Clinical trial NCT02698176
Conditions: NUT Midline Carcinoma (NMC) Triple Negative Breast Cancer (TNBC) Non-small Cell Lung Cancer (NSCLC) Castration-resistant Prostate Cancer (CRPC)
Keywords: OTX015 MK-8628
Sponsor: Merck Sharp & Dohme LLC
Start date: 2016-05-04; Completion date: 2017-04-26
Enrollment: 13 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a study to determine the recommended dose of birabresib (MK-8628)(formerly known as OTX015) for further studies in participants with advanced nuclear protein in testis (NUT) midline carcinoma (NMC), triple negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), or castration-resistant prostate cancer (CRPC). This is a two-part parallel study: Part A will establish the recommended dose by evaluating dose limiting toxicity (DLT), safety, discontinuation, and early efficacy and Part B will enroll participants with NMC only and will evaluate safety and efficacy in this population.

Detailed description:
The sponsor decided to terminate the program after evaluation of safety and efficacy data at the dose levels tested (Part A). The decision to discontinue the birabresib program was based on limited efficacy signals and was not due to safety-related concerns. No participants entered or were treated in Part B of the study.

Arms: arm 1: Participants in the CRPC cohort in Part A of the study received birabresib 20 mg orally (PO), twice a day (BID), in a fasted state for 21 consecutive days per cycle. Participants received birabresib in continuous cycles up to 24 months. arm 2: Participants in the NMC cohort in Part A of the study received birabresib 20 mg PO, BID, in a fasted state for 21 consecutive days per cycle. Participants received birabresib in continuous cycles up to 24 months. arm 3: Participants in the TNBC cohort in Part A of the study received birabresib 20 mg PO, BID, in a fasted state for 21 consecutive days per cycle. Participants received birabresib in continuous cycles up to 24 months. arm 4: Participants (up to 30) in Part B will receive birabresib at one dose level below the dose currently being administered in Part A of the study. Once the recommended Phase 2 dose (RP2D) from Part A is established, participants in Part B will receive birabresib at the RP2D. Participants will continue receiving birabresib at an assigned/adjusted dose level for continuous cycles up to 24 months.
Interventions: intervention 1: Birabresib
Intervention descriptions: intervention 1: Administered as an oral capsule in a fasted state

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Official Protocol Title: 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 Advanced Solid Tumors 
NCT number: 
NCT02698176 
Document Date: 
21-Nov-2016 


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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.
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 Dose Exploration Trial with MK-8628, a Small Molecule Inhibitor of the 
Bromodomain and Extra-Terminal (BET) Proteins, in Subjects with Selected Advanced Solid 
Tumors
IND NUMBER:  123,715
EudraCT NUMBER:  2015-005488-18


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TABLE OF CONTENTS
SUMMARY OF CHANGES................................................................................................ 11
1.0
TRIAL SUMMARY.................................................................................................. 13
2.0
TRIAL DESIGN........................................................................................................ 14
Trial Design ........................................................................................................... 14
2.1
Trial Diagram........................................................................................................ 15
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
Other Objectives (Exploratory)........................................................................... 17
3.3
4.0
BACKGROUND & RATIONALE.......................................................................... 17
Background ........................................................................................................... 17
4.1
Pharmaceutical and Therapeutic Background .................................................... 17
4.1.1
4.1.1.1
NUT Midline Carcinoma ............................................................................. 18
4.1.1.2
Non-Small Cell Lung Cancer....................................................................... 19
4.1.1.3
Triple-Negative Breast Cancer .................................................................... 20
4.1.1.4
Castration-Resistant Prostate Adenocarcinoma........................................... 21
MK-8628 Metabolism – Cytochrome P450 Interactions.................................... 22
4.1.2
MK-8628 – Ongoing Clinical Trials in Advanced Solid Tumors....................... 22
4.1.3
Rationale................................................................................................................ 23
4.2
Rationale for the Trial and Selected Subject Population .................................... 23
4.2.1
Rationale for Dose Selection/Regimen/Escalation ............................................. 25
4.2.2
4.2.2.1
Starting Dose for This Trial ......................................................................... 26
4.2.2.2
Maximum Dose/Exposure for This Trial..................................................... 28
4.2.2.3
Rationale for Dose Interval and Trial Design .............................................. 28
Rationale for Endpoints ...................................................................................... 28
4.2.3
4.2.3.1
Safety Endpoints .......................................................................................... 28
4.2.3.1.1
Primary Safety Endpoint:...................................................................... 28
4.2.3.1.2
Secondary Safety Endpoints ................................................................. 28
4.2.3.2
Pharmacokinetic Endpoints ......................................................................... 28


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4.2.3.3
Pharmacodynamic Endpoints....................................................................... 29
4.2.3.4
Efficacy Endpoints....................................................................................... 30
4.2.3.4.1
Secondary Efficacy Endpoints: RECIST or PCWG -based 
Response Rate....................................................................................... 30
4.2.3.4.2
Exploratory Efficacy Endpoints............................................................ 30
4.2.3.5
Planned Exploratory Biomarker Research................................................... 30
4.2.3.6
Future Biomedical Research........................................................................ 30
Benefit/Risk ........................................................................................................... 31
4.3
5.0
METHODOLOGY ................................................................................................... 31
Entry Criteria........................................................................................................ 31
5.1
Diagnosis/Condition for Entry into the Trial ...................................................... 31
5.1.1
Subject Inclusion Criteria.................................................................................... 31
5.1.2
Subject Exclusion Criteria .................................................................................. 33
5.1.3
Trial Treatment(s) ................................................................................................ 34
5.2
Dose Selection/Modification .............................................................................. 35
5.2.1
5.2.1.1
Dose Selection (Preparation) ....................................................................... 35
5.2.1.2
Dose Escalation (Part A).............................................................................. 35
5.2.1.3
NMC Cohort (Part B)................................................................................... 37
5.2.1.4
Dose Limiting Toxicity................................................................................ 37
5.2.1.5
Recommended Phase II Dose ...................................................................... 39
5.2.1.6
Dose Adaptation........................................................................................... 39
Timing of Dose Administration .......................................................................... 41
5.2.2
5.2.2.1
Premedication .............................................................................................. 41
Trial Blinding...................................................................................................... 41
5.2.3
Randomization or Treatment Allocation............................................................ 42
5.3
Stratification.......................................................................................................... 42
5.4
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 42
5.5
Medications......................................................................................................... 42
5.5.1
Rescue Medications & Supportive Care............................................................. 43
5.6
Supportive Care Guidelines ................................................................................ 43
5.6.1
5.6.1.1
General Guidelines for Clinically Significant Toxicities............................. 43
5.6.1.2
Hepatic Laboratory Abnormalities .............................................................. 44


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Diet/Activity/Other Considerations..................................................................... 44
5.7
Diet...................................................................................................................... 44
5.7.1
Potential Phototoxicity........................................................................................ 44
5.7.2
Contraception...................................................................................................... 44
5.7.3
Use in Pregnancy ................................................................................................ 47
5.7.4
Use in Nursing Women....................................................................................... 47
5.7.5
Subject Withdrawal/Discontinuation Criteria................................................... 47
5.8
Subject Replacement Strategy............................................................................. 48
5.9
Beginning and End of the Trial ........................................................................... 48
5.10
Clinical Criteria for Early Trial Termination ................................................... 48
5.11
6.0
TRIAL FLOW CHART ........................................................................................... 49
7.0
TRIAL PROCEDURES ........................................................................................... 52
Trial Procedures ................................................................................................... 52
7.1
Administrative Procedures.................................................................................. 52
7.1.1
7.1.1.1
Informed Consent......................................................................................... 52
7.1.1.1.1
General Informed Consent.................................................................... 52
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 53
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 53
7.1.1.3
Subject Identification Card .......................................................................... 53
7.1.1.4
Medical History ........................................................................................... 53
7.1.1.5
Prior and Concomitant Medications Review ............................................... 53
7.1.1.5.1
Prior Medications.................................................................................. 53
7.1.1.5.2
Concomitant Medications..................................................................... 53
7.1.1.6
Assignment of Screening Number............................................................... 54
7.1.1.7
Assignment of Treatment/Randomization Number..................................... 54
7.1.1.8
Trial Compliance (Medication).................................................................... 54
Clinical Procedures/Assessments........................................................................ 55
7.1.2
7.1.2.1
Adverse Event (AE) Monitoring.................................................................. 55
7.1.2.2
Full Physical Exam ...................................................................................... 55
7.1.2.3
Eastern Cooperative Oncology Group (ECOG) Performance Status .......... 55
7.1.2.4
Vital Signs.................................................................................................... 55


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7.1.2.5
Electrocardiogram (ECG) ............................................................................ 55
7.1.2.6
Tumor Imaging and/or Bone Scan............................................................... 56
7.1.2.6.1
CT, MRI and/or Chest X-Ray............................................................... 56
7.1.2.6.2
Bone Scan ............................................................................................. 56
7.1.2.6.3
Assessment of Disease.......................................................................... 56
Laboratory Procedures/Assessments .................................................................. 57
7.1.3
7.1.3.1
Laboratory Safety and Other Evaluations (Hematology, Chemistry,   
Coagulation and Other)................................................................................ 57
7.1.3.1.1
Urine or Serum β-hCG.......................................................................... 58
7.1.3.2
Pharmacokinetic/Pharmacodynamic Evaluations ........................................ 58
7.1.3.2.1
PK Sample Collection (Plasma) ........................................................... 58
7.1.3.2.2
PK Assay Method and Parameters Analyzed ....................................... 59
7.1.3.2.3
PD Sample Collection........................................................................... 59
7.1.3.2.4
Serum Tumor Markers.......................................................................... 59
7.1.3.3
Planned Genetic Analysis Sample Collection.............................................. 60
7.1.3.4
Future Biomedical Research Sample Collection ......................................... 60
Other Procedures................................................................................................. 60
7.1.4
7.1.4.1
Withdrawal/Discontinuation........................................................................ 60
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 60
7.1.4.2
Blinding/Unblinding .................................................................................... 61
7.1.4.3
Domiciling ................................................................................................... 61
7.1.4.4
Calibration of Critical Equipment................................................................ 61
Visit Requirements.............................................................................................. 61
7.1.5
7.1.5.1
Screening...................................................................................................... 61
7.1.5.2
Treatment Period.......................................................................................... 62
7.1.5.3
End of Treatment ......................................................................................... 62
7.1.5.4
Post-Treatment............................................................................................. 62
Assessing and Recording Adverse Events .......................................................... 62
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 63
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 64
7.2.2
Immediate Reporting of Adverse Events to the Sponsor.................................... 64
7.2.3
7.2.3.1
Serious Adverse Events ............................................................................... 64


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7.2.3.2
Events of Clinical Interest............................................................................ 65
7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting ............ 66
Evaluating Adverse Events ................................................................................. 66
7.2.4
Sponsor Responsibility for Reporting Adverse Events ...................................... 69
7.2.5
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 69
Statistical Analysis Plan Summary ..................................................................... 69
8.1
Responsibility for Analyses/In-House Blinding ................................................. 70
8.2
Hypotheses/Estimation ......................................................................................... 70
8.3
Analysis Endpoints ............................................................................................... 70
8.4
Safety Endpoints ................................................................................................. 70
8.4.1
Efficacy/Pharmacokinetics/Pharmacodynamics Endpoints ................................ 70
8.4.2
Analysis Populations............................................................................................. 71
8.5
Efficacy Analysis Populations ............................................................................ 71
8.5.1
Safety Analysis Populations ............................................................................... 71
8.5.2
Statistical Methods................................................................................................ 71
8.6
Statistical Methods for Efficacy Analyses .......................................................... 71
8.6.1
Statistical Methods for Safety Analyses ............................................................. 71
8.6.2
Summaries of Baseline Characteristics, Demographics, and Other Analyses .... 71
8.6.3
Interim Analyses ................................................................................................... 72
8.7
Multiplicity ............................................................................................................ 72
8.8
Sample Size and Power Calculations .................................................................. 72
8.9
Subgroup Analyses and Effect of Baseline Factors ........................................... 73
8.10
Compliance (Medication Adherence).................................................................. 73
8.11
Extent of Exposure................................................................................................ 73
8.12
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 73
Investigational Product ........................................................................................ 73
9.1
Packaging and Labeling Information ................................................................. 73
9.2
Clinical Supplies Disclosure................................................................................. 73
9.3
Storage and Handling Requirements.................................................................. 74
9.4
Discard/Destruction/Returns and Reconciliation .............................................. 74
9.5
Standard Policies................................................................................................... 74
9.6


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10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 74
Confidentiality....................................................................................................... 74
10.1
Confidentiality of Data ....................................................................................... 74
10.1.1
Confidentiality of Subject Records..................................................................... 74
10.1.2
Confidentiality of Investigator Information........................................................ 75
10.1.3
Confidentiality of IRB/IEC Information............................................................. 75
10.1.4
Compliance with Financial Disclosure Requirements....................................... 75
10.2
Compliance with Law, Audit and Debarment ................................................... 76
10.3
Compliance with Trial Registration and Results Posting Requirements ........ 77
10.4
Quality Management System............................................................................... 78
10.5
Data Management................................................................................................. 78
10.6
Publications ........................................................................................................... 78
10.7
11.0
LIST OF REFERENCES......................................................................................... 79
12.0
APPENDICES........................................................................................................... 88
Merck Code of Conduct for Clinical Trials........................................................ 88
12.1
Collection and Management of Specimens for Future Biomedical 
12.2
Research................................................................................................................. 90
Understanding the Intent, Scope and Public Health Benefits of 
12.3
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff ...................................................................................... 94
ECOG Performance Status................................................................................ 105
12.4
Calculation of Renal Clearance......................................................................... 106
12.5
Non-Exhaustive List of Drugs and Substances with the Potential to 
12.6
Interfere with CYP3A4 and CYP2A6............................................................... 107
Guidance for Potential Drug-Induced Liver Injury (DILI)............................ 108
12.7
Purpose.............................................................................................................. 108
12.7.1
Introduction....................................................................................................... 108
12.7.2
Close Observation Recommendations .............................................................. 109
12.7.3
Hepatic Assessment Flow Chart ....................................................................... 110
12.7.4
Factors to Consider in Assessing Potential DILI .............................................. 110
12.7.5
12.7.5.1 Study Medication....................................................................................... 111
12.7.5.2 Treatment ................................................................................................... 111
12.7.5.3 Signs and Symptoms (associated with the potential DILI event) .............. 111


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12.7.5.4 Confounding Variables .............................................................................. 111
12.7.5.5 Evaluation algorithm for potential DILI if there are no other clinical 
reasons ....................................................................................................... 112
12.7.5.6 Potential diagnosis ..................................................................................... 115
12.7.5.7 Overall clinical impression ........................................................................ 115
12.7.5.8 Treatment plan ........................................................................................... 115
Contacts............................................................................................................. 115
12.7.6
References......................................................................................................... 115
12.7.7
Response Evaluation Criteria in Solid Tumors (RECIST)............................. 116
12.8
Imaging Technique ........................................................................................... 116
12.8.1
Evaluation of Lesions ....................................................................................... 116
12.8.2
Definition of Best Overall Tumor Response..................................................... 117
12.8.3
References......................................................................................................... 118
12.8.4
Prostate Cancer Clinical Trials Working Group (PCWG2) Response 
12.9
Criteria................................................................................................................. 119
PSA ................................................................................................................... 119
12.9.1
Measureable Soft-Tissue Lesions ..................................................................... 119
12.9.2
Bone .................................................................................................................. 120
12.9.3
References......................................................................................................... 122
12.9.4
List of Abbreviations .......................................................................................... 123
12.10
13.0
SIGNATURES......................................................................................................... 127
Sponsor's Representative ................................................................................... 127
13.1
Investigator.......................................................................................................... 127
13.2


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LIST OF TABLES
    
Table 1: Adequate Organ Function Laboratory Values.......................................................... 32
Table 2:  Trial Treatments – Part A: Dose Escalation ............................................................ 34
Table 3:  Trial Treatments – Part B: NMC Cohort................................................................. 34
Table 4:  Dose Escalation Scheme.......................................................................................... 35
Table 5:  Modified Toxicity Probability Interval (mTPI) Design........................................... 36
Table 6:  Dosing Scheme for NMC Cohort ............................................................................ 37
Table 7:  Dose Modification Guidelines for Drug-Related Adverse Events .......................... 39
Table 8: MK-8628 Dose and Schedule Modifications ........................................................... 41
Table 9: Laboratory Tests....................................................................................................... 57
Table 10: PK Sample Collection Timing................................................................................ 58
Table 11:  PD Sample Collection Timing............................................................................... 59
Table 12: Evaluating Adverse Events.................................................................................... 67
Table 13:  Bayesian credible interval for DLT rate estimate and confidence interval for 
ORR estimate for different sample sizes and number of events................................. 72
Table 14: Product Descriptions.............................................................................................. 73
Table 15:  Evaluation of response in target lesions .............................................................. 116
Table 16:  Evaluation of non-target lesions.......................................................................... 116
Table 17:  Overall response in subjects with target (+/– non-target) disease....................... 117
Table 18:  Best overall response........................................................................................... 118
Table 19:  The Prostate Cancer Clinical Trials Working Group (PCWG2) Response 
Criteria ...................................................................................................................... 121


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LIST OF FIGURES
          
Figure 1:  Dose Escalation Scheme ........................................................................................ 15
Figure 2:  NMC Cohort Dosing Scheme ................................................................................ 16
Figure 3:  PK comparison of QD versus BID......................................................................... 27
Figure 4: Dose-dependent changes in BET protein target gene expression .......................... 29
Figure 5:  Hepatic Assessment Flow Chart........................................................................... 110


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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
1.0
2.1;
2.2;
5.2;
5.2.1.3;
5.2.1.4;
5.2.1.6;
5.3;
6.0;
8.1;
8.9
Trial Summary;
Trial Design;
Trial Diagram;
Trail Treatment(s);
NMC Cohort (Part B);
Dose Limiting Toxicity;
Dose Adaptation;
Randomization or Treatment Allocation;
Trial Flow Chart;
Statistical Analysis Plan Summary;
Sample Size and Power Calculation
An additional cohort of up to 
30 NMC subjects has been 
added for treatment in a parallel 
cohort (Part B). NMC subjects 
enrolled in Part B will be 
treated at one dose level below 
the current dose level from the 
dose escalation part of the 
study (Part A).
To allow access to treatment 
for patients with this rare and 
aggressive 
cancer 
when 
treatment slots are unavailable 
in the dose escalation part of 
the study (Part A), while 
assessing safety, tolerability, 
pharmacokinetic/ 
pharmacodynamic parameters , 
anti-tumor activity and any 
additional 
scientific 
data. 
Priority for treatment allocation 
will be to enroll into Part A of 
the study (Dose Escalation). If 
there are no slots available in 
Part A at the time the NMC 
subject is identified, the subject 
will be enrolled and allocated 
to treatment in Part B (NMC 
Cohort).


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ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
1.0
Trial Summary
Revised withdrawal criteria of treatment 
interruption for > 2 weeks to be due to 
toxicity, as opposed to due to any reason.
Text updated to align with 
subject 
withdrawal 
criteria 
outlined in Section 5.8.
4.1.3
MK-8628 – Ongoing Clinical 
Trials in Advanced Solid 
Tumors
Updated the data reported in this section 
from this ongoing study to include up to 
date enrollment and response figures.
Updated the data reported in 
this section from this ongoing 
study to include up to date 
enrollment 
and 
response 
figures.
5.1.2
Inclusion criteria
Removed the guideline for allowing 
inclusion of subjects with an INR of <3 if 
being treated with anti-vitamin K therapy.
The use of anti-vitamin K 
therapy is prohibited on study, 
so 
this 
criterion 
is 
not 
applicable.
5.1.2
Inclusion criteria
Added an exception to allow NMC 
patients included with an interval of ≥ 2 
weeks since chemotherapy, as opposed to 
the standard 3 week interval.
Due to the high risk for rapid 
disease progression in this 
indication, and provided any 
previously 
administered 
therapies meet the remaining 
criteria for wash-out in terms of 
half-lives, 
shortening 
the 
standard window can provide a 
faster time to treatment for 
subjects with this rare and 
aggressive cancer.
5.1.3
Exclusion criteria
Added language clarifying that subjects 
with treated and stable CNS metastases are 
eligible.
Text added for clarity.


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1.0 TRIAL SUMMARY
Abbreviated Title
MK-8628 Solid Tumor Trial
Sponsor Product Identifiers
MK-8628
Trial Phase
Ib
Clinical Indication
Treatment of subjects with selected advanced solid tumors, including 
NUT midline carcinoma (NMC), non-small-cell lung cancer 
(NSCLC), triple negative breast cancer (TNBC) and castration-
resistant prostate cancer (CRPC).
Trial Type
Interventional
Type of control
No treatment control
Route of administration
Oral
Trial Blinding
Unblinded Open-label
Treatment Groups
Part A: Dose Escalation
MK-8628 20 mg, twice a day, continuous, 21 consecutive days/cycle;
MK-8628 30 mg, twice a day, continuous, 21 consecutive days/cycle;
MK-8628 40 mg, twice a day, continuous, 21 consecutive days/cycle
Part B: NMC Cohort
MK-8628 10 mg, twice a day, continuous, 21 consecutive days/cycle;
MK-8628 20 mg, twice a day, continuous, 21 consecutive days/cycle;
MK-8628 30 mg, twice a day, continuous, 21 consecutive days/cycle;
MK-8628 40 mg, twice a day, continuous, 21 consecutive days/cycle
Number of trial subjects
Approximately a maximum of 72 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 2 years 
from the time the first subject signs the informed consent until the last 
subject’s last study-related phone call or visit.
Duration of Participation
Each subject will participate in the trial from the time the subject signs 
the Informed Consent Form (ICF) through the final protocol-specified 
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 toxicity
(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. Tumor measurements are to be made every 6 
weeks and bone scans will be performed every 12 weeks until 
progressive disease is observed.
A list of abbreviations used in this document can be found in Section 12.10.


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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 advanced solid tumors (NMC, NSCLC, TNBC and CRPC), to be
conducted in conformance with Good Clinical Practices (GCP).
The study will be conducted in two parallel parts: The primary objective will be evaluated in 
a dose escalation study (Part A), and additional NMC subjects will be treated in a parallel 
cohort (Part B).
Part A: Dose Escalation:
This dose escalation study will evaluate a twice-daily (BID) dosing regimen to establish the 
recommended phase II dose (RP2D). Subjects will be included in at least nine centers 
worldwide. 
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 (Ji design) [1]. Up to 
three dose levels (DL) will be evaluated: 20, 30 and 40 mg BID, continuous, 21-day cycles. 
Up to 14 subjects will be enrolled per DL, depending on the occurrence of DLT (see Sections
5.2.1.2 and 5.2.1.4) during the first 21 days of treatment. Thus up to 42 subjects evaluable for 
DLT will be enrolled in Part A.
Subjects will undergo a dose and/or schedule modification in the event of toxicity (see 
Section 5.2.1.6 and 5.6.1.1).
The RP2D will be selected based on a multi-faceted decision taking into account safety, 
tolerability, early efficacy signal, pharmacokinetic (PK) exposure and pharmacodynamic 
(PD) markers. The primary endpoint driving dose selection is the DLT rate, with weight 
given to the highest DL tolerated (<25% DLT rate) (see Section 5.2.1.5).
Part B: NMC Cohort:
An additional cohort of NMC subjects will be treated in a parallel study. This study will only 
include NMC subjects. The primary purpose of this part of the study is to allow access to 
treatment for patients with this rare and aggressive cancer when treatment slots are 
unavailable in Part A (Dose Escalation), while assessing safety, tolerability, 
pharmacokinetic/pharmacodynamic parameters, anti-tumor activity and any additional 
scientific data. Priority for treatment allocation will be to enroll into Part A of the study 
(Dose Escalation). If there are no slots available in Part A at the time the NMC subject is 
identified, the subject will be enrolled and allocated to treatment in Part B (NMC Cohort).


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As in Part A, dose administration will be continuous for 21 consecutive days per cycle (21-
day cycles). NMC subjects enrolled in Part B will be treated at one dose level below the 
current dose level from the dose escalation study in Part A. Therefore, a starting dose of 10 
mg BID will be administered, and up to four dose levels will be evaluated: 10, 20, 30 and 40 
mg BID, continuous, 21-day cycles. Once the RP2D is established, newly enrolled NMC 
subjects in Part B may be treated at the RP2D.
Subjects will undergo a dose and/or schedule modification in the event of toxicity (see 
Section 5.2.1.6 and 5.6.1.1).
Up to 30 NMC subjects will be enrolled in Part B.
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 for Part A of the study is depicted in Figure 1.
Figure 1: Dose Escalation Scheme
The trial design for Part B of the study is depicted in Figure 2.


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Figure 2: NMC Cohort Dosing Scheme
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Objectives for this trial are to be evaluated for single-agent MK-8628 administered orally to 
subjects with selected solid tumors (NMC, NSCLC, TNBC or CRPC) as follows:
Primary Objective(s) & Hypothesis(es)
3.1
(1) Objective: To determine the recommended phase II dose (RP2D).
Secondary Objective(s) & Hypothesis(es)
3.2
(1) Objective:  To assess the safety and tolerability.
(2) Objective: 
To 
characterize 
pharmacokinetic
(see 
Section
4.2.3.2) 
and 
pharmacodynamic (see Section 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 Solid Tumors (RECIST) v1.1 or Prostate Cancer Clinical Trials Working 
Group (PCWG2) as assessed by investigator radiologic review.


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Other Objectives (Exploratory)
3.3
(1) Objective:  Evaluate antitumor activity using progression-free survival (PFS) by 
RECIST v1.1 or PCWG2 as assessed by investigator radiologic review, and overall 
survival (OS).
(2) Objective: 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 BRDs, 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 BRD testis-specific protein 
(BRDT) may accommodate two acetyl-lysines in a single site [15][19]. 
The BET family of BRD proteins, which includes BRD2, BRD3, BRD4, and BRDT, are 
epigenetic reader proteins that bind acetylated lysine residues on histones playing critical 
roles in cellular proliferation and cell-cycle progression [20]. BRD4 binds to the positive 


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transcription elongation factor b (P-TEFb), a cyclin-dependent kinase, and stimulates 
ribonucleic acid (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.
4.1.1.1
NUT Midline Carcinoma
NUT midline carcinoma (NMC) is an aggressive subtype of squamous cell carcinoma (SCC) 
defined by chromosomal rearrangement of the gene nuclear protein in testis (NUT). In most 
cases, NUT on chromosome 15 is fused to BRD4 on chromosome 19 [28], providing the first 
indication of a link between BRDs and cancer. Human BRD4 was first identified as a result 
of its involvement in NMC. A minor NMC subset has alternative rearrangements that create 
BRD3-NUT fusion genes. These genetic rearrangements of the BRD3 and BRD4 loci in 
which in-frame chimeric proteins of the N-terminal BRDs of BRD3 or BRD4 with NUT, 
give rise to a uniformly fatal SCC subtype, [29]. The somatic alteration defining NMC is a 
t(15;19)(q14;p13.1) chromosomal translocation that results in a fusion protein between the 
BET proteins BRD3 or BRD4 and the nuclear protein NUT [30].
With a median survival time of 6.7 months [31], NMC is far more aggressive than typical 
non-cutaneous SCC. The lack of effective treatments means a diagnosis of NMC comes with 
substantial clinical challenges. NMC has no organ or tissue of origin and can occur anywhere 
but most commonly along the midline, with typical sites being the head, neck and 
mediastinum. However, cases arising in the bladder, pancreas, adrenal gland, kidney and 
salivary gland have been described [32], challenging the notion that this is strictly a midline 
neoplasm. Although rare, the true incidence of NMC is still unknown because it is frequently 
confused with common forms of SCC that arise most often in the aero-digestive tract; NMC 
is still undoubtedly underdiagnosed. 
The key to the diagnosis of NMC is a high index of suspicion coupled with molecular testing. 
Given that NUT expression is restricted to the testes, the tumor can be diagnosed with 
virtually 100% specificity by immunohistochemistry (IHC) for NUT protein expression [33]. 


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Because NMC cannot be diagnosed by morphology alone, and occurs in many organs and 
across a wide range of ages (from neonates to the elderly), it is recommended that testing for 
NUT expression by immunohistochemistry (IHC) be performed in all poorly differentiated 
non-cutaneous carcinomas that lack glandular differentiation [34]. 
The optimal treatment for patients with NMC is unclear. Although a number of therapeutic 
regimens have been used, the overall effectiveness of chemotherapy is questionable. In the 
series by Bauer et al., gross total resection was associated with improved survival, both PFS 
and OS [31]. Intriguingly, these tumors seem to respond well to early administration of 
radiotherapy. 
Given that the disruption of complexes containing BRD proteins is a critical facet of NMC 
pathogenesis and that that these proteins are key oncogenic drivers for this cancer [28], it was 
hypothesized that an agent that would block the biological activity of BRD4-NUT and/or 
BRD3-NUT may be an effective therapy for NMC. Recent laboratory studies have suggested 
that the NUT fusion protein results in aberrant histone acetylation and blockade of 
differentiation. Efforts have been made to develop targeted therapeutic approaches such as 
direct acting inhibitors of the BRD3 and BRD4 bromodomains. MK-8628, an orally 
bioavailable small molecule inhibitor of BRD2, BRD3 and BRD4 has been shown to inhibit 
the growth of Ty82 BRD-NUT carcinoma in nude mice by 79% [35].
4.1.1.2
Non-Small Cell Lung Cancer
Approximately 50%-60% of NSCLC patients have at least one identifiable driver mutation, 
with the most common mutations being the Kirsten ras (KRAS) gene (24%-27%) and the 
epidermal growth factor receptor (EGFR) gene (13%-22%), with translocations involving 
anaplastic lymphoma kinase (ALK) in another 5%-6% [36][37][38]. Several additional 
mutations have been identified.
KRAS, like other RAS family of oncogenes, encodes a guanine triphosphate-binding protein 
involved in cellular growth, differentiation, and apoptosis by interacting with multiple 
effectors. KRAS mutations are typically mutually exclusive of EGFR mutations, occurring in 
different patient populations [37][39][40]. In a retrospective series of 1036 patients, 
multivariate analysis demonstrated that the presence of a KRAS mutation was associated 
with a shorter OS (HR 1.21, p = 0.048) [41]. Mutant KRAS is a strong activator of mitogen-
activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways [42], and 
the inhibition of KRAS-dependent MAPK and PI3K pathways results in MYC 
dephosphorylation [43][44], which contributes to its degradation. In support of MYC as a 
therapeutic target in NSCLC, Soucek et al. reported regression of KRAS-induced lung 
adenocarcinoma upon systemic expression of a dominant-negative MYC inhibitory peptide 
(OMOMYC) [45]. Furthermore, in vivo experiments using a similar KRAS-induced cancer 
model confirmed that the BET bromodomain inhibitor, JQ1, prompts tumor regression in 
mutant KRAS mouse lung cancers [46].  In the same report, preclinical models showed that 
JQ1 exerts anti-proliferative activity in a diverse panel of NSCLC cell lines with different 
mutational profiles [46]. This study suggested that KRAS-mutant NSCLC harboring a 
concurrent liver kinase B1 (LKB1) loss-of-function mutation is comparatively more resistant.
However, meta-analyses examining co-mutation rates in non-small cell lung cancer find that 
<5% of patients carry both KRAS activating and the LKB1 inactivating mutations [47].


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A subgroup of NSCLC patients have tumors containing an inversion in chromosome 2 that 
juxtaposes the 5' end of the echinoderm microtubule-associated protein-like 4 (EML4) gene 
with the 3' end of the ALK gene, resulting in the novel fusion oncogene EML4-ALK [48]. 
This fusion oncogene rearrangement is transforming both in vitro and in vivo and defines a 
distinct clinicopathologic subset of NSCLC.
A recent preclinical report indicates that MK-8628 is broadly active in both EMLA4-ALK 
positive and negative NSCLC cell lines, and its sensitivity is not correlated to basal levels of 
BRDs, c-MYC, N-MYC, BCL2 or p21 [49]. In sensitive NSCLC cell lines, MK-8628 results 
in a rapid and sustained downregulation of c-MYC or N-MYC. In addition, MK-8628 
exhibits in vitro additive activity when combined with crizotinib in ALK positive NSCLC 
cell lines. Preclinical studies relying on genetic or pharmacologic disruption of either MYC 
or BET protein function point toward a broad potential of MK-8628 to impair NSCLC tumor 
growth across a range of genetically diverse backgrounds.
4.1.1.3
Triple-Negative Breast Cancer
Triple negative breast cancer (TNBC) is a distinct subset of breast cancer defined by the lack 
of IHC expression of the estrogen receptor (ER), progesterone receptor (PgR) and human 
epidermal growth factor receptor 2 (HER2), accounting for approximately 15%-20% of 
breast cancer patients. According to the American Society of Clinical Oncology (ASCO)
guideline recommendations, breast cancer is considered negative for ER or PgR if less than 
1% of tumor cell nuclei are immunoreactive [50], and negative for HER2 if either the IHC 
score is 0 or 1+, or Fluorescence In Situ Hybridization (FISH) average gene copy < 4 signals 
per cell nucleus [51].
TNBC terminology is confusing since it reflects a heterogeneous population [52] with a more 
complex molecular transcriptome than is suggested by the triple-negative IHC expression. 
Classification of breast tumors by their gene expression signature revealed distinct subtypes 
with important implications for outcome [53][54]. Of these subtypes, which include HER2-
enriched, luminal A, luminal B, and basal-like breast cancer (BLBC), the latter has the 
poorest prognosis [55]. Gene expression analysis demonstrates that the molecular signature 
of TNBC generally overlaps with basal-like breast cancer, with concordance rates of 70%-
90% [56][57]. However, not all TNBC can be defined as basal-like breast cancer [55][58], as 
a small minority of BLBC patients do in fact, have some ER and HER2 expression. TNBC is 
also associated with Breast Cancer gene (BRCA)-related breast cancer, although the 
incidence of BRCA mutations in TNBC varies from 16% to 42% [59][60]. Other 
mechanisms resulting in downregulation of BRCA1/2, including epigenetic alterations and 
overexpression of BRCA1 inhibitors [61][62][63][64], are also associated with TNBC and 
likely contribute to aneuploidy and genomic instability characteristics of this subgroup. 
Chemotherapy remains the core option for TNBC patients. However, treatment with 
cytotoxic chemotherapy produces mixed results and has a variable impact on long-term 
prognosis [65][66][67][68]. In the neoadjuvant setting, TNBC exhibits a better response to 
chemotherapy compared with non-TNBC [69]. Patients who do not respond well to 
preoperative chemotherapy have a high risk of relapse within the first 2 years and worse OS 
(3-year survival, 68% versus 94% pathological complete response non-responders versus 
responders) [65][70][71][72][73]. 


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Metastatic TNBC is an aggressive disease that is associated with a high proliferation index 
[74], visceral and central nervous system (CNS) metastases [69][75][76], and poor outcome 
despite treatment. Median survival of advanced TNBC is at best 12 months [77], much 
shorter than the duration of survival seen in other subtypes of advanced breast cancer. The 
most dramatic improvements in survival are associated with targeted therapy. However, 
TNBC trials of targeted therapy as single agents or in combination with chemotherapy, 
despite a strong biological rationale in many cases, have been less promising, resulting in 
modest gains in PFS and no gains in OS [77]. Retrospective evaluations of anti-angiogenic 
agents have demonstrated encouraging efficacy signals in TNBC, with a doubling of PFS in 
select trials [78][79][80][81]. However, PFS gains remain modest (∼3 months) [79][80]. 
Therefore, identification of more active therapies for TNBC patients remains an important 
clinical challenge.
MYC expression was found to be disproportionally elevated in TNBC, and in primary 
tumors, MYC signaling did not predict response to neoadjuvant conventional chemotherapy 
but was associated with shortened disease-free survival [82]. Furthermore, a recent report on 
TNBC indicates that the interaction with BRD4 is critical for the oncogenic function of 
Twist, a key activator of epithelial-mesenchymal transition. In addition, pharmacologic 
inhibition of the Twist-BRD4 association reduces invasion, cancer stem cell-like properties, 
and tumorigenicity of TNBC cells [83].
4.1.1.4
Castration-Resistant Prostate Adenocarcinoma
Patients who develop metastatic castration-resistant prostate cancer (CRPC) invariably 
succumb to the disease. Progression to CRPC after androgen deprivation therapy is 
predominantly driven by deregulated androgen receptor (AR) signaling [84][85][86]. 
Maintenance of AR signaling is the most common resistance mechanism that patients with 
advanced prostate cancer develop after conventional hormone treatments [87]. AR 
amplification, mutation and alternative splicing have all been suggested as potential 
resistance mechanisms to anti-androgen treatments [85][88][89]. Over one half of CRPC 
patients have at least one of these aberrations in the AR pathway [90].
Despite the success of recently approved therapies targeting AR signaling, such as 
abiraterone 
[91][92][93]
and 
second-generation 
anti-androgen 
therapy 
including 
enzalutamide [94][95], durable responses are limited, presumably owing to acquired 
resistance. 
Recent preclinical studies showed that AR-signaling-competent human CRPC cell lines are 
preferentially sensitive to BET bromodomain inhibition [96]. BRD4 physically interacts with 
the N-terminal domain of the AR and can be disrupted by the BET inhibitor JQ1 [13][23]. 
Like the direct AR antagonist enzalutamide, JQ1 disrupted AR recruitment to target gene 
loci. By contrast with enzalutamide, JQ1 functions downstream of AR, and more potently 
abrogated BRD4 localization to AR target loci and AR-mediated gene transcription, 
including induction of the TMPRSS2-ERG gene fusion and its oncogenic activity [96]. 
Furthermore, in vivo, BET bromodomain inhibition was found to be more efficacious than 
direct AR antagonism in CRPC xenograft mouse models. As BET inhibitors function 
downstream of AR, these compounds may be effective in the context of AR-mediated 
resistance, including compensatory mechanisms involving related steroid hormone receptors 
that are also likely to require BET bromodomain functioning.


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MK-8628 Metabolism – Cytochrome P450 Interactions
4.1.2
Results from MK-8628 incubations either with individual recombinant cytochrome P450 
(CYP) 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 
uridine 
diphosphate 
(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 half maximal inhibitory 
concentration (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 21 x 10-6 cm/s apical-to-basal) across cell monolayers and is a 
phosphoglycolate phosphatase (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 Advanced Solid Tumors
4.1.3
Study MK-8628-P003 (previously known as OTX015_108), a Phase Ib study in subjects
with selected advanced solid tumors (NMC, NSCLC with either rearranged ALK or KRAS
mutation, and CRPC) was started (first subject enrolled) on 05 November 2014.  The main 
objective of this study was to determine the recommended Phase II dose, with a dose 
escalation of once-daily dosing regimens assessed.  A total of 46 subjects were treated as of 
October 2016. Two out of five NMC subjects treated at Dose Level (DL) 1 on the continuous 
regimen (80 mg once daily [QD], 21/21 days) achieved objective responses (2 confirmed 
partial responses [PRs]). The preliminary recommended dose / schedule for phase 2 studies 
in solid tumors was 80 mg/day continuous dosing. Following dose escalation, an expansion 
cohort was authorized to enroll and treat 6 additional NMC patients at this dose level. As of 
October 2016, one patient remains ongoing from this cohort and is currently being treated in 
Cycle 17, with a confirmed PR in Cycle 10. At DL1, four DLTs were observed in 4 out of 16 
subjects treated according to the continuous regimen (80 mg QD, 21/21 days), consisting of 
two prolonged grade 3 thrombocytopenia lasting more than 7 days, 1 grade 4 
thrombocytopenia and 1 grade 3 hyperbilirubinemia/transaminitis lasting more than 48 hours. 
No DLT was observed in 13 subjects treated according to the intermittent regimen (i.e., 100 
mg QD, 7/21 days). At DL2, two DLTs have been observed in 2 out of 4 subjects treated 
according to the continuous regimen (100 mg QD, 21/21 days) consisting of one grade 4 
thrombocytopenia, and one case of a treatment interruption for > 7 days due to grade 2 
nausea/anorexia that did not fulfill the DLT definition, but was considered as a DLT by the 
investigator. No DLT was observed in 3 subjects treated according to the intermittent 
regimen (i.e. 120 mg QD, 7/21 days). At DL3, 160 mg QD, 7/21 days, no DLTs were 
observed in 6 subjects treated.
By literature survey, several mechanisms can be invoked to explain an observation of clinical 
hyperbilirubinemia including competitive inhibition of transporters/enzymes involved in the 
disposition of bilirubin and/or its conjugates. Preliminary results of in vitro experiments 


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using parent compound only suggest that MK-8628 can weakly inhibit OATP1B1 (IC50 > 5 
µM), OATP1B3 (IC50 = 3 µM), and BSEP (IC50 > 10 µM) in a concentration-dependent 
manner, while no concentration-dependent inhibition of MRP2 or MRP3 has been observed. 
In addition, MK-8628 can weakly inhibit UGT1A1 (IC50 = 10 µM), the primary enzyme 
involved in the conjugation of bilirubin. Feasibility assessments of future experiments to 
elucidate the mechanism of clinical hyperbilirubinemia are ongoing.
Additionally,
prior to opening Study MK-8628-P003, MK-8628 was provided for
compassionate use treatment of patients with BRD-NUT midline carcinoma at one clinical 
center.  A total of 5 patients were treated at a dose of 80 mg QD continuously for at least 
21 days.  Two of these patients achieved dramatic objective responses (2 complete responses 
[CRs]).
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 advanced solid tumors with the potential to 
respond to BET inhibition (NMC, NSCLC, TNBC and CRPC) will receive MK-8628 orally 
to determine the recommended dose (RD) for phase II studies. Two QD evaluations were 
evaluated in parallel in a previous study. 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. The first clue linking BRD4 with cancer was 
identification of the BRD4-NUT fusion oncogene which was recognized as an important
mechanism in NMC. Besides the chromosomal rearrangement-induced NMC, other studies 
have also indicated that BRDs may contribute to cancer development through different 
mechanisms. Knockdown of BRD4 exhibited a robust antileukemic activity against AML in 
vitro and in vivo. Other recent studies with small molecule inhibitors of the BET proteins 
revealed the critical role of BRD4 in the development of several hematopoietic and somatic 
cancers. Accordingly, small molecule inhibitors targeting BET, such as MK-8628, have been 
proven to be a promising drug for cancer therapy.
Mutant KRAS is a strong activator of the MAPK and PI3K pathways, and the inhibition of 
KRAS-dependent MAPK and PI3K pathways results in the dephosphorylation of MYC 
which contributes to its degradation. Recent studies in NSCLC preclinical models reported 
that the BET bromodomain inhibitors, MK-8628 and its analog JQ1, exert remarkable 
antitumor activity in NSCLC harboring KRAS mutation. However, the concurrent mutation 
in KRAS and LKB1 genes abrogates effects of these BET inhibitors. Furthermore, in vivo 
experiments using genetically engineered mouse lung cancer models confirmed that JQ1 
prompts tumor regression in mutant Kras mouse lung cancers, and sensitivity both in vitro 
and in vivo was found to be mediated by MYC downregulation. MK-8628 is also broadly 
active in several NSCLC cell lines harboring EML4-ALK gene fusion supporting its further 


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clinical development in patients with either KRAS mutated or ALK positive NSCLC. In 
order to explore the clinical implications of inducing changes in expressions of various 
intracellular pathways by disrupting the complexes containing BRD as a result of treatment 
on BET inhibitors like MK-8628, this study has adopted to not restrict the study population 
to only RAS mutated or ALK positive patients, but rather to allow all comers for NSCLC.
MYC expression was found to be disproportionally elevated in TNBC, and in primary 
tumors, MYC signaling was associated with shortened disease-free survival. A recent report 
on TNBC indicates that the interaction with BRD4 is critical for the oncogenic function of 
Twist, a key activator of epithelial-mesenchymal transition. In addition pharmacologic 
inhibition of the Twist-BRD4 association reduces invasion, cancer stem cell-like properties, 
and tumorigenicity of TNBC cells highlighting the use of MK-8628 in this poor prognosis 
tumor.
In CRPC, the BET inhibitor JQ1 disrupts AR recruitment to target gene loci and functions 
downstream of AR, and abrogated BRD4 localization to AR target loci and AR-mediated 
gene transcription. In addition, in vivo, BET bromodomain inhibition was found to be more 
efficient than direct AR antagonism in CRPC xenograft mouse models. As BET inhibition 
functions downstream of AR, MK-8628 may be effective in the context of AR-mediated 
resistance, including compensatory mechanisms involving related steroid hormone receptors 
that are also likely to require BET bromodomain function.
As of 30-June-2015, no pediatric patients have been treated with MK-8628. Based on the 
age of rats used in the toxicology studies (~5 weeks at study initiation which is equivalent to 
10 to 12 years in humans for overall development of the central nervous system and 
reproductive systems), the current toxicology data supports treatment with MK-8628 in 
children 10 years of age and older. Additionally, a model-based extrapolation of adult 
pharmacokinetic data was conducted to provide the basis for initial dosing of MK-8628 in an 
expanded patient population to include adolescents ≥15 years of age.  The pharmacokinetic 
model developed for this purpose utilized 941 concentration-time samples from adult 
subjects enrolled on protocols MK-8628-P001, MK-8628-P002, and MK-8628-P003 with 
doses from 10 mg to 160 mg.  The adult subjects in the model development dataset 
encompassed a wide range of body weight, from 44.5 kg to 127 kg.  The 50th percentile 
weight for a 15 year old adolescent falls within this range based on the weight-for-age 
growth charts published by the Centers for Disease Control and Prevention (56 kg for 15 year 
old male/ 52 kg for female) [97].  Parameter scaling for MK-8628 apparent oral clearance 
(CL/F) and volume of distribution (V/F) was performed by standard weight-based allometric 
principles and for both CL/F and V/F, the estimated exponents were ~0.4, suggesting 
minimal influence of weight on MK-8628 pharmacokinetic disposition from 44.5 to 127 kg.
Simulations from the final pharmacokinetic model were conducted at the proposed 20 mg, 30 
mg and 40mg BID dose for both a typical weight adult (72 kg) and 50th percentile for a 15 
year old adolescent.  Based on these projections, substantial overlap in steady-state trough 
concentration (e.g. Day 8 Cmin) is predicted for adolescents 15 years of age and older 
compared to a typical weight adult. The typical simulated trough concentrations for pediatric 
body weight in the range of 52 to 56 kg fall below the observed levels attained at the 120 mg 
QD dose in adults.  Together, these results support the use of the same flat dosing approach 
for subjects ≥15 years of age as that used in the adult population.


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Taken together, preclinical data and results from the ongoing Phase I hematologic study 
provide the rationale for investigating MK-8628 in selected solid tumors.
Rationale for Dose Selection/Regimen/Escalation
4.2.2
Preliminary results are available from the current solid tumor Phase I study (MK-8628-003, 
previously known as OTX015_108) (see Section 4.1.3). As of January 2016, 47 patients were 
enrolled and 46 patients have been treated with doses ranging from 80 mg to 160 mg QD at 
both continuous and discontinuous regimens. The preliminary recommended dose / schedule 
for phase 2 studies in solid tumors was 80 mg/day continuous dosing. An expansion cohort 
was authorized to enroll and treat 6 additional NMC patients at this dose level. As of August 
2016, one patient remains ongoing from this cohort and is currently being treated in Cycle 
14, with a confirmed PR in Cycle 10.
In
the previous hematologic Phase I study (MK-8628-001, previously known as 
OTX015_104), a dose escalation was completed and preliminary results of the cohort 
expansion are available. As of June 2015, a total of 87 subjects had been included in the dose 
escalation part in the two cohorts (acute leukemia [AL] and other hematologic malignancies 
[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. The main dose limiting toxicities reported 
are thrombocytopenia, fatigue, gastrointestinal toxicities, as well as asymptomatic bilirubin 
increases and Factor VII decreases.DLT of thrombocytopenia was the prevalently observed 
adverse event (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 in 
hematological malignancies with >33% of DLT in this cohort. Based on preliminary results 
from the ongoing solid tumor Phase I study (MK-8628-003), patients with solid tumors 
(without compromised bone marrow) are expected to tolerate higher MK8628 doses than 
those with hematologic malignancies; thus their maximum tolerated dose is predicted to be 
higher. Therefore, 40 mg BID is included as the highest dose level for evaluation in this 
study.
Preliminary clinical activity has been observed at a range of dose levels, including objective 
responses at 40 mg QD (1 CR), 80 mg (complete response with incomplete blood count 
recovery [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 acute myeloid leukemia (AML) post-
myelodysplastic syndrome (MDS) subjects, 18 AML non-MDS related (i.e. de novo, 
secondary to chemotherapy or myeloproliferative disorder [MPD]) subjects, and 15 diffuse 
large B-cell lymphoma (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 


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after clarification (related to aspergilliosis), and one subject with AML had a dose reduction 
due to poor tolerance (asthenia, anorexia, dysgueusia 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)
4.2.2.1
Starting Dose for This Trial
Data are 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 
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 [98]. Notable epigenetic agents where this phenomenon is 
observed include Food and Drug Administration (FDA) approved Deoxyribonucleic acid 
(DNA) methyltransferase (DNMT) inhibitors such as 5-azacitidine and decitabine [99]. 
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 DNMTs 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 [98].
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 [100]. Enhanced preclinical efficacy seen with the BET inhibitor JQ1 and 
MK-8628 with more frequent dosing (BID versus QD) seen in preclinical evaluations [100]
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 3
demonstrate that a 40 mg BID dose attains significantly higher Ctrough than a similar daily 


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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 80 mg administered as BID 
(i.e., max of 40 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 3 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). 
Median daily area under the plasma concentration versus time curve (AUC) of 40 mg BID is 
similar to 80 mg QD. However, there is a large difference in median trough concentration 
(bottom graph). 
Figure 3: PK comparison of QD versus BID


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4.2.2.2
Maximum Dose/Exposure for This Trial
The maximum dose for the BID regimen in this study will be the highest dose level tolerated 
(<25% DLT rate).
4.2.2.3
Rationale for Dose Interval and Trial Design
The purpose of this trial is to determine the recommended phase II dose (RP2D) of MK-8628 
for further trials in subjects with selected solid tumors 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 (Ji design).
Rationale for Endpoints
4.2.3
4.2.3.1
Safety Endpoints
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 RP2D 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.
4.2.3.1.2 Secondary Safety Endpoints
A secondary objective of this trial is to determine the safety and tolerability of MK-8628
across subjects with selected advanced solid tumors (NMC, NSCLC, TNBC and CRPC)
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 Common 
Terminology Criteria for Adverse Events (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, events of clinical 
interest (ECI), serious adverse events (SAE), fatal SAEs, and laboratory changes.
4.2.3.2
Pharmacokinetic Endpoints
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, time to peak concentration (Tmax), AUC[0-∞], 
volume of distribution at steady state (Vdss), terminal half-life (t1/2), steady state, and 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.


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4.2.3.3
Pharmacodynamic Endpoints
Inhibition of BET proteins by MK-8628 leads to alterations in the transcription of messenger 
RNA (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 4 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 
of genes may represent a PD biomarker of response. Potential limitations of this assay 
include patient-to-patient 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.    
Figure 4: Dose-dependent changes in BET protein target gene expression
Dose-dependent changes in BET protein target gene expression in human whole blood ex 
vivo. Whole blood from 6 normal healthy volunteers was treated with either vehicle (0.1% 
dimethyl sulfoxide [DMSO]) or increasing concentrations of MK-8628. After 4 hours, whole 
blood was lysed (PAXgene tube) and mRNA extracted for quantitative polymerase chain 
reaction (qPCR) analysis of candidate BET target genes. Data were normalized (∆cycle 
threshold [Ct]) by peptidylpropyl isomerase B (PPIB) and plotted for all six individuals as 
change in ΔCt.


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4.2.3.4
Efficacy Endpoints
4.2.3.4.1 Secondary Efficacy Endpoints: RECIST or PCWG -based Response Rate
A secondary efficacy objective of this trial is to evaluate the anti-tumor activity of MK-8628
in subjects with selected advanced solid tumors (NMC, NSCLC, TNBC and CRPC). 
Secondary efficacy endpoints include (1) ORR, defined as the percentage of subjects who 
have achieved confirmed complete response (CR) or partial response (PR) according to 
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (see Section 12.8) or Prostate 
Cancer Clinical Trials Working Group (PCWG2) (see Section 12.9), as assessed by 
investigator radiologic review; (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; and 
(3) DCR, defined as the percentage of subjects who have achieved stable disease or 
confirmed complete response (CR) or confirmed partial response (PR) according to RECIST 
v1.1 or PCWG2, by the investigator review
4.2.3.4.2 Exploratory Efficacy Endpoints
Exploratory efficacy endpoints include (1) PFS, defined as the time from allocation to the 
first documented disease progression according to RECIST v1.1 or PCWG2 as assessed by 
investigator radiologic review, or death due to any cause, whichever occurs first, and (2) OS.
4.2.3.5
Planned Exploratory Biomarker Research
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.
4.2.3.6
Future Biomedical Research
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 


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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.
5.0 METHODOLOGY
Entry Criteria
5.1
Diagnosis/Condition for Entry into the Trial
5.1.1
Male/Female subjects with non-small cell lung cancer, triple negative breast cancer or 
castration-resistant prostate cancer of at least 18 years of age, and male/female subjects with  
NUT midline carcinoma of at least 16 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. Have signed informed consent/assent prior to initiation of any study-specific 
procedures and treatment. For study subjects who are legal minors, the parent or legal 
guardian must also sign the consent/assent form. The subject may also provide 
consent/assent for Future Biomedical Research. However, the subject may participate 
in the main trial without participating in Future Biomedical research.
2. Have histologically or cytologically confirmed diagnosis of one of the following 
advanced or metastatic solid tumors for which standard therapy either does not exist 
or has proven ineffective, intolerable or inacceptable for the subject:
a) NUT midline carcinoma (NMC)(ectopic expression of NUT protein as 
determined by IHC and/or detection of BRD-NUT gene translocation as 
determined by FISH)
b) Non-small cell lung cancer (NSCLC): all comers without gene rearrangement or 
mutational restrictions
c) Triple negative breast cancer (TNBC) defined according to ASCO 
recommendations [50][51]
d) Castration-resistant prostate cancer (CRPC)
3. Have at least one measurable lesion as per RECIST version 1.1., except for CRPC 
subjects who may be enrolled with objective evidence of disease as per Prostate 
Cancer Clinical Trials Working Group (PCWG2) criteria.


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4. For NSCLC, TNBC and CRPC subjects, be age ≥18 years at the time of informed 
consent; for NMC subjects, be age ≥16 years at the time of informed consent.
5. Have a life expectancy ≥ 3 months.
6. Have an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 1.
7. Demonstrate adequate organ function (adequate bone marrow reserve, renal and liver 
function) as defined in Table 1. (Note: All screening labs should be performed within 
10 days of treatment initiation).
Table 1: Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1.5 x109/L
Platelets
≥150 x109/L
Hemoglobin
≥ 9.0 g/dL
*Note: subject must not have had a blood 
transfusion within 7 days of screening in 
meeting this criteria
Renal
Creatinine clearance
≥30 mL/min calculated according to the 
Cockroft 
and 
Gault 
formula 
or 
Modification of Diet in Renal Disease 
(MDRD) formula for subjects aged > 65 
years (see Section 12.5)
Hepatic
Total bilirubin
≤ 1.25 X upper limit of normal (ULN) OR
In case of liver involvement, ≤ 2 x ULN 
will be allowed
Aspartate aminotransferase (AST)
(SGOT) and alanine aminotransferase 
(ALT) (SGPT)
< 3 X ULN 
Alkaline Phosphatase
If > 2.5 X ULN, then liver fraction should 
be ≤ 2.5 X ULN
Chemistry
Serum albumin
For NSCLC, CRPC and TNBC: 
≥ 3.0 g/dL
For NMC:
≥ 2.0 g/dL
Coagulation
International Normalized Ratio (INR)
≤ 1.5 
8. Have an interval of ≥ 3 weeks (or ≥ 2 weeks for NMC patients) 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).


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9. CRPC subjects must maintain ongoing androgen deprivation therapy with a 
gonadotropin releasing hormone (GnRH) analogue, antagonist or orchiectomy 
providing serum testosterone is < 50 ng/dL (<1.7 nmol/L).
10. Subjects receiving bisphosphonate or denosumab therapy must be on stable doses for 
at least 4 weeks before initiating study treatment
11. 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.
12. 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.
13. Male subjects of childbearing potential must agree to use an adequate method of 
contraception as outlined in Section 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.
Subject Exclusion Criteria
5.1.3
The subject must be excluded from participating in the trial if the subject:
1. Has inability to swallow oral medications or presence of a gastrointestinal disorder 
(e.g. malabsorption) deemed to jeopardize intestinal absorption of MK-8628.
2. Has persistent grade >1 clinically significant toxicities related to prior antineoplastic 
therapies (except for alopecia); stable sensory neuropathy ≤ grade 2 National Cancer
Institute (NCI)-CTCAE v. 4.0 is accepted.
3. Has known primary CNS malignancy or symptomatic or untreated CNS metastases.
Treated and stable CNS metastases are allowed.
4. Has a history of prior or concomitant malignancies (other than excised non-melanoma 
skin cancer or cured in situ cervical carcinoma) within 3 years of signing informed 
consent.
5. 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).
6. Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
7. Has known active Hepatitis B (e.g. hepatitis B surface antigen [HBsAg] reactive) or 
Hepatitis C (e.g. hepatitis C viral [HCV] RNA [qualitative] is detected).
8. Has any of the following cardiac-related conditions:
a.
Congestive heart failure or angina pectoris (except if medically controlled)
b. Previous history of myocardial infarction (within 1 year of study entry)


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c.
Uncontrolled hypertension (defined as systolic blood pressure > 140 mmHg, 
and/or diastolic blood pressure > 90 mmHg, and not adequately managed by 
anti-hypertensive medication)
d. Uncontrolled arrhythmias 
9. Has participated in another clinical trial or treatment with any investigational drug
(excluding anticancer treatments) within 30 days prior to study entry.
10. Has other concomitant anticancer treatment, except the use of anti-androgens in 
CRPC subjects.
11. Has concomitant therapy with strong CYP3A4 inhibitors or inducers.
12. Is currently using therapeutic anticoagulation (e.g. warfarin, heparin, etc.) (Must be 
stopped at least 7 days prior to the first dose of MK-8628). Low-dose low molecular 
weight heparin (LMWH) is permitted.
13. Has a history or current evidence of any condition, therapy, lab abnormality or other 
circumstance that might expose the subject to risk by participating in the trial, 
confound the results of the trial, or interfere with the subject’s participation for the 
full duration of the trial.
14. Is pregnant or breast-feeding.
Trial Treatment(s)
5.2
The treatments to be used in this trial are outlined below in Table 2 and Table 3.
Table 2: Trial Treatments – Part A: Dose Escalation
Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/Treatment Period
MK-8628
20 mg
BID
Oral
Continuous / 21 days per cycle
MK-8628
30 mg
BID
Oral
Continuous / 21 days per cycle
MK-8628
40 mg
BID
Oral
Continuous / 21 days per cycle
Table 3: Trial Treatments – Part B: NMC Cohort
Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/Treatment Period
MK-8628
10 mg
BID
Oral
Continuous / 21 days per cycle
MK-8628
20 mg
BID
Oral
Continuous / 21 days per cycle
MK-8628
30 mg
BID
Oral
Continuous / 21 days per cycle
MK-8628
40 mg
BID
Oral
Continuous / 21 days per cycle
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 and Table 3 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.


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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
5.2.1.1
Dose Selection (Preparation)
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.
5.2.1.2
Dose Escalation (Part A)
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].
Starting from 20 mg BID, up to three planned dose levels may be evaluated: 20 mg BID, 30 
mg BID 40 mg BID (all continuous daily). See Table 4 and Table 5 for the dose escalation 
scheme.
Table 4: 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 
(Table 5)
DL 2
30
DL 3
40
* Evaluated during the first 21 days of treatment


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Table 5: 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%
Subjects may be enrolled continuously, such that the number of subjects who are enrolled 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. 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 subjects out of the first 
6 subjects develop a DLT, the dose will be de-escalated to the next lower dose level. If ≥4 
out of the first 6 subjects 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 5 by continuing enrollment as follows. As stated above, 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 5).  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 5). 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 starting dose level (DL1) indicates stopping of 
the trial. Escalation (E) at the highest dose level (DL3) indicates staying at that level. Note 
that while 25% has been the target toxicity rate used to generate the guidelines in Table 5, the 
observed rate of subjects with DLT at the RP2D may be slightly above or below 25%.


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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 entry throughout the study, 
or at a reduced dose according to toxicity encountered. Subjects will undergo a dose and/or 
schedule modification in the event of toxicity (see Section 5.2.1.6 and 5.6.1.1).
5.2.1.3
NMC Cohort (Part B)
An additional cohort of NMC subjects will be treated in a parallel study. This study will only 
include NMC subjects. Priority for treatment allocation will be to enroll into Part A of the 
study (Dose Escalation). If there are no slots available in Part A at the time the NMC subject 
is identified, the subject will be enrolled and allocated to treatment in Part B (NMC Cohort).
As in Part A, dose administration will be continuous for 21 consecutive days per cycle (21-
day cycles). NMC subjects enrolled in Part B will be treated at one dose level below the 
current dose level from the dose escalation study in Part A. Therefore, a starting dose of 10 
mg BID will be administered, and up to four dose levels will be evaluated: 10, 20, 30 and 40 
mg BID, continuous, 21-day cycles. Once the RP2D is established, newly enrolled NMC 
subjects in Part B may be treated at the RP2D. See Table 6 for the dosing scheme for the 
NMC Cohort study.
Table 6: Dosing Scheme for NMC Cohort
Dose Level
(DL)
Current Dose Level from Part A: 
Dose Escalation
Dose to Treat in Part B: NMC 
Cohort
DL1
20 mg BID, continuous
10 mg BID, continuous
DL2
30 mg BID, continuous
20 mg BID, continuous
DL3
40 mg BID, continuous
30 mg BID, continuous
RP2D*
N/A
20, 30 or 40 mg BID, continuous
*Once the RP2D is established, newly enrolled NMC subjects in Part B may be treated at the 
RP2D.
Subjects will receive MK-8628 at the DL they were assigned at entry throughout the study, 
or at a reduced dose according to toxicity encountered. Subjects will undergo a dose and/or 
schedule modification in the event of toxicity (see Section 5.2.1.6 and 5.6.1.1).
5.2.1.4
Dose Limiting Toxicity
For the dose escalation part of this study (Part A), a 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
•
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
•
Febrile neutropenia Grade 3 or Grade 4
Non-hematologic toxicity
•
Grade 4 non-hematologic toxicity (not laboratory)
•
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.
•
Any Grade 3 or 4 non-hematologic laboratory abnormality, if:
•
medical intervention is required, or
•
the abnormality leads to hospitalization, or
•
the abnormality persists for > 1 week
•
Any of the following liver test abnormalities are observed (see also Section 12.7):
•
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
Other
•
Any drug-related AE which caused the subject to discontinue treatment during Cycle 1
•
Any study drug-related toxicity resulting in a subject missing ≥20% of planned doses 
during Cycle 1.
•
Any treatment-related toxicity which causes a greater than 2 week delay in initiation of 
Cycle 2.
•
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. 


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5.2.1.5
Recommended Phase II Dose 
The recommended phase II dose (RP2D) will be determined 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). All other facets will be considered supportive. It 
is important to note that dose selection in this study aims to assess a RP2D 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.
5.2.1.6
Dose Adaptation
The Common Terminology Criteria for Adverse Events version 4.0 (CTCAE 4.0) must be
used to grade the severity of adverse events. 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 7 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.
Table 7: 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
1, 2
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 
lower
dose 
level 
(Table 8)
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 
lower
dose 
level 
(Table 8)
Toxicity does not 
resolve within 2 
weeks of last dose.
Permanent 
discontinuation 
should 
be 
considered for any 
severe 
or 
life-
threatening event
Non-Hematologic 
1, 2
No
N/A
N/A
N/A


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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
Laboratory 
Abnormalities
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 
resolve within 
1 week: treat 
vat same dose 
and schedule
Laboratory 
abnormalities 
do not resolve 
within 1 week: 
may 
consider 
resuming 
treatment 
at 
next 
lower
dose 
level 
(Table 8)
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 
lower
dose 
level 
(Table 8)
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 
lower
dose 
level 
(Table 8)
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 lower dose level (Table 
8). For subjects treated at DL1 (20 mg BID), 10 mg BID will be evaluated.


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Table 8: 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
DL 3
40 mg BID continuous
30 mg BID continuous
Note: Dose modification for 10 mg BID continuous will only include dose interruption and no 
further reduction is allowed.
For subjects enrolled in Part B of the study (NMC Cohort), the same guidelines for dose 
modifications should be followed.
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±2 hours apart).  The definition of a fasted state is 
that 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 will be skipped. Subjects are 
to be instructed that if they vomit or skip 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 registration.
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).
5.2.2.1
Premedication
No systematic premedication will be given at least during the first cycle. See Section 5.5.1 
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.


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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 at the time of registration. 
For NMC subjects, priority for treatment allocation will be to enroll into Part A of the study 
(Dose Escalation). If there are no slots available in Part A at the time the NMC subject is 
identified, the subject will be enrolled and allocated to treatment in Part B (NMC Cohort).
Stratification
5.4
No stratification based on age, sex or other characteristics will be used in this trial.
Concomitant Medications/Vaccinations (Allowed & 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:
•
Supportive treatment of symptoms/AEs or standard treatment of concomitant 
conditions, including corticosteroids, aspirin, transfusion support, and antibiotics, 
•
Growth factors (Granulocyte-colony stimulating factor [G-CSF], erythropoietin [EPO]
etc.) after cycle 1.
•
For CRPC subjects, maintenance treatment with ongoing androgen deprivation therapy 
with a gonadotropin releasing hormone (GnRH) analogue or antagonist is mandatory 
providing serum testosterone is < 50 ng/dL (<1.7 nmol/L), unless the subject had 
previous bilateral orchiectomy as part of his hormone therapy.
•
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). Palliative radiation therapy 
(for analgesia) is authorized only if the irradiated field does not include target lesions.


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•
Bisphosphonates or denosumab given at stable doses for ≥ 4 weeks prior to study start. 
Bisphosphonates or denosumab are permitted from cycle 3.
•
Prophylactic low-dose LMWH, as defined by local institutional practices; INR must be 
monitored in accordance with local institutional practices. Subjects who develop 
venous thromboembolic events during study requiring therapeutic levels of LMWH 
must be closely monitored for their platelet counts.
Not allowed:
•
Other concurrent investigational drugs, agents or devices or any other therapy for 
cancer treatment.
•
Any drugs given with a prophylactic intent during the first cycle.
•
Concurrent treatment with strong CYP3A4 interfering drugs/substances is not 
permitted. The concomitant use of other CYP3A4 interfering drugs or any CYP2A6 
interfering drug is allowed provided a careful follow-up of laboratory results that may 
be influenced by the concomitant agent is performed (e.g. INR if the concomitant 
agent is an anticoagulant, blood cell counts if the concomitant drug is hematotoxic 
must be followed up more frequently than required by the protocol).
Note: CYP3A4 inhibitors/inducers/substrates are listed in Section 12.6. 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.
•
Use of therapeutic anticoagulation (e.g. warfarin, heparin, etc.). Must be stopped at 
least 7 days prior to the first dose of MK-8628.
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.
5.6.1.1
General Guidelines for Clinically Significant Toxicities
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 5.2.1.6.
All adverse events should be monitored closely, with supportive care provided according to 
institutional standards.


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5.6.1.2
Hepatic Laboratory Abnormalities
All trial subjects with liver test abnormalities should be monitored 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. Drug induced liver injury (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 12.7 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 nm with a molar extinction coefficient (MEC) of 
>1000 L·mol-1·cm-1, it is recommended that subjects avoid sun and ultraviolet (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
(3) has a congenital or acquired condition that prevents childbearing.


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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 
(described above) from the day of study medication initiation (or 14 days prior to the 
initiation of study 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.


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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
•
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.


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Use in 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.
Use in 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
•
Subject withdrawal of consent
•
Subject non-compliance
•
Treatment interruption for > 2 weeks for toxicity (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 shrinkage not 
meeting standard response criteria, but which could improve with additional treatment, or 3) 


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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.
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).
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
Subjects enrolled into both Part A (Dose Escalation) and Part B (NMC Cohort) will follow the same visit schedule and procedures 
outlined in the trial flow chart below:
Screening 
Phase
Treatment Phaseq
Cycle = 21 days
End of 
Treatment
Post Treatment Phase
Treatment Cycle/Title:
Pre-study / 
Screening 
(Visit 1)
Cycle 1 and 2
Cycle 3 and beyond
Treatment 
Discontinuation 
Visit
Safety Follow 
Up Visit
Follow Up 
Visitsa
Cycle Day:
1
4
8
11
15
18
1
8j
15j
Date of 
discontinuation
30 days post 
last treatment 
Every 6 weeks 
post treatment 
discontinuation
Scheduling Window Days:
-14 to -1
±1
±3
±3
±3
±3
±3
±3
+5
±3
Administrative Procedures
Informed Consentb
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
X
X
Diagnosis 
& 
prior 
treatments 
for 
malignancy
X
Baseline symptoms & complaints
X
MK-8628 Administration/Dispensing
MK-8628 Administration/Dispensing
BID Continuouslyc, 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
X


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Screening 
Phase
Treatment Phaseq
Cycle = 21 days
End of 
Treatment
Post Treatment Phase
Treatment Cycle/Title:
Pre-study / 
Screening 
(Visit 1)
Cycle 1 and 2
Cycle 3 and beyond
Treatment 
Discontinuation 
Visit
Safety Follow 
Up Visit
Follow Up 
Visitsa
Cycle Day:
1
4
8
11
15
18
1
8j
15j
Date of 
discontinuation
30 days post 
last treatment 
Every 6 weeks 
post treatment 
discontinuation
Scheduling Window Days:
-14 to -1
±1
±3
±3
±3
±3
±3
±3
+5
±3
ECOG Performance Status (PS)
X
X
X
Height
X
Vital Signs (heart rate, blood pressure, 
temperature, and weight)
X
X
X
X
X
X
X
X
Xj
Xj
X
12-Lead Electrocardiogram (ECG)
X
Xd
Xd
X
CT, MRI, chest X-ray (posterior-anterior 
and lateral)
Xe
Xe
Xa,e
Xa,e
Bone scan (CRPC subjects)
Xf
Xf
Xa,f
Xa,f
Adverse Events Monitoring
X
X
X
X
X
X
X
X
X
X
Xg
Xg
Laboratory Procedures/Assessments
Complete Blood Count (CBC)h
Xi
Xi
X
X
X
X
X
Xh
Xh,j
Xh,j
X
Serum Chemistryh
Xi
Xi
X
X
Xh
Xh,j
Xh,j
X
PT (INR), aPTT and Factor VII
X
Xi
X
X
Urinalysis
X
Urine Pregnancy Test – if applicablek
X
Tumor markersl
Xl
Xl
X
Xl
Xl
PK Blood (Plasma) Sampling
Xm
Xn
Xn
PD Blood Sampling
Xo
Xo
Blood for Genetic Analysisp
X


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a.
In subjects who discontinue study therapy without documented disease progression, every effort should be made to continue monitoring their disease status by radiologic 
imaginge,f * 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. *Note: This includes bone scans for CRPC subjects every 12 weeks ±3 days. If subjects have stable disease, partial response, or complete response, they should 
continue on this assessment schedule. The timing for these assessments should continue the same imaging schedule from the treatment phase; Imaging, and if applicable, 
bone scans, should occur at any time where there is clinical suspicion of progression;
b.
For study subjects who are legal minors, the parent or legal guardian must also sign the consent/assent form;
c.
MK-8628 is to be administered orally with water in a fasted state, and as part of a BID regimen (twice daily, approximately 12±2 hours apart). Dosing not performed at the 
same time (±2h) as on other days will be skipped. Subjects are to be instructed that if they vomit or skip their dose in that time frame, it is not to be replaced;
d.
On Cycle 1 Day 1, conduct 12-lead ECG immediately before intake of the morning study dose, then again 1 and 2 hours after the intake of the morning study dose. Conduct 
additional 12-lead ECGs immediately before the morning intake on Day 1 of odd subsequent cycles (e.g. Cycle 3, 5, 7 etc.);
e.
Radiologic exams (CT, MRI, chest X-ray) performed as part of the subject’s standard follow-up within 4 weeks prior to the first treatment cycle, are acceptable. Radiologic 
assessment will be performed every 2 cycles (6 weeks) (± 3 days) as per RECIST 1.1 or PCWG2 until progression, by calendar date starting from Cycle 1 Day 1 (not 
adjusted for cycle or treatment days). Scans used for tumor measurements may be requested for central review; 
f.
Bone scans are mandatory in CRPC subjects and will be performed every 4 cycles (12 weeks) (± 3 days) until progression, by calendar date starting from Cycle 1 Day 1 (not 
adjusted for cycle or treatment days). Scans used may be requested for central review;
g.
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;
h.
From Cycle 3 on, in the absence of ≥ grade 2 abnormalities, these tests will be performed every cycle on Day 1, otherwise they are to be done weekly until resolution to 
baseline levels or < grade 2;
i.
Screening CBC and serum chemistry measurements must be taken within 7 days of the first dose of study treatment; All laboratory assessments (e.g. CBC,  serum chemistry, 
PT [INR], aPTT, Factor VII, and PSA [if applicable]) on Cycle 1 Day 1 must be taken prior to the first dose;
j.
From Cycle 3 on, in the absence of ≥ grade 2 abnormalities requiring weekly CBC and serum chemistry measurements, these visits may be conducted via a documented 
telephone contact with the Investigator or Sub-Investigator. Adverse events and concomitant medications will be reviewed; blood tests and vital signs will not be required;
k.
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;
l.
As appropriate for tumor type; For CRPC subjects, Prostate Specific Antigen (PSA) measurements are mandatory, and will be performed at screening, and then on Day 1 of 
every cycle starting with Cycle 2;;
m.
Pharmacokinetics will be performed in cycle 1 only. Samples will be collected immediately prior to the first dose (T0) on day 1, 20min±5min, 1h±10min, 2h15min±10min, 
3h15min±10min, 8h+1h, and 12h±2h post-dose (immediately before the second daily dose on day 1);
n.
Steady-state PK blood samples will be collected on days 8 (±1 days) and 15 (±2 days) of cycle 1, and day 1 of cycle 2 (day 22, ±3 days), prior to the morning drug intake;
o.
PD blood samples will be collected immediately prior to the first dose on day 1, 3h15min±10min, 8h±1h and 12h±2h post-dose, and immediately prior to the first dose on 
day 8 only;
p.
Blood for Genetic Analysis samples should be collected prior to the first dose only at Cycle 1 Day 1. Details for collection can be found in Section 7.1.3.3.
q.
During the treatment phase, the assessment schedule for scheduled visits, collection of blood for labs, and other study procedures should be held/delayed to correspond with 
any dose hold – in other words, study visits and assessments coincide with the dosing calendar (cycle/treatment day), not the actual calendar. There is one notable exception 
to this – radiologic scans for tumor assessments (including bone scans and PSA measurements) should be conducted every 6 weeks (or 12 weeks for bone scan/PSA) by 
calendar date starting from Cycle 1 Day 1.


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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
7.1.1.1
Informed Consent
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.
7.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
7.1.1.3
Subject Identification Card
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.
7.1.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. Medical history 
will include all active conditions, and any previously diagnosed conditions that are 
considered clinically significant by the Investigator. A detailed medical history must be 
documented, including non-cancer medical history and concurrent illnesses.
Diagnosis and prior treatments for malignancies will be documented (a confirmatory 
diagnosis of NUT midline carcinoma or NSCLC at screening is not required).
7.1.1.5
Prior and Concomitant Medications Review
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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7.1.1.6
Assignment of Screening Number
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.  
7.1.1.7
Assignment of Treatment/Randomization Number
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.  This unique number is 
termed a randomization number throughout the protocol for operational purposes. 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.
7.1.1.8
Trial Compliance (Medication)
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. The subject will note the number of 
capsules taken, the time of administration, as well as any reactions including the date/time in 
a specific subject’s diary.
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 for > 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
7.1.2.1
Adverse Event (AE) Monitoring
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.
7.1.2.2
Full Physical Exam
The investigator or qualified designee will perform a complete physical exam during the 
screening period. Clinically significant findings should be recorded as medical history. 
Starting with Cycle 1, perform a full physical exam prior to trial administration on Day 1 of 
each cycle. After the first dose of trial treatment, new clinically significant abnormal findings 
should be recorded as AEs. Perform a final physical exam during the post-treatment follow-
up period.
7.1.2.3
Eastern Cooperative Oncology Group (ECOG) Performance Status
The investigator or designee will assess the ECOG status (see Section 12.4) at screening, 
prior to trial administration on Day 1 of each cycle, and during the post-treatment follow-up 
period.
7.1.2.4
Vital Signs
The investigator or qualified designee will take vital signs at screening, prior to trial 
administration on Day 1 of each cycle, and during the post-treatment follow-up period as 
specified in the Trial Flow Chart. Vital signs include heart rate, blood pressure, body 
temperature and weight. Height will be measured at screening only.
7.1.2.5
Electrocardiogram (ECG)
A standard 12-lead ECG will be performed using local standard procedures at screening. 
Clinically significant abnormal findings should be recorded as medical history. 
On Cycle 1 Day 1, conduct 12-lead ECGs immediately before intake of the morning study 
dose, then again 1 and 2 hours after the intake of the morning study dose. Conduct additional 
12-lead ECGs immediately before the morning intake on Day 1 of odd subsequent cycles 
(e.g. Cycle 3, 5, 7 etc.). 


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7.1.2.6
Tumor Imaging and/or Bone Scan
7.1.2.6.1 CT, MRI and/or Chest X-Ray
For tumor evaluation, a CT, MRI and/or chest X-ray (posterior-anterior and lateral) will be 
performed every 6 weeks (± 3 days) by calendar date starting from Cycle 1 Day 1 (not 
adjusted for cycle or treatment days). These assessments will be performed on approximately 
Day 1 of every 2nd cycle (C3, C5, C7, etc.), as clinically indicated by the subjects diagnosis. 
Scans used may be requested for central review. Effort should be made to maintain the same 
imaging modality throughout the study.
In subjects who discontinue study therapy without documented disease progression, every 
effort should be made to continue monitoring their disease status by radiologic imaging 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 every 6 
weeks ±3 days assessment schedule. The timing for these assessments should continue the 
same imaging schedule from the treatment phase. Imaging should occur at any time where 
there is clinical suspicion of progression.
7.1.2.6.2 Bone Scan 
A bone scan is mandatory for CRPC subjects, and will be performed every 12 weeks (± 3 
days) by calendar date starting from Cycle 1 Day 1 (not adjusted for cycle or treatment days). 
These assessments will be performed on approximately Day 1 of every 4th cycle (C5, C9, 
C13 etc.). Scans used may be requested for central review. Effort should be made to maintain 
the same imaging modality throughout the study.
In CRPC subjects who discontinue study therapy without documented disease progression, 
every effort should be made to continue these bone scans every 12 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 every 12 weeks ±3 days assessment 
schedule. The timing for these assessments should continue the same imaging schedule from 
the treatment phase. Bone scans should occur at any time where there is clinical suspicion of 
progression.
7.1.2.6.3 Assessment of Disease
Tumor lesions will be assessed throughout the study according to RECIST criteria (version 
1.1) [101] (see Section 12.8). Any tumor shrinkage, in terms of percentage of tumor 
regression, will be reported even if it does not meet RECIST criteria for response. While 
RECIST criteria (version 1.1) do not require confirmation of objective response in clinical 
studies where response rate is not the study primary endpoint, as a convincing proof-of-
concept of antitumor activity, efforts should be made to confirm objective response at least 4 
weeks apart.
For CRPC subjects, PSA response rates will be measured according to the PCWG2 criteria 
[102] (see Section 12.9). RECIST v1.1 is used to assess soft tissue disease [101]. Progression 


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of bone disease is defined using PCWG2 criteria, namely a confirmed increase of at least two 
new lesions on a bone scan. 
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.
7.1.3.1
Laboratory 
Safety
and 
Other
Evaluations 
(Hematology, 
Chemistry,   
Coagulation and Other)
Laboratory tests for hematology, chemistry, coagulation and other are specified in Table 9.
These tests are to be performed locally per institutional standards.
Table 9: Laboratory Tests
Hematology
Chemistry
Urinalysisb
Other
Hematocrit
Albumin
Blood
Serum 
β-human 
chorionic gonadotropin 
(β-hCG)a
Hemoglobin
Alkaline phosphatase
Glucose
Urine pregnancy testa
Platelet count
Alanine 
aminotransferase 
(ALT)
Protein
Prothrombin 
Time 
(PT) (INR)d
White Blood Cell (total and 
differential)
Aspartate 
aminotransferase 
(AST)
Specific gravity 
Activated 
Partial 
Thromboplastin Time 
(aPTT)d
Red Blood Cell Count
Carbon 
dioxide 
(CO2
or 
bicarbonate)b
Microscopic 
exam, 
if 
abnormal 
results 
are 
noted
Factor VII
Calcium
PSAe
Chloride
Creatininec
Glucose
Phosphorus
Potassium
Sodium
Total Bilirubin  
Direct 
Bilirubin, 
if 
total 
bilirubin is elevated above the 
upper limit of normal
Total protein
Blood Urea Nitrogen or Urea
Uric acid
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.


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Hematology
Chemistry
Urinalysisb
Other
d  Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all subjects. Any 
subject receiving anticoagulant therapy should have coagulation factors monitored closely throughout the trial.
e   CRPC subjects only.
7.1.3.1.1 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. These tests are to 
be performed locally per institutional standards. The subject must be excluded in the event of 
a positive or borderline-positive serum test result.
7.1.3.2
Pharmacokinetic/Pharmacodynamic Evaluations
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 10 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±2h 
(immediately before the second daily dose on day 1). Subjects will remain in clinic or be 
hospitalized for a minimum of 12±2 hours for PK sampling on day 1. 
In addition, a single blood sample will be collected from all subjects 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 12 h after the previous evening dose. The timing of the 
previous dose should be recorded.
Table 10: 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 hr 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 chromatography coupled with 
mass spectrometry detection.
The following parameters will be determined as appropriate, and may include trough (Cmin) 
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/efficacy findings.
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 11 below), and timing 
of collections should align with the collection of the PK samples at the same timepoints 
described in Table 11 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±2h (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).
Table 11: 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 hr post-morning dose
5
Cycle 1 Day 8
Pre-morning dose
7.1.3.2.4 Serum Tumor Markers
Serum tumor markers, according to indication, will be measured; as far as possible, 
subsequent measures must be made in the same laboratory. These tests are to be performed 
locally per institutional standards. For CRPC subjects, the PSA measurements are mandatory, 
and will be performed at screening, and then on Day 1 of every cycle starting with Cycle 2. 
For other indications, the following non-exhaustive list of indication-specific tumor markers 
may be optionally considered for testing: CEA, CA 15-3, or CA 27.29 for Breast cancer, etc.


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7.1.3.3
Planned Genetic Analysis Sample Collection
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.
Sample collection, storage and shipment instructions for plasma samples will be provided in 
the Procedure Manual.
7.1.3.4
Future Biomedical Research Sample Collection
The following specimens are to be obtained as part of Future Biomedical Research:
-
DNA for future research.
Other Procedures
7.1.4
7.1.4.1
Withdrawal/Discontinuation
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 
 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.
PPD


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7.1.4.2
Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
7.1.4.3
Domiciling
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.
7.1.4.4
Calibration of Critical Equipment
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 – as required for inclusion labs and trial assessments

Imaging equipment – as required for study objectives
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.
7.1.5.1
Screening
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
Each candidate subject will be examined before starting the study to determine eligibility for 
participation as set forth in Section 5.1. Screening procedures may be repeated after 
consultation with the Sponsor. Screening procedures are to be performed within 14 days prior 
to the first dose of trial treatment except for the following:

For women of reproductive potential, a urine pregnancy test will be performed within 
72 hours prior to the first dose of trial treatment.

Complete blood count and serum chemistry measurements which must be performed 
within 7 days of the first dose of study treatment.


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
Radiologic assessments can be obtained up to 4 weeks prior to the first dose of trial 
treatment.
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.
7.1.5.2
Treatment Period
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
7.1.5.3
End of Treatment
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.  For each subject, record 
the date that study treatment is permanently discontinued, along with the reason for treatment 
discontinuation.
7.1.5.4
Post-Treatment
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures
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 visit will be performed 30 days (+5 days) after 
the last MK-8628 intake.
In subjects who discontinue study therapy without documented disease progression, every 
effort should be made to continue monitoring their disease status by radiologic imaging*
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. *Note: This 
includes bone scans for CRPC subjects every 12 weeks (±3 days). If subjects have stable 
disease, partial response, or complete response, they should continue on this assessment 
schedule. The timing for these assessments should continue the same imaging schedule from 
the treatment phase. Imaging, and if applicable, bone scans, should occur at any time where 
there is clinical suspicion of progression.
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-
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.


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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.
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 hours). 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.
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 


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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), 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 
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
7.2.3.1
Serious Adverse Events
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.


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●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose.
Refer to Table 12 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 
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.
7.2.3.2
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until 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).


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Events of clinical interest for this trial include:
1. 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. 
2. 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).
3. an elevated total bilirubin lab value that is greater than or equal to 2X the upper limit 
of normal.
4. 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 12.7.
5. 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.
7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting
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 12: 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 statistical analysis plan (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 Advanced Solid Tumors
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
ORR, DOR and DCR based on the best overall response from tumor 
evaluations performed every 2 cycles, according to RECIST v1.1 or 
PCWG2 as assessed by investigator radiologic review.
Statistical Methods for Key 
Efficacy/Immunogenicity/ 
Pharmacokinetic Analyses
ORR and DCR will be estimated using an exact method based on the 
binomial distribution (Clopper-Pearson interval).
Statistical Methods for Key 
Safety Analyses
Counts and percentage of DLT will be provided. 80% Bayesian credible 
interval 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 data from the most 
recent cohort of subjects evaluable for DLT will be performed.
Multiplicity
This is an estimation 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 
advanced or metastatic solid tumors. The small numbers per cohort are not 
intended for statistical hypotheses. 
Up to 72 evaluable subjects (up to 6-14 per three dose levels in the dose 
escalation part [Part A] and up to 30 in the NMC cohort [Part B]) will be 
included. The final sample size will depend on the number of subjects 
experiencing DLTs at each DL, and may be increased if the RP2D is not 
reached and additional DLs 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 dose level-specific cohorts.
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 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 RECIST 
v1.1 or PCWG2 as assessed by investigator radiologic 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 RECIST v1.1 or PCWG2 as assessed by 
investigator radiologic 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 RECIST v1.1 or PCWG2 as assessed by investigator radiologic 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) (see Section 4.2.3.2).
Pharmacodynamics
Incidence and severity of AEs along with PK parameters will be analyzed in relation to the 
most pertinent biomarker(s), if any (see Section 4.2.3.3).


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Analysis Populations
8.5
Efficacy Analysis Populations
8.5.1
Treatment Full Analysis Set (FAS), also known as evaluable for efficacy: subjects who 
receive at least one dose of study drug.
Safety Analysis Populations
8.5.2
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.
Statistical Methods
8.6
This section describes the statistical methods that 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 Efficacy Analyses
8.6.1
ORR and DCR with 95% confidence intervals will be estimated using Exact method based 
on binomial distribution (Clopper-Pearson interval).
DOR will be estimated by Kaplan-Meier method.
Statistical Methods for Safety Analyses
8.6.2
Count and percentage of DLT will be provided. 80% Bayesian credible interval for 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. 95% confidence interval for rate of AE of clinical interest will be estimated 
using an exact method based on the binomial distribution (Clopper-Pearson interval).
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 
three subjects of each regimen 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 advanced or 
metastatic solid tumors. The small numbers per cohort are not intended for statistical 
hypotheses. 
Up to 42 evaluable subjects will be included in the dose escalation cohort (Part A). There 
will be a maximum of 14 subjects at each of the pre-specified dose levels for DLT 
evaluation. The final sample size will depend on the number of subjects experiencing DLTs 
at each dose level, and may be increased if the RP2D is not reached and additional dose 
levels are required. For ORR, the sample size will be dependent on the number of subjects in 
each tumor type. Table 13 below provides Bayesian credible interval and confidence interval
with different number of events or responses for sample sizes of 6 and 14 to characterize the 
precision of estimates for DLT rate and ORR, respectively. Up to 30 subjects will be 
included in the NMC cohort (Part B). Except for DLT, other safety and efficacy endpoints 
will be reported for each dose level pooling the dose escalation cohort and NMC cohort 
together.
Table 13: Bayesian 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% Bayesian
credible interval
95% Bayesian
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)


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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.
Clinical Supplies will be provided by the Sponsor as summarized in Table 14.  
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 14: Product Descriptions
Product Name 
& Potency
Dosage Form
MK-8628 10 mg
Gelatin capsules (white, size 3)
MK-8628 20 mg
Gelatin capsules (green, size 3)
MK-8628 40 mg
Gelatin capsules (white, size 0)
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.


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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 
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 


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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 
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.  


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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.
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 


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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 
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 


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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 
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. 


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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 
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.
11.0 LIST OF REFERENCES
1.
Ji, Y., and Wang, S.-J. (2013). Modified toxicity probability interval design: a safer and 
more reliable method than the 3 + 3 design for practical phase I trials. J. Clin. Oncol. 
Off. J. Am. Soc. Clin. Oncol. 31, 1785–1791.
2.
Dang, C.V., Le, A., and Gao, P. (2009). MYC-induced cancer cell energy metabolism 
and therapeutic opportunities. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 15, 
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3.
Kim, J., Chu, J., Shen, X., Wang, J., and Orkin, S.H. (2008). An extended 
transcriptional network for pluripotency of embryonic stem cells. Cell 132, 1049–1061.
4.
Beroukhim, R., Mermel, C.H., Porter, D., Wei, G., Raychaudhuri, S., Donovan, J., 
Barretina, J., Boehm, J.S., Dobson, J., Urashima, M., et al. (2010). The landscape of 
somatic copy-number alteration across human cancers. Nature 463, 899–905.


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5.
Stewart, T.A., Pattengale, P.K., and Leder, P. (1984). Spontaneous mammary 
adenocarcinomas in transgenic mice that carry and express MTV/myc fusion genes. 
Cell 38, 627–637.
6.
Leder, A., Pattengale, P.K., Kuo, A., Stewart, T.A., and Leder, P. (1986). 
Consequences of widespread deregulation of the c-myc gene in transgenic mice: 
multiple neoplasms and normal development. Cell 45, 485–495.
7.
Harris, A.W., Pinkert, C.A., Crawford, M., Langdon, W.Y., Brinster, R.L., and Adams, 
J.M. (1988). The E mu-myc transgenic mouse. A model for high-incidence spontaneous 
lymphoma and leukemia of early B cells. J. Exp. Med. 167, 353–371.
8.
Soucek, L., Jucker, R., Panacchia, L., Ricordy, R., Tatò, F., and Nasi, S. (2002). 
Omomyc, a potential Myc dominant negative, enhances Myc-induced apoptosis. 
Cancer Res. 62, 3507–3510.
9.
Jain, M., Arvanitis, C., Chu, K., Dewey, W., Leonhardt, E., Trinh, M., Sundberg, C.D., 
Bishop, J.M., and Felsher, D.W. (2002). Sustained loss of a neoplastic phenotype by 
brief inactivation of MYC. Science 297, 102–104.
10.
Fukazawa, T., Maeda, Y., Matsuoka, J., Yamatsuji, T., Shigemitsu, K., Morita, I., 
Faiola, F., Durbin, M.L., Soucek, L., and Naomoto, Y. (2010). Inhibition of Myc 
effectively targets KRAS mutation-positive lung cancer expressing high levels of Myc. 
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Wilke, J., Wilder-Romans, K., Dhanireddy, S., Engelke, C., et al. (2014). Therapeutic 
targeting of BET bromodomain proteins in castration-resistant prostate cancer. Nature 
510, 278–282.
97.
Kuczmarski RJ, Ogden CL, Guo SS, Grummer-Strawn LM, Flegal KM, Mei Z, et al. 
2000 CDC Growth Charts for the United States: methods and development. Vital 
Health Stat 11. 2002; 246:1-190.
98.
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.
99.
Issa, J., Kantarjian, H., Kirkpatrick, P. (2005). Azacitidine. Nature Rev Drug Disc 4, 
275-276.
100. Mertz, J., Conery, A., Bryant, B., Sandy, P., Balasubramanian, S., Mele, D., Bergeron, 
L, Sims III, R. (2011). Targeting MYC dependence in cancer by inhibiting BET 
bromodomains. PNAS 108:40, 1669-16674.
101. Eisenhauer, E.A., Therasse, P., Bogaerts, J., Schwartz, L.H., Sargent, D., Ford, R., 
Dancey, J., Arbuck, S., Gwyther, S., Mooney, M., et al. (2009). New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J 
Cancer 45, 228–247.
102. Scher, H.I., Halabi, S., Tannock, I., Morris, M., Sternberg, C.N., Carducci, M.A., 
Eisenberger, M.A., Higano, C., Bubley, G.J., Dreicer, R., et al. (2008). Design and end 
points of clinical trials for patients with progressive prostate cancer and castrate levels 
of testosterone: recommendations of the Prostate Cancer Clinical Trials Working 
Group. J. Clin. Oncol. 26, 1148–1159.


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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.


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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 
mailbox 
 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.
PPD


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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 
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 
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
PPD


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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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ECOG Performance Status
12.4
ECOG
Characteristics
0
Normal activity. Fully active, able to carry on all pre-disease performance 
without restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., 
light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% of 
waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to 
bed or chair more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care.
Totally confined to bed or chair.
5
Dead
* As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair


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Calculation of Renal Clearance
12.5
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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Non-Exhaustive List of Drugs and Substances with the Potential to Interfere with 
12.6
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.
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Guidance for Potential Drug-Induced Liver Injury (DILI)
12.7
Purpose
12.7.1
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
12.7.2
Hepatotoxicity is injury or damage to the liver that may be associated with impaired liver 
function [1].  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 [2].  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)[3].
As stated in the United States Food and Drug Administration (FDA) “Guidance for Industry -
Drug-Induced Liver Injury: Premarketing Clinical Evaluation” [4]; hepatocellular injury 
(usually detected by serum aminotransferase elevations [AT]) can be caused by drugs that 
rarely, if ever, cause severe DILI (e.g., aspirin, tacrine, statins, and heparin), as well as by 
drugs that do cause such injury.  The frequency of serum AT elevations also is not a good 
indicator of a potential for severe DILI because drugs such as tacrine (not a cause of severe 
DILI) can cause AT elevations in as many as 50 percent of patients.  Very high levels of 
observed ATs may be a somewhat better indicator of potential for severe DILI, but the most 
specific indicator is evidence of altered liver function accompanying or promptly following 
evidence of hepatocellular injury.
The single clearest (most specific) predictor found to date of a drug’s potential for severe 
hepatotoxicity, is the occurrence of hepatocellular injury (AT elevation) accompanied by 
increased serum total bilirubin (TBL) not explained by any other cause, such as viral 
hepatitis or exposure to other hepatotoxins, and without evidence of cholestasis, together 
with an increased incidence of AT elevations in the overall trial population compared to 
control.  Increased plasma prothrombin time, or its international normalized ratio (INR), a 
consequence of reduced hepatic production of Vitamin K-dependent clotting factors, is 
another potentially useful measure of liver function that might suggest the potential for 
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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) [5][6].  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
12.7.3
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 
Section 12.7.5).

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 12.7.5 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 12.7.5.5 for details.)

Consider gastroenterology or hepatology consultation.  
In general, treatment with study therapy should be stopped if the laboratory criteria for 
potential DILI are met.  Please refer to the specific discontinuation criteria in the 
protocol as appropriate.
Hepatic Assessment Flow Chart
12.7.4
Figure 5: Hepatic Assessment Flow Chart
Factors to Consider in Assessing Potential DILI
12.7.5
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.


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12.7.5.1 Study Medication
Considerations should include the following: What was the time interval between 
administration of study medication and the laboratory abnormality(ies)? What is the status of 
study medication use: Continuing? Interrupted? Discontinued?  Was the subject re-
challenged with study medication?
12.7.5.2 Treatment
Record any concomitant treatments.
12.7.5.3 Signs and Symptoms (associated with the potential DILI event)
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
12.7.5.4 Confounding Variables
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


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Category
Examples of Confounding Variables
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
12.7.5.5 Evaluation algorithm for potential DILI if there are no other clinical reasons
Note: If clear etiology for the laboratory abnormalities has been confirmed, Stage 1 and 2 
testing may not be required.  In this case, consultation with the Sponsor is recommended.
Stage 1 work-up should be performed within 48-72 hours:

ALT

AST

Bilirubin: total, direct, indirect

Alkaline phosphatase (ALP)

Prothrombin Time (PT)/international normalized ratio (INR) 

Creatine phosphokinase (CPK)

Manual eosinophil count (if automated count was elevated) 

Toxicology 
screen 
for 
drugs 
of 
abuse 
(including 
ethanol) 
and 
for 
acetaminophen/paracetamol level should also be sent.  Investigators may order 
additional toxicology tests as clinically indicated.

Evaluate 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


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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)
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.


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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
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.


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12.7.5.6 Potential diagnosis
What diagnosis do the history, clinical course, and laboratory tests suggest?
12.7.5.7 Overall clinical impression
What are the investigator’s overall clinical impressions (e.g., differential diagnosis, potential 
alternative causes)?
12.7.5.8 Treatment plan
What is the plan for treatment and follow-up?
Contacts
12.7.6
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
12.7.7
1. Navarro, VJ and JR Senior, 2006, Drug-Related Hepatotoxicity, N Eng J Med, 
354(7):731-9.
2. Björnsson, E and R Olsson, 2005, Outcome and Prognostic Markers in Severe Drug-
Induced Liver Disease, Hepatology, 42(2):481-9.
3. 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 
4. FDA Guidance for Industry - Drug-Induced Liver Injury: Premarketing Clinical 
Evaluation, July 2009
www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidan
ces/UCM174090.pdf
5. 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.
6. 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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Response Evaluation Criteria in Solid Tumors (RECIST)
12.8
Tumor lesions will be assessed throughout the study according to RECIST criteria (version 
1.1) [1]. Any tumor shrinkage, in terms of percentage of tumor regression, will be reported 
even if it does not meet RECIST criteria for response. While RECIST criteria (version 1.1) 
do not require confirmation of objective response in clinical studies where response rate is 
not the study primary endpoint, as a convincing proof-of-concept of antitumor activity, 
efforts should be made to confirm objective response at least 4 weeks apart.
Imaging Technique
12.8.1
To ensure comparability, the baseline and subsequent tumor measurements to assess response 
should be performed using identical imaging techniques (i.e., preferably the same machine, 
contrast agent and standard volume of contrast agent, etc.).
Evaluation of Lesions
12.8.2
Table 15: Evaluation of response in target lesions
Complete Response (CR)
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to 
<10 mm.
Partial Response (PR)
At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters.
Progression (PD)
At least a 20% increase in the sum of diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that 
is the smallest on study). 
In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. 
The appearance of one or more new lesions is also considered progression)
Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameters 
while on study.
Table 16: Evaluation of non-target lesions
Complete Response (CR)
Disappearance of all non-target lesions. All lymph nodes must be non-
pathological in size (<10 mm short axis) 
Non-CR / Non-PD
Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits.
Progression (PD)
Unequivocal progression of existing non-target lesions; see Section 4.3.4 of 
Eisenhauer et al., 2009 for further details. 
Note: the appearance of one or more new lesions is also considered 
progression. Unequivocal progression of existing non-target lesions, other 
than pleural effusions without cytological proof of neoplastic origin, in the 
opinion of the treating investigator (in this circumstance an explanation 
must be provided)1. 
1Although clear progression of non-target lesions only is exceptional, in such circumstances, the opinion of the 
treating physician should prevail and the progression status should be confirmed later by the Medical Monitor.


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Definition of Best Overall Tumor Response
12.8.3
The best overall response is the best response recorded between the start and the end of 
treatment, as described below. Overall response is calculated for each assessment time point 
according to Table 17.
Table 17: Overall response in subjects with target (+/– non-target) disease
Target lesions
Non-target lesions
New lesions
Overall response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all 
evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NE, not evaluable
The best overall response is determined once all data for a given subject are available. Table 
18 below summarizes the best overall tumor response.


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Table 18: Best overall response
Overall response
First time point
Overall response
Subsequent time 
points
Best overall response
CR
CR
CR
CR
PR
SD, PD or PR1
CR
SD
SD provided minimum criteria for SD duration met, 
otherwise, PD
CR
PD
SD provided minimum criteria for SD duration met, 
otherwise, PD
CR
NE
SD provided minimum criteria for SD duration met, 
otherwise NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD duration met, 
otherwise, PD
PR
NE
SD provided minimum criteria for SD duration met, 
otherwise NE
NE
NE
NE
CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NE, not evaluable
1. If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease 
meeting PR criteria relative to baseline, makes the disease PD at that point (since disease must have 
reappeared after CR). Best response would depend on whether minimum duration for SD was met. However, 
sometimes CR may be claimed when subsequent scans suggest small lesions were likely still present and in 
fact the subject had PR, not CR at the first time point. Under these circumstances, the original CR should be 
changed to PR and the best response is PR.
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration”. Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
For equivocal findings of progression (e.g. very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment. If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected.
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/ biopsy) before 
confirming the complete response status.
References
12.8.4
1. Eisenhauer, E.A., Therasse, P., Bogaerts, J., Schwartz, L.H., Sargent, D., Ford, R., 
Dancey, J., Arbuck, S., Gwyther, S., Mooney, M., et al. (2009). New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J 
Cancer 45, 228–247.


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Prostate Cancer Clinical Trials Working Group (PCWG2) Response Criteria
12.9
For CRPC subjects, PSA response rates will be measured according to the PCWG2 criteria 
[1]. RECIST v1.1 is used to assess soft tissue disease [2]. Progression of bone disease is 
defined using PCWG2 criteria, namely a confirmed increase of at least two new lesions on a 
bone scan.
PSA
12.9.1
For control/relief/eliminate end points
The PCWG2 advises against reporting PSA response rates because they are of little value 
given the uncertain significance of a defined degree of decline from baseline, be it 50% or 
30%, and no criterion has been shown prospectively to be a surrogate of clinical benefit [3]. 
To report PSA-based outcomes, PCWG2 recommends that the percentage of change in PSA 
from baseline to 12 weeks (or earlier for those who discontinue therapy), as well as the 
maximum decline in PSA that occurs at any point after treatment be reported for each subject
using a waterfall plot [4]. Waterfall plots provide a broader and more sensitive display of 
data, and are more informative until a validated surrogate of clinical benefit becomes 
available. PCWG2 recommends that the same waterfall plot be used to illustrate outcomes 
for noncytotoxic agents. It discourages the use of changes in PSA-doubling time or PSA 
slope as a primary end point, given that their clinical significance is uncertain, and also 
recommends avoiding reporting duration of PSA control, as described in PCWG1 guidelines, 
because its interpretation varies between investigators.
For delay/prevent end points
PCWG2 defines PSA progression as the date that a 25% or greater increase and an absolute 
increase of ≥2 ng/mL from the nadir is documented, which is confirmed by a second value 
obtained 3 or more weeks later. This will be used to determine both PSA progression and 
response duration. This recommendation recognizes that variations in progression times 
might occur simply on the basis of the rate of PSA rise. Where no decline from baseline is 
documented, PCWG2 defines PSA progression as a 25% increase from the baseline value 
along with an increase in absolute value of 2 ng/mL or more (rather than 5 ng/mL) after 12 
weeks of treatment.
Measureable Soft-Tissue Lesions
12.9.2
For control/relieve/eliminate end points
PCWG2 accepts with modifications RECIST criteria for evaluating drugs or approaches 
anticipated to produce tumor regression. The modifications are that changes in nodal and 
visceral sites be recorded and reported separately, and lymph nodes in the pelvis must 
measure at least 2 cm in their greatest diameter to be considered target lesions. PCWG2 also 
recommends that the complete elimination of disease at a particular site be recorded 
separately. PCWG2 reinforces the recommendation in RECIST that any favorable change 
should be confirmed using a second follow-up scan. As with changes in PSA, PCWG2 
suggests that changes in the size of the target lesions be reported as a waterfall plot to 
facilitate comparison between studies. 


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For prevent/delay end points
Progression in a nodal or visceral site should also be defined using RECIST, with the 
recognition that, for some therapies, early unfavorable changes may not accurately reflect 
disease status. As noted, a lymphocytic infiltration of a tumor mass after successful 
immunization may result in an enlarged soft-tissue lesion that could be an early indication 
that the treatment is working. Further, because the effects of some agents (non-cytotoxic) 
may be delayed, the degree of increase in tumor size at the first 12-week assessment should 
also be confirmed before it is considered a treatment failure.
Bone
12.9.3
Given the frequency of bone involvement in patients with progressive, castration-resistant 
disease, the decreased emphasis of early changes in PSA, and the increased availability of 
cytostatic agents, reliable methods to assess changes in bone are of increasing importance. 
PCWG2 recognizes that standards for using MRI and positron emission tomography (PET) to 
assess bone metastases are under active investigation, so only radionuclide bone scans are 
considered here. PCWG2 also recognizes that there are no validated criteria for response on 
radionuclide bone scan. 
For control/relieve/eliminate end points
PCWG2 recommends that post-treatment changes be recorded simply as either “no new 
lesions” or “new lesions.” However, progression at the first scheduled assessment should be 
confirmed on a second scan performed 6 or more weeks later, in the absence of clearly 
worsening soft-tissue (nodal and visceral) disease or disease-related symptoms. In the rare 
case where visible lesions disappear, this too should be confirmed at the next scheduled 
assessment. 
For prevent/delay end points
Progressing disease on bone scan is considered when a minimum of two new lesions is 
observed. PCWG1 made the provision that a worsening bone scan on the first follow-up 
manifests tumor “flare”; PCWG2 does not recommend performing a follow-up bone scan 
before 12 weeks of treatment unless clinically indicated. At the first 12-week reassessment, 
defining disease progression requires a confirmatory scan (which shows additional new 
lesions compared with the first follow-up scan) performed 6 or more weeks later, because 
lesions visible at the 12-week assessment may represent disease that was not detected on the 
pretreatment scan. When further progression is documented on the confirmatory scan, the 
date of progression recorded for the trial, is the date of the first scan that shows the change.
Note that symptoms will not be evaluated in this phase Ib study.


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Table 19: The Prostate Cancer Clinical Trials Working Group (PCWG2) Response Criteria
Variable
PCWG2 Criteria [1]
PSA
For control/relieve/eliminate end points:
Record the percent change from baseline (rise or fall) at 12 weeks, and 
separately, the maximal change (rise or fall) at any time using a waterfall plot
Progression:
Decline from baseline: record time from start of therapy to first PSA increase 
that is ≥ 25% and ≥ 2 ng/mL above the nadir, and which is confirmed by a 
second value 3 or more weeks later (i.e., a confirmed rising trend)
The requirement of an increase of 5 ng/mL is decreased to 2 ng/mL, and the 
requirement for a 50% increase is reduced to 25%
Recording the duration of PSA decline of little value
No decline from baseline:
PSA progression ≥ 25% and ≥ 2 ng/mL after 12 weeks
Soft-tissue 
lesions
For control/relieve/eliminate end points:
Use RECIST with caveats
Only report changes in lymph nodes that were ≥ 2 cm in diameter at baseline
Record changes in nodal and visceral soft tissue sites separately
Record complete elimination of disease at any site separately
Confirm favorable change with second scan
Record changes using waterfall plot
For delay/prevent end points:
Use RECIST criteria for progression, with additional requirement that 
progression at first assessment be confirmed by a second scan 6 or more weeks 
later
Note that for some treatments, a lesion may increase in size before it decreases
Bone
For control/relieve eliminate end points:
Record outcome as new lesions or no new lesions
First scheduled reassessment:
No new lesions: continue therapy
New lesions: perform a confirmatory scan 6 or more weeks later
Confirmatory scan:
No new lesions: continue therapy
Additional new lesions: progression
Subsequent scheduled reassessments:
No new lesions: continue
New lesions: progression
For prevent/delay end points (progression):
The appearance of ≥ 2 new lesions, and, for the first reassessment only, a 
confirmatory scan performed 6 or more weeks later that shows a minimum of 2 
or more additional new lesions
The date of progression is the date of the first scan that shows the change
PSA, prostate-specific antigen


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References
12.9.4
1. Scher, H.I., Halabi, S., Tannock, I., Morris, M., Sternberg, C.N., Carducci, M.A., 
Eisenberger, M.A., Higano, C., Bubley, G.J., Dreicer, R., et al. (2008). Design and 
end points of clinical trials for patients with progressive prostate cancer and castrate 
levels of testosterone: recommendations of the Prostate Cancer Clinical Trials 
Working Group. J. Clin. Oncol. 26, 1148–1159.
2. Eisenhauer, E.A., Therasse, P., Bogaerts, J., Schwartz, L.H., Sargent, D., Ford, R., 
Dancey, J., Arbuck, S., Gwyther, S., Mooney, M., et al. (2009). New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J 
Cancer 45, 228–247.
3. Fleming, M.T., Morris, M.J., Heller, G., and Scher, H.I. (2006). Post-therapy changes 
in PSA as an outcome measure in prostate cancer clinical trials. Nat. Clin. Pract. 
Oncol. 3, 658–667.
4. Seidman, A.D., Scher, H.I., Petrylak, D., Dershaw, D.D., and Curley, T. (1992). 
Estramustine and vinblastine: use of prostate specific antigen as a clinical trial end 
point for hormone refractory prostatic cancer. J. Urol. 147, 931–934.


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List of Abbreviations
12.10
ADL
Activities of daily living
AE
Adverse Event
AL
Acute Leukemia
ALK
Anaplastic Lymphoma Kinase
ALT (or SGPT)
Alanine Aminotransferase (serum glutamic-pyruvic transaminase)
ALP
Alkaline Phosphatase
AML
Acute Myeloid Leukemia
ANA
Antinuclear antibody
ANC
Absolute neutrophil count
APAP
N-Acetyl-p-Aminophenol (acetaminophen)
aPTT
Activated Partial Thromboplastin Time
AR
Androgen receptor
ASaT
All Subjects as Treated
ASCO
American Society of Clinical Oncology
AST (or SGOT)
Aspartate Aminotransferase (serum glutamic-oxaloacetic transaminase)
AT
Aminotransferase(s)
AUC
Area Under The Plasma Concentration Versus Time Curve
BCL2
B-cell lymphoma 2
BET
Bromodomain and Extraterminal
β-hCG
Serum β-human chorionic gonadotropin 
BID
Twice Daily
BLBC
Basal-like breast cancer
BRCA (1 and 2)
Breast cancer genes 1 and 2
BRD
Bromodomain
BRD2
Bromodomain-containing gene 2
BRD3
Bromodomain-containing gene 3
BRD4
Bromodomain-containing gene 4
BRDT
BRD Testis-Specific Protein
BSEP
Bile salt export pump
CA 15-3
Cancer Antigen 15-3
CA 27.29
Cancer Antigen 27.29
CBC
Complete Blood Count
CEA
Carcinoembryonic Antigen
CFR
Code of Federal Regulations
CL
Total Plasma Clearance
CL/F
Oral clearance
cm
centimeter
Cmax
Maximum Concentration 
Cmin
Minimum Concentration
CMV
Cytomegalovirus
CNS
Central Nervous System
CO2
Carbon dioxide
CPK
Creatine phosphokinase
CRU
Clinical Research Unit
Ct
Cycle threshold
CT
Computerized Tomography scan
Ctrough
Trough concentration
CR
Complete Response
CRi
Complete Response with incomplete blood count recovery
CRPC
Castration-Resistant Prostate Cancer
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
CTFG
Clinical Trial Facilitation Group


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CYP
Cytochrome P450 enzyme
CYP2A6
Cytochrome P450, family 2, subfamily A, polypeptide 6
CYP2C9
Cytochrome P450, family 2, subfamily C, polypeptide 9
CYP2C19
Cytochrome P450, family 2, subfamily C, polypeptide 19
CYP3A4
Cytochrome P450, family 3, subfamily A, polypeptide 4
D
De-escalate
DCR
Disease Control Rate
DDI
Drug-drug interaction
DILI
Drug-induced liver injury
dL
deciliter
DL
Dose Level
DLBCL
Diffuse large B-cell lymphoma
DLT
Dose Limiting Toxicity
DMSO
Dimethyl sulfoxide
DNA
Deoxyribonucleic acid
DNMT
DNA methyltransferase
DOR
Duration of Response
DU
Dose unacceptably toxic
E
Escalate
EBV
Epstein-Barr Virus
ECG
Electrocardiogram
ECI
Events of clinical interest
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EGFR
Epidermal Growth Factor Receptor
EML4
Echinoderm Microtubule-Associated Protein-Like 4
EPO
Erythropoietin 
ER
Estrogen Receptor
ERC
Ethics Review Committee
ERCP
Endoscopic Retrograde Cholangiopancreatography
ERG
Erythroblast transformation-specific related gene
FAS
Full Analysis Set
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FDAMA
Food and Drug Administration Modernization Act
FISH
Fluorescence In Situ Hybridization
FSH
Follicle stimulating hormone
g
gram
GCP
Good Clinical Practices
G-CSF
Granulocyte-colony stimulating factor
GGT
Gamma-glutamyl transferase
GnRH
Gonadotropin Releasing Hormone
HBcAb
Hepatitis B core antibody
HBeAg
Hepatitis B e antigen
HBsAb
Hepatitis B surface antibody
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C virus
HER2
Human Epidermal Growth Factor Receptor 2
HIV
Human immunodeficiency virus
hr
hour
IB
Investigators Brochure
IC50
Half maximal inhibitory concentration
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IgG
Immunoglobulin G


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IgM
Immunoglobulin M
IHC
Immunohistochemistry
INR
International Normalized Ratio
IRB
Institutional Review Board
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
IV
Intravenous
IWRS
Interactive Web Response System
JQ1
small-molecule inhibitor of BET bromodomain chromatin-associated
proteins
kg
kilogram
KRAS
Kirsten rat sarcoma viral oncogene homolog
L
liter
LKB1
Liver kinase B1
LMWH
Low Molecular Weight Heparin
MAPK
Mitogen-activated protein kinase
MDRD
Modification of Diet in Renal Disease
MDS
Myelodysplastic syndrome
MEC
Molar extinction coefficient
mg
milligrams
mL
milliliter
µM
Micromolar
mm
millimeter
mmHg
Millimeters of mercury
MPD
Myeloproliferative disorder
MRCP
Magnetic Resonance Cholangiopancreatography
MRI
Magnetic Resonance Imaging 
mRNA
Messenger RNA
MRP2
Multi-drug resistance-associated protein 2
MRP3
Multi-drug resistance-associated protein 3
mTPI
Modified Toxicity Probability Interval
MYC (or c-MYC)
v-myc avian myelocytomatosis viral oncogene homolog
NASH
Non-alcoholic steatohepatitis
NCI
National Cancer Institute
NE
Not evaluable
ng
nanogram
nmol
nanomole
NMC
NUT Midline Carcinoma
N-MYC
V-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog
NSAID
Nonsteroidal anti-inflammatory drug
NSCLC
Non-Small Cell Lung Cancer
NUT
Nuclear Protein in Testis
OATP1B1
Organic anion-transporting polypeptide, 1B1
OATP1B3
Organic anion-transporting polypeptide, 1B3
OHM
Other Hematologic Malignancies
ORR
Objective Response Rate
OS
Overall Survival
p21
P21/Ras protein
Papp
Apparent permeability
PCWG2
Prostate Cancer Clinical Trials Working Group
PD
Pharmacodynamics
PD
Progressive Disease
PET
Positron emission tomography
PFS
Progression-Free Survival
P-gP
Phosphoglycolate phosphatase
PgR
Progesterone Receptor


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PI3K
Phosphoinositide 3-kinase
PK
Pharmacokinetics
POC
Proof of concept
PPIB
Peptidylpropyl isomerase B
PR
Partial Response
PS
Performance Status
PSA
Prostate Specific Antigen
PT
Prothrombin Time
P-TEFb
Positive Transcription Elongation Factor b
QD
Once Daily
OTC
Over the counter
qPCR
Quantitative polymerase chain reaction
RAS
P21/Ras protein
RD
Recommended dose
RECIST
Response Evaluation Criteria In Solid Tumors
RNA
Ribonucleic acid
RP2D
Recommended Phase II Dose
S
Stay at current dose
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SCC
Squamous Cell Carcinoma
SD
Stable Disease
SOP
Standard Operating Procedure
sSAP
Supplemental Statistical Analysis Plan
t1/2
Terminal Half-Life
TBL
Serum total bilirubin
Tmax
Time to Peak Concentration
TMPRSS2
Transmembrane protease, serine 2
TNBC
Triple Negative Breast Cancer
Ty82
Human thymic carcinoma cell line
UDP
Uridine diphosphate
UGT
Uridine diphosphate glucuronosyltransferase
UGT1A1
Uridine diphosphate glucuronosyltransferase 1 family, polypeptide A1
UGT1A3
Uridine diphosphate glucuronosyltransferase 1 family, polypeptide A3
UGT1A7
Uridine diphosphate glucuronosyltransferase 1 family, polypeptide A7
UGT1A8
Uridine diphosphate glucuronosyltransferase 1 family, polypeptide A8
UGT1A9
Uridine diphosphate glucuronosyltransferase 1 family, polypeptide A9
UGT1A10
Uridine diphosphate glucuronosyltransferase 1 family, polypeptide A10
ULN
Upper Limit of Normal
UV
Ultraviolet
Vdss
Volume of Distribution At Steady State
V/F
Volume of distribution


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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