Clinical trial NCT02684617
Conditions: rrCLL rrMM rrDLBCL
Sponsor: Merck Sharp & Dohme LLC
Start date: 2016-03-29; Completion date: 2020-04-06
Enrollment: 75 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the safety and efficacy of pembrolizumab (MK-3475) used in combination with dinaciclib (MK-7965) in the treatment of relapsed or refractory chronic lymphocytic leukemia (rrCLL), multiple myeloma (rrMM), or diffuse large B-cell lymphoma (rrDLBCL).

Detailed description:

Arms: arm 1: Participants with refractory chronic lymphocytic leukemia (rrCLL) received an infusion of pembrolizumab 200 mg followed by infusion of dinaciclib 7 mg/m\^2 on Cycle 1 Day 1, and infusion of dinaciclib 10 mg/m\^2 alone on Cycle 1 Day 8. Participants then received an infusion of pembrolizumab 200 mg followed by infusion of dinaciclib 14 mg/m\^2 on Cycles 2-35 Day 1 and infusion of dinaciclib 14 mg/m\^2 alone on Cycles 2-35 Day 8. Each cycle is 21 days. arm 2: Participants with relapsed or refractory multiple myeloma (rrMM) received an infusion of pembrolizumab 200 mg followed by infusion of dinaciclib 7 mg/m\^2 on Cycle 1 Day 1, and infusion of dinaciclib 10 mg/m\^2 alone on Cycle 1 Day 8. Participants then received an infusion of pembrolizumab 200 mg followed by infusion of dinaciclib 14 mg/m\^2 on Cycles 2-35 Day 1 and infusion of dinaciclib 14 mg/m\^2 alone on Cycles 2-35 Day 8. Each cycle is 21 days. arm 3: Participants with relapsed or refractory diffuse large B-cell lymphoma (rrDLBCL) received an infusion of pembrolizumab 200 mg followed by infusion of dinaciclib 7 mg/m\^2 on Cycle 1 Day 1, and infusion of dinaciclib 10 mg/m\^2 alone on Cycle 1 Day 8. Participants then received an infusion of pembrolizumab 200 mg followed by infusion of dinaciclib 14 mg/m\^2 on Cycles 2-35 Day 1 and infusion of dinaciclib 14 mg/m\^2 alone on Cycles 2-35 Day 8. Each cycle is 21 days.
Interventions: intervention 1: pembrolizumab intervention 2: dinaciclib
Intervention descriptions: intervention 1: 200 mg administered as an intravenous (IV) infusion on Day 1 of infusion Cycles 1-35. Each cycle is 21 days. intervention 2: dinaciclib 7 mg/m\^2 administered as an IV infusion on Day 1 of infusion Cycle 1, dinaciclib 10 mg/m\^2 administered as an IV infusion on Day 8 of infusion Cycle 1, dinaciclib 14 mg/m\^2 administered as an IV infusion on Days 1 and 8 of infusion Cycles 2-35. Each cycle is 21 days.

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
Document Date: 
Phase Ib Trial of Pembrolizumab (MK-3475) in Combination 
with Dinaciclib (MK-7965) in Subjects with Hematologic 
Malignancies (KEYNOTE-155)
12-MAR-2020
NCT02684617


PRODUCT:  MK-3475 
1
PROTOCOL/AMENDMENT NO.: 155-05 
MK-3475-155-05 FINAL PROTOCOL
12-MAR-2020
CONFIDENTIAL
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A.
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, NJ 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File
Binder (or equivalent).
TITLE:
Phase Ib Trial of Pembrolizumab (MK-3475) in Combination with Dinaciclib (MK-7965) in 
Subjects with Hematologic Malignancies (KEYNOTE-155)
IND NUMBER:  Pembrolizumab 118,604; Dinaciclib 114,461
EudraCT NUMBER:  Not Applicable
NCT NUMBER:  NCT02684617
 
 
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CONFIDENTIAL
TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................... 11
SUMMARY OF CHANGES................................................................................................ 13
1.0
TRIAL SUMMARY.................................................................................................. 15
2.0
TRIAL DESIGN........................................................................................................ 16
Trial Design ........................................................................................................... 16
Trial Diagram........................................................................................................ 17
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 18
Primary Objective(s) & Hypothesis(es).............................................................. 18
Secondary Objective(s) & Hypothesis(es)........................................................... 18
Other Objectives ................................................................................................... 18
4.0
BACKGROUND & RATIONALE.......................................................................... 19
Background ........................................................................................................... 19
Pharmaceutical and Therapeutic Background .................................................... 19
Pembrolizumab ............................................................................................ 19
Dinaciclib..................................................................................................... 20
Pre-clinical and Clinical Trials ........................................................................... 20
Pembrolizumab ............................................................................................ 20
Dinaciclib..................................................................................................... 21
Pembrolizumab in Combination with Dinaciclib ........................................ 21
Rationale................................................................................................................ 21
Rationale for the Trial and Selected Subject Population .................................... 21
Rationale for Dose Selection/Regimen............................................................... 21
Pembrolizumab ............................................................................................ 21
Dinaciclib..................................................................................................... 22
Rationale for Endpoints ...................................................................................... 23
Efficacy Endpoints....................................................................................... 23
Safety Endpoints.......................................................................................... 23
Pharmacokinetic Endpoints ......................................................................... 24
 
 
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Planned Exploratory Biomarker Research................................................... 24
Future Biomedical Research........................................................................ 25
Benefit/Risk ........................................................................................................... 26
5.0
METHODOLOGY ................................................................................................... 26
Entry Criteria........................................................................................................ 26
Diagnosis/Condition for Entry into the Trial ...................................................... 26
Subject Inclusion Criteria.................................................................................... 26
Subject Exclusion Criteria .................................................................................. 30
Trial Treatment(s) ................................................................................................ 32
Dose Selection/Modification .............................................................................. 33
Dose Selection (Preparation) ....................................................................... 33
Pembrolizumab ............................................................................................ 33
5.2.1.2.1
Pembrolizumab Dose Modification...................................................... 33
Dinaciclib..................................................................................................... 39
5.2.1.3.1
Premedication for Dinaciclib for rrCLL and rrDLBCL........................ 40
5.2.1.3.2
Premedication for Dinaciclib for rrMM................................................ 41
5.2.1.3.3
Dinaciclib Dose Modifications ............................................................. 42
5.2.1.3.4
Dinaciclib Dose Evaluation .................................................................. 45
Definition of Dose-Limiting Toxicity.......................................................... 48
Replacement of Subjects in the Dose Evaluation Period............................. 48
Timing of Dose Administration.......................................................................... 49
Trial Blinding/Masking....................................................................................... 49
Randomization or Treatment Allocation............................................................ 49
Stratification.......................................................................................................... 49
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 49
Acceptable Concomitant Medications ................................................................ 50
Prohibited Concomitant Medications and Therapies.......................................... 50
Rescue Medications & Supportive Care............................................................. 51
Diet/Activity/Other Considerations..................................................................... 52
Diet...................................................................................................................... 52
Contraception...................................................................................................... 52
Pregnancy............................................................................................................ 54
 
 
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Use in Nursing Women....................................................................................... 54
Subject Withdrawal/Discontinuation Criteria................................................... 54
Discontinuation of Treatment ............................................................................. 54
Withdrawal from the Trial .................................................................................. 55
Subject Replacement Strategy............................................................................. 55
Beginning and End of the Trial ........................................................................... 55
Clinical Criteria for Early Trial Termination ................................................... 55
6.0
TRIAL FLOW CHART ........................................................................................... 56
7.0
TRIAL PROCEDURES ........................................................................................... 61
Trial Procedures ................................................................................................... 61
Administrative Procedures.................................................................................. 61
Informed Consent......................................................................................... 61
7.1.1.1.1
General Informed Consent.................................................................... 61
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 61
Inclusion/Exclusion Criteria ........................................................................ 62
Subject Identification Card .......................................................................... 62
Medical History ........................................................................................... 62
Prior and Concomitant Medications Review............................................... 62
7.1.1.5.1
Prior Medications.................................................................................. 62
7.1.1.5.2
Concomitant Medications..................................................................... 62
7.1.1.5.3
Prior Cancer Treatment Details ............................................................ 62
7.1.1.5.4
Subsequent Antineoplastic Therapy ..................................................... 63
Assignment of Screening Number............................................................... 63
Assignment of Treatment/Randomization Number..................................... 63
Trial Compliance ......................................................................................... 63
Clinical Procedures/Assessments........................................................................ 64
Oncologic Disease Details........................................................................... 64
Full Physical Exam ...................................................................................... 64
Electrocardiogram........................................................................................ 64
Vital Signs.................................................................................................... 64
Eastern Cooperative Oncology Group Performance Status......................... 64
 
 
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CONFIDENTIAL
Adverse Event Monitoring........................................................................... 64
Criteria for Assessment of Disease.............................................................. 65
7.1.2.7.1
Disease Assessment During Trial......................................................... 65
7.1.2.7.2
Disease Assessment of Immunotherapeutic Agents ............................. 65
7.1.2.7.3
Disease Progression Assessments......................................................... 65
Assessment of Disease and Tumor Response.............................................. 66
7.1.2.8.1
CLL Response Assessments ................................................................. 66
7.1.2.8.2
Multiple Myeloma Response Assessments: ......................................... 67
Myeloma Laboratory Testing Disease Measurements................... 67
Imaging for Subjects with Myeloma Bone Disease....................... 67
7.1.2.8.3
DLBCL Disease Response Assessment................................................ 68
Biopsy Collection and Correlative Studies Blood Collection...................... 68
Laboratory Procedures/Assessments .................................................................. 69
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 70
Pregnancy Test............................................................................................. 71
Evaluations for Subjects with CLL.............................................................. 71
Evaluations for Subjects with MM .............................................................. 71
Pharmacokinetic/Pharmacodynamic Evaluations........................................ 71
Blood Collection for Anti-pembrolizumab Antibodies ............................... 71
Blood Collection for Correlative and Biomarker Studies............................ 72
Planned Genetic Analysis Sample Collection.............................................. 72
Future Biomedical Research........................................................................ 72
Other Procedures................................................................................................. 72
Withdrawal/Discontinuation........................................................................ 72
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 72
7.1.4.1.2
Lost to Follow-up.................................................................................. 73
Blinding/Unblinding .................................................................................... 73
Domiciling ................................................................................................... 73
Calibration of Critical Equipment................................................................ 73
Visit Requirements.............................................................................................. 74
Screening...................................................................................................... 74
Treatment Period.......................................................................................... 74
Post-Treatment Visits................................................................................... 74
 
 
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7.1.5.3.1
Safety Follow-Up Visit......................................................................... 75
Efficacy Follow-up Visits............................................................................ 75
7.1.5.4.1
Follow-Up Post-Allogeneic Stem Cell Transplantation....................... 75
7.1.5.4.2
Survival Follow-up ............................................................................... 75
7.1.5.4.3
Survival Status...................................................................................... 76
Assessing and Recording Adverse Events .......................................................... 76
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor.......................................................................................................... 77
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 77
Immediate Reporting of Adverse Events to the Sponsor.................................... 78
Serious Adverse Events ............................................................................... 78
Events of Clinical Interest............................................................................ 79
7.2.3.2.1
Follow-Up Post-Allogeneic Stem Cell Transplantation....................... 80
Protocol-Specific Exceptions to Serious Adverse Event Reporting............ 80
Evaluating Adverse Events................................................................................. 81
Sponsor Responsibility for Reporting Adverse Events ...................................... 85
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 85
Statistical Analysis Plan Summary ..................................................................... 85
Responsibility for Analyses/In-House Blinding ................................................. 86
Hypotheses/Estimation ......................................................................................... 86
Analysis Endpoints ............................................................................................... 86
Efficacy Endpoints.............................................................................................. 86
Safety Endpoints ................................................................................................. 87
Analysis Populations............................................................................................. 87
Statistical Methods................................................................................................ 87
Objective Response Rate .................................................................................... 87
Duration of Response.......................................................................................... 88
Progression-Free Survival................................................................................... 88
Overall Survival.................................................................................................. 88
Statistical Methods for Safety Analyses ............................................................. 89
Other Analyses.................................................................................................... 89
Interim Analysis.................................................................................................... 89
Sample Size and Power Calculation.................................................................... 90
 
 
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CONFIDENTIAL
Multiplicity ............................................................................................................ 90
Subgroup Analyses and Effect of Baseline Factors ........................................... 90
Compliance (Medication Adherence).................................................................. 91
Extent of Exposure................................................................................................ 91
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 91
Investigational Product ........................................................................................ 91
Packaging and Labeling Information ................................................................. 91
Clinical Supplies Disclosure................................................................................. 92
Storage and Handling Requirements.................................................................. 92
Discard/Destruction/Returns and Reconciliation .............................................. 92
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 92
Confidentiality....................................................................................................... 92
Confidentiality of Data ....................................................................................... 92
Confidentiality of Subject Records..................................................................... 92
Confidentiality of Investigator Information........................................................ 93
Confidentiality of IRB/IEC Information............................................................. 93
Compliance with Financial Disclosure Requirements....................................... 93
Compliance with Law, Audit and Debarment ................................................... 94
Compliance with Trial Registration and Results Posting Requirements ........ 95
Quality Management System............................................................................... 96
Data Management................................................................................................. 96
Publications ........................................................................................................... 96
11.0
LIST OF REFERENCES......................................................................................... 98
12.0
APPENDICES......................................................................................................... 101
Merck Code of Conduct for Clinical Trials...................................................... 101
Collection and Management of Specimens for Future Biomedical 
Research............................................................................................................... 103
Understanding the Intent, Scope and Public Health Benefits of 
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff .................................................................................... 109
ECOG Performance Status................................................................................ 120
 
 
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CONFIDENTIAL
Recommended Supportive Care Guidelines for Tumor Lysis Syndrome 
Prevention and Treatment in Subjects with CLL and DLBCL ..................... 121
Drugs that Interact with CYP3A4..................................................................... 123
Revised iwCLL Response Guidelines................................................................ 124
International Myeloma Working Group criteria for response assessment 
in multiple myeloma (IMWG criteria).............................................................. 127
Lymphoma Disease Response Criteria ............................................................. 129
Lymphoma B Symptoms and Constitutional Symptoms ................................ 130
Common Terminology Criteria for Adverse Events V4.0 .............................. 131
Abbreviations ...................................................................................................... 132
13.0
SIGNATURES......................................................................................................... 136
Sponsor's Representative ................................................................................... 136
Investigator.......................................................................................................... 136
 
 
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CONFIDENTIAL
LIST OF TABLES
  
Table 1
Subject Inclusion Criteria - Adequate Organ Function....................................... 28
Table 2
Trial Treatments.................................................................................................. 32
Table 3
Dosing Schedule of Pembrolizumab and Dinaciclib .......................................... 32
Table 4
Dose Modification and Toxicity Management Guidelines for Immune-
Related Adverse Events Associated with Pembrolizumab................................ 34
Table 5
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines.......................................................................................................... 38
Table 6
Premedication for Dinaciclib for rrCLL and rrDLBCL...................................... 41
Table 7
Premedication for Dinaciclib for rrMM.............................................................. 42
Table 8
Dinaciclib Dose Modification for Hematologic Toxicity................................... 43
Table 9
Dinaciclib Dose Modification for Nonhematologic Toxicity............................. 44
Table 10
Dinaciclib Dose................................................................................................... 45
Table 11
Dinaciclib Dose Levels....................................................................................... 45
Table 12
Probability of Observing the Number (%) of Subjects with DLT ...................... 46
Table 13
Monitoring Guidance in Dose Evaluation (Target DLT Rate of 30%) .............. 47
Table 14
Bone Marrow or Lymph Node Biopsy Assessments.......................................... 69
Table 15
Tissue Collection for Correlative Biomarkers Studies ....................................... 69
Table 16
Laboratory Tests ................................................................................................. 70
Table 17
Evaluating Adverse Events................................................................................. 82
Table 18
Censoring Rules for PFS..................................................................................... 88
Table 19
Analysis Methods for Efficacy Endpoints (Signal Detection)............................ 89
Table 20
Precision (95% Confidence Intervals) for Range of Observed ORR (33% -
83%)................................................................................................................... 90
Table 21
Product Descriptions........................................................................................... 91
 
 
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CONFIDENTIAL
LIST OF FIGURES
Figure 1
Trial Design ........................................................................................................ 17
 
 
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
MK-3475-155-05
12-MAR-2020
To include a limit to survival follow-up in order to end the study.
MK-3475-155-04
15-DEC-2017
To provide the most current information supporting a pembrolizumab 200 mg 
fixed dose, based on recent data generated in the pembrolizumab development 
program.
To add/clarify language in alignment with pembrolizumab current label, 
including addition of myocarditis grade clarification and actions for dose 
modification evaluations.
To introduce flexibility of survival status activities to ensure that current and 
complete survival data are available at the time of database locks.
MK-3475-155-03
24-OCT-2017
Addition of Arm B, combination treatment of pembrolizumab and MK-4280 in 
subjects with relapsed or refractory diffuse large B-cell lymphoma or relapsed 
or refractory indolent lymphomas. Each disease setting is an unmet medical 
need.  Preclinical and clinical data for pembrolizumab have established 
antitumor activity in multiple tumor types, including hematologic malignancies. 
In preclinical trials, LAG-3 has been shown to be produced in elevated levels in 
hematologic malignancies, and blockage of LAG-3 and PD-L1 has 
demonstrated synergistic antitumor activity in solid tumors.  An ongoing first-
in-human trial investigating the combination of MK-4280 and pembrolizumab 
in advanced solid tumors, preliminary antitumor activity of this combination 
has been observed.
Enrollment of subjects with rrDLBCL into Arm A or B cohorts will occur in 
parallel with treatment allocation accomplished by alternating assignment using 
an interactive voice response system/integrated web response system until 
 
 
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Document
Date of Issue
Overall Rationale
enrollment into the Arm A rrDLBCL cohort is complete. Because initially both 
Arm A and B will be enrolling subjects with rrDLBCL concurrently, the 
enrollment into treatment cohorts will be automated to eliminate investigator 
selection bias and to initiate Arm B enrollment.
MK-3475-155-02
02-FEB-2017
To add inclusion criterion #7 for cardiac function suitable for hydration 
guidance and to update inclusion criteria #1, #11, #15, #16, #20 for 
clarification.
To add exclusion criterion #17 to exclude subjects with known HIV infection, 
and exclusion criteria#20 and #24 to exclude subjects with CLL and DLBCL 
with Richter’s Transformation; and to update exclusion criterion #18 for 
clarification.
MK-3475-155-01
20-MAY-2016
To add the exclusion criterion: “Has a history of (non-infectious) pneumonitis 
that required steroids or current pneumonitis,” to clarify that patients who may 
have a history of pneumonitis are excluded from the study (when applicable).
MK-3475-155-00
11-DEC-2015
Original protocol
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
2.1
6.0
7.1.5.4
Trial Design
Trial Flow Chart
Follow-up Visits
Updated the follow-up duration 
after discontinuation to at least 
12 months and/or until the end 
of the trial.
To allow for early closure of 
the trial.
1.0
2.1
5.1.2
5.2.1.3.1
Trial Summary
Trial Design
Subject Inclusion Criteria
Premedication for Dinaciclib 
for rrCLL and rrDLBCL
Added a note to explain that the 
rrCLL cohort was closed due to 
lack of accrual.
To update status of the CLL 
arm
7.1.5.4.1
Follow-Up 
Post-Allogeneic 
Stem Cell Transplantation
Updated post-SCT follow-up to 
allow for completion of follow-
up when the trial ends.
To allow for early closure of 
the trial.
 
 
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ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
4.1.1.1
Pembrolizumab
Updated 2 reference citation 
DocIDs.
To allow proper linking at 
finalization.
4.2.3.5 
7.1.1.1.2 
12.2
Future Biomedical Research
Consent and Collection of 
Specimens for Future 
Biomedical Research
Collection and Management of 
Specimens 
for 
Future 
Biomedical Research
Removed references to Future 
Biomedical Research “sub-
trial.”
Template update
7.1.5.4
Efficacy Follow-up Visits
Updated the heading name.
Template 
update 
for 
clarification.
7.1.5.4.2
Survival Follow-up
Added new template language 
on timing of survival follow-up
Template 
update 
for 
clarification.
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
Phase Ib trial of pembrolizumab (MK-3475) in combination with 
dinaciclib (MK-7965) in subjects with hematologic malignancies 
(KEYNOTE-155)
Trial Phase
Phase Ib
Clinical Indication
Treatment of subjects with relapsed or refractory chronic lymphocytic 
leukemia, multiple myeloma (rrMM), or diffuse large B-cell 
lymphoma (rrDLBCL). 
Note: The rrMM cohort was closed to enrollment on 07-AUG-2017 
due to lack of efficacy, and all subjects with rrMM were discontinued 
from treatment.  Remaining subjects with rrMM are in survival 
follow-up.
Note: The rrCLL cohort was closed to enrollment on 30-APR-2019 
due to lack of accrual, and all subjects with rrCLL have discontinued 
from treatment.  Remaining subjects with rrCLL are in survival 
follow-up.
Trial Type
Interventional
Type of control
No treatment control
Route of administration
Intravenous (IV)
Trial Blinding
Unblinded Open-label
Treatment Groups
Combination of pembrolizumab and dinaciclib
Number of trial subjects
Approximately 102 to a maximum of 138 subjects will be enrolled.
Estimated duration of trial
The sponsor estimates that the trial will require approximately 36
months 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 for up to approximately 
26 months. Trial participation is defined as the period from the time 
the subject signs the Informed Consent Form through the final contact.  
After a screening phase of 28 days, each subject will receive
combination treatment for a maximum of 35 cycles (approximately 
2 years) or until documented disease progression by investigator 
assessment, unacceptable adverse event(s), intercurrent illness that 
prevents further administration of treatment, subject withdraws 
consent, pregnancy of the subject, noncompliance with trial treatment 
or procedure requirements, or administrative reasons.  After the end of 
treatment each subject will be followed for 30 days for a Safety 
Follow-Up Visit.  Subjects who discontinue for reasons other than 
disease progression will have post-treatment follow-up for disease 
status until disease progression, initiating a non-trial cancer treatment, 
withdrawing consent, or becoming lost to follow-up.  All subjects will 
be followed by telephone for overall survival until death, withdrawal 
of consent, or the end of the trial.
A list of abbreviations used in this document can be found in Section 12.12.
 
 
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2.0 TRIAL DESIGN
Trial Design
This is a Phase Ib non-randomized, multi-site, open-label trial of dinaciclib (MK-7965) in 
combination with pembrolizumab (MK-3475) in subjects with relapsed or refractory chronic 
lymphocytic leukemia (rrCLL), multiple myeloma (rrMM) or diffuse large B-cell lymphoma
(rrDLBCL) to be conducted in conformance with Good Clinical Practices. Subjects who 
meet the eligibility criteria will be enrolled to receive dinaciclib in combination with 
pembrolizumab.
Note: The rrMM cohort was closed to enrollment on 07-AUG-2017 due to lack of 
efficacy, and all subjects with rrMM discontinued from treatment.  Remaining subjects 
with rrMM are in survival follow-up.
Note: The rrCLL cohort was closed to enrollment on 30-APR-2019 due to lack of 
accrual, and all subjects with rrCLL have discontinued from treatment.  Remaining 
subjects with rrCLL are in survival follow-up.
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.
The trial will enroll an initial cohort of 12 subjects for Dose Evaluation.  At least 3 subjects 
each with rrCLL, rrMM, or rrDLBCL will be enrolled in this cohort.  During Dose 
Evaluation, subjects will receive dinaciclib and pembrolizumab as described in Table 2 and
Table 3.
In Cycle 1, pembrolizumab 200 mg intravenous (IV) (30-minute infusion) will be 
administered on Day 1; dinaciclib 7 mg/m2 IV (2-hr infusion) will be administered on Day 1, 
and 10 mg/m2 IV on Day 8.  Each cycle is 21 days (Q3W).  In Cycle 2 and beyond, 
pembrolizumab will be administered on Day 1, and dinaciclib 14 mg/m2 will be administered 
on Day 1 and Day 8. Disease response assessments will be performed every 3 cycles for 
rrCLL and rrDLBCL, and at the beginning of each cycle (except Cycle 1) for rrMM.
In the Dose Evaluation phase, safety data will be reviewed by the trial team.  If 4 or fewer 
subjects experience dose-limiting toxicities (DLTs) (Section 5.2.1.4) in the first 2 cycles, 
3 disease-specific expansion cohorts will be opened for Signal Detection.  If 5 or more 
subjects experience DLTs within the first 12 subjects in the first 2 cycles, a lower dose of 
dinaciclib (Table 11) will be studied in up to 24 subjects (Section 5.2.1.3.4).
In the Signal Detection phase, approximately 30 subjects each with rrCLL, rrMM, or 
rrDLBCL will be enrolled in separate cohorts. The Dose Evaluation and Signal Detection 
phases will further evaluate safety and characterize preliminary efficacy.
In the Signal Detection phase, an interim analysis for safety and an efficacy interim analysis 
for futility will be conducted for each cohort after 12 subjects have been enrolled and the last 
subject has completed the first response assessment (ie, after Cycle 3 for CLL and rrDLBCL, 
and after Cycle 2 for rrMM), or otherwise discontinued trial treatment.  Enrollment will be 
paused during the interim analysis (Section 8.7).  The results will be reviewed by the trial
 
 
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team.  Enrollment may resume in that cohort if the results of the safety and efficacy analysis
justify continuing.
Subjects will continue on treatment until disease progression (PD) (Section 7.1.2.7 and 
Section 7.1.2.8), unacceptable adverse event (AE), or treatment has been completed (ie,
35 cycles [approximately 2 years]). Subjects who discontinue treatment before PD, including 
subjects who discontinue treatment for bone marrow transplantation or to receive any other 
treatment, will be followed every 12 weeks for at least 12 months until PD is documented or 
until the end of the trial.
The primary objective of the trial is to evaluate the safety and tolerability of the combination
of pembrolizumab and dinaciclib in subjects with hematologic malignancies.  Secondary 
objectives by tumor type include the ORR, duration of response (DOR), progression-free 
survival (PFS), and overall survival (OS).  
Trial Diagram
The trial design is depicted in Figure 1.
All subjects will receive pembrolizumab and dinaciclib.
In Dose Evaluation, at least 3 subjects each with rrCLL, rrMM, or rrDLBCL will be enrolled in the initial cohort of 12. If 
there are ≥ 5 subjects with DLTs within the initial cohort of 12 subjects in Dose Evaluation, dinaciclib dosing will be 
evaluated according to Section 5.2.1.3.4 and Table 11. 
A safety analysis will be performed after the 12 subjects in the Dose Evaluation cohort have had at least 2 cycles or have 
discontinued treatment or died due to study drug(s)-related toxicity.
Figure 1
Trial Design
 
 
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3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
1) Objective: In both the Dose Evaluation and Signal Detection phases, evaluate the 
safety and tolerability of dinaciclib in combination with pembrolizumab
Secondary Objective(s) & Hypothesis(es)
1) Objective:  Within each disease type of the Signal Detection phase, evaluate ORR 
according to investigator assessment using the disease-specific criteria (Section 
7.1.2.7)
2) Objective:  To evaluate the ORR (complete remission [CR] + partial response [PR]) 
of the combination of pembrolizumab and dinaciclib within each disease type, ie,
CLL based on International Workshop on Chronic Lymphocytic Leukemia (iwCLL)
guidelines [1], MM based on International Myeloma Working Group (IMWG) 
criteria for response assessment in multiple myeloma [2], and DLBCL based on the 
Revised Response Criteria for Malignant Lymphoma [3]
3) Objective: Within each disease type of the Signal Detection phase, evaluate DOR
and PFS according to investigator assessment using the disease-specific criteria 
(Section 7.1.2.7); and OS
Other Objectives
1) Objective: To examine treatment effect on cluster of differentiation (CD)4, CD8, and 
quantitative immunoglobulins in subjects with rrCLL
2) Objective: To determine if known prognostic markers in rrCLL (immunoglobulin 
heavy chain [IgVH], CD38, and Beta-2 microglobulin) predict for response to 
treatment  
3) Objective: To estimate dinaciclib exposure following a 2-hour IV infusion in the 
subject population
4) Objective:  To compare the extent of pre-pembrolizumab programmed cell death
ligand-1 (PD-L1) expression in tumor biopsies for pembrolizumab responders versus 
non-responders
5) Objective:  To investigate the relationship between candidate efficacy biomarkers 
and antitumor activity of the treatments administered using pre- and post-treatment 
samples and local testing results
6) Objective: To explore the relationship between genomic variation and response to 
the treatment(s) administered. Variation across the human genome (germline and 
tumor) will be analyzed for association with clinical data collected in this trial
 
 
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4.0 BACKGROUND & RATIONALE
Background
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the programmed cell death-1 (PD-1) receptor, thus 
inhibiting its interaction with PD-L1 and programmed cell death ligand 2 (PD-L2).  Based on 
preclinical in vitro data, pembrolizumab has high affinity and potent receptor blocking 
activity for PD-1.  Pembrolizumab has an acceptable preclinical safety profile and is in 
clinical development as an IV immunotherapy for advanced malignancies. Keytruda® 
(pembrolizumab) is indicated for the treatment of subjects across a number of indications.  
For more details on specific indications, refer to the Investigator’s Brochure (IB).  In this 
trial, pembrolizumab combination therapies will be tested for safety and preliminary efficacy 
in B-cell malignancies, with the intent of identifying combination that may broaden initial 
responses to treatment or re-sensitize treatment-resistant cancers.
Pharmaceutical and Therapeutic Background
Pembrolizumab
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [4].  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis in various 
malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector T-
cells/FoxP3+ regulatory T cells (Tregs) correlates with improved prognosis and long-term 
survival in many solid malignancies, such as ovarian, colorectal, and pancreatic cancer; 
hepatocellular carcinoma; malignant melanoma; and renal cell carcinoma. Tumor-infiltrating 
lymphocytes can be expanded ex vivo and reinfused, inducing durable objective tumor 
responses in cancers such as melanoma [5] [6].
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated T 
cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an 
immunoglobulin (Ig) superfamily member related to CD28 and cytotoxic T-lymphocyte-
associated antigen-4 (CTLA-4) that has been shown to negatively regulate antigen receptor 
signaling upon engagement of its ligands (PD-L1 and/or PD-L2) [7] [8].  
The structure of murine PD-1 has been resolved [9].  PD-1 and family members are type I 
transmembrane glycoproteins containing an Ig Variable-type domain responsible for ligand 
binding and a cytoplasmic tail that is responsible for the binding of signaling molecules.  The 
cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif and an immunoreceptor tyrosine-based switch motif (ITSM).  
Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to 
ITSM within its cytoplasmic tail, leading to the dephosphorylation of effector molecules such 
as CD3 zeta (CD3ζ), protein kinase C-theta, and zeta-chain-associated protein kinase, which 
are involved in the CD3 T-cell signaling cascade [8] [10] [11] [12].  The mechanism by 
which PD 1 down modulates T-cell responses is similar to, but distinct from that of CTLA-4 
as both molecules regulate an overlapping set of signaling proteins [13] [14].  
 
 
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As a consequence, the PD-1/PD-L1 pathway is an attractive target for therapeutic 
intervention in heme malgnancies.
Dinaciclib
Dinaciclib (MK-7965) is a novel, potent, small-molecule inhibitor of cyclin-dependent 
kinases (CDKs), which is being developed for the treatment of human malignancies.  The 
aqueous solubility of dinaciclib drug substance is pH dependent, ranging from over 
10 mg/mL at pH 3.5 to approximately 1 mg/mL at pH 7 or higher.
The mammalian cell cycle is a non-redundant process that integrates extracellular signaling, 
DNA synthesis, and mitosis [15] [16].  The CDKs are a family of serine/threonine kinases 
that function as critical regulators of the mammalian cell cycle [15] [17].  As their name 
suggests, CDKs are allosterically activated following association with a cyclin partner.  
CDK1 and CDK2 are closely related (90% identical) members of this family that play
overlapping and essential roles during cell division [15] [17].  Aberrant regulation of CDK1 
and CDK2 in cancer cells occurs through a variety of well-documented genetic mechanisms, 
including cyclin amplification and mutation of specific CDK inhibitor proteins [18] [19] [20]
[21] [22].
Coordinated CDK2/CDK1 activity is required for appropriate regulation of S phase entry 
(DNA synthesis), suppression of apoptosis in late S phase, S phase exit, and entry into 
mitosis [15] [17].  Inhibition of CDK2/CDK1 in tumors is predicted to provoke cell-cycle 
arrest and apoptosis [23].  The lack of appropriate cell-cycle regulation in tumor cells 
predicts an increased tendency towards apoptosis in tumor cells, compared to normal tissue 
[23].  Hence, inhibition of the essential, rate-limiting activities of CDK2 and CDK1 
represents an attractive therapeutic strategy for oncology indications.
CDK inhibitors that have entered clinical trials include flavopiridol and UCN 01.  The 
development of both of these drugs has been complicated by significant binding to human 
serum proteins, which results in extremely long elimination half-lives (253 to 1660 hours for 
UCN 01) [24] and low free levels of drug leading to a lack of activity in early trials 
(flavopiridol) [25].  In contrast, in vitro discovery studies show that dinaciclib is 
approximately 87% protein bound in human plasma.
Pre-clinical and Clinical Trials
Refer to the current IBs for pembrolizumab and dinaciclib for information on pre-clinical and 
clinical trials.
Pembrolizumab
Ongoing clinical trials with pembrolizumab are being conducted in a wide variety of solid 
tumors and hematologic malignancies.  Pembrolizumab has been administered to more than 
9600 subjects in clinical trials.    For trial details, refer to the pembrolizumab IB.
Preliminary results from an ongoing trial from cohorts of subjects with relapsed/refractory 
hematologic malignancies (Hodgkin lymphoma, primary mediastinal large B-cell lymphoma,
non-Hodgkin lymphoma) treated with pembrolizumab demonstrated high response rates and 
meaningful durations of response [26] [27] [28] (data on file, Merck Inc.).
 
 
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On 03-JUL-2017, the Food and Drug Administration (FDA) placed a clinical hold based on 
safety data in multiple myeloma trials involving the pembrolizumab plus IMiD combination
(pomalidomide, lenalidomide, or thalidomide).  The FDA determined that the risks of 
pembrolizumab plus pomalidomide or lenalidomide outweighed any potential benefit for 
subjects with MM.  In those trials, the treatment phase was closed and subjects moved into 
the long-term safety and survival follow-up.  Separate from this, on 07-AUG-2017, the rrMM
cohort of this trial was stopped due solely to lack of efficacy.  No safety concerns were seen. 
Subjects in this cohort were discontinued from treatment and moved to long-term follow-up.
Dinaciclib
Dinaciclib has been administered to more than 363 subjects enrolled in Phase 1 and Phase 2 
clinical trials, using various doses and schedules, in various solid tumors and hematologic 
malignancies.  
Preliminary results from dose-finding Phase 1 and Phase 2 trials of dinaciclib in subjects with 
various malignancies, including with relapsed/refractory CLL, MM, and lymphoma,
demonstrated various rates of responses [29] [30] (data on file, Merck Inc.).  For trial details,
refer to the dinaciclib IB.
Pembrolizumab in Combination with Dinaciclib
Enhanced antitumor activity was observed with the combination of pembrolizumab and 
dinaciclib in a preclinical trial using a solid tumor syngeneic model (MC38).  There were no 
significant safety findings with the combination (data on file, Merck Inc.).
Rationale
Rationale for the Trial and Selected Subject Population
This trial of the combination of pembrolizumab and dinaciclib, will be conducted in subjects 
with relapsed or refractory CLL, MM, or DLBCL.  As defined by the eligibility criteria, each 
setting is an unmet medical need.  Note: The rrMM cohort was closed to enrollment on 07-
AUG-2017 due to lack of efficacy, and all subjects discontinued from treatment.  Remaining 
subjects with rrMM are in survival follow-up.
Preclinical and clinical data for each of pembrolizumab and dinaciclib as monotherapies (or 
combined with other chemotherapeutics) have demonstrated antitumor activity in various 
tumor types, including hematologic malignancies.  
This trial will evaluate the safety and tolerability of the combination of pembrolizumab and 
dinaciclib in subjects with relapsed or refractory CLL, MM, or DLBCL, as well as evaluate 
the efficacy of the combination.  
Rationale for Dose Selection/Regimen
Pembrolizumab
The planned dose of pembrolizumab for this trial is 200 mg Q3W. Based on the totality of 
data generated in the Keytruda® development program, 200 mg Q3W is the appropriate dose 
 
 
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of pembrolizumab across all indications, regardless of tumor type. As outlined below, this 
dose is justified by: 

Clinical data from 8 randomized studies demonstrating flat dose- and exposure-
efficacy relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W)

Clinical data showing meaningful improvement in benefit-risk, including overall 
survival at 200 mg Q3W across multiple indications

Pharmacology data showing full target saturation in both systemic circulation 
(inferred from pharmacokinetic [PK] data) and tumor (inferred from physiologically
based pharmacokinetic [PBPK] analysis) at 200 mg Q3W
Among the 8 randomized dose-comparison studies, a total of 2262 subjects were enrolled 
with melanoma and non-small cell lung cancer, covering different disease settings 
(treatment-naïve, previously treated, PD-L1 enriched and all-comers) and different treatment 
settings (monotherapy and in combination with chemotherapy). Five studies compared 
2 mg/kg Q3W versus 10 mg/kg Q2W (KN001 B2, KN001 D, KN002, KN010 and KN021), 
and 3 studies compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 B3, KN001 F2 and 
KN006). All of these studies demonstrated flat dose- and exposure-response relationships 
across the doses studied, representing an approximate 5- to 7.5-fold difference in exposure. 
The 2 mg/kg (or 200 mg fixed-dose) Q3W provided similar responses to the highest doses 
studied. Subsequently, flat dose-/exposure-response relationships were also observed in other 
tumor types including head and neck cancer, bladder cancer, gastric cancer and classical 
Hodgkin lymphoma, confirming 200 mg Q3W as the appropriate dose, independent of the 
tumor type. These findings are consistent with the mechanism of action of pembrolizumab, 
which acts by interaction with immune cells, and not via direct binding to cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK 
data in KN001 evaluating target-mediated drug disposition conclusively demonstrated 
saturation of PD-1 in systemic circulation at doses much lower than 200 mg Q3W. Secondly, 
a PBPK analysis was conducted to predict tumor PD-1 saturation over a wide range of tumor 
penetration and PD-1 expression. This evaluation concluded that pembrolizumab at 200 mg 
Q3W achieves full PD-1 saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other subject covariates on exposure, has shown that the fixed-dosing 
provides similar control of PK variability as weight-based dosing, with considerable overlap 
in the distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. 
Supported by these PK characteristics, and given that fixed-dose has advantages of reduced 
dosing complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was 
selected for evaluation across all pembrolizumab protocols.
Dinaciclib
Dinaciclib was rapidly eliminated from plasma; mean terminal phase half-life values ranged 
from 2 to 3 hours.  There was a dose-related increase in exposure with doses from 0.33 to 
58 mg/m2.  Dinaciclib did not accumulate in plasma upon weekly or Q3W multiple dosing. 
Coadministration of dinaciclib with aprepitant, an antiemetic agent, did not affect the 
pharmacokinetics of dinaciclib.
 
 
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Phase 1 dose-escalation trials investigating two different IV dosing schedules of dinaciclib 
have determined the maximum administered dose and the RPTD for each schedule.  Safety 
and PK data from these trials support the doses selected for further evaluation of dinaciclib.  
In the first Phase 1 trial (PN001), dinaciclib was administered as a 2-hour IV infusion on 
Days 1, 8, and 15 of a 28-day cycle to subjects with advanced malignancy refractory to 
conventional treatment.  In subjects with solid tumors, a maximum administered dose of 
14 mg/m2 was reached in the PN001 trial, with an RPTD of 12 mg/m2.  The trial included an 
expansion cohort, at the RPTD of 12 mg/m2, exploring safety and tolerability in subjects with 
MM or NHL.  In Arm B of the PN001 trial, dose exploration to minimize the incidence of 
tumor lysis syndrome (TLS) in subjects with CLL revealed an RPTD of 7>10>14 mg/m2
(Days 1, 8, and 15, respectively) in Cycle 1 and 14 mg/m2 in Cycle 2 and thereafter (28-day 
cycles).  
A Phase 1 trial examining dinaciclib administered as a 2-hour IV infusion given Q3W in a 
similar subject population (PN002) has determined an RPTD of 50 mg/m2.  In the acute 
leukemia trial (PN005), a planned safety analysis of intrasubject dose escalation from 
dinaciclib at 50 mg/m2 to 70 mg/m2, starting in Cycle 2, concluded that the 70 mg/m2 dose is 
safe.
Rationale for Endpoints
Efficacy Endpoints
The primary efficacy objective for both arms of this trial is to evaluate the antitumor activity 
of pembrolizumab in combination with dinaciclib in subjects with rrCLL, rrMM, or 
rrDLBCL.  The primary efficacy endpoint will be ORR as assessed by the investigator, 
according to tumor-specific response criteria.  Objective response rate is an acceptable 
measure of clinical benefit to demonstrate a new antineoplastic combination therapy.  
Other secondary efficacy endpoints will include DOR, PFS, and OS.  These endpoints are 
commonly accepted endpoints by both regulatory authorities and the oncology community.
Safety Endpoints
The safety and tolerability of pembrolizumab in combination with dinaciclib in subjects with 
rrCLL, rrMM, or rrDLBCL will be characterized in this trial.  The safety analysis will be 
based on subjects who experienced toxicities as defined by Common Toxicity Criteria for 
Adverse Events (CTCAE).  Safety will be assessed by quantifying the toxicities and grades 
experienced by subjects who have received pembrolizumab in combination with dinaciclib, 
including serious adverse events (SAEs) and events of clinical interest (ECIs).
Safety will be assessed by reported AEs using CTCAE, Version 4.0.  The attribution to drug, 
time-of-onset, duration of the event, its resolution, and any concomitant medications 
administered will be recorded.  AEs will be analyzed including but not limited to all AEs, 
SAEs, fatal AEs, and laboratory changes.  
 
 
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Pharmacokinetic Endpoints
The PK endpoints of this trial are to define:

the plasma concentration profile and estimate dinaciclib exposure following a 2-hour 
IV infusion, and 

the 
plasma 
concentration 
profile 
of 
pembrolizumab
exposure 
following 
administration of combination therapy.  
Plasma concentrations of dinaciclib and pembrolizumab will be determined using validated 
high performance liquid chromatography-tandem mass spectrometry methods.  
Plasma drug concentration versus time data collected for PK purposes will be analyzed. 
Additionally, correlations between the model-estimated drug exposure and other subject
characteristics, such as concomitant medication, available AEs, or pharmacodynamic data,
may be explored.
Planned Exploratory Biomarker Research
Biomarker research to identify factors important for pembrolizumab therapy may be pursued.  
For example, pre- and post-dose bone marrow biopsies, lymph node biopsies, and blood 
samples from this trial
may undergo flow cytometric, proteomic, genomic, and 
transcriptional analyses at a central laboratory.  Lymph node biopsies, bone marrow 
aspirates, saliva, and/or blood samples will be evaluated using DNA sequencing.  Using both 
pre- and post-treatment tumor biopsies and/or blood samples (serum or plasma), change in 
baseline of candidate biomarkers may also be assessed using Nanostring/ RNAseq for gene 
expression.
Additional research may evaluate factors important for predicting responsiveness or 
resistance to pembrolizumab or dinaciclib therapy and other immunologic targets.  In 
addition, biomarker assay characterization may be performed to evaluate factors important 
for the identification of biomarkers.
Assays may include but are not be limited to:
Multiplex Flow Cytometric Analysis
Emerging data suggest that blockade of the PD-1/PD-L1 pathway results in enhanced T-cell 
mediated immune response.  To test the hypothesis that T-cell activation mediated by 
pembrolizumab treatment correlates with clinical response, total T-cell count and T-cell 
subsets in peripheral blood, eg, naïve, activated, memory, and regulatory T cells, will be 
assessed pre- and post-dose and in both responders and non-responders.  Natural killer cells 
enumeration will also be performed pre-
and post-dose in both responders and 
non-responders.
 
 
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Transcriptional Analyses
mRNA expression profiling in archival material, lymph node samples, and blood samples 
will be completed to assess gene expression and to attempt to define a gene set critical for 
clinical response to pembrolizumab.  The hypothesis to be tested is that pembrolizumab 
responders will exhibit a “stalled Cytotoxic T Lymphocyte” response within the tumor 
reflected in the physical proximity between PD-1 and PD-L1 expression and the presence of 
an aborted (eg, weak but discernible) interferon-gamma transcriptional program will be 
detectable by profiling analyses.  Global profiling will also be pursued.
Expression of individual genes related to the immune system may also be evaluated such as 
immune signatures and critical cytokines (eg, interleukin-10).
Gene Sequencing
New data are emerging that suggest we can define certain tumor types as having high 
mutational burden.  There is a potential that this hypermutated state may correlate with 
response to pembrolizumab therapy, and/or that the converse, ‘hypomutated’ state may 
correlate with non-response.
Genome-wide whole exome sequencing may be performed from archival material, lymph 
node samples, and blood samples to assess genomic events such as but not limited to 
mutational burden as well as to evaluate fusion and amplification events such as 9p24.1 
amplification.
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 AEs, the data might inform optimal use of therapies in the 
subject population. This research contributes to understanding genetic determinants of 
efficacy and safety associated with the treatments in this trial.
Anti-Pembrolizumab Antibodies
Formation of antidrug antibodies (ADAs) can potentially confound drug exposures at 
therapeutic doses, and prime for subsequent infusion-related toxicities. Incidence of ADAs 
and neutralizing ADAs will be evaluated. Correlations between the presence/absence in 
subjects of ADAs with PK and pharmacodynamic markers, activity, and safety of 
pembrolizumab may be explored.
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 
 
 
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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 Future Biomedical Research are presented in Section 12.2 - Collection and Management 
of Specimens for Future Biomedical Research.  Additional informational material for 
institutional review boards/ethics committees (IRBs/ERCs) and investigational site staff is 
provided in Section 12.3.
Benefit/Risk
Subjects in clinical trials generally cannot expect to receive direct benefit from treatment 
during participation, as clinical trials are designed to provide information about the safety 
and effectiveness of an investigational medicine.
Preclinical and clinical data for pembrolizumab and dinaciclib have demonstrated antitumor 
activity in various tumor types, including hematologic malignancies.  Enhanced antitumor 
activity was observed with the combination of pembrolizumab and dinaciclib in preclinical 
studies using a solid tumor syngeneic model (MC38).  There were no significant safety 
findings with the combination.  Based on the available preclinical and clinical information, 
the benefit/risk of the pembrolizumab plus dinaciclib combination appears reasonable to 
evaluate in a Phase Ib clinical trial. 
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying IBs and informed consent documents.
5.0 METHODOLOGY
Entry Criteria
Diagnosis/Condition for Entry into the Trial
Male/Female subjects who are at least 18 years of age on the day of signing informed consent 
with histologically confirmed diagnosis of rrCLL, rrMM, or rrDLBCL will be enrolled in this 
trial.
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
All Subjects:
1. Be willing and able to provide written informed consent/assent for the trial.  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. Be ≥ 18 years of age on day of signing informed consent.
3. Female subjects of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of trial medication.  If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be 
required.
 
 
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4. Female subjects of childbearing potential must be willing to use an adequate method of 
contraception as outlined in Section 5.7.2 - Contraception, for the course of the trial
through 120 days after the last dose of trial medication.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject.
5. Male subjects of childbearing potential must agree to use an adequate method of 
contraception as outlined in Section 5.7.2 - Contraception, starting with the first dose of 
trial therapy through 120 days after the last dose of trial therapy.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject.
6. Must have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group 
(ECOG) Performance Scale.
7. Cardiac function suitable for hydration guidelines outlined in Table 6 and Table 7 per 
investigator and/or cardiologist.
8. Be able to provide newly obtained (within 3 months) bone marrow biopsy material for 
biomarker analysis. If bone marrow biopsy was performed within 3 months before 
screening but subject had anticancer treatment after biopsy, the bone marrow biopsy and 
aspiration should be repeated.
 
 
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9. Must demonstrate adequate organ function as defined below (Table 1):
Table 1
Subject Inclusion Criteria - Adequate Organ Function
System
Laboratory Value
Hematological
ANC
> 1,500/µL (unless due to marrow involvement)
Plateletsa
≥ 100,000/µL (≥30,000/µL for CLL)
Hemoglobina
≥8.0 g/dL or ≥1.24 mmol/La
Renal
Creatinine OR
Measured or calculatedb creatinine clearance
(GFR can also be used in place of creatinine or 
creatinine clearance) 
≤ 1.5 X ULN OR
≥ 60.0 mL/min for subject with creatinine levels > 1.5 
X institutional ULN
Hepatic
Total bilirubin
≤ 1.5 X ULN OR
Direct bilirubin ≤ ULN for subjects with total bilirubin 
levels > 1.5 ULN
AST and ALT
≤ 2.5 X ULN OR
≤ 5 X ULN for subjects with liver metastases
Coagulation
INR or
PT
aPTT
≤ 1.5 X ULN unless subject is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants
Abbreviations:  ALT (SGPT) = alanine aminotransferase (serum glutamic pyruvic transaminase); 
ANC = absolute neutrophil count; aPTT = activated partial thromboplastin time; AST (SGOT) = aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); CLL = chronic lymphocytic leukemia; 
GFR=glomerular filtration rate; INR = international normalized ratio; PT = prothrombin time; PTT = partial 
thromboplastin time; ULN=upper limit of normal.
a Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) 
transfusion within last 2 weeks.
b Creatinine clearance should be calculated per institutional standard.
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines for the administration of 
specific chemotherapies.
CLL –Note: The rrCLL cohort was closed to enrollment on 30-APR-2019 due to lack of 
accrual, and all subjects with rrCLL have discontinued from treatment.  Remaining 
subjects with rrCLL are in survival follow-up.
10. Confirmed diagnosis of CLL as defined by 2008 iwCLL criteria.
11. Subjects must have received at least one prior therapy.
12. Must meet one or more of the following consensus criteria for initiating treatment:

Progressive disease or marked splenomegaly and/or lymphadenopathy,

Anemia (hemoglobin < 11 g/dL) or thrombocytopenia (platelets < 100,000/mm3),

Unexplained weight loss ≥ 10% of body weight over preceding 6 months

National Cancer Institute CTCAE Grade 2 or 3 fatigue,
 
 
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
Fevers >100°F/38°C or night sweats for greater than 2 weeks without evidence of 
infection,

Progressive lymphocytosis, with an increase > 50% over a 2-month period or a 
doubling time < 6 months.
MM - Note: The rrMM cohort was closed to enrollment on 07-AUG-2017 due to lack of 
efficacy, and all subjects discontinued from treatment.  
13. Has a confirmed diagnosis of active MM and measurable disease defined as:

Serum monoclonal protein (M-protein) levels ≥ 0.5 g/dL or

Urine monoclonal protein (M-protein) levels ≥200 mg/24-hrs or

For subjects without measurable serum and urine M-protein levels, an abnormal 
serum free light chain ratio (FLC k/l) with involved FLC level ≥100 mg/L.  (Normal 
serum FLC k/l value: 0.26-1.65).
14. Must have undergone prior treatment with ≥ 2 treatment lines of anti-myeloma therapy 
and must have failed their last line of treatment defined as documented disease 
progression during or within 60 days of completing their last anti-myeloma therapy 
(refractory to last line of treatment)
15. Prior anti-myeloma treatments must have included an IMiD (pomalidomide, 
lenalidomide, or thalidomide) AND proteasome inhibitor (bortezomib, carfilzomib, or 
ixazomib) alone or in combination and subject must have failed therapy with an IMiD 
OR proteasome inhibitor defined as one of the following:

Refractory: Documented progressive disease on or within 60 days of completing 
treatment with an IMiD and/or proteasome inhibitor OR

Relapsed and refractory: In case of prior response (≥PR) to an IMiD or proteasome 
inhibitor, subjects must have relapsed within 6 months after stopping treatment with 
an IMiD and/or proteasome inhibitor-containing regimens.
DLBCL
16. Has a histologically confirmed diagnosis of DLBCL.
17. Subjects must have progressed following at least 2 lines of previous therapy, including 
progression after an autologous stem cell transplant (SCT), or are not a candidate (per
institutional criteria) for an autologous stem cell transplant. Subjects who are ineligible 
for standard treatment or who have withdrawn from standard treatment due to 
unacceptable toxicity warranting discontinuation of that treatment and precluding 
retreatment with the same agent before progression of disease will also be eligible.
18. Have measurable disease, defined as at least one lesion that can be accurately measured 
in at least 2 dimensions with spiral computed tomography (CT) scan.  Minimum 
measurement must be > 15 mm in the longest diameter or > 10 mm in the short axis.
19. Be able to provide newly obtained (within 3 months) core or excisional biopsy from 
lymph node or extranodal location for biomarker analysis.  If bone marrow biopsy was 
performed 3 months before screening but subject had anti-cancer treatment after biopsy, 
the bone marrow biopsy and aspiration should be repeated.
 
 
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Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
All Subjects:
1. Is currently participating and receiving trial therapy or has participated in a trial of an 
investigational agent and received trial therapy or used an investigational device within 
28 days before trial Day 1.
2. Treatment with a cytochrome P450 3A4 (CYP3A4) strong inhibitor or inducer within 7 
days
prior to enrollment.  See Section 12.6 for information about strong 
inhibitors/inducers of CYP3A4.
3. Treatment with anticancer therapy or thoracic radiation therapy within 14 days before the 
first dose of treatment. 
Exception:  Subjects with CLL may receive ibrutinib (or similar for CLL) up to 
7 days before trial Day 1. 
4. Has known clinically active central nervous system involvement.
5. Has a known history of immunosuppression or is receiving systemic steroid therapy or 
any other form of systemic immunosuppressive therapy within 7 days prior to the first 
dose of trial treatment.  

The use of physiologic doses of corticosteroids may be approved after consultation 
with the Sponsor.
6. Has had a prior anticancer monoclonal antibody within 4 weeks prior to trial Day 1 or 
who has not recovered (ie, ≤ Grade 1 or at baseline) from AEs due to agents administered 
more than 4 weeks earlier.
7. Grade 2 or higher nonhematological toxicities from prior therapy.  Residual toxicity of 
Grade 1 from prior therapy or persistent treatment-related Grade 1 neurotoxicity will be 
allowed.
Note:  If subject received major surgery, they must have recovered adequately from the 
toxicity and/or complications from the intervention prior to starting therapy.
Note: Toxicity that has not recovered to ≤ Grade 1 is allowed if it meets the inclusion 
requirements for laboratory parameters defined for each tumor type.
8. Has undergone prior allogeneic hematopoetic stem cell transplantation within the last 
5 years. (Subjects who have had a transplant greater than 5 years ago are eligible as long 
as there are no symptoms of Graft versus Host Disease.)
9. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, 
or in situ cervical cancer that has undergone potentially curative therapy.
10. Has active autoimmune disease that has required systemic treatment in past 2 years (ie,
with use of disease modifying agents, corticosteroids or immunosuppressive drugs).  
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement 
 
 
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therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment and is allowed.
11. Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis.
12. Has an active infection requiring intravenous systemic therapy.
13. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial.
14. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit through 
120 days after the last dose of trial treatment.
15. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 anti-CD137, or 
anti-CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically 
targeting T-cell co-stimulation or checkpoint pathways) or CAR-T cell therapy or with an 
agent directed to another stimulatory or co-inhibitory T-cell receptor.
16. Previously treated with a CDK inhibitor (eg, dinaciclib or flavopiridol).
17. Has a known history of human immunodeficiency virus (HIV) infection.  No HIV testing 
is required unless mandated by local health authority.
18. Has a known history of or is positive for hepatitis B (hepatitis B surface antigen [HBsAg] 
reactive) or hepatitis C (hepatitis C virus [HCV] RNA [qualitative] is detected).  
19. Has received a live vaccine within 30 days prior to first dose.
20. Has known current symptomatic congestive heart failure, unstable angina pectoris, or 
cardiac arrhythmia.
CLL
21. Subject with Richter's Transformation.
MM
22. Subjects with non-secretory or oligo-secretory myeloma, plasma cell leukemia, or 
Waldenström's macroglobulinemia.
23. History of primary amyloidosis, hyperviscosity or POEMS syndrome (plasma cell 
dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and 
skin changes).
DLBCL
24. Subjects with primary mediastinal B-cell lymphoma.
25. Subject with Richter's Transformation.
 
 
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Trial Treatment(s)
The treatments to be used in this trial are outlined below in Table 2.
Table 2
Trial Treatments
Drug 
Dose/ 
Potency
Dose 
Frequency
Route of 
Administration
Treatment Period
Use
Pembrolizumab 
(MK-3475)
200 mg
Every 21 
days
IV infusion
Until PD, or up to a 
maximum of 35 cycles
(approximately 
2 
years)
Investigational
Dinaciclib 
(MK-7965)
14 
mg/m2
(Cycle 
1 
dosing 
per 
Table 3)
Table 3
IV infusion
Until PD, or up to a 
maximum of 35 cycles
(approximately 
2 
years)
Investigational
Abbreviations:  IV = intravenous; PD = progressive disease.
Subjects will receive pembrolizumab and dinaciclib as described in Table 3.  In Cycle 1, 
pembrolizumab 200 mg IV (30-minute infusion) will be administered on Day 1; dinaciclib 
7 mg/m2 IV (2-hour infusion) will be administered on Day 1, and 10 mg/m2 IV on Day 8.  
Each cycle is 21 days.  In Cycle 2 and beyond, pembrolizumab will be administered on 
Day 1, and dinaciclib 14 mg/m2 will be administered on Day 1 and Day 8.
Table 3
Dosing Schedule of Pembrolizumab and Dinaciclib
Cycle
Day
Pembrolizumab
Dinaciclib
Cycle 1
1
200 mg
7 mg/m2
8
-
10 mg/m2
15
-
-
Cycle 2+
1
200 mg
14 mg/m2
8
-
14 mg/m2
15
-
-
If there are ≥ 5 subjects with DLTs within the initial cohort of 12 subjects in Dose 
Evaluation, dinaciclib dosing will be evaluated according to Section 5.2.1.3.4 and Table 13.
Trial treatment should begin on the day of treatment allocation or as close as possible to the 
date on which the subject is allocated/assigned.  Treatment allocation by non-random 
assignment will be done using an IVRS/IWRS.  
Dinaciclib and pembrolizumab will be provided centrally by the Sponsor or locally by the 
trial site, subsidiary or designee, depending on local country operational or regulatory 
requirements.
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.
 
 
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Dose Selection/Modification
Dose Selection (Preparation)
The rationale for selection of doses to be used in this trial is provided in Section 4.0 
Background and Rationale.
Pembrolizumab should be administered before dinaciclib.  If one trial drug is held, the other 
trial drug should also be held. Details on the preparation and administration of trial 
treatments are provided in the Pharmacy Manual.
The investigator may attribute each toxicity event to dinaciclib alone, or pembrolizumab 
alone, or to the combination and
use dose modification according to
Table 4
(pembrolizumab), Table 8 (dinaciclib), and Table 9 (dinaciclib).  If a subject experiences 
toxicities that are attributed to combination regimen as a whole and there are conflicting 
recommendations for the individual agents, follow the most conservative dose adjustment 
recommended (dose reduction appropriate to the most severe toxicity) or consult with the 
Sponsor.
Pembrolizumab
Pembrolizumab 200 mg will be administered as a 30-minute IV infusion Q3W on Day 1 of 
each cycle.  Sites should make every effort to target infusion timing to be as close to 
30 minutes as possible.  However, given the variability of infusion pumps from site to site, a 
window of -5 minutes and +10 minutes is permitted (ie, infusion time is 
30 minutes: -5 min/+10 min).
5.2.1.2.1 Pembrolizumab Dose Modification
Dose Modification and Toxicity Management for Immune-Related Adverse Events 
Associated with Pembrolizumab
Adverse events associated with pembrolizumab exposure may represent an immunologic 
etiology. These immune-related AEs (irAEs) may occur shortly after the first dose or several 
months after the last dose of pembrolizumab treatment and may affect more than on body 
system simultaneously. Therefore, early recognition and initiation of treatment is critical to 
reduce complications.  Based on existing clinical trial data, most irAEs were reversible and 
could be managed with interruptions of pembrolizumab, administration of corticosteroids 
and/or other supportive care. For suspected irAEs, ensure adequate evaluation to confirm 
etiology or exclude other causes. Additional procedures or tests such as bronchoscopy, 
endoscopy, skin biopsy may be included as part of the evaluation. Based on the severity of 
irAEs, withhold or permanently discontinue pembrolizumab and administer corticosteroids. 
Dose modification and toxicity management guidelines for irAEs associated with 
pembrolizumab are provided in Table 4.
 
 
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Table 4
Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Events Associated with 
Pembrolizumab
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment 
should be initiated if irAEs cannot be controlled by corticosteroids.
Immune-
Related AEs
Toxicity 
Grade 
or 
Conditions 
(CTCAEv4.0)
Action Taken to 
Pembrolizumab
irAE 
Management 
with 
Corticosteroid 
and/or 
Other 
Therapies 
Monitor and Follow-up 
Pneumonitis 
Grade 2
Withhold 

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor 
participants 
for 
signs 
and 
symptoms of pneumonitis

Evaluate 
participants 
with 
suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment

Add 
prophylactic 
antibiotics 
for 
opportunistic infections
Grade 3 or 4, or 
recurrent Grade 2
Permanently 
discontinue
Diarrhea / Colitis 
Grade 2 or 3
Withhold

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor participants for signs and symptoms 
of enterocolitis (ie, diarrhea, abdominal 
pain, blood or mucus in stool with or 
without fever) and of bowel perforation 
(ie, peritoneal signs and ileus).
 
 
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Immune-
Related AEs
Toxicity 
Grade 
or 
Conditions 
(CTCAEv4.0)
Action Taken to 
Pembrolizumab
irAE 
Management 
with 
Corticosteroid 
and/or 
Other 
Therapies 
Monitor and Follow-up 
Grade 4
Permanently 
discontinue

Participants with ≥ Grade 2 diarrhea 
suspecting 
colitis 
should 
consider 
GI 
consultation and performing endoscopy to 
rule out colitis. 

Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion.
AST 
/ 
ALT 
elevation 
or 
Increased 
bilirubin
Grade 2
Withhold

Administer corticosteroids (initial 
dose of 0.5-1 mg/kg prednisone or 
equivalent) followed by taper

Monitor with liver function tests (consider 
weekly or more frequently until liver 
enzyme value returned to baseline or is 
stable
Grade 3 or 4 
Permanently 
discontinue

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper
T1DM 
or 
Hyperglycemia
Newly 
onset 
T1DM or 
Grade 
3 
or 
4 
hyperglycemia 
associated 
with 
evidence of -cell 
failure
Withhold

Initiate 
insulin 
replacement 
therapy 
for 
participants 
with 
T1DM 

Administer anti-hyperglycemic in 
participants with hyperglycemia 

Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes.
Hypophysitis
Grade 2
Withhold

Administer 
corticosteroids 
and 
initiate hormonal replacements as 
clinically indicated.  

Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)
Grade 3 or 4 
Withhold 
or 
permanently 
discontinue1
 
 
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Immune-
Related AEs
Toxicity 
Grade 
or 
Conditions 
(CTCAEv4.0)
Action Taken to 
Pembrolizumab
irAE 
Management 
with 
Corticosteroid 
and/or 
Other 
Therapies 
Monitor and Follow-up 
Hyperthyroidism 
Grade 2
Continue 

Treat with non-selective beta-
blockers 
(eg, 
propranolol) 
or 
thionamides as appropriate 

Monitor for signs and symptoms of thyroid 
disorders. 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Hypothyroidism
Grade 2-4
Continue 

Initiate 
thyroid 
replacement 
hormones (eg, levothyroxine or 
liothyronine) per standard of care

Monitor for signs and symptoms of thyroid 
disorders. 
Nephritis 
and 
Renal 
dysfunction
Grade 2
Withhold 

Administer 
corticosteroids 
(prednisone 
1-2 
mg/kg 
or 
equivalent) followed by taper.

Monitor changes of renal function
Grade 3 or 4 
Permanently 
discontinue
Myocarditis
Grade 1 or 2
Withhold

Based 
on 
severity 
of 
AE 
administer corticosteroids

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3 or 4
Permanently 
discontinue
 
 
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Immune-
Related AEs
Toxicity 
Grade 
or 
Conditions 
(CTCAEv4.0)
Action Taken to 
Pembrolizumab
irAE 
Management 
with 
Corticosteroid 
and/or 
Other 
Therapies 
Monitor and Follow-up 
All 
other 
immune-related 
AEs
Intolerable/ 
persistent Grade 2
Withhold

Based on type and severity of AE 
administer corticosteroids 

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3
Withhold 
or 
discontinue based 
on the type of 
event.  Events that 
require 
discontinuation 
include 
and 
not 
limited 
to:  
Guillain-Barre 
Syndrome, 
encephalitis
Grade 
4 
or 
recurrent Grade 3 
Permanently 
discontinue
1.
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  
NOTE: For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be 
resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).  
Abbreviations:  AE = adverse event; ALT =alanine aminotransferase; AST =aspartate aminotransferase; irAE = immune-related adverse event; 
GI = gastrointestinal; IV = intravenous; T1DM = type 1 diabetes mellitus. 
 
 
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Dose Modification and Toxicity Management of Infusion Reactions Related to 
Pembrolizumab
Pembrolizumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 5.  
Table 5
Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at Subsequent 
Dosing
Grade 1
Mild reaction; infusion 
interruption 
not 
indicated; intervention 
not indicated
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
None
Grade 2
Requires 
therapy 
or 
infusion 
interruption 
but responds promptly 
to 
symptomatic 
treatment 
(eg, 
antihistamines, 
NSAIDs, narcotics, IV
fluids); 
prophylactic 
medications indicated 
for ≤24 hrs
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:

IV fluids

Antihistamines

NSAIDs

Acetaminophen

Narcotics
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
If symptoms resolve within 1 hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (eg, from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose.
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further trial drug treatment
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion 
of 
pembrolizumab 
with:
Diphenhydramine 50 mg po 
(or 
equivalent 
dose 
of 
antihistamine).
Acetaminophen 
500-1000 
mg po (or equivalent dose 
of analgesic).
 
 
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NCI CTCAE Grade
Treatment
Premedication at Subsequent 
Dosing
Grades 3 or 4
Grade 3:
Prolonged 
(ie, 
not 
rapidly responsive to 
symptomatic 
medication and/or brief 
interruption 
of 
infusion); recurrence of 
symptoms 
following 
initial 
improvement; 
hospitalization 
indicated 
for 
other 
clinical sequelae (eg, 
renal 
impairment, 
pulmonary infiltrates)
Grade 4:
Life-threatening; 
pressor or ventilatory 
support indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:

Epinephrine**

IV fluids

Antihistamines

NSAIDs

Acetaminophen

Narcotics

Oxygen

Pressors

Corticosteroids
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be 
used immediately.
Subject is permanently discontinued from 
further trial drug treatment.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during 
the period of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov
Abbreviations:  CTCAE = Common Toxicity Criteria for Adverse Events; IV = intravenous; NCI = National Cancer 
Institute; NSAID = nonsteroidal anti-inflammatory drug; po = oral.
Other Allowed Dose Interruption for Pembrolizumab 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to trial therapy. Subjects should be 
placed back on trial therapy within 3 weeks of the scheduled interruption, unless otherwise 
discussed with the Sponsor. The reason for interruption should be documented in the 
subject's trial record.
Dinaciclib
Dinaciclib is administered as described in Table 2 and Table 3.  IV infusion components (IV 
infusion bag and tubing) with contact surfaces made of polyvinyl chloride or non-polyvinyl 
chloride material are acceptable for use with dinaciclib.  Under no circumstances will the 
dose be administered in less than a 2-hour period.  A central venous catheter is not required 
 
 
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for infusion of dinaciclib; however, if the subject has a central venous catheter in place it is 
recommended that it be used for the infusion.
Body surface area will be calculated by the site using the weight obtained at each cycle and 
the height obtained at screening. Body surface area will be recalculated at the beginning of 
every cycle and the dinaciclib dosage adjusted if the calculated dose would change > 5% 
from previous.
5.2.1.3.1 Premedication for Dinaciclib for rrCLL and rrDLBCL
Note: The rrCLL cohort was closed to enrollment on 30-APR-2019 due to lack of accrual, 
and all subjects with rrCLL have discontinued from treatment.  Remaining subjects with 
rrCLL are in survival follow-up.
Premedication and supportive care for dinaciclib is required for all subjects with rrCLL and 
rrDLBCL and is summarized in Table 6.
For subjects with rrCLL and rrDLBCL who will receive rasburicase as a premedication, 
glucose-6-phosphate dehydrogenase deficiency (G6PD) testing should be completed locally 
when required in subjects at higher risk of G6PD deficiency (eg, subjects of African or 
Mediterranean ancestry).  These subjects should be tested and found to have adequate levels 
before treatment with rasburicase.
Subjects with rrCLL and rrDLBCL will be admitted to the inpatient service to begin Cycle 1 
so as to facilitate aggressive hydration prior to and close monitoring during the first dose of 
dinaciclib on Cycle 1 Day 1 and Day 2. 
Monitor the subject for laboratory TLS and cytokine release syndrome (CRS) during and 
after the first administration of dinaciclib as described in Section 12.5 for Supportive Care 
Guidelines for TLS Prevention and Management.
Absent severe TLS complicating dinaciclib administration, subsequent therapy will be 
delivered on an outpatient basis (Section 12.5).
 
 
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Table 6
Premedication for Dinaciclib for rrCLL and rrDLBCL
Agent/Drug
Dose
Route
Schedule
Premedication a, b
Rasburicase
0.2 mg/kg or per 
institutional 
standard
IV
2 hrs prior to C1D1
dose; 
thereafter 
at 
investigator discretion
Antiemetic with a 
serotonin-receptor 
antagonist
Per drug label or 
institutional 
standard
Per drug label or 
institutional 
standard
Prior to each dose 
according to label or 
institutional standard
Dexamethasone
12 mg
IV
30 min prior to each 
dose
Kayexalate 
(or 
equivalent)
30 g
PO
At least 30 min prior, 
if serum potassium 
≥4.0 
mmol/L 
in 
Cycle 1 only
Supportive Care a
Oral 
phosphate 
binder, 
such 
as 
calcium acetate or 
equivalent
Calcium 
acetate 
1334 mg
Calcium acetate 
PO
12 and 2 hrs prior to 
each dose
IV hydration with 
0.45% 
sodium 
chloride 
sterile 
solution, or other 
appropriate 
IV 
solution
Subjects with CLL and DLBCL: C1D1: 200 ml/hr for ≥10 hrs 
prior to initiation of, during and continuing for ≥10 hrs after 
completion of dinaciclib infusion.
Subsequent infusions: 200 ml/hr for ≥1 hr prior to initiating, 
during and continuing for ≥ 2 hrs after completion of dinaciclib 
infusion.
Herpes zoster virus prophylaxis (valacyclovir 500 mg PO daily or acyclovir 400 mg PO 
BID or institutional standard
Pneumocystis pneumonia (previously known as P. carinii) prophylaxis (Bactrim DS 1 
tablet PO BID Monday-Wednesday-Friday or dapsone 100 mg PO daily or institutional 
standard).
Subjects with documented evidence of current/previous hepatitis B should receive 
antiviral prophylaxis during and for 6 months beyond last treatment.
a Institutional equivalents may be used for all premedications with the exception of rasburicase. Supportive 
care guidelines should be followed as above; however, if subject clinical condition requires modification to 
the dose, route, or schedule then institutional standards may be used only after consultation with the Sponsor.
b  If TLS is not observed, these guidelines may be revised.
Abbreviations:  BID = twice daily; C1D1 = Cycle 1 Day1; CLL = chronic lymphocytic leukemia; DLBCL = diffuse 
large B-cell lymphoma; IV = intravenous; PO = oral; TLS = tumor lysis syndrome.
5.2.1.3.2 Premedication for Dinaciclib for rrMM
Note: The rrMM cohort was closed to enrollment on 07-AUG-2017 due to lack of efficacy 
and all subjects discontinued from treatment.  Remaining subjects with rrMM are in survival 
follow-up.
 
 
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Premedication and supportive care for dinaciclib is required for all subjects with rrMM and is 
summarized in Table 7.
Subjects with rrMM will receive Cycle 1 Day 1 dose and all subsequent doses of dinaciclib 
on an outpatient basis.  
Table 7
Premedication for Dinaciclib for rrMM
Agent/Drug
Dose
Route
Schedule
Premedication a, b
Antiemetic with a 
serotonin-receptor 
antagonist
Per drug label or 
institutional 
standard
Per drug label or 
institutional 
standard
Prior to each dose 
according to label 
or institutional 
standard
Dexamethasone
12 mg
IV
30 min prior to 
each dose
Supportive Care a
Oral phosphate 
binder, such as 
calcium acetate or 
equivalent
Calcium acetate 
1334 mg
Calcium acetate 
PO
12 and 2 hrs prior 
to each dose
IV hydration with 
0.45% NaCl sterile 
solution, or other 
appropriate IV 
solution
C1D1 and Subsequent infusions: 200 ml/hr for ≥ 1 hr prior to 
initiating, during, and continuing for ≥1 hrs after completion of 
dinaciclib infusion
Herpes zoster virus prophylaxis (valacyclovir 500 mg PO daily or acyclovir 400 mg PO 
BID or institutional standard
Pneumocystis jiroveci pneumonia (previously known as P. carinii) prophylaxis 
(Bactrim DS 1 tablet PO BID Monday-Wednesday-Friday or dapsone 100 mg PO daily 
or institutional standard).
Subjects with documented evidence of current/previous hepatitis B should receive 
antiviral prophylaxis during and for 6 months beyond last treatment.
a Institutional equivalents may be used for all premedications with the exception of rasburicase. Supportive 
care guidelines should be followed as above; however, if subject clinical condition requires modification to 
the dose, route, or schedule then institutional standards may be used only after consultation with the Sponsor.
b If TLS is not observed, these guidelines may be revised.
Abbreviations:  BID = twice daily; C1D1 = Cycle 1 Day1; NaCl = sodium chloride; IV = intravenous; PO = oral; 
TLS = tumor lysis syndrome.
5.2.1.3.3 Dinaciclib Dose Modifications
Dinaciclib dose modifications for hematologic toxicity will be based on laboratory and 
clinical assessment performed on Day 1 of each cycle.  The dinaciclib dose will not be 
reduced for cytopenias that have resolved by Day 1 of the next cycle.  Dose adjustments or 
delays due to hematologic toxicity apply to Day 1 of each cycle.  There will be no 
adjustments for Day 8 hematologic results.  Dose delays and modifications for dinaciclib due 
to hematologic toxicity are described in Table 8.  Dose delays and modification for dinaciclib
for nonhematologic toxicity are described in Table 9.  Dose levels to be used for dinaciclib 
dose modification are described in Table 10.  If dinaciclib is held on Day 1, pembrolizumab 
 
 
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should be held as well.  If Day 8 toxicity causes dose delay, subject should be retested within
visit window in order to identify earliest dosing opportunity. If dose cannot be given within
visit window, then Day 8 dose should be skipped.
Table 8
Dinaciclib Dose Modification for Hematologic Toxicity
Criteria for Start of Each Cycle
Actiona
If ANC≥1.0 x 109/L at C1D1 predose, then actiona
should be taken if ANC at subsequent Day 1 
predose is <1.0 x 109/L
If ANC<1.0 x 109/L at C1D1 predose, then actiona
should be taken if ANC at subsequent Day 1 
predose is more than 20% lower than C1D1 
predose level
Delay for up to 3 weeks until recovery.  Reduce 
subsequent doses by 1 dose level.  Discontinue subject 
if already at the lowest dose level or if the subject’s 
ANC has not recovered in 3 weeks.
If platelet count≥50 x 109/L at C1D1 predose, then 
actiona should be taken if platelet count at 
subsequent Day 1 predose is <50 x 109/L
If platelet count <50 x 109/L at C1D1 predose, 
then actiona should be taken if platelet count at 
subsequent Day 1 predose is more than 20% lower 
than C1D1 predose level
Delay for up to 3 weeks until recovery.  Reduce 
subsequent doses by 1 dose level.  Discontinue subject 
if already at the lowest dose level or if the subject’s 
platelet count has not recovered in 3 weeks.
aAction is applied regardless of toxicity causality. If a subject’s count recovers within the +/-3 day visit window, then no 
dose reduction is required.  However, if subject’s count recovers outside the +/-3 day visit window, then dose reduction 
guidance outlined above applies. Must hold both pembrolizumab and dinaciclib if a hold is required.
Abbreviations:  ANC = absolute neutrophil count; C1D1 = Cycle 1 Day 1.
For any nonhematologic toxicity that results in dose delay, treatment may be delayed for up 
to 3 weeks until resolution of toxicity to ≤Grade 1 (Table 9). 
 
 
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Table 9
Dinaciclib Dose Modification for Nonhematologic Toxicity
Criteria
Action
TLS requiring dialysis
Reduce subsequent doses by one dose level.  Resume treatment, as 
an inpatient, only after complete recovery with return to baseline 
lactate dehydrogenase and electrolytes.  If well tolerated, further 
treatment may continue as an outpatient.  If TLS requiring dialysis 
occurs after dose reduction, the subject must be discontinued.
Post-treatment hyperkalemia with K+ 
rising above ULN, occurring during 
dose-escalation in Cycle 1
Manage hyperkalemia per standard of care.  Continue with the 
current dose of dinaciclib and delay dose-escalation until dinaciclib 
can be administered without a rise in K+.  For example, post-
treatment hyperkalemia is noted on C1D1 following 7 mg/m2 dose.  
C1D8 dose is not escalated and treatment continues at 7 mg/m2 with 
no hyperkalemia.  C2D1 dose is increased to 10 mg/m2 and C2D8
dose is increased to 14 mg/m2. 
Any diarrhea
Diarrhea should be treated with oral loperamide 4 mg followed by 
loperamide 2 mg after each additional episode of diarrhea to a 
maximal dose of 16 mg per day, provided there is no clinical 
evidence of infectious diarrhea.
≥ Grade 3 diarrhea after loperamide
Reduce subsequent doses by one dose level.  Discontinue subject 
who continues to experience ≥ Grade 3 diarrhea despite dose 
reduction and loperamide.  Discontinue subject if already at the 
lowest dose level. 
≥ Grade 3 nausea/vomiting
Add antiemetic agents as appropriate.  Reduce subsequent doses by 
one dose level, only if subject continues to have ≥ Grade 3 toxicity 
despite maximum antiemetic therapy.  Discontinue subject with 
persistent ≥ Grade 3 nausea/vomiting despite dose reduction and 
antiemetics.  Discontinue subject if already at the lowest dose level. 
Bilirubin ≥ 2 x ULN, serum 
creatinine ≥ 3 x ULN or calculated 
creatinine clearance < 50 mL/min
Delay for up to 3 weeks until recovery of bilirubin ≥ 2 x ULN or 
serum creatinine ≥3 x ULN.  Reduce subsequent doses by one dose 
level.  Discontinue subject if already at the lowest dose level or if 
subject has not recovered in 3 weeks. 
All other clinically relevant toxicities 
≥ Grade 3
Delay for up to 3 weeks until recovery to ≤ Grade 1 toxicity.  
Reduce subsequent doses by one dose level.  Discontinue subject 
who continues to experience ≥ Grade 3 toxicity despite dose 
reduction.  Discontinue subject if already at the lowest dose level or 
if subject has not recovered in 3 weeks. 
Abbreviations: C = cycle; D = Day; K+ = potassium; TLS = tumor lysis syndrome; ULN = upper limit of normal.
 
 
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Table 10
Dinaciclib Dose
Dose of Dinaciclib at Time of Adverse Event Requiring Dose Reduction
Dose to use for Next Dose
14 mg/m2
10 mg/m2
10 mg/m2
7 mg/m2
7 mg/m2
discontinue
For a subject who has had dose reductions, dose escalation of dinaciclib to the next dose 
level is permitted provided that the subject remains on trial after receiving 2 additional cycles 
of combination treatment without ≥Grade 2 toxicity and upon consultation with sponsor.  
Tumor Lysis Syndrome
The Cairo and Bishop criteria will be used to define TLS (Section 12.5) [31].  
Using the Cairo-Bishop definition of laboratory TLS, K, calcium (Ca), phosphorus (P), and 
uric acid will be evaluated at 3 and 5 hours after the start of the first dinaciclib infusion 
(Cycle 1 Day 1) as part of a TLS work-up (Section 12.5).  Subjects with a positive TLS 
work-up should remain in the hospital and follow-up should be initiated. If necessary, 
subjects must be admitted overnight for observation.
TLS is defined as any 2 of the following serum levels within 3 days before or 7 days after 
initiation of dinaciclib, assuming adequate hydration and administration of a hypo-uremic:

Uric acid levels of > 476 µmol/L (8 mg/dL), or a 25% increase from Baseline

Potassium (K+) levels of > 6 mmol/L (6 mEq/L), or a 25% increase from Baseline

Phosphorus levels of > 1.45 mmol/L (4.5 mg/dL), or a 25% increase from Baseline

Calcium levels of < 1.75 mmol/L (7 mg/dL), or a 25% decrease from Baseline
5.2.1.3.4 Dinaciclib Dose Evaluation
During Dose Evaluation, the first 12 subjects will receive pembrolizumab 200 mg on Day 1 
of each cycle and Dose Level 0 of dinaciclib as described in Table 3 and Table 11.
Table 11
Dinaciclib Dose Levels
Dose Level
Dose of Dinaciclib
Level 0
C1D1: 7 mg/m2;  C1D8: 10 mg/m2;  C2D1+: 14 mg/m2
Level -1
C1D1: 7 mg/m2;  C1D8: 10 mg/m2;  C2D1+: 10 mg/m2
Level -2
C1D1: 7 mg/m2;  C1D8: 7 mg/m2;  C2D1+: 7 mg/m2
C1D1: Cycle 1 Day 1
C1D8: Cycle 1 Day 8
C2D1+: Cycle 2 Day 1 and beyond.
 
 
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DLTs observed in Cycle 1 and Cycle 2 will be used to evaluate the dose level.  If 4 or fewer 
subjects at Dose Level 0 have a DLT, the Signal Detection phase of the trial will be opened. 
Table 12 below summarizes the probabilities of observing the numbers and percentages of 
subjects under different assumptions of true DLT rate θ0, which can be interpreted as the 
one-sided p-values for testing the null hypothesis that the true DLT rate is less than θ0.  
These criteria are considered non-binding guidelines; recommendations would not be based 
solely on statistical grounds, as many other factors (ie, all aspects of the data from the trial)
may be part of the decision process.
Table 12
Probability of Observing the Number (%) of Subjects with DLT
Observed Number
(%) of Subjects
Probabilities (p-values) Under Different Assumptions
θ0 = 0.20
θ0 = 0.25
θ0 = 0.30
θ0 = 0.35
θ0 = 0.40
2 (16.7%)
3 (25.0%)
4 (33.3%)
5 (41.7%)
6 (50.0%)
0.442
0.205
0.073
0.019
0.004
0.609
0.351
0.158
0.054
0.014
0.747
0.507
0.276
0.118
0.039
0.849
0.653
0.417
0.213
0.085
0.917
0.775
0.562
0.335
0.158
The probabilities (p-values) for the monitoring of the first 12 subjects were calculated from Binomial distribution.
If there are ≥ 5 subjects with DLTs within the initial 12 subjects at Dose Level 0, up to 24 
additional subjects may be enrolled using a design based on Ji et al. [32] (Table 13).  If the 
monitoring guidance indicates escalation (“E”) from Dose Level -1 to Dose Level 0, a 
maximum of 5 additional subjects will be evaluated at Dose Level 0, up to 17 subjects in all.  
Therefore, a minimum of 12 subjects (Dose Level 0), and although highly unlikely, a 
maximum of 41 subjects evaluable for DLT assessment (up to 17 at Dose Level 0 plus 12 
each at Dose Levels -1 and -2), may be needed for Dose Evaluation. The pembrolizumab 
dose will not be changed.  
If ≥ 5 subjects with DLTs are observed at Dose Level 0, the dose level of dinaciclib will be 
reduced (Table 11) to Level -1 (7 > 10 > 10 mg/m2) to begin a new cohort of 3 subjects.  
Using Table 13, starting at the upper left corner, monitor the number of subjects and if the 
number of subjects/DLTs at Dose Level -1 reaches a “D” (de-escalate), then the dose level 
will be reduced to Level -2, and a cohort of 3 subjects will be enrolled at that dose level and 
monitored using Table 13 starting at the upper left corner (ie, the first 3 subjects at Dose 
Level -2).  
At Dose Level -2, an “E” (escalate) would trigger an increase to Level -1, and enrollment and 
evaluation will continue at Level -1 from where it previously left off.
At Dose Level -1, an “E” (escalate) would trigger an increase to Level 0 and would resume at 
the number of subjects where it previously left off, or if it stopped at 12, would continue 
from subjects 13 up to 17.  There is no dose escalation above Dose Level 0. 
If the dinaciclib dose level is reduced to below Level 0, due to the potential complexity of 
trying to ensure balanced distribution of tumor types across the enrollment groups for dose 
evaluation, there are no restrictions regarding the minimum or maximum number of subjects 
 
 
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with CLL, MM, or DLBCL enrolled in these cohorts.  This (no restriction) also applies if the 
dose is resumed back to Level 0.  
All decisions regarding dose levels for subject enrollment and dosing will be made by the 
Sponsor and communicated to the investigators. 
Note that while 30% is the target DLT rate used to generate the dose-adjustments in
Table 13, the observed rate of DLTs at the maximum tolerated dose may vary slightly above 
or below 30%.
Table 13
Monitoring Guidance in Dose Evaluation (Target DLT Rate of 30%)
Number of Toxicities
Number of Subjects Treated at Current Dose Level a
3
4
5
6
7
8
9
10
11
12
13a
14a
15a
16a
17a
0
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
1
S
E
E
E
E
E
E
E
E
E
E
E
E
E
E
2
D
S
S
S
S
E
E
E
E
E
E
E
E
E
E
3
DU
DU
D
S
S
S
S
S
S
E
E
E
E
E
E
4
DU
DU
DU
D
D
S
S
S
S
S
S
S
E
E
5
DU
DU
DU
DU
D
D
S
S
S
S
S
S
S
6
DU
DU
DU
DU
DU
DU
D
D
S
S
S
S
7
DU
DU
DU
DU
DU
DU
DU
D
D
S
S
8
DU
DU
DU
DU
DU
DU
DU
DU
DU
D
9
DU
DU
DU
DU
DU
DU
DU
DU
DU
10
DU
DU
DU
DU
DU
DU
DU
DU
E = Escalate to the next higher dose level.
S = Stay at the current dose level.
D = De-escalate to the next lower dose level.
DU = Current dose level is unacceptably toxic.
Target DLT rate = 30%; a=.05, b=.05, k1=1.25; k2=0.5; pow=1.
Source:  Ji et al. 2007) [32]
a A maximum of 12 subjects will be used to evaluate Dose Levels -1 and -2; subjects 13-17 are only used to 
evaluate Dose Level 0 if ≥ 5 subjects in initial group of 12 at Dose Level 0 experience DLT and Table 10
indicates escalation (E) from Dose Level -1 back to Dose Level 0.
 
 
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Definition of Dose-Limiting Toxicity
DLTs will be defined from toxicities observed during Cycles 1 and 2.  The occurrence of any 
of the following toxicities during these periods, if assessed by the investigator to be possibly, 
probably, or definitely related to pembrolizumab or dinaciclib will be considered a DLT:
1. Grade 4 nonhematologic toxicity (not laboratory)
2. Grade 4 hematologic toxicity lasting > 7 days, except thrombocytopenia
a.
Grade 4 thrombocytopenia of any duration
b. Grade 3 thrombocytopenia is a DLT if associated with bleeding;
3. Any Grade 3 nonhematologic toxicity (not laboratory), with the exception of Grade 3 
nausea, vomiting, or diarrhea, which will not be considered a DLT unless lasting 
more than 3 days despite optimal supportive care.
4. Any Grade 3 or Grade 4 nonhematologic laboratory abnormality, if:

medical intervention is required, or

the abnormality leads to hospitalization, or

the abnormality persists for > 1 week
5. Febrile neutropenia Grade 3 or Grade 4
6. Any drug-related AE which caused subject to discontinue treatment during Cycles 1 
or 2
7. Grade 5 toxicity
8. Any treatment-related toxicity which causes a > 2-week delay in initiation of Cycle 2 
or Cycle 3 
Replacement of Subjects in the Dose Evaluation Period
In order to determine safety, all subjects selected must meet the criteria for evaluability in 
Cycles 1 and 2.  Subjects are considered non-evaluable for DLT assessment and will be 
replaced if:

They are enrolled but not treated

They discontinue from the trial prior to completing all the safety evaluations other 
than treatment-related AEs

If they receive less than 90% of the total pembrolizumab or dinaciclib in Cycles 1 and 
2 (eg, because the infusion had to be discontinued due to an infusion reaction) and did 
not experience a DLT.
Non-evaluable subjects will not be counted toward the total for Dose Evaluation.  If a subject 
experiences a DLT in Cycles 1 or 2, trial treatment may be discontinued following discussion 
between the Sponsor and investigator.  However, if the subject is deriving clinical benefit 
from the trial treatment, the subject may be allowed to continue after discussion between the 
Sponsor and the investigator.
 
 
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Timing of Dose Administration
Pembrolizumab and dinaciclib dosing and schedules are described in Section 5.2.
Trial treatment may be administered up to 3 days before or after the scheduled dosing date 
for each infusion due to administrative reasons.
Missed doses (ie, Day 8) should be skipped, not delayed, if not given within the allowed 
window.
Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons 
(eg, elective surgery, unrelated medical events, radiotherapy, subject vacation, and holidays) 
not related to trial therapy. Subjects should be placed back on trial therapy within 3 weeks of 
the scheduled interruption. The reason for interruption should be documented in the subject's 
trial record. Dosing interruptions should be discussed with the Sponsor.
Details on the preparation and administration of dinaciclib and pembrolizumab are provided 
in the Pharmacy Manual.  
Trial Blinding/Masking
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
Randomization or Treatment Allocation
Subjects participating in this trial will be allocated by non-random assignment.
Stratification
No stratification based on age, sex or other characteristics will be used in this trial.
Concomitant Medications/Vaccinations (Allowed & Prohibited)
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.
All medication taken by the subject within 4 weeks prior to enrollment and all concomitant 
therapy taken by the subject during the trial up until 30 days after administration of the last 
dose of trial treatment are to be recorded on the electronic case report form.  The identity of 
the therapy, the dose and the dates started and stopped (or notation of "continuing", as 
appropriate), and the reason for use must be recorded.
 
 
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Acceptable Concomitant Medications
Medications required to treat AEs or concurrent illnesses, are allowed during the trial.  
Antiemetics, including serotonin-receptor antagonists, metoclopramide, prochlorperazine, or 
thietylperazine, are allowed throughout the trial.  
Contraceptive medications, as per Section 5.7.2, are also allowed. Physiologic replacement 
doses of glucocorticoids are allowed.
Erythropoietin therapy and granulocyte colony-stimulating factor (G-CSF) are allowed at the 
discretion of the investigator.  Erythropoietin therapy should be used in accordance with the 
American Society of Clinical Oncology/American Society of Hematology or the National 
Comprehensive Cancer Network guidelines [33].  
G-CSF should be used in accordance with the American Society of Clinical Oncology 
guidelines [34]. Growth factors are not allowed to be used in order to boost a subject’s 
hematology parameters if the subject is found to be ineligible based on the laboratory results 
performed at screening.
G-CSF for primary prophylaxis during Cycle 1 in Dose Evaluation is prohibited.
Prohibited Concomitant Medications and Therapies
The medications, supplement, and other substances prohibited prior to Screening are listed in 
Section 5.1.3 with the subject exclusion criteria.
Dinaciclib:
Dinaciclib is metabolized by the human hepatic enzyme CYP3A4. In vitro metabolism
studies indicated that dinaciclib is a competitive inhibitor of CYP1A2, as well as an 
irreversible metabolism-dependent inhibitor of CYP3A4/5.  Coadministration of dinaciclib 
with strong CYP3A4/5 inhibitors may increase the concentration of dinaciclib, and 
coadministration of dinaciclib with
strong
CYP3A4/5 inducers may
decrease the 
concentration of dinaciclib. 
Since dinaciclib is a substrate of CYP3A4, concomitant use of other drugs that are strong 
inhibitors or inducers of CYP3A4 is prohibited while the subject is enrolled in this trial
except for required steroid premedication. See Section 12.6 for information about strong 
inhibitors/inducers of CYP3A4.
If the use of a medication that is a strong CYP3A4 inhibitor or inducer is medically necessary 
and an alternate therapeutic agent that is not a strong inhibitor or inducer of CYP3A4 is not 
available, then the subject must discontinue treatment with dinaciclib.
The investigator should be alerted if the subject is taking any agent known to affect or with 
the potential to affect selected CYP450 isoenzymes. 
Additional information regarding drug interactions with cytochrome P450 isoenzymes can be 
found at the following website: http://medicine.iupui.edu/clinpharm/ddis/.  
 
 
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Pembrolizumab and dinaciclib:  Subjects are prohibited from receiving the following 
therapies during the Screening and Treatment phase of this trial:

Antineoplastic systemic chemotherapy, biological therapy, or immunotherapy

G-CSF for primary prophylaxis during Cycle 1 in Dose Evaluation

Granulate-macrophage colony-stimulating factor (GM-CSF)

Investigational agents other than pembrolizumab and dinaciclib

Radiation therapy 
o
Note:  Radiation therapy to a symptomatic soft tissue lesion, bone lesions, or to 
the brain may be allowed after consultation with Sponsor.
o
Thoracic radiation therapy is not allowed within 14 days before the first dose of 
treatment.   

Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, yellow fever, rabies, Bacillus 
Calmette–Guérin, and oral typhoid vaccine.  Seasonal influenza vaccines for injection 
are generally killed virus vaccines and are allowed; however intranasal influenza 
vaccines (eg, Flu-Mist®) are live attenuated vaccines, and are not allowed.

Glucocorticoids for any purpose other than as a premedication for protocol 
treatments, and to modulate symptoms from an event of clinical interest of suspected 
immunologic etiology.
o
The use of physiologic doses of corticosteroids for use in subjects with 
conditions may be approved after consultation with the Sponsor.  

Grapefruit juice

Strong inhibitors/inducers of CYP3A4 (except for required steroid premedication 
[Section 12.6]).
Subjects may receive other medications that the investigator deems to be medically 
necessary.
The Exclusion Criteria describes other medications which are prohibited in this trial.
There are no prohibited therapies during the Post-Treatment Follow-up Phase. Subjects must 
be discontinued from the active follow-up phase if they begin a non-trial treatment for their 
underlying disease.
Rescue Medications & Supportive Care
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  
Suggested supportive care measures for the management of AEs with potential immunologic 
etiology are outlined along with the dose modification guidelines in Section 5.2.1.  Where 
appropriate, these guidelines include the use of oral or IV treatment with corticosteroids, as 
well as additional anti-inflammatory agents if symptoms do not improve with administration 
 
 
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of corticosteroids.  Note that several courses of steroid tapering may be necessary as 
symptoms may worsen when the steroid dose is decreased.  For each disorder, attempts 
should be made to rule out other causes such as metastatic disease or bacterial or viral 
infection, which might require additional supportive care.  The treatment guidelines are 
intended to be applied when the investigator determines the events to be related to 
pembrolizumab. 
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the investigator does not need to follow the treatment guidance. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.
Diet/Activity/Other Considerations
Diet
Subjects should refrain from grapefruit or grapefruit juice during the trial (Section 5.5.2).
Contraception 
Pembrolizumab or dinaciclib may have adverse effects on a fetus in utero.  Furthermore, it is 
not known if pembrolizumab or dinaciclib 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 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 follicle-stimulating hormone
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 trial drug and for 120 days after the 
last dose of trial drug by complying 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 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 Ethical 
Review Committees (ERCs) / Institutional Review Boards (IRBs).  Periodic 
abstinence (eg, 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 trial medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the trial.  In order to participate in 
the trial subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of trial medication initiation (or 14 days prior to the initiation 
of trial medication for oral contraception) throughout the trial period up to 120 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 trial.
 
 
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Pregnancy
If a subject inadvertently becomes pregnant while on treatment, the subject will be 
immediately 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 SAE (eg, death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn).  The trial 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 trial personnel at the site must be informed immediately and the 
pregnancy must be reported to the Sponsor and followed as described in Section 7.2.2.
Use in Nursing Women
It is unknown whether dinaciclib or pembrolizumab are 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
Discontinuation of Treatment
Discontinuation of treatment does not represent withdrawal from the trial.
As certain data on clinical events beyond treatment discontinuation are important to the 
study, they must be collected through the subject’s last scheduled follow-up, even if the 
subject has discontinued treatment.  Therefore, all subjects who discontinue trial treatment
prior to completion of the treatment period will still continue to participate in the trial as 
specified in Section 6.0 - Trial Flow Chart and Section 7.1.5.3 – Post Treatment Visits.
Subjects may discontinue treatment at any time for any reason or be dropped from treatment
at the discretion of the investigator should any untoward effect occur.  In addition, a subject 
may be discontinued from treatment by the investigator or the Sponsor if treatment is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.  
Specific details regarding procedures to be performed at treatment discontinuation are 
provided in Section 7.1.4 – Other Procedures.
A subject must be discontinued from treatment but continue to be monitored in the trial for 
any of the following reasons:
o
The subject or subject’s legally acceptable representative requests to discontinue 
treatment.
o
Confirmed radiographic disease progression outlined in Section 7.1.2.7 (exception if 
the Sponsor approves treatment continuation).
o
Unacceptable AEs as described in Section 7.2.
o
Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment.  Exceptions include basal cell carcinoma of 
 
 
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the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has 
undergone potentially curative therapy.
o
Intercurrent illness other than another malignancy as noted above that prevents 
further administration of treatment.
o
Recurrent Grade 2 pneumonitis.
o
A confirmed positive serum pregnancy test.
o
Noncompliance with trial treatment or procedure requirements.
o
Investigator’s decision to withdraw the subject.
For subjects who are discontinued from treatment but continue to be monitored in the trial, 
see Section 6.0 – Trial Flow Chart, and Section 7.1.5.3 – Post Treatment Visits for those 
procedures to be completed at each specified visit.
Withdrawal from the Trial
A subject must be withdrawn from the trial if the subject or subject’s legally acceptable 
representative withdraws consent from the trial.
If a subject withdraws from the trial, they will no longer receive treatment or be followed at 
scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the trial 
including the procedures to be performed should a subject repeatedly fail to return for 
scheduled visits and/or if the study site is unable to contact the subject, as well as specific 
details regarding withdrawal from Future Biomedical Research are outlined in Section 7.1.4 
– Other Procedures.
Subject Replacement Strategy
Subjects in the Dose Evaluation period may be replaced as described in Section 5.2.1.5.
Beginning and End of the Trial
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
The clinical trial may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the trial population as 
a whole is unacceptable.  In addition, further recruitment in the trial or at (a) particular trial 
site(s) may be stopped due to insufficient compliance with the protocol, GCP and/or other 
applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
 
 
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6.0 TRIAL FLOW CHART
Trial Period:
Screening 
Phase
Treatment Cycles (21-day cycles)
To Be Repeated Beyond 3 Cycles
End of Treatment
Post-Treatment
Treatment Cycle (21 Day cycles)
Screeningb
Cycle 1 
Cycle 2
Cycle 3 +
Every 3 
Cycles (ie, 
Cycle 4, 7, 10, 
etc)
Discon
Post-
Treatment 
Safety 
Follow-up
Efficacy 
Follow-up 
Visits
Survival 
Follow-up
Cycle Day a
(± 3 days unless otherwise specified)
-28 to -1
1
8
1
8
1
8
1 (± 7 d)
At time of 
Discon
30 days 
post 
Discon v
Every 12 
weeks 
post 
Discon 
(± 14 d)
Every 12 
weeks 
(± 14 d)
Administrative Procedures
Informed Consent c
X
Informed Consent for Future Biomedical 
Research d
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics and Medical History
X
Prior Treatment Review
X
Concomitant Medication Review e
X
X
X
X
X
X
X
X
X
Post-trial Anticancer Therapy Status f
X
X
Survival g
X
Pembrolizumab Administration
X
X
X
Dinaciclib Administration
X
X
X
X
X
X
Clinical Procedures/Assessments
Full Physical Examination
X
X
X
X
X
X
X
12-Lead Electrocardiogram
X
Height h
X
Vital Signs and Weight h
X
X
X
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
Adverse Event Review
X
X
X
X
X
X
X
X
X
CLL: CT of Neck, Chest, Abdomen, and Pelvis
X
X
X
X
CLL:  Disease Response Assessment
X
X
X
X
CLL: Constitutional Symptoms
X
X
X
X
MM: Disease Response Assessment i
X
X
X 
X
X
MM: Skeletal Survey j
X
PRN
MM: MRI or CT/PET for Extramedullary Soft 
Tissue Plasmacytoma j
X
PRN
 
 
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Trial Period:
Screening 
Phase
Treatment Cycles (21-day cycles)
To Be Repeated Beyond 3 Cycles
End of Treatment
Post-Treatment
Treatment Cycle (21 Day cycles)
Screeningb
Cycle 1 
Cycle 2
Cycle 3 +
Every 3 
Cycles (ie, 
Cycle 4, 7, 10, 
etc)
Discon
Post-
Treatment 
Safety 
Follow-up
Efficacy 
Follow-up 
Visits
Survival 
Follow-up
Cycle Day a
(± 3 days unless otherwise specified)
-28 to -1
1
8
1
8
1
8
1 (± 7 d)
At time of 
Discon
30 days 
post 
Discon v
Every 12 
weeks 
post 
Discon 
(± 14 d)
Every 12 
weeks 
(± 14 d)
DLBCL: PET/CT Neck, Chest, Abdomen, and 
Pelvis k
X
X
X
X
DLBCL:  Lymphoma B Symptoms
X
X
X
X
DLBCL:  Disease Response Assessment n
X
X
X
X
Laboratory Procedures/Assessments:  Analysis Performed by Local Laboratory
CBC with Differential
X
X
X
X
X
X
X
X
X
Comprehensive Blood Chemistry Panel
X
X
X
X
X
X
X
X
X
Urinalysis
X
Β2 Microglobulin
X
hCG l
X
X
X
X
X
X
PT (INR) and aPTT y
X
Thyroid Tests (T3 [or FT3 per Local Standard]; 
FT4, and TSH)
X
X
CLL:
FISH, to Include Probes for del 17p, del 
13q, del 11q, trisomy 12
X
IgVH Mutational Statusu
X
CD38 Level
X
X
CD4, CD8
X
X
Quantitative Serum Immunoglobulins x
X
X
X
G6PD Screening m
X
Bone Marrow Biopsy and Aspiration  n
X
PRN
TLS 
labs: 
Potassium, 
Calcium, 
Phosphorus, Uric Acid (3 and 5 hrs After 
Start)
X
 
 
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Trial Period:
Screening 
Phase
Treatment Cycles (21-day cycles)
To Be Repeated Beyond 3 Cycles
End of Treatment
Post-Treatment
Treatment Cycle (21 Day cycles)
Screeningb
Cycle 1 
Cycle 2
Cycle 3 +
Every 3 
Cycles (ie, 
Cycle 4, 7, 10, 
etc)
Discon
Post-
Treatment 
Safety 
Follow-up
Efficacy 
Follow-up 
Visits
Survival 
Follow-up
Cycle Day a
(± 3 days unless otherwise specified)
-28 to -1
1
8
1
8
1
8
1 (± 7 d)
At time of 
Discon
30 days 
post 
Discon v
Every 12 
weeks 
post 
Discon 
(± 14 d)
Every 12 
weeks 
(± 14 d)
Multiple Myeloma
Serum 
Protein 
Electrophoresis 
± 
Immunofixation o
X
X
X i
X
24 hr Urine Protein Electrophoresis ±
Immunofixation o, p
X
X
X i
X
Serum Free Light Chain Assay o, q
X
X
X i
X
Immunoglobulin quantification
X
Bone Marrow Biopsy
and Aspiration, 
with Morphology, IHC, Cytogenetics by 
Standard Karyotyping, FISH Panel n
X
PRN
DLBCL:
Lymph Node/Extranodal Lesion Biopsyn
X
PRN
Bone Marrow Biopsy and Aspiration n
X
PRN
G6PD Screening m
X
TLS 
labs: 
Potassium, 
Calcium, 
Phosphorus, Uric Acid (3 and 5 hrs After 
Start)
X
Laboratory Procedures/Assessments:  Analysis Performed by Central Laboratory
Whole 
Blood 
for 
Correlative 
Studies 
(RNA/DNA) 
X
X
X
Blood for Biomarker Studies (Plasma and 
Serum)
X
X
X
Blood for Genetic Analysis r
X
Saliva for Genetic Analysis r
X
Pembrolizumab Pharmacokinetic
Level and 
Anti-Pembrolizumab Antibodies w
X
X
X
Pharmacokinetics (Dinaciclib) s
X
X t
 
 
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Abbreviations: aPTT = activated partial thromboplastin time; -hCG = beta human chorionic gonadotrophin; CBC = complete blood count; CLL = chronic lymphocytic leukemia; 
CR = complete remission; CT = computed tomography; Discon = discontinuation; DLBCL = diffuse large B-cell lymphoma; ECOG = Eastern Cooperative Oncology Group; 
FDG = fluorodeoxyglucose;
FISH =
flourescence in situ hybridization; FT4
=
thyroxinea; G6PD = glucose-6-phosphate dehydrogenase deficiency; 
IHC = immunohistochemistry; MM = multiple myeloma; MRI = magnetic resonance imaging; PET = positron-emission tomography; PRN = perform as needed; 
PT (INR) = prothrombin time (international normalized ratio);SAE = serious adverse events; T3 = triothyronine; TSH = thyroid stimulating hormone (thyrotropin); TSL = tumor 
lysis syndrome.
a.
In general, assessments/procedures are to be performed prior to trial treatment on each cycle day unless otherwise specified. In general, the window for each visit is ±3 days 
unless otherwise noted.  Trial treatment should begin on the day of treatment allocation or as close as possible to the date on which the subject is allocated/assigned.
b. Screening visit procedures must be performed within 28 days before Day 1 unless otherwise noted.  
c.
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 (ie, within 28 days prior to the first dose of trial treatment).  A 
screening number will be assigned when the trial informed consent is signed.  Refer to Section 7.1.1.1.1 and Section 7.1.1.7.
d. Signing the informed consent for Future Biomedical Research samples is optional.  Detailed instructions for the management of specimens for future biomedical research are 
provided in the Procedures Manual and Section 7.1.1.1.2.
e.
Prior medications – Record all medications taken within 28 days of the screening visit.  Concomitant medications – Enter new medications started during the trial through the 
30-day Safety Follow-up visit.  Record all medications taken for SAEs. Refer to Section 7.1.1.5 for additional details.
f.
In subjects who discontinue trial therapy without documented disease progression, every effort should be made to continue monitoring their disease status by radiologic 
imaging (or laboratory for MM) every 12 weeks (± 14 days) for at least 12 months or until (1) the start of new anticancer treatment, (2) documented disease progression, (3) 
death, or (4) the end of the trial, whichever occurs first.
g.
After subjects who experience confirmed site-assessed PD or who start a new anti-cancer therapy, each subject will be contacted by telephone for survival approximately 
every 12 weeks (± 14 days) until the subject withdraws consent, is lost to follow-up, death, or the trial ends, whichever occurs first. In addition, upon Sponsor request, subjects 
may be contacted for survival status at any time during the course of the trial.  
h. Vital signs are collected at all visits/cycles and include temperature, pulse, blood pressure, respiratory rate, and weight. Height will be measured at screening (Visit 1) only.
i.
For subjects with MM, perform disease assessments at the beginning of every cycle (except Cycle 1). Imaging and disease assessments are not to be delayed for cycle delays
j.
For subjects with MM, perform skeletal survey at screening to assess for bone disease. Imaging for plasmacytoma at screening is only done in subjects that have a 
plasmacytoma.  After baseline, perform skeletal surveys or imaging for plasmacytoma if clinically indicated (Section 7.1.2.8.2).
k. For subjects with DLBCL, perform PET/CT during screening.  On-trial perform disease assessments using PET/CT if PET-avid at baseline; otherwise CT may be used 
(Section 7.1.2.8.3). 
 
 
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l.
For women of reproductive potential, a urine pregnancy test should be performed within 72 hours prior to first dose of trial treatment.  If urine pregnancy results cannot be 
confirmed as negative, a serum pregnancy test performed by the local trial site laboratory will be required.  Monthly pregnancy testing should be conducted as per local 
regulations where applicable. All women who are being considered for participation in the trial, and who are not surgically sterilized or postmenopausal, must be tested for 
pregnancy within 72 hours of each cycle of trial treatment and 30 days post-treatment.  
m. For subjects with CLL and DLBCL who will receive rasburicase as a premedication, G6PD testing should be completed locally when required in subjects at higher risk of 
G6PD deficiency (eg, subjects of African or Mediterranean ancestry).  These subjects should be tested and found to have adequate levels before treatment with rasburicase 
(Section 5.2.1.3.1).
n. All subjects must provide newly obtained (within 3 months) bone marrow biopsy material for biomarker analysis at screening.  If bone marrow biopsy was performed within 
3 months before screening but subject had anticancer treatment after biopsy, the bone marrow biopsy and aspiration should be repeated.  If bone marrow biopsy was performed 
within 3 months before screening but subject has not had anticancer treatment after biopsy, the bone marrow biopsy and aspiration does not need to be repeated.  Subjects with 
rrDLBCL must provide core or excision biopsy of a lymph node or extranodal lesion (performed within 3 months) at screening.  For MM, bone marrow analysis will include bone 
marrow morphology, IHC, Cytogenetics by standard karyotyping, FISH panel.  Post-baseline bone marrow or lymph node (DLBCL) assessments should be performed to confirm 
response as defined by disease-specific criteria, or as clinically indicated.  For DLBCL, subsequent bone marrow assessment will only be performed in subjects who have bone 
marrow involvement at screening. A bone marrow biopsy assessment should be performed to confirm CR (if subject had bone marrow involvement at screening) and as clinically 
indicated.
o. Baseline serum and urine M protein (24 hr) levels will be assessed by electrophoresis and immunofixation.  Free light chain (FLC) levels and ratio will also be assessed.  If 
serum M protein by electrophoresis (SPEP) is ≥ 1g/dL at baseline, SPEP will be assessed after each cycle.  Post-baseline serum: immunofixation needed only in absence of M-
spike.  Post-baseline: perform all serum, urine, and FLC analyses as needed to confirm response per criteria. 
p. If baseline urine M protein (24 hr) by electrophoresis (UPEP) ≥ 200 mg, collect urine (24 hr) after each cycle.  Otherwise, assess urine protein (24 hr) as needed to confirm 
response per criteria. 
q. FLC post-baseline: for subjects with non-secretory myeloma (SPEP < 1 g/dL and UPEP < 200 mg/24 hr) at baseline, but serum light chain ≥ 10 mg/dL, serum FLC will be 
assessed after each cycle.  Otherwise, assess FLC as needed to confirm response per criteria.
r.
Refer to Section 7.1.3 Laboratory Procedures/Assessments and the Procedures Manual for additional details.  For CLL cohort only: Saliva for genetic analysis for CLL 
subjects is to be sent to the Central Lab and not performed locally.
s.
Blood samples for dinaciclib PK will be collected on Cycle 3 Day 1 (14 mg/m2) at the following times: pre-dose, and 1 hour, 2 hours (end of infusion), 3 hours and 5 hours 
after the start of the infusion.  Refer to Section 7.1.3.5 and the Procedures Manual for additional details.
t.
NOT to be repeated at every cycle thereafter.
u. A historical IgVH mutational status result is to be permitted for CLL subjects.
v. The mandatory safety follow-up visit should be conducted approximately 30 days after the last dose of trial treatment or before the initiation of a new antineoplastic treatment,
whichever comes first.
w. Blood samples for pembrolizumab PK levels and anti-pembrolizumab antibodies will be collected within 24 hours before infusion at Cycle 1 Day 1, at the time of 
discontinuation and post treatment safety follow up (30 days after the last dose of trial treatment or before the initiation of a new antineoplastic treatment, whichever comes first).
x. Quantitative immunoglobulins will be collected predose on Cycle 1 Day 1, every 3 cycles while subject is on trial drug, and post-treatment safety follow-up (30 days after the 
last dose of trial treatment or before the initiation of a new antineoplastic treatment, whichever comes first).
y. PT (INR) and aPTT are required at screening only and to be performed more frequently if clinically indicated for subject on anticoagulants.
 
 
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7.0 TRIAL PROCEDURES
Trial Procedures
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
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.
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.
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 
 
 
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performing any procedure related to Future Biomedical Research.  A copy of the informed 
consent will be given to the subject.
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.
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.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
Medical History
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the investigator. Details regarding the disease 
for which the subject has enrolled in this trial will be recorded separately and not listed as 
medical history.
Prior acute and/or chronic Graft versus Host Disease, maximum grade, and dates will be 
collected.
Prior and Concomitant Medications Review
7.1.1.5.1 Prior Medications
The investigator or qualified designee will review prior medication use and record prior 
medication taken by the subject within 28 days before starting the trial. Treatment for the 
disease for which the subject has enrolled in the trial will be recorded separately and not 
listed as a prior 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 through the Safety Follow-up visit.
Record all medications taken for SAEs and ECIs as defined in Section 7.2. 
7.1.1.5.3 Prior Cancer Treatment Details
The investigator or qualified designee will review all prior cancer treatments including but 
not limited to systemic treatments, prior transplantation, radiation, and surgeries and record 
in the trial database.
 
 
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7.1.1.5.4 Subsequent Antineoplastic Therapy
The investigator or qualified designee will review all new antineoplastic therapy initiated 
after the last dose of trial treatment.  
Collect transplant parameters after trial treatment to include the conditioning regimen, date, 
and type of transplant.
If a subject initiates a new antineoplastic therapy within 30 days after the last dose of trial 
treatment, the 30-day Safety Follow-up visit must occur before the first dose of the new 
therapy.  Once new antineoplastic therapy has been initiated, the subject will move into 
survival follow-up.
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.  
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.  The assigned 
screening number will become the subjects' treatment/randomization number. 
Once a 
treatment/randomization number is assigned to a subject, it can never be re-assigned to 
another subject.
A single subject cannot be assigned more than 1 treatment/randomization number.
Trial Compliance
Interruptions from the protocol specified treatment plan for ≥3 weeks require consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on subject management.
Administration of dinaciclib and pembrolizumab will be done by the investigator and/or trial 
staff.  The total volume of pembrolizumab infused will be compared to the total volume 
prepared to determine compliance with each dose administered.
The instructions for preparing and administering dinaciclib and pembrolizumab will be 
provided in the Pharmacy Manuals. 
 
 
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Clinical Procedures/Assessments
Oncologic Disease Details
The investigator or qualified designee will obtain prior and current details regarding 
oncologic disease status.
DLBCL subtypes, including germinal center B-cell–like (GCB), activated B-cell–like (ABC),
and unclassified (not fitting the criteria for either ABC or GCB DLBCL subtypes), are 
requested.  Other known pathology and biology parameters, such as T-cell/histiocyte-rich B-
cell lymphoma, Epstein-Barr virus positive lymphoma, MYC, B-cell lymphoma 2 (BCL2)
gene rearrangement, expression and MYC gene alterations, should be recorded if data are 
available.
Full Physical Exam
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  At this visit, clinically significant abnormal findings should be recorded as 
medical history.  A full physical exam should be performed during screening and repeated as 
per the frequency defined in the Trial Flow Chart (Section 6.0).  After the first dose of trial 
treatment, new clinically significant abnormal findings should be recorded as AEs.
Electrocardiogram
A standard 12-lead electrocardiogram will be performed using local standard procedures at 
screening.  Clinically significant abnormal findings should be recorded as medical history.
Vital Signs
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart (Section 6.0).  Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.  Height will be measured at screening only.
Eastern Cooperative Oncology Group Performance Status
The investigator or qualified designee will assess ECOG status (Section 12.4) at screening, 
on Day 1 of Q3W cycle and discontinuation of trial treatment as specified in the Trial Flow 
Chart (Section 6.0).
Adverse Event 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.  AEs will be graded and recorded throughout the trial and during the follow-up 
period according to National Cancer Institute’s CTCAE Version 4.0 (Section 12.11).  
Toxicities will be characterized in terms regarding seriousness, causality, toxicity grading, 
and action taken with regard to trial treatment.
Refer to Section 7.2 for detailed information regarding the assessment and recording of AEs.
 
 
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Criteria for Assessment of Disease
Antitumor activity of dinaciclib and pembrolizumab will be evaluated locally using the 
following criteria:

CLL:  iwCLL guidelines [1]

MM:  International uniform response criteria for multiple myeloma [2]

DLBCL:  Revised Response Criteria for Malignant Lymphoma [3]
7.1.2.7.1 Disease Assessment During Trial
Disease assessments should be performed locally per the frequency defined in the Trial Flow 
Chart (Section 6.0).  There is a ± 7-day window for assessments performed after Day 1.  
Disease assessments or scans should not be delayed for delays in cycle starts.  
Images and/or laboratory assessments may be requested by the Sponsor for independent 
review.
7.1.2.7.2 Disease Assessment of Immunotherapeutic Agents 
Immunotherapeutic agents such as pembrolizumab may produce antitumor effects by 
potentiating endogenous cancer-specific immune responses, which may be functionally 
anergic.  The response patterns seen with such an approach may extend beyond the typical 
time course of responses seen with cytotoxic agents, and can manifest a clinical response 
after an initial increase in tumor burden or even the appearance of new lesions.  Standard 
response assessment criteria may not provide a complete response assessment of 
immunotherapeutic agents such as pembrolizumab.  Therefore, in the setting where a 
subject’s assessment shows PD, trial drug may be continued at the discretion of the 
investigator until the next disease response assessment provided that the subject’s clinical 
condition is stable.  However, imaging should occur at any time when there is clinical 
suspicion of progression.
Refer to Section 7.1.2.7.3 for confirmation assessment requirements when a subject’s disease 
response assessment shows PD.  
7.1.2.7.3 Disease Progression Assessments 
A subject with progression of disease documented at a disease response assessment may 
continue trial treatment until the next response assessment, provided the subject’s clinical 
condition is stable.  However, a response assessment should occur at any time where there is 
clinical suspicion of progression.
Subjects may only receive treatment while waiting for confirmation of PD if the following 
criteria are met:

Absence of signs and symptoms (including worsening of laboratory values) indicating 
disease progression

No decline in ECOG performance status
 
 
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
Absence of rapid progression of disease 

Absence of progressive tumor at critical anatomical sites 
After the first disease response assessment, it is at the discretion of the investigator to keep a 
clinically stable subject on trial treatment or to stop trial treatment until a repeat assessment 
is performed.  Subjects who are deemed clinically unstable after first disease response 
assessment should not continue trial treatment and must be discontinued from the trial. 
Subjects who are deemed clinically unstable are not required to have repeat imaging for 
confirmation.  
For subjects noted to have progression of disease at a time point beyond the disease response 
assessment, the investigator, upon consultation with the Sponsor, may keep a clinically stable 
subject on trial treatment as long as the subject is deriving clinical benefit.
Sponsor recommendation is that the subject should be on trial treatment for at least 8 weeks 
in order to confirm disease progression and at least 2 consecutive assessments with minimum 
of 2 weeks of time between assessments are required unless there is a clinical compromise in 
which case the subject may be discontinued after consultation with the Sponsor.
Assessment of Disease and Tumor Response
7.1.2.8.1 CLL Response Assessments
Disease assessments or scans performed as part of routine clinical management are 
acceptable for use as the screening scan if they are of diagnostic quality and performed 
within 28 days prior to Cycle 1 Day 1.
CT scans of the neck, chest, abdomen, and pelvis will be obtained at screening within 28 
days of Cycle 1 Day 1.  Follow-up CT scans of the neck should be performed if enlarged 
lymph nodes (defined as ≥1.5 cm) are detected on the screening CT neck scan or if 
medically indicated by the discretion of the treating physician.
CT scans will be repeated every 3 cycles (approximately 9 weeks) despite any delays in 
treatment.  CT scans will be read locally. 
Response will be determined locally according to the iwCLL criteria, using results of the 
subject's CT scan, hematology laboratory results (complete blood counts), and presence of
CLL symptoms as described in Section 12.7. Response assessments should be completed in 
conjunction with the subject's CT scan schedule.
If medically appropriate, a confirmatory assessment of the initial progression event 
should be performed within 9 weeks. A CT scan of the neck (if indicated), chest, abdomen
and pelvis and hematology laboratory (complete blood counts) will be obtained, and the
presence of CLL symptoms will be determined at each response assessment time point.
 
 
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7.1.2.8.2 Multiple Myeloma Response Assessments:
Myeloma Laboratory Testing Disease Measurements
Baseline
For subjects with MM, collect serum and urine samples within 28 days of Cycle 1 Day 1 for 
baseline disease assessment.  Baseline serum and urine (24 hr) M protein levels will be 
assessed by electrophoresis and immunofixation. Free light chain (FLC) levels and ratio will 
also be assessed.
Serum electrophoresis (SPEP)
If serum M protein by electrophoresis (SPEP) ≥ 1 g/dL at baseline, SPEP will be assessed 
after each cycle.
Urine electrophoresis (UPEP)
If urine M protein (24 hr) by electrophoresis (UPEP) ≥ 200 mg, UPEP (24 hr) will be 
assessed after each cycle.
FLC
For subjects with non-secretory myeloma (SPEP < 1 g/dL and UPEP < 200 mg/24 hr) at 
baseline, but serum light chain ≥ 10 mg/dl, serum FLC will be assessed after each cycle. 
Best Response
Laboratory assessments should be repeated to confirm best response, including SPEP and 
UPEP, serum and urine immunofixation, and FLC. Bone marrow biopsy is recommended to 
confirm CR. 
Response will be determined locally according to IMWG criteria [2] described in Section 
12.8.
Imaging for Subjects with Myeloma Bone Disease
Skeletal survey by conventional radiography must be performed at screening within 28 days 
of Cycle 1 Day 1 to determine the extent of the subject’s myeloma bone disease. The use of 
conventional or low dose CT scan or magnetic resonance imaging (MRI) bone survey is 
acceptable. A skeletal survey performed as standard of care prior to signing consent can be 
used for screening if performed within 28 days of Cycle 1 Day 1.
During the course of the trial, skeletal surveys should be performed as clinically indicated. If 
suspected disease progression, the same modality of imaging used at screening should be 
performed for assessment of progression. The development of a compression fracture does 
not necessarily exclude antitumor response if not related to disease progression. Bone lesions 
should be considered as non-measurable disease and recorded as such.
For subjects with extramedullary soft tissue plasmacytomas, an MRI, CT, or positron 
emissions tomography (PET)/CT should be performed at baseline within 28 days of Cycle 1
Day 1. An MRI, CT, or PET/CT performed as standard of care prior to signing consent can 
be used for screening if performed within 28 days of Cycle 1 Day 1. During the course of the 
trial, subsequent imaging should be performed as clinically indicated (whether or not an 
 
 
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extramedullary soft tissue plasmacytoma was present at baseline) and at the time of a CR or 
stringent CR (sCR) assessment. The same modality of imaging used at screening should be 
performed for subsequent assessments. 
At any time a subject develops bone pain or there is a suspicion of new bone disease or 
extramedullary soft tissue plasmacytoma indicative of disease progression, appropriate 
imaging according to clinical practice should be performed to confirm disease progression.
7.1.2.8.3 DLBCL Disease Response Assessment
Disease assessments or scans performed as part of routine clinical management are 
acceptable for use as the screening scan if they are of diagnostic quality and performed 
within 28 days prior to Cycle 1 Day 1.  CT and PET should be used throughout the trial.  For 
lymphomas that are not PET-avid at screening, PET does not need to be repeated in follow-
up assessments.   
The site trial team must review pre-trial images to confirm the subject has measurable disease 
as defined in the inclusion criteria.  
PET/CT scans of the chest, abdomen, and pelvis will be repeated every 3 cycles (9 weeks) or 
when medically indicated despite any delays in treatment.
PET/CT scans of the neck should be performed if enlarged lymph nodes are detected during
the PE exam or if otherwise medically indicated by the discretion of the treating physician.
PET/CT scans will be read locally.
Response assessment by CT or PET/CT is based on the Revised Response Criteria for 
Malignant Lymphoma [3] described in Section 12.9. If complete remission is documented by 
both CT and FDG-PET, subsequent assessments may be by CT only, with PET used only if 
relapse or recurrence is suspected. Local reading (investigator assessment with site radiology 
reading) will be used to determine subject eligibility and for subject management.  
Assessment of lymphoma B symptoms should occur with each lymphoma disease response 
assessment (Section 12.10). If a subject has radiographically progressive disease but is 
clinically stable and suspicious for pseudo-progression, the subject can continue trial
treatment after consultation with the Sponsor. Additionally, the subject should be rescanned 
within 4 to 6 weeks for confirmation. The subject should discontinue trial treatment if they 
meet discontinuation criteria described in Sections 5.8.1, 7.1.2.7.2, and 7.1.2.7.3.  
Biopsy Collection and Correlative Studies Blood Collection
All subjects enrolled into this trial must be able to provide a bone marrow biopsy sample or 
newly obtained core or excisional biopsy (fine needle aspirate not adequate) to be submitted 
for characterization.  Subjects with rrDLBCL must also provide a core or excisional biopsy
add of lymph node or extranodal lesion at Screening.  If the investigator deems that a biopsy 
is unsafe or not indicated for other reasons, a Sponsor consultation is required.
Biopsies done previously within 3 months before screening are permitted to be used for this 
trial.  If bone marrow biopsy was performed within 3 months before screening but the subject
had anticancer treatment after biopsy, the bone marrow biopsy and aspirate should be 
repeated.
 
 
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Biopsy sites should be selected so that subsequent biopsies can be performed at the same 
location.  Tumors that are inaccessible or contraindicated due to subject safety concerns are 
exempt from this requirement. DLBCL subtypes, GCB, ABC, and unclassified (not fitting 
the criteria for either ABC or GCB DLBCL subtypes), need to be classified and recorded.
Other known pathology and biology parameters, such as T-cell/histiocyte-rich B-cell 
lymphoma, Epstein-Barr virus  positive lymphoma, MYC, BCL2 gene rearrangement, 
expression and MYC gene alterations, should be recorded if data is available.
Bone marrow and lymph node biopsies will be collected as per Table 14.
Table 14
Bone Marrow or Lymph Node Biopsy Assessments
Tumor type
Timing of Biopsy
CLL: Bone marrow biopsy and aspiration
Screening; to confirm CR, or as clinically indicated
MM: Bone marrow biopsy and aspiration
Screening; to confirm CR, sCR, or as clinically indicated
DLBCL: Lymph node or extranodal lesion
biopsy, bone marrow biopsy (aspiration only 
at screening if bone marrow biopsy was 
performed >3 months before screening and the 
subject had a subsequent anticancer treatment).
Screening; to confirm CR (if subject had bone marrow 
involvement at screening), or as clinically indicated
All subjects will have lymph node or extranodal lesion 
biopsy
performed during screening.
Bone 
marrow 
biopsy/aspirate may be performed during screening or an
archived bone marrow will be collected at Screening. 
Subsequent bone marrow assessments will only be 
performed in subjects who have bone marrow involvement 
at screening.
Abbreviations:  CLL = chronic lymphocytic leukemia; CR = complete response; DLBCL = diffuse large B-cell lymphoma; 
MM = multiple myeloma; sCR = stringent complete response.
Tissue for correlative biomarker studies should be collected as per Table 15.
Table 15
Tissue Collection for Correlative Biomarkers Studies
Indication
Timing of Correlative Blood Collection
Whole Blood for RNA/DNA:
Pre-dose 
on 
C1DI, 
pre-dose 
on 
C2D1, 
Discontinuation
Blood for biomarker studies (plasma and serum)
Pre-dose 
on 
C1D1, 
pre-dose 
on 
C2D1, 
Discontinuation
Blood for genetic analysis
Pre-dose on C1D1
CLL: Saliva for genetic analysis
Pre-dose on C1D1
Abbreviations:  C1D1 = Cycle 1 Day 1; C2D1 = Cycle 2 Day 1; CLL = chronic lymphocytic leukemia.
Laboratory Procedures/Assessments
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 Trial Procedures 
Manual.  Refer to the Trial Flow Chart (Section 6) for the timing of laboratory assessments.
 
 
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Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Table 16.  Except 
for analyses of biomarkers or other prognostic indicators (proteomics, genetics, 
transcriptional analysis, pharmacokinetics, antibodies), all tests will be analyzed locally.
Table 16
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Pregnancy test (serum or 
urine)a
Hemoglobin
Alkaline phosphatase
Glucose
PT/INR
Platelet count
Alanine aminotransferase
Protein
aPTT
WBC 
(total 
and 
differential)d
Aspartate aminotransferase
Specific gravity 
Total T3 or free T3, FT4, 
and TSHb
RBC
Bicarbonatec
Microscopic 
exam, 
if 
abnormal results are noted
B2 microglobulin
G6PD (as necessary)
Absolute 
lymphocyte countd
Calcium
Chloride
Absolute neutrophil 
countd
Creatinine
Glucose
LDH
Phosphorus
Potassium
Sodium
Total bilirubin  
Direct bilirubin
Total protein
Uric Acid
Blood urea nitrogen
a
Perform on women of childbearing potential only 72 hours prior to Day 1 of Cycle 1.  All women who are being 
considered for participation in the trial, and who are not surgically sterilized or postmenopausal, must be tested for 
pregnancy within 72 hours of each cycle of trial treatment and 30 days post-treatment.
b
T3 is preferred; if not available free T3 may be tested. 
c
If this test is not done as part of local standard of care, this test does not need to be performed.  
d
Report % or absolute results per standard of practice. Report the results in the same manner throughout the trial.
Abbreviations: aPTT = activated partial thromboplastin time; G6PD = glucose-6-phosphate dehydrogenase deficiency; 
INR = international normalized ratio; LDH = lactic dehydrogenase; PT = prothrombin time; RBC = red blood cells; 
WBC = white blood cells.
 
 
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Pregnancy Test
All women who are being considered for participation in the trial, and who are not surgically 
sterilized or postmenopausal, must be tested for pregnancy within 72 hours of each cycle of 
trial treatment and 30 days post-treatment.  If a urine test is positive or not evaluable, a serum 
test will be required.  Subjects must be excluded/discontinued from the trial in the event of a 
positive or borderline-positive test result.
Evaluations for Subjects with CLL
For subjects with CLL, at baseline assess for constitutional symptoms and analyze blood or 
serum as appropriate for the following (all analyses local).  Repeat at post-baseline as needed 
(Section 6).

Fluorescence in situ hybridization (FISH) or cytogenetics for del17p, del13q, del11q, 
trisomy 12, 

IgVH mutational status (mutated is ≥2% difference from germline)

CD38 (percentage of CLL cells expressing CD38)

CD4, CD8

Quantitative serum immunoglobulins (IgA, IgG, IgM)
Evaluations for Subjects with MM
For subjects with MM, baseline bone marrow analysis (local) will include morphology, 
immunohistochemistry, 
cytogenetics 
by 
standard 
karyotyping, 
and 
FISH 
panel. 
Additionally, baseline quantitative serum immunoglobulins (IgA, IgG, IgM) are required.  
Repeat these studies if post-baseline bone marrow is done (Section 6).
Pharmacokinetic/Pharmacodynamic Evaluations
Blood samples will be obtained to measure pharmacokinetics of serum dinaciclib on Cycle 3 
Day 1 and of serum pembrolizumab as per the Trial Flow Charts (Section 6). If the infusion 
is being given through a central venous catheter, either arm may be used to obtain 
pharmacokinetic samples.
Blood Collection for Anti-pembrolizumab Antibodies
Sample collection, storage, and shipment instructions for serum samples will be provided in 
the procedure manual.  Anti-pembrolizumab antibody samples should be drawn according to 
the collection schedule (Section 6).  Every effort should be taken to collect samples at 30 
days after end of treatment (or before the subject starts new anticancer therapy, whichever 
comes first) for pembrolizumab pharmacokinetic level and anti-pembrolizumab antibodies.  
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the operations/laboratory manual. 
 
 
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Blood Collection for Correlative and Biomarker Studies
Any leftover samples from the correlative and biomarker blood studies will be stored for 
future biomedical research if the subject signs the Future Biomedical Research consent. 
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the operations/laboratory manual. 
Planned Genetic Analysis Sample Collection
Sample collection, storage, and shipment instructions for Planned Genetic Analysis samples 
will be provided in the Procedures Manual.  Samples should be collected for planned analysis
of associations between genetic variants in germline/tumor DNA and drug response.  If a
documented law or regulation prohibits (or local IRB/Independent Ethics Committee [IEC]
does not approve) sample collection for these purposes, then such samples should not be
collected at the corresponding sites.  Leftover DNA extracted from planned genetic analysis 
samples will be stored for future biomedical research only if subject signs the Future
Biomedical Research consent.
Future Biomedical Research
The following specimens are to be obtained as part of Future Biomedical Research:

DNA for future research

Leftover bone marrow biopsy samples

Leftover lymph node biopsies

Leftover DNA and RNA from correlative studies

Leftover plasma and serum from biomarker studies
Other Procedures
Withdrawal/Discontinuation
Subjects who discontinue/withdraw from treatment prior to completion of the treatment
regimen should be encouraged to continue to be followed for all remaining study visits.
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events.
7.1.4.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main trial 
are still available, the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@merck.com), and a form will be provided by the Sponsor to 
 
 
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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.
7.1.4.1.2 Lost to Follow-up
If a subject fails to return to the clinic for a required trial visit and/or if the site is unable to 
contact the subject, the following procedures are to be performed:

The site must attempt to contact the subject and reschedule the missed visit.  If the 
subject is contacted, the subject should be counseled on the importance of 
maintaining the protocol-specified visit schedule.

The investigator or designee must make every effort to regain contact with the 
subject at each missed visit (eg, phone calls and/or a certified letter to the 
subject’s last known mailing address or locally equivalent methods). These 
contact attempts should be documented in the subject’s medical record.

Note:  A subject is not considered lost to follow-up until the last scheduled visit 
for the individual subject.  The amount of missing data for the subject will be 
managed via the pre-specified data handling and analysis guidelines.
Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
Domiciling
Subjects with CLL or DLBCL will report to the clinical research unit on Day -1 prior to the 
scheduled day of trial drug administration on Cycle 1 Day 1 and remain in the unit until 
approximately 10 hours post-dose on Day 1.  At the discretion of the investigator, subjects 
may be requested to remain in the clinical research unit longer.
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 
 
 
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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 trial objectives

Infusion equipment - as required for administering drug product.
See protocol-specified guidance in the Administrative Binder, Procedures Manual, Pharmacy 
Manual, and Site Imaging Manual.
Visit Requirements
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
Screening
Approximately 28 days prior to treatment allocation/randomization, potential subjects will be 
evaluated to determine that they fulfill the entry requirements as set forth in Section 5.1.  
Screening procedures may be repeated after consultation with the Sponsor.
Written consent for the main trial must be obtained prior to performing any protocol-specific 
procedure.  Results of a test performed prior to the subject signing consent as part of routine 
clinical management are acceptable in lieu of a screening test if performed within the 
specified time frame.  Screening procedures are to be completed within 28 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.  If urine pregnancy results cannot be 
confirmed as negative, a serum pregnancy test will be required (performed by the 
local trial site laboratory).
Subjects may be rescreened 1 time after initially failing to meet the inclusion/exclusion 
criteria.  Results from assessments performed during the initial screening period are 
acceptable in lieu of a repeat screening test if performed within the specified time frame and 
the inclusion/exclusion criteria is met.
Treatment Period
Visit requirements are outlined in Section 6– Trial Flow Chart.  Specific procedure-related 
details are provided above in Section 7.1 – Trial Procedures.
Post-Treatment Visits
Antineoplastic treatments started after trial treatment completion are collected during Follow-
up and Survival Follow-up.
 
 
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7.1.5.3.1 Safety Follow-Up Visit
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new antineoplastic treatment, 
whichever comes first.  All AEs that occur prior to the Safety Follow-Up Visit should be 
recorded.  Subjects with an AE of Grade > 1 will be followed until the resolution of the AE 
to Grade 0-1 or until the beginning of a new antineoplastic therapy, whichever occurs first.  
SAEs that occur within 90 days of the end of treatment or before initiation of a new 
antineoplastic treatment should also be followed and recorded.
Efficacy Follow-up Visits
Subjects who complete the protocol-required cycles of treatment or who discontinue trial 
treatment for a reason other than confirmed PD will move into the Follow-Up Phase and 
should be assessed every 12 weeks (± 14 days) for at least 12 months to monitor disease 
status (Section 6).  Every effort should be made to collect information regarding disease
response status until the start of new antineoplastic therapy, documented PD by investigator 
assessment, death, or end of the trial.  Information regarding post-trial antineoplastic 
treatment will be collected if new treatment is initiated.
7.1.5.4.1 Follow-Up Post-Allogeneic Stem Cell Transplantation
For subjects who have an allogeneic SCT within 24 months of last dose of pembrolizumab or 
before the end of the trial, transplant parameters will be collected, and specific events will be 
collected as ECIs for 18 months from the date of the allogeneic transplant or until the end of 
the trial, to include graft-versus-host-disease, hepatic veno-occlusive disease and/or 
sinusoidal syndrome, febrile syndrome (a steroid-requiring febrile illness without an 
infectious cause), pulmonary complications, immune-mediated AEs, critical illness, and 
transplant-related mortality, for all grades, and regardless of relationship to trial drug. 
Additional medically important AEs post-allogeneic SCT may be submitted at the 
investigator’s discretion (Section 7.2.3.2.1).  If available and relevant to an event post-
allogeneic SCT, concomitant medications and/or laboratory results may also be reported.
Post-allogenic-SCT ECIs that occur after the normal safety follow-up period must be 
assessed for seriousness and causality and reported to the sponsor as follows: within 24 hours 
if serious regardless of causality or if non-serious and considered to be drug related; and 5 
calendar days if non-serious and not considered to be drug related.
Guidance on details to be collected and suggested events to be reported can be found in the 
Procedure Manual. 
7.1.5.4.2 Survival Follow-up
Once a subject experiences confirmed disease progression or starts a new antineoplastic 
therapy, the subject moves into the survival follow-up phase and should be contacted by 
telephone every 12 weeks (± 14 days) to assess for survival status until death, withdrawal of 
consent, or the end of the trial, whichever occurs first. The first survival follow-up 
assessment should be scheduled as described below: 
 
 
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For participants who discontinue treatment intervention and who will not enter the efficacy 
follow-up phase, the first survival follow-up assessment will be scheduled 12 weeks after the 
discontinuation visit and/or safety follow-up visit (whichever is last).  
For participants who completed assessments in the efficacy follow-up phase, the first 
survival follow-up assessment will be scheduled 12 weeks after the last efficacy assessment 
follow-up visit has been performed.
7.1.5.4.3 Survival Status
To ensure current and complete survival data are available at the time of database locks, 
updated survival status may be requested during the course of the trial by the Sponsor. For 
example, updated survival status may be requested prior to but not limited to an external Data 
Monitoring Committee review, interim and/or final analysis. Upon Sponsor notification, all 
participants who do not/will not have a scheduled trial visit or trial contact during the 
Sponsor-defined time period will be contacted for their survival status (excluding participants 
that have a previously recorded death event in the collection tool).
Assessing and Recording Adverse Events
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.
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.
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 
 
 
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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 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 
Sponsor
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose for pembrolizumab defined as any dose of ≥ 1000 mg (5 times the protocol-defined 
dose), and for dinaciclib defined as any dose > 70 mg/m2. No specific information is 
available on the treatment of overdose of pembrolizumab or dinaciclib. In the event of 
overdose, pembrolizumab or dinaciclib 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 
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
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.  Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 120 days following cessation of Sponsor’s product, or 30 
days following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier, must be reported by the investigator.  All reported pregnancies must be 
 
 
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followed to the completion/termination of the pregnancy.
Pregnancy outcomes of 
spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal 
death, intrauterine death, miscarriage and stillbirth must be reported as serious events 
(Important Medical Events). If the pregnancy continues to term, the outcome (health of 
infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them), including the pregnancy of a male subject's female partner 
that occurs during the trial.
Pregnancies and lactations of subjects and female partners of male subjects from the time the 
consent form is signed but before treatment allocation/randomization must be reported by the 
investigator if they cause the subject to be excluded from the trial, or are the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.  Pregnancies and lactations of subjects 
and female partners of male subjects that occur from the time of treatment 
allocation/randomization through 14 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
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 
 
 
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as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.
●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose.
Refer to Table 17 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 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, 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.
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).
7.2.3.2.1 Follow-Up Post-Allogeneic Stem Cell Transplantation
For subjects who have an allogeneic SCT within 24 months of last dose of pembrolizumab or 
before the end of the trial, transplant parameters will be collected, and specific ECIs will be 
collected for 18 months from the date of the allogeneic transplant, to include graft-versus-
host-disease, hepatic veno-occlusive disease and/or sinusoidal syndrome, febrile syndrome (a 
steroid-requiring febrile illness without an infectious cause), pulmonary complications, 
immune-mediated AEs, critical illness, and transplant-related mortality for all grades, and 
regardless of relationship to trial drug. Additional medically important AEs post-allogeneic 
SCT may be submitted at the investigator’s discretion.
Post-allogenic SCT events of ECIs that occur after the normal safety follow-up period and 
before the end of the trial must be assessed for seriousness and causality and reported to the 
sponsor as follows: within 24 hours if serious regardless of causality or if non-serious and 
considered to be drug related; and 5 calendar days if non-serious and not considered to be 
drug related.
Guidance on details to be collected and suggested events to be reported can be found in the 
Procedure Manual.
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 trial.
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 trial will be forwarded to global safety as a SAE within 
24 hours of determination that the event is not progression of the cancer under trial.
 
 
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Evaluating Adverse Events
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.
For studies in which multiple agents are administered as part of a combination regimen, the 
investigator may attribute each adverse event causality to the combination regimen or to a 
single agent of the combination.  In general, causality attribution should be assigned to the 
combination regimen (i.e., to all agents in the regimen). However, causality attribution may 
be assigned to a single agent if in the investigator’s opinion, there is sufficient data to support 
full attribution of the adverse experience to the single agent.
 
 
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Table 17
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?
 
 
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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
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.
 
 
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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
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 trial.  Changes to 
analyses made after the protocol has been finalized, but prior to final database lock, will be 
documented in a supplemental statistical analysis plan and referenced in the Clinical Trial Report 
(CSR) for the trial.  Post hoc exploratory analyses will be clearly identified in the CSR.  
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized in the Statistical Analysis Plan 
Summary below; the comprehensive plan is provided in Sections 8.2 to 8.12.
Unless indicated otherwise, statistical analyses will be performed separately for Dose 
Evaluation and Signal Detection of this trial.  For Signal Detection, statistical analyses will 
be performed separately by cohort.
Statistical Analysis Plan Summary
Trial Design Overview
This trial, entitled “Phase Ib Trial of Pembrolizumab (MK-3475) in 
Combination with Dinaciclib (MK-7965) in Subjects with Hematologic 
Malignancies (KEYNOTE-155)” is a multicenter, multiple-cohort, non-
randomized trial of dinaciclib (MK-7965) in combination with pembrolizumab 
(MK-3475) in subjects with relapsed or refractory CLL, MM, or DLBCL.  After 
a Dose Evaluation phase, the cohorts (CLL, MM, DLBCL) will be enrolled for 
Signal Detection.
Treatment Assignment
In Dose Evaluation, 12 subjects (at least 3 subjects each with rrCLL, rrMM, or 
rrDLBCL) meeting inclusion/exclusion criteria will receive pembrolizumab and 
dinaciclib at the initial dose (Dose Level 0) as described in Table 3 and 
Table 11; Dose Levels -1 and -2 will be evaluated with no restriction on the 
distribution of disease types rrCLL, rrMM, and rrDLBCL.  If and when the 
safety criteria for Dose Evaluation are met, Signal Detection will use the same 
doses of pembrolizumab and dinaciclib.
Analysis Populations
In Signal Detection, the primary analysis population for both efficacy and safety 
assessments is the “All Subjects as Treated” (ASaT) population, defined as all 
subjects who receive at least one dose of trial medication (pembrolizumab or
dinaciclib).
Primary Endpoint(s)
The primary endpoint is DLT (as defined in Section 5.2.1.4).  
Key 
Secondary 
Endpoints
1.
ORR according to investigator assessment using the overall population and 
for disease-specific criteria (as applicable) 
2.
DOR
3.
PFS
4.
OS
Statistical Methods for 
In Signal Detection, the point estimate of the ORR will be calculated as well as 
 
 
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Key Efficacy Analyses
a 95% 2-sided exact confidence interval.
Statistical Methods for 
Key Safety Analyses
In Dose Evaluation, descriptive statistics will be used to evaluate the DLT rate.  
Summary statistics (counts, percentage, mean, standard deviation, etc.) will be 
provided for the safety endpoints as appropriate.
Interim Analyses
In Signal Detection, both safety and efficacy will be assessed prior to full 
enrollment within each cohort.  In terms of efficacy, a cohort may terminate if 
inadequate efficacy is observed (0 responses out of first 12 evaluable subjects in 
the MM and DLBCL cohorts; 2 or fewer out of 12 for the CLL cohort); refer to
Section 8.7 for details.
Multiplicity
No adjustment for multiplicity is planned. 
Sample Size and Power 
The minimum and maximum overall sample size for this trial is 102 and 131
subjects, respectively (ie, 12 to 41 from Dose Evaluation plus 90 from Signal 
Detection).  Assuming a 5% non-evaluable rate (ie, not evaluable for DLT in 
Dose Evaluation or not treated in Signal Detection), a maximum of 138 subjects 
would be enrolled in this trial.
In Signal Detection, with 30 subjects in the experimental arm (pembrolizumab +
dinaciclib), the maximum half-width of the two-sided 95% confidence interval 
for ORR within each cohort is 19%.  
Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this trial will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This trial is being conducted as an open-label trial; therefore, subjects, investigators, and 
Sponsor personnel will be aware of subject treatment assignments after each subject is 
enrolled and treatment is assigned.
Hypotheses/Estimation
No formal hypotheses are to be tested in this trial; objectives of the trial are stated in 
Section 3.
Analysis Endpoints
Efficacy Endpoints
Efficacy endpoints will be based on investigator assessment using the disease-specific 
criteria outlined in Section 7.1.2.8.
Primary
Objective Response Rate
ORR is defined as the proportion of subjects in the analysis population who achieved at least 
a partial response according to the disease-specific criteria (CR+PR for CLL and DLBCL; 
sCR+CR+VGPR (very good partial remission)+PR for MM).
 
 
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Secondary
Duration of Response
For subjects who demonstrated a response (PR or better), DOR is defined as the time from 
first documented evidence of response until first documented evidence of disease progression 
or death due to any cause, whichever occurs first.
Progression-Free Survival
PFS is defined as the time from first dose of trial treatment to the first documented evidence 
of disease progression or death due to any cause, whichever occurs first.
Overall Survival
OS is defined as the time from first dose of trial treatment to death due to any cause.  
Safety Endpoints
Safety measurements are described in Section 7.2.
Analysis Populations
In Dose Evaluation, subjects are considered to be evaluable for DLT assessment if the 
subjects meet all the following criteria:

Subjects enrolled and received at least one dose of trial medication.

Subject did not discontinue within the first 2 cycles, or subject experienced a DLT 
prior to completing the first 2 cycles of treatment
In Signal Detection, the analyses of efficacy and safety endpoints are based on the ASaT
population. Subjects will be included if they receive at least 1 dose of trial medication.
At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 dose of trial 
treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
Statistical Methods
This section provides the statistical details for analyses of efficacy and safety endpoints. 
A summary of the primary analysis strategy for the primary and secondary efficacy endpoints 
is provided in Table 19.
The analyses will be performed for Signal Detection only, separately within each cohort.  In 
Dose Evaluation, subject listings for these endpoints (ORR, DOR, PFS, and OS) will be 
provided.
Objective Response Rate
The analysis of ORR will consist of the point estimate and 95% 2-sided exact confidence 
interval using the Clopper-Pearson method, which will have at least 95% coverage of the true 
rate.  
 
 
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Duration of Response
The analysis of DOR will consist of Kaplan-Meier estimates.  DOR data will be censored on 
the date of the last disease assessment documenting absence of progressive disease for 
subjects who do not have tumor progression and are still on trial at the time of an analysis, 
are given antitumor treatment other than the trial treatment, or are removed from trial prior to 
documentation of tumor progression.
Progression-Free Survival
The non-parametric Kaplan-Meier method will be used to estimate the PFS curve.  
Additional details, including censoring rules for those subjects without PD, are summarized 
in Table 18. 
Table 18
Censoring Rules for PFS
Situation
Analysis
No PD and no death; new anticancer 
treatment is not initiated
Censored at last disease assessment 
No PD and no death; new anticancer 
treatment is initiated
Censored at last disease assessment before new 
anticancer treatment
PD or death documented after ≤ 1 
missed disease assessment
Progressed at date of documented PD or death
PD or death documented after ≥ 2 
missed disease assessments
Progressed at date of documented PD or death
No PD and no death and lost to follow-
up after ≥2 missed disease assessments
Censored at last disease assessment 
Abbreviation:  PD = progressive disease.
Overall Survival
The median OS, if reached, will be estimated in the given analysis population.  In addition, 
the Kaplan-Meier method will be used to estimate the survival curve.
 
 
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Table 19
Analysis Methods for Efficacy Endpoints (Signal Detection)
Endpoint/Variable
Statistical Method
Analysis 
Population
Missing Data Approach
Primary:
ORR
–
by
investigator 
assessment 
using
disease-
specific criteriaa
2-sided 
95% 
exact 
confidence interval
ASaT
Subjects with missing data 
are 
considered 
non-
responders.
Secondary:
DOR 
–
by 
investigator 
assessment 
using
disease-
specific criteriaa
Summary statistics using 
Kaplan-Meier method
All 
responders
Non-responders 
are 
excluded in analysis.
PFS 
–
by 
investigator 
assessment 
using
disease-
specific criteriaa
Summary statistics using 
Kaplan-Meier method
ASaT
Censored at last assessment 
(see Table 18 for additional 
details)
OS
Summary statistics using 
Kaplan-Meier method
ASaT
Censored at last assessment
a CLL based on iwCLL guidelines [1]; MM based on IMWG criteria [2]; DLBCL based on the Revised Response Criteria 
for Malignant Lymphoma [3].
Abbreviations:  ASaT = all subjects as treated; DOR = duration of response; ORR = objective response rate; OS = overall 
survival; PFS = progression-free survival.
Statistical Methods for Safety Analyses
In both Dose Evaluation and Signal Detection, safety and tolerability will be assessed by
clinical review of all relevant parameters, including AEs, ECIs, laboratory tests, and vital
signs.  Summary statistics (counts, percentage, mean, standard deviation, etc.) will be
provided for the safety endpoints as appropriate.
See Section 8.8 for statistical details on the dose evaluation of pembrolizumab plus dinaciclib
conducted in Dose Evaluation.
Other Analyses
Baseline characteristics will be assessed by the use of tables and/or graphs.  No statistical 
hypothesis tests will be performed on these characteristics.  The number and percentage of 
subjects screened, allocated, the primary reasons for screening failure, and the primary 
reason for discontinuation will be displayed.  Demographic variables (eg, age, gender), 
baseline characteristics, primary and secondary diagnoses, and prior and concomitant 
therapies will be summarized by descriptive statistics or categorical tables.
Additional exploratory analyses will be described in the supplemental statistical analysis 
plan.
Interim Analysis
In Signal Detection, a futility analysis will be conducted separately within each cohort. After 
the first 12 subjects are evaluable for efficacy (treated and with at least one post-baseline 
 
 
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disease assessment), the ORR will be evaluated according to the disease-specific criteria.  
Enrollment would not be paused within a cohort during the futility evaluation.  For the MM 
and DLBCL cohorts, if 0 responses are observed among the 12 subjects, which would rule 
out an ORR of 17% with 90% confidence (1-sided), the cohort may be terminated; for the 
CLL cohort, if 2 or fewer responses are observed among the 12 subjects, which would rule 
out an ORR of 39% with 90% confidence (1-sided), the totality of the data including both 
safety and efficacy will be evaluated to decide whether or not to continue enrollment in that 
cohort. 
Sample Size and Power Calculation
In the Dose Evaluation phase, a minimum of 12 subjects will be evaluated at Dose Level 0. 
A potential maximum of 41 subjects may be evaluated across dose levels for DLTs as 
described in Section 5.2.1.3.4.  Twelve subjects evaluated at Dose Level 0 is not entirely 
based on statistical grounds but would allow for at least 3 evaluated per disease (rrCLL, 
rrMM, and rrDLBCL) with an overall statistical assessment of the DLT rate as described in 
Table 12.
In Signal Detection phase, the proposed sample size is 30 subjects for the primary analysis 
population (ASaT) for each cohort (CLL, MM, DLBCL), 90 in all.  With 30 subjects in each 
cohort, the maximum half-width of the two-sided 95% exact confidence interval for ORR 
within each cohort is 19%.  Table 20 describes examples of 95% confidence intervals per 
cohort across a possible range of ORRs.
Table 20
Precision (95% Confidence Intervals) for Range of Observed ORR (33% - 83%)
Number of responses/Number of treated subjects (ORR) 
95% 2-sided Confidence Intervala
10/30 (33%)
15/30 (50%)
20/30 (67%)
25/30 (83%)
(17, 53)
(31, 69)
(47, 83)
(65, 94)
a
exact (Clopper-Pearson) confidence limit for the binomial proportion.
Abbreviation:  ORR = objective response rate.
Thus, the minimum and maximum overall sample size for this trial is 102 and 131 subjects, 
respectively, 12 to 41 subjects from Dose Evaluation plus 90 from Signal Detection. 
Assuming a 5% non-evaluable rate (ie, not evaluable for DLT in Dose Evaluation or not 
treated in Signal Detection), a maximum of 138 subjects would be enrolled in this trial.
Multiplicity
No multiplicity adjustment is planned in this trial. 
Subgroup Analyses and Effect of Baseline Factors
Point estimate of the ORR (with an exact two-sided 95% confidence interval) will be 
provided within each disease cohort.  For subgroups such as age (≤65 vs > 65 years), sex 
(female vs male), race (white vs non-white) and region (US, ex-US), ORR 95% confidence 
interval will be provided if the subgroup sample size is adequate.
 
 
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Compliance (Medication Adherence)
Drug accountability data for trial treatment (pembrolizumab and dinaciclib) will be collected 
during the trial. Compliance with trial treatment administration will be measured by subjects: 
1) receiving unscheduled trial agent infusions/injections; 2) missing an infusion/injection. 
Numbers and percentages of subjects and infusion/injection visits with any deviation in these 
measures will be reported.
Extent of Exposure
The extent of exposure for pembrolizumab and dinaciclib will be summarized as duration of 
treatment in cycles. Dose intensity will also be summarized as appropriate.
9.0 LABELING, PACKAGING,
STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
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 21.
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 21
Product Descriptions
Product Name & Potency
Dosage Form
Source / Additional 
Information
Pembrolizumab (MK-3475) 50 
mg
Lyophilized powder for IV 
injection
Provided 
centrally 
by 
the 
Sponsor
Pembrolizumab (MK-3475) 100 
mg/4mL
Solution for infusion
Provided 
centrally 
by 
the 
Sponsor.  However, solution will 
not be supplied at the initiation 
of the trial.  It is considered a 
back-up formulation.
Dinaciclib 
(MK-7965) 
5 mg/mL
Solution for infusion
Provided 
centrally 
by 
the 
Sponsor
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
 
 
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Open-label vials will be provided for subject dosing.
Clinical Supplies Disclosure
The 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.
Storage and Handling Requirements
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
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.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
Confidentiality of Data
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
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
 
 
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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
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
The Sponsor is required to record the name and address of each IRB/IEC member 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
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor or through a secure password-protected electronic portal provided by the 
 
 
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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
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 
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.  
 
 
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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
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Merck, as 
Sponsor of this trial, will review this protocol and submit the information necessary to fulfill 
these requirements.  Merck entries are not limited to FDAMA/FDAAA mandated trials. 
Information posted will allow subjects to identify potentially appropriate trials for their 
 
 
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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
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
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
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
 
 
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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.
 
 
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11.0 LIST OF REFERENCES
[1]
Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, 
et al. Guidelines for the diagnosis and treatment of chronic lymphocytic 
leukemia: a report from the International Workshop on Chronic Lymphocytic 
Leukemia updating the National Cancer Institute-Working Group 1996 
guidelines. Blood 2008;111(12):5446-56.
[2]
Durie BGM, Harousseau J-L, Miguel JS, BladéJ, Barlogie B, Anderson K. 
International uniform response criteria for multiple myeloma. Leukemia 
2006;20:1467-73.
[3]
Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. 
Revised response criteria for malignant lymphoma. J Clin Oncol 2007;25:579-86.
[4]
Disis ML. Immune regulation of cancer. J Clin Oncol 2010;28(29):4531-8.
[5]
Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et 
al. 
Adoptive 
cell 
transfer 
therapy 
following 
non-myeloablative 
but 
lymphodepleting chemotherapy for the treatment of patients with refractory 
metastatic melanoma. J Clin Oncol 2005;23(10):2346-57.
[6]
Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. 
Treatment of metastatic melanoma with autologous CD4+ T cells against NY-
ESO-1. N Engl J Med 2008;358(25):2698-703.
[7]
Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev 
Immunol 2005;23:515-48.
[8]
Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor 
inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-
containing tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci U S A 
2001;98(24):13866-71.
[9]
Zhang X, Schwartz J-CD, Guo X, Bhatia S, Cao E, Chen L, et al. Structural and 
functional analysis of the costimulatory receptor programmed death-1. Immunity 
2004;20:337-47.
[10]
Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 
associate with immunoreceptor tyrosine-based switch motif of programmed death 
1 upon primary human T cell stimulation, but only receptor ligation prevents T 
cell activation. J Immunol 2004;173:945-54.
[11]
Sheppard K-A, Fitz LJ, Lee JM, Benander C, George JA, Wooters J, et al. PD-1 
inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta 
signalosome and downstream signaling to PKCtheta. FEBS Lett. 2004;574:37-41.
 
 
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[12]
Riley JL. PD-1 signaling in primary T cells. Immunol Rev 2009;229:114-25.
[13]
Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi 
SV, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct 
mechanisms. Mol Cell Biol 2005;25(21):9543-53.
[14]
Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and 
autoimmunity. Immunol Rev 2010;236:219-42.
[15]
Lees JA, Weinberg RA. Tossing monkey wrenches into the clock: New ways of 
treating cancer. Proc Natl Acad Sci USA 1999;96:4221-3.
[16]
Shapiro GI. Cyclin-dependent kinase pathways as targets for cancer treatment. J 
Clin Oncol 2006;24(11):1770-83.
[17]
Schwartz GK, Shah MA. Targeting the cell cycle: A new approach to cancer 
therapy. J Clin Oncol 2005;23(36):9408-21.
[18]
Buschges R, Weber RG, Actor B, Lichter P, Collins VP, Reifenberger G. 
Amplification and expression of cyclin D genes (CCND1, CCND2 and CCND3) 
in human malignant gliomas. Brain Pathol. 1999 Jul;9(3):435-42.
[19]
Lammie GA, Fantl V, Smith R, Schuuring E, Brookes S, Michalides R, et al. 
D11S287, a putative oncogene on chromosome 11q13, is amplified and expressed 
in squamous cell and mammary carcinomas and linked to BCL-1. Oncogene. 
1991 Mar;6(3):439-44.
[20]
Tsuda H, Bandera CA, Birrer MJ, Hashiguchi Y, Berkowitz RS, Mok SC. Cyclin 
E amplification and overexpression in clear cell adenocarcinoma of the ovary. 
Oncology 2004;67:291-9.
[21]
Hutter G, Scheubner M, Zimmermann Y, Kalla J, Katzenberger T, Hubler K, et 
al. Differential effect of epigenetic alterations and genomic deletions of CDK 
inhibitors [p16(INK4a), p15(INK4b), p14(ARF)] in mantle cell lymphoma. 
Genes Chromosomes Cancer 2006;45:203-10.
[22]
Chim CS, Wong ASY, Kwong YL. Epigenetic Inactivation of the CIP/KIP Cell-
Cycle Control Pathway in Acute Leukemias. Am J Hematol 2005;80:282-7.
[23]
Chen YNP, Sharma SK, Ramsey TM, Jiang L, Martin MS, Baker K, et al. 
Selective killing of transformed cells by cyclinycyclin-dependent kinase 2 
antagonists. Proc Natl Acad Sci U S A 1999;96:4325-9.
[24]
Kortmansky J, Shah MA, Kaubisch A, Weyerbacher A, Yi S, Tong W, et al. 
Phase I trial of the cyclin-dependent kinase inhibitor and protein kinase C 
inhibitor 7-hydroxystaurosporine in combination with fluorouracil in patients 
with advanced solid tumors. J Clin Oncol 2005;23(9):1875-84.
 
 
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[25]
Brown JR. Chronic lymphocytic leukemia: A niche for Flavopiridol? Clin Cancer 
Res 2005;11(11):3971-3.
[26]
Moskowitz CH, Ribrag V, Michot JM, Martinelli G, Zinzani PL, Gutierrez M, et 
al. PD-1 Blockade with the Monoclonal Antibody Pembrolizumab (MK-3475) in 
Patients with Classical Hodgkin Lymphoma after Brentuximab Vedotin Failure: 
Preliminary Results from a Phase 1b Study (KEYNOTE-013) [abstract]. Blood. 
2014;124(21 Suppl). Abstract no. 290.
[27]
Zinzani PL, Ribrag V, Moskowitz CH, Michot JM, Kuruvilla J, Balakumaran A, 
et al. Phase 1b study of pembrolizumab in patients with relapsed/refractory 
primary mediastinal large B-cell lymphoma: results from the ongoing 
KEYNOTE-013 trial [abstract]. Abstracts of the American Society of 
Hematology 58th Annual Meeting and Exposition; 2016 Dec 3-6; San Diego, 
CA: ASH; 2016. p. 4.
[28]
Armand P, Shipp MA, Ribrag V, Michot J, Zinzani PL, Kuruvilla J et al. 
Pembrolizumab in patients with classical hodgkin lymphoma after brentuximab 
vedotin failure: long-term efficacy from the phase 1b keynote-013 study 
[abstracts]. Abstracts of the American Society of Hematology 58th Annual 
meeting and exposition; 2016 Dec 3-6; San Diego, CA: ASH; 2016.
[29]
Flynn JM, Jones JA, Andritsos L, Blum KA, Johnson AJ, Hessler J, et al. Phase I 
study of the CDK inhibitor dinaciclib (SCH 727965) in patients (pts) with 
relapsed/refractory CLL. [Abstract]. J Clin Oncol 2011;29:1.
[30]
Baiocchi RA, Flynn JM, Jones JA, Blum KA, Hofmeister CC, Poon J, et al. Early 
evidence of anti-lymphoma activity of the cyclin dependent kinase inhibitor 
dinaciclib (SCH 727965) in heavily pre-treated low grade lymphoma and diffuse 
large cell lymphoma patients [Abstract]. Blood 2010;116:1-2.
[31]
Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and 
classification. Br J Haematol 2004;127:3-11.
[32]
Ji Y, Li Y, Bekele BN. Dose-finding in phase I clinical trials based on toxicity 
probability intervals. Clin Trials 2007;4:235-44.
[33]
Rizzo JD, Lichtin AE, Woolf SH, Seidenfeld J, Bennett CL, Cella D, et al. Use of 
epoetin in patients with cancer: evidence-based clinical practice guidelines of the 
American Society of Clinical Oncology and the American Society of 
Hematology. Blood 2002;100(7):2303-20.
[34]
Smith TJ, Khatcheressian J, Lyman GH, Ozer H, Armitage JO, Balducci L, et al. 
2006 update of recommendations for the use of white blood cell growth factors: 
an evidence-based clinical practice guideline. J Clin Oncol 2006;24(19):3187-
205.
 
 
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12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
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
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 7.1.3.9 – Future Biomedical 
Research 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 Merck 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 Merck or designees and research 
will be monitored and reviewed by a committee of our scientists and clinicians.
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 Future 
Biomedical Research.
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.  Information contained on the consent form alone cannot be traced 
 
 
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to any specimens, test results, or medical information once the specimens have been 
rendered de-identified
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.  
Each informed consent approved by an ethics committee is assigned a unique tracking 
number.  The tracking number on this document will be used to assign specimen 
permissions for each specimen into the Entrusted Keyholder’s Specimen Database.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of both consent and acquisition of Future Biomedical Research 
specimens will be captured in the electronic Case Report Forms (eCRFs).  
Reconciliation of both forms will be performed to assure that only appropriately-
consented specimens are used for Future Biomedical Research purposes. Any 
specimens for which such an informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
[insert: Blood specimens for DNA or RNA isolation will usually be obtained at a time 
when the subject is having blood drawn for other trial purposes. OR Buccal swab 
specimens for DNA isolation will be obtained at a time when the subject is having 
other trial procedures conducted.] Specimens like tissue and bone marrow will 
usually be obtained at a time when the subject is having such a procedure for clinical 
purposes.
Specimens will be collected and sent to the laboratory designated for the trial where 
they will be processed (e.g., DNA or RNA extraction, etc) following the Merck 
approved policies and procedures for specimen handling and preparation.
If specimens are collected for a specific genotype or expression analysis as an 
objective to the main trial, this analysis is detailed in the main body of this protocol 
(Section 8.0 – Statistical Analysis Plan).  These specimens will be processed, 
analyzed, and the remainder of the specimen will be destroyed.  The results of these 
analyses will be reported along with the other trial results.  A separate specimen will 
be obtained from properly-consented subjects in this protocol for storage in the 
biorepository for Future Biomedical Research.
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, Merck has developed secure policies and procedures.  All 
specimens will be de-identified as described below. 
 
 
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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.  
This first code will be replaced with a second code at a Merck designated storage/lab 
facility.  The second code is linked to the first code via a second key. The specimen is 
now double coded.  Specimens with the second code are sometimes referred to as de-
identified specimens. The use of the second code provides additional confidentiality and 
privacy protection for subjects over the use of a single code.  Access to both keys would 
be needed to link any data or specimens back to the subject's identification.
The second code is stored separately from the first code and all associated personal 
specimen identifiers.  A secure link, the second key, will be utilized to match the second 
code to the first code to allow clinical information collected during the course of the trial 
to be associated with the specimen.  This second key will be transferred under secure 
procedures by the Merck designated facility to an Entrusted Keyholder at Merck.  The 
second code will be logged into the primary biorepository database at Merck and, in this 
database, this identifier will not have identifying demographic data or identifying clinical 
information (i.e., race, sex, age, diagnosis, lab values) associated with it. The specimen 
will be stored in a designated biorepository site with secure policies and procedures for 
specimen storage and usage.
The second key can be utilized to reconstruct the link between the results of future 
biomedical research and the clinical information, at the time of analysis.  This linkage 
would not be possible for the scientist conducting the analysis, but can only be done by 
the Merck Entrusted Keyholder under strict security policies and procedures.  The Merck 
Entrusted Keyholder will link the information and then issue a de-identified data set for 
analysis.  The only other circumstance by which future biomedical research data would 
be directly linked to the full clinical data set would be those situations mandated by 
regulatory authorities (e.g., EMEA, FDA), whereby this information would be directly 
transferred to the regulatory authority.
5. Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good 
scientific practices.  However, exploratory analyses will not be conducted under the 
highly validated conditions usually associated with regulatory approval of diagnostics.  
The scope of research performed on these specimens is limited to the investigation of the 
variability in biomarkers that may correlate with a clinical phenotype in subjects.
Analyses utilizing the Future Biomedical Research specimens may be performed by 
Merck, or an additional third party (e.g., a university investigator) designated by Merck.  
The investigator conducting the analysis will be provided with double coded specimens.  
Re-association of analysis results with corresponding clinical data will only be conducted 
by the Merck Entrusted Keyholder.  Any contracted third party analyses will conform to 
the specific scope of analysis outlined in the contract.  Future Biomedical Research 
specimens remaining with the third party after the specific analysis is performed will be 
 
 
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returned to the sponsor or destroyed and documentation of destruction will be reported to 
Merck.
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 Merck using the designated mailbox 
(clinical.specimen.management@merck.com) and a form will be provided by Merck 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 Merck 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 acquisition.  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 Merck 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 Merck policies and procedures and 
this destruction will be documented in the biorepository database.
8. Data Security
Separate databases for specimen information and for results from Future Biomedical 
Research will be maintained by Merck.  This is done to separate the future exploratory 
test results (which include genetic data) from the clinical trial database thereby 
maintaining a separation of subject number and these results.  The separate databases are 
accessible only to the authorized Sponsor 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 in international 
standards (e.g., ISO17799) to protect against unauthorized access.  The Merck Entrusted 
Keyholder maintains control over access to all specimen data.  These data are collected 
for future biomedical research purposes only and will not be used for any other purpose.
 
 
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9. Reporting of Future Biomedical Research Data to Subjects
There is no definitive requirement in either authoritative ethical guidelines or in relevant 
laws/regulations globally that research results have to be, in all circumstances, returned to 
the trial participant.  Some guidelines advocate a proactive return of data in certain 
instances.  No information obtained from exploratory laboratory studies will be reported 
to the subject or family, and this information will not be entered into the clinical database 
maintained by Merck on subjects.  Principle reasons not to inform or return results to the 
subject include: lack of relevance to subject health, limitations of predictive capability, 
concerns of misinterpretation and absence of good clinical practice standards in 
exploratory research typically used for diagnostic testing.
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 as 
to how to offer clinical diagnostic  testing (paid for by Merck) to subjects enrolled and 
will be advised that counseling should be made available for all who choose to participate 
in this diagnostic testing. 
If any exploratory results are definitively associated with clinical significance after 
completion of a clinical trial, Merck will publish the results without revealing specific 
subject information, inform all trial sites who participated in the Merck clinical trial and 
post anonymized results on our website or other accredited website(s) that allow for 
public access (e.g., disease societies who have primary interest in the results) in order that 
physicians and patients may pursue clinical diagnostic testing if they wish to do so.
10. Gender, Ethnicity and Minorities
Although many diagnoses differ in terms of frequency by ethnic population and gender, 
every effort will be made to recruit all subjects diagnosed and treated on Merck clinical 
trials for future biomedical research.  When trials with specimens are conducted and 
subjects identified to serve as controls, every effort will be made to group specimens 
from subjects and controls to represent the ethnic and gender population representative of 
the disease under current investigation.
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 [ie, only leftover samples are being retained].)
Merck 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.
It is necessary for subject-related data (i.e., ethnicity, diagnosis, drug therapy and dosage, 
age, toxicities, etc.) to be re-associated to double coded specimens at the time of data 
analysis.  These subject data will be kept in a separate, secure Merck database, and all 
specimens will be stripped of subject identifiers.  No information concerning results 
obtained from future biomedical research will be entered into clinical records, nor will it 
be released to outside persons or agencies, in any way that could be tied to an individual 
subject.
 
 
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12. Self-Reported Ethnicity
Subjects who participate in future biomedical research will be asked to provide self-
reported ethnicity.  Subjects who do not wish to provide this data may still participate in 
future biomedical research.
13. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
14. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
 
 
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Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff
 
 
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111
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112
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113
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12-MAR-2020
CONFIDENTIAL
 
 
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114
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12-MAR-2020
CONFIDENTIAL
 
 
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115
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12-MAR-2020
CONFIDENTIAL
 
 
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116
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12-MAR-2020
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117
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12-MAR-2020
CONFIDENTIAL
 
 
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118
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12-MAR-2020
CONFIDENTIAL
 
 
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119
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12-MAR-2020
CONFIDENTIAL
 
 
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ECOG Performance Status
Grade
Description
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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Recommended Supportive Care Guidelines for Tumor Lysis Syndrome 
Prevention and Treatment in Subjects with CLL and DLBCL
1. Subjects with CLL and DLBCL will be admitted to the inpatient service the day prior 
to dinaciclib treatment for a minimum of the first treatment (C1D1 dose).
2. Premedication and IV hydration for dinaciclib for CLL and DLBCL are described in 
Section 5.2.1.3.1 (Table 6).
3. Using the Cairo-Bishop definition of laboratory TLS, K, calcium, potassium, and uric 
acid will be evaluated at 3 and 5 hours after the start of the first dinaciclib infusion 
(C1D1) as part of a TLS work- up (Section 5.2.1.3.3).  Subjects with a positive TLS 
work-up should remain in the hospital and follow-up should be initiated. If necessary, 
subjects must be admitted overnight for observation.

If serum potassium > 4.5 mmol/L, then the subject should receive a 30 g dose of 
Kayexalate (or equivalent).

If serum potassium > 5.0 mmol/L, then the subject should receive 10 units of IV 
regular insulin and one ampule of D50 IV.  During this time period, trial
treatment administration should be discontinued.

If serum potassium > 5.5 mmol/L, then the subject should be considered for 
emergent intermittent or continuous hemodialysis.
During this time period, trial treatment administration should be discontinued.
Subjects who do not have laboratory TLS may receive Dose 2 (Day 8) of Cycle 1, as well as 
all subsequent therapies, as an outpatient.
This will allow inpatient monitoring of subjects during the most critical window of 
vulnerability to tumor lysis, yet allow subjects who tolerate dinaciclib to eventually be 
treated in the outpatient setting.
4. Subjects who develop clinical evidence of CRS or who have hyperkalemia requiring 
dialysis will receive immediate steroid therapy with 20 mg of IV dexamethasone (or 
equivalent).  CRS is described in the NCI CTCAE current version.  It occurs during 
or shortly after drug infusion and generally resolves within 24 hours of completing 
the infusion. Generally, the first manifestation of this syndrome is tachycardia 
followed by a constellation of symptoms.  Subjects starting therapy with a normal 
pulse whose rate increases to >100 beats per minute post-therapy should be 
administered therapy for CRS.  The signs and symptoms of CRS may include allergic 
reaction (including drug fever), arthralgia, bronchospasm, cough, dizziness, dyspnea, 
fatigue, headache, hypertension or hypotension, myalgia, nausea, pruritus, rash, 
rigors, chills, sweating, tachycardia, tumor pain, urticaria, and vomiting.
5. Subjects who require dialysis for hyperkalemia and/or other symptoms of TLS will be 
administered prophylactic antibiotics for gram-negative organisms (Zosyn 4.5 g IV 
every 8 hours or equivalent) and gram-positive organisms (vancomycin 1 g IV every 
12 hours or equivalent) until dialysis is discontinued.
 
 
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6. Subjects requiring intervention for TLS or demonstrating CRS symptoms should have 
their serum electrolytes, phosphate, calcium and magnesium checked every 8 to 12 
hours post-therapy.  If treatment is required, Amphojel or equivalent phosphate-
binding agents are recommended.  In this setting, calcium supplementation should 
only be given for symptomatic hypocalcemia to avoid renal precipitation of calcium 
phosphate crystals.
7. Subject may be discharged home the morning following the first dinaciclib infusion 
once their chemistry laboratory results have been reviewed by the treating physician.
8. It is recommended to inform the local renal consultant service of inpatient admissions 
for the first dinaciclib treatment for each subject. Administration of the first dinaciclib 
dose should occur at the beginning of the day.
 
 
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Drugs that Interact with CYP3A4
Information for drug interactions with cytochrome P450 isoenzymes can be found at
http://medicine.iupui.edu/flockhart/.
 
 
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Revised iwCLL Response Guidelines
CLL response assessment is based on the 2008 International Workshop (iwCLL) guidelines (Blood
2008;111:5446-5456) with the following clarifications/revisions.
NCI-WG CLL Response Criteria
A
Complete Remission (CR)
Requires ALL of the following criteria as assessed at least 2 months after completion of therapy:
Peripheral blood lymphocytes (x109/L)
Lymphadenopathy
Hepatomegaly or splenomegaly
Symptoms
Blood counts:
Neutrophils (x109/L), and
Platelets (x109/L), and
Hemoglobin (g/dL)
Bone marrow
<4
None by physical exam and CT scan
None by physical exam and CT scan
None
>1.5 without need for exogenous growth factors
>100 without need for exogenous growth factors
>11 without red blood cell transfusion or need for 
exogenous erythropoietin
For subjects in clinical trials, at least 2 months after the last
treatment and if clinical and laboratory criteria for CR has
been achieved:
normal cellularity for age; <30% of
nucleated cells are lymphocytes; no lymphoid nodules. If
hypocellular, repeat bone marrow biopsy at 4 weeks, or
until peripheral blood counts have recovered (time interval
should not exceed 6 months after last treatment).
CR with Incomplete Marrow Recovery (CRi)
Meets all criteria for CR but have persistent anemia or thrombocytopenia or neutropenia related to drug
toxicity
Nodular Partial Remission
Meets all criteria for CR but lymphoid nodules are present in the bone marrow sample obtained at least 2
months after last treatment.
Partial Remission (PR)
The following criteria must be documented for a minimum of 2 months:
 
 
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Blood lymphocytes, and
Lymphadenopathy, and
≥50% decrease from baseline
≥50% decrease in the sum products of up to 6 lymph nodes
or in the largest diameter of the enlarged lymph node(s)
from baseline.
and
No increase in any lymph node, an no new enlarged 
lymph node (in lymph nodes <2 cm, an increase of < 25% 
is not considered significant)
Liver or spleen (if abnormal before therapy)
Plus, one or more of the following:
Neutrophils
Platelets 
Hemoglobin
≥50% decrease from baseline (CT scan [clinical trials]
or palpitation [general practice])
>1.5 x109/L (1500/µL) without need for exogenous growth 
factors
>100 x109/L (100,000/µL), or 50% improvement over 
baseline, without need for exogenous growth factors
>11 g/dL (110 g/L), or 50% improvement over baseline, 
without red blood cell transfusion or need for exogenous 
erythropoietin
Progressive Disease (PD)
Characterized by at least one of the following during or after therapy:
 
 
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Lymphadenopathy
Liver or spleen
Blood lymphocytes
Cytopenia
Other
New lesion, such as enlarged lymph nodes (>1.5 cm), 
splenomegaly, hepatomegaly, or other organ
infiltrates or ≥50% increase in greatest determined 
diameter of any previous site
≥50% increase from previous noted enlargement or the de
novo appearance of hepatomegaly or splenomegaly
≥50% increase with ≥5000 B lymphocytes per 
microliter
Progression of cytopenia attributable to CLL which 
occurs at least 3 months after treatment as documented
by:
- decrease of Hb levels by >20 g/L or to >100 g/L
- decrease of platelets by >50% or to <100x109/L
if the marrow biopsy demonstrates an infiltrate of 
clonal CLL cells
Transformation to a more aggressive histology (e.g., 
Richter syndrome)
Stable disease (SD)
Subjects who have not achieved a CR or a PR, and who have not exhibited PD
A   Blood. 2008;111:5446-5456.
 
 
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International Myeloma Working Group criteria for response assessment in 
multiple myeloma (IMWG criteria)
Durie et al.  International uniform response criteria for multiple myeloma.  Leukemia.  2006; 
20:1467-1473.
 
 
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Lymphoma Disease Response Criteria
Cheson et al.  Revised Response Criteria for Malignant Lymphoma.  J Clin Oncol.  2007; 
25:579-586.
Criteria for lymphoma disease assessment:
 
 
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Lymphoma B Symptoms and Constitutional Symptoms
Lymphoma B Symptoms:
Lymphoma B symptoms are a set of clinical criteria used in the initial diagnosis and 
treatment of Hodgkin Lymphoma.  These criteria are used in this trial as part of the initial 
assessment of Lymphoma disease staging and as a measure of the response to trial treatment.
The criteria are as follows: 

Unexplained weight loss of more than 10% of the body weight during the 6 months 
before initial staging investigation; 

Unexplained, persistent, or recurrent fever with temperatures above 38°C during the 
previous month; and 

Recurrent drenching night sweats during the previous month.
Source:  Lister TA, Crowther D, Sutcliffe, SB, et al. Report of a committee convened to discuss the evaluation and 
staging of patients with Hodgkin's disease: Cotswolds meeting. J Clin Oncol 1989;7:1630-1636.
Constitutional Symptoms:
For all subjects with CLL, constitutional symptoms should be assessed at the time points 
described in Section 6.0 and Section 7.1.3.3.
Constitutional symptoms, defined as any one or more of the following disease-related 
symptoms or signs:

Unintentional weight loss of 10% or more within the previous 6 months;

Significant fatigue (ie, ECOG PS 2 or worse; inability to work or perform usual 
activities);

Fevers higher than 100.5°F or 38.0°C for 2 or more weeks without other evidence of 
infection; or

Night sweats for more than 1 month without evidence of infection.
Source: Hallek M, Cheson BD, Catovsky D, et al.  Guidelines for the diagnosis and treatment of chronic 
lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the 
National Cancer Institute–Working Group 1996 guidelines. Blood. 2008 Jun 15; 111(12): 5446–5456.
 
 
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Common Terminology Criteria for Adverse Events V4.0
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be 
used
for AE
reporting. 
(http://ctep.cancer.gov/reporting/ctc.html).
 
 
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Abbreviations
Abbreviation/Term
Definition
ABC
activated B-cell–like
ADA(s)
antidrug antibody(ies)
AE(s)
adverse event(s)
ALT 
alanine transaminase
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
ASaT
all subjects as treated
AST
aspartate aminotransaminase
hCG
beta-human chorionic gonadotropin
BID
twice daily
BCL2
B-cell lymphoma 2
Ca
calcium
CBC
complete blood count
CD
cluster of differentiation
CDK
cyclin-dependent kinase
CFR
Code of Federal Regulations
CI
principal coordinator
CLL
chronic lymphocytic leukemia
CR
complete remission
CRS
cytokine release syndrome
CSR
clinical trial report
CT
computed tomography
CTCAE
Common Toxicity Criteria for Adverse Events
CTLA-4
cytotoxic T-lymphocyte-associated antigen-4
CYP3A4
cytochrome P450 3A4
DLBCL
diffuse large B ell lymphona
DLT
dose-limiting toxicities
DNA
deoxyribonucleic acid
DOR
duration of response
 
 
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Abbreviation/Term
Definition
ECI
events of clinical interest
ECOG
Eastern Cooperative Oncology Group
EDC
electronic data capture
EMEA
European Medicines Evaluation Agency
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FDAMA
Food and Drug Administration Modernization Act
FDG
fluorodeoxyglucose
FIH
first in human
FISH
flourescence in situ hybridization
FLC
free light chain
G6PD
glucose-6-phosphate dehydrogenase deficiency
GCB
germinal center B-cell–like 
GCP
Good Clinical Practice
G-CSF
granulocyte colony stimulating factor
GFR
glomerular filtration rate
GI
gastrointestinal
HBsAg
hepatitis B surface antigen
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
ICH
International Council on Harmonization
Ig
immunoglobulin
IgG4
immunoglobulin G4
IgVH
immunoglobulin heavy chain
IMiD
pomalidomide, lenalidomide, or thalidomide
IMWG
International Myeloma Working Group criteria for response 
assessment in multiple myeloma 
INR
International normalized ratio
irAE
immune-related adverse events
IRBs/ERCs
institutional review boards/ethics committees
 
 
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Abbreviation/Term
Definition
ITSM
immunoreceptor tyrosine-based switch motif
IUD
intrauterine device
IV
intravenous
IVRS/IWRS
interactive voice response system/ integrated web response 
system
iwCLL
International Workshop on Chronic Lymphocytic Leukemia
K
potassium
mAb
monoclonal antibody 
MM
multiple myeloma
MRI
magnetic resonance imaging
mRNA
messenger ribonucleic acid
MSD
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
NHL
non-Hodgkin lymphoma
NSAID(s)
non-steroidal anti-inflammatory drugs
ORR
objective response rate
OS
overall survival
P
phosphorus
PBPK
physiologically based pharmacokinetic
PD
progressive disease
PD-1
programmed cell death-1
PD-L1
programmed death-ligand 1
PD-L2
programmed death-ligand 2
PET
positron-emission tomography
PFS
progression-free survival
PK
pharmacokinetics
PO, po
orally
POEMS syndrome
plasma cell dyscrasia with polyneuropathy, organomegaly, 
endocrinopathy, monoclonal protein, and skin changes
PR
partial remission
PT
prothrombin time
PTT
partial thromboplastin time
 
 
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Abbreviation/Term
Definition
Q2W
every 2 weeks
Q3W
every 3 weeks
RNA
ribonucleic acid
RPTD
recommended Phase 2 dose
rrCLL
relapsed or refractory chronic lymphocytic leukemia
rrDLBCL
relapsed or refractory diffuse large B-cell lymphoma
rrMM
relapsed or refractory multiple myeloma
SAE(s)
serious adverse event(s)
sCR
stringent complete remission
SCT
stem cell transplant
SPEP
serum M protein by electrophoresis
T1DM
type 1 diabetes mellitus
T3
triothyronine
Tregs
regulatory T cells
TLS
tumor lysis syndrome
ULN
upper limit of normal
UPEP
urine M protein by electrophoresis
 
 
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13.0 SIGNATURES
Sponsor's Representative
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
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 – Assessing and Recording Adverse Events.  I also agree to handle 
all clinical supplies provided by the Sponsor and collect and handle all clinical specimens in 
accordance with the protocol.  I understand that information that identifies me will be used 
and disclosed as described in the protocol, and that such information may be transferred to 
countries that do not have laws protecting such information.  Since the information in this 
protocol and the referenced Investigator’s Brochure is confidential, I understand that its 
disclosure to any third parties, other than those involved in approval, supervision, or conduct 
of the trial is prohibited.  I will ensure that the necessary precautions are taken to protect such 
information from loss, inadvertent disclosure or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
 
 
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