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
Confounding Variables
12.8.4.4
What are the relevant medical history and findings?  What is the differential diagnosis? What 
risk factors does the subject 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 subject 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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Evaluation Algorithm for Potential DILI if there are No Other Clinical Reasons
12.8.4.5
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 subject 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:
o
More detailed history of symptoms and prior or concurrent illness
o
Aminotransferase values obtained prior to the study or administration of study 
medication
o
Alcohol consumption (recent and historical)
o
Acetaminophen (APAP)/paracetamol use 
o
New prescription, concomitant, or non-prescription (including herbal and 
other dietary supplements) medications
o
Unusual foods (e.g. mushrooms) or special diets. Consumption of seasonal 
foods.
o
Recreational drug use
o
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/ischaemic hepatopathy
o
Obesity/abdominal adiposity (record weight, height, and waist circumference)
o
Occupational history and history of exposure to chemical agents or other 
environmental toxins
o
Recent travel (last three [3] years)
 
 
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o
Transfusion history

Perform the following required laboratory tests: 
o
Albumin
o
Eosinophils (percentage and absolute; obtain manual count if automated count 
is elevated)
o
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)
o
Human Immunodeficiency Virus (HIV) testing (obtain appropriate consent 
prior to testing, if required locally)
o
Evaluation for autoimmune hepatitis: 

Serum gamma globulin levels/ serum protein electrophoresis

Antinuclear antibody (ANA) 

Anti-mitochondrial antibody (if ALP or TBL >ULN)
o
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:
o
Genetic test for Gilbert's disease if there is a suspicious history. Ensure 
appropriate subject consent is obtained for this test.
o
Viral hepatitis E (IgG and IgM, obtain appropriate consent prior to testing, if 
required locally) 
o
Anti-smooth muscle antibody 
o
Anti-liver-kidney microsomal antibody 
o
Anti-soluble liver antigen
 
 
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o
Serologies for the following:

Cytomegalovirus (CMV) (IgG, IgM)

Epstein-Barr Virus (EBV) (IgG, IgM)

Herpes simplex

Toxoplasmosis

Varicella

Parvovirus
o
Ceruloplasmin
o
Serum alpha-1 anti trypsin
o
Genetic test for hemochromatosis. Ensure appropriate subject consent is 
obtained for this test 
o
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 

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.
Potential Diagnosis
12.8.4.6
What diagnosis do the history, clinical course, and laboratory tests suggest?
Overall Clinical Impression
12.8.4.7
What are the investigator’s overall clinical impressions (e.g., differential diagnosis, potential 
alternative causes)?
Treatment Plan
12.8.4.8
What is the plan for treatment and follow-up?
 
 
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Contacts
12.8.5
If you have any questions, please refer to your Sponsor contact list for the following Merck 
personnel:
- Clinical Research Associate or Subsidiary Monitor
- Clinical Monitor
- Clinical Scientist
References
12.8.6

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/
UCM174090.pdf

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.
 
 
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Non-Exhaustive List of Drugs and Substances with the Potential to Interfere with 
12.9
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%.
Strong CYP3A4 
inducers
Strong CYP3A4 inhibitors
Moderate 
CYP3A4 inducers
Moderate CYP3A4 inhibitors
avasimibe
carbamazepine
phenytoin
rifampicin
St John’s wort1
boceprevir
clarithromycin
conivaptan
grapefruit juice1
indinavir
itraconazole
ketoconazole
lopinavir
mibefradil
nefazodone
nelfinavir
posaconazole
ritonavir 
saquinavir
telaprevir
telithromycin
tipranavir
voriconazole
amobarbital
dexamethasone
efavirenz
felbamate
nevirapine
omeprazole
phenobarbital
pioglitazone
primidone
rifabutin
tamoxifen
troglitazone
atazanavir 
amiodarone
amprenavir
aprepitant
cimetidine
cyclosporine
darunavir
delavirdine
diltiazem 
erythromycin
fluconazole
fosamprenavir
imatinib
miconazole
suboxone 
verapamil
CYP3A Sensitive substrates
CYP3A Substrates with a Narrow 
Therapeutic Range
alfentanil
aprepitant
budesonide 
buspirone
conivaptan
darifenacin
darunavir
dasatinib
dronedarone 
eletriptan, 
eplerenone, 
everolimus
felodipine
indinavir
fluticasone
lopinavir
lovastatin
lurasidone
maraviroc
midazolam
nisoldipine
quetiapine
saquinavir
sildenafil
simvastatin
sirolimus
tolvaptan
tipranavir
triazolam
vardenafil
alfentanil
astemizole
cisapride
cyclosporine
dihydroergotamine
ergotamine
fentanyl
pimozide
quinidine
sirolimus
tacrolimus
terfenadine
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
 
 
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List of Abbreviations
12.10
AE
Adverse Event
AL
Acute Leukemia
ALK
Anaplastic Lymphoma Kinase
ALT
Alanine Aminotransferase
ALL
Acute Lymphoblastic Leukemia
AML
Acute Myeloid Leukemia
AP
Alkaline Phosphatase
AST
Aspartate Aminotransferase
AUC
Area Under The Plasma Concentration Versus Time Curve
BET
Bromodomain and Extraterminal
BID
Twice Daily
BRD
Bromodomain
BRDT
BRD Testis-Specific Protein
CBC
Complete Blood Count
CFR
Code of Federal Regulations
CL
Total Plasma Clearance
Cmax 
Peak Concentration 
Cmin
Residual Concentration
CNS
Central Nervous System
CT-scan
Computerized Tomography scan
CR
Complete Response
CRPC
Castrate-Resistant Prostate Cancer
DCF
Data Correction Form
DL
Dose Level
DLT
Dose Limiting Toxicity
eCRF
Electronic Case Report Form
EML4
Echinoderm Microtubule-Associated Protein-Like 4
ER
Estrogen Receptor
FISH
Fluorescence In Situ Hybridization
GnRH
Gonadotropin Releasing Hormone
Hb
Hemoglobin
HER2
Human Epidermal Growth Factor Receptor 2
IEC
Independent Ethics Committee
ICF
Informed Consent Form
IHC
Immunohistochemistry
INR
International Normalized Ratio
IRB
Institutional Review Board
KRAS
Kirsten Ras
LDH
Lactate Dehydrogenase
LMWH
Low Molecular Weight Heparin
MRI
Magnetic Resonance Imaging 
MTD
Maximum Tolerated Dose
mTPI
Modified Toxicity Probability Interval
NCI-CTCAE
National Cancer Institute -Common Toxicity Criteria for Adverse Events
NMC
NUT Midline Carcinoma
NSCLC
Non-Small Cell Lung Cancer
NUT
Nuclear Protein in Testis
OHM
Other Hematologic Malignancies
OS
Overall Survival
PCWG2
Prostate Cancer Clinical Trials Working Group
PD
Progressive Disease
PFS
Progression-Free Survival
PgR
Progesterone Receptor
 
 
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Product:  MK-8628 
119
Protocol/Amendment No.: 005-02 
MK-8628-005-02 Final Protocol
29-Sep-2017
Confidential
PIL
Patient Information Leaflet
PK
Pharmacokinetics
PR
Partial Response
PS
Performance Status
P-TEFb
Positive Transcription Elongation Factor b
QD
Once Daily
RBC
Red Blood Cells
RECIST
Response Evaluation Criteria In Solid Tumors
SAE
Serious Adverse Event
SAERF
Serious Adverse Event Report Form
SAR
Suspected Adverse Reaction
SCC
Squamous Cell Carcinoma
SD
Stable Disease
SMC
Safety Monitoring Committee
SUSAR
Serious, Unexpected Suspected Adverse Reaction
t1/2
Terminal Half-Life
Tmax
Time to Peak Concentration
ULN
Upper Limit of Normal
UPN
Unique Patient Number
UPLC-MS/MS
Ultra Performance Liquid Chromatography, with tandem Mass Spectrometry 
Vdss
Volume of Distribution At Steady State
WBC
White Blood Cell
 
 
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Product:  MK-8628 
120
Protocol/Amendment No.: 005-02 
MK-8628-005-02 Final Protocol
29-Sep-2017
Confidential
13.0 SIGNATURES
Sponsor's Representative
13.1
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
13.2
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – TRIAL PROCEDURES (Assessing and Recording Adverse 
Events).  I also agree to handle all clinical supplies provided by the Sponsor and collect and 
handle all clinical specimens in accordance with the protocol.  I understand that information 
that identifies me will be used and disclosed as described in the protocol, and that such 
information may be transferred to countries that do not have laws protecting such 
information.  Since the information in this protocol and the referenced Investigator’s 
Brochure is confidential, I understand that its disclosure to any third parties, other than those 
involved in approval, supervision, or conduct of the trial is prohibited.  I will ensure that the 
necessary precautions are taken to protect such information from loss, inadvertent disclosure 
or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
 
 
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