Clinical trial NCT02906332
Conditions: Multiple Myeloma
Sponsor: Hackensack Meridian Health
Start date: 2016-12-12; Completion date: 2022-05-01
Enrollment: 12 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open-label, Phase II, single center trial of pembrolizumab (MK-3475), lenalidomide and dexamethasone in subjects with high risk Multiple Myeloma (hrMM) post high-dose chemotherapy with autologous stem cell transplantation (ASCT).

Patients with high-risk MM defined as those with one of the following abnormalities who have undergone induction therapy followed by single or tandem melphalan -based ASCT will be considered eligible.

Detailed description:
The primary objectives of this trial are to establish the progression free survival (PFS) of ASCT followed by consolidative therapy with pembrolizumab plus lenalidomide and dexamethasone and to evaluate the safety of pembrolizumab plus lenalidomide and dexamethasone following ASCT. The immunological analysis of cells and cytokines pre and post-therapy will be determined from patient bone marrow aspirate and peripheral blood samples as exploratory objectives. The overall composition of the gut microbiome will also be determined in patient stool samples.

Patients will be followed by response, EFS/PFS/OS and safety endpoints on an every 3 week basis. Bone marrow aspirate specimens will be obtained at screening and at completing of the study and peripheral blood specimens will be obtained on a monthly basis to evaluate in correlative studies.

Arms: arm 1: This is an open label study.

* Pembrolizumab 200 mg IV every 3 weeks and lenalidomide 25 mg po daily x 14 days and dexamethasone 40 mg po once weekly for a 21-day cycle x 2 cycles.
* This is followed by pembrolizumab 200 mg every 3 weeks and lenalidomide 25 mg po daily x 14 days for a 21-day cycle x 2 cycles for a total of 4 cycles.
Interventions: intervention 1: Pembrolizumab intervention 2: Lenalidomide intervention 3: Dexamethasone
Intervention descriptions: intervention 1: Pembrolizumab 200 mg IV every 3 weeks x 2 cycles. This is followed by followed by pembrolizumab 200 mg IV every 3 weeks for 2 additional cycles. intervention 2: Lenalidomide 25 mg po daily x 14 days once weekly for a 21-day cycle x 2 cycles. This is followed by lenalidomide 25 mg po daily x 14 days for a 21-day cycle x 2 cycles for 2 additional cycles. intervention 3: Dexamethasone 40 mg po once weekly for a 21-day cycle x 2 cycles only.

Protocol documents:
Prot_SAP_000.pdf: 
Pembrolizumab (MK-3475), Biran N, HUMC
TITLE: A phase II trial of the anti -PD-1 monoclonal antibody Pembrolizumab (MK-3475)
+ Lenalidomide + Dexamethasone as post autologous transplant consolidation in patients
with high-risk multiple myeloma
IND NUMBER: 130634
VERSION DATE:
19 August 2016
SPONSOR:
Noa Biran, M.D.
Hackensack University Medical Center
30 Prospect Avenue
Hackensack, NJ 07601
SUPPORTER:
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.
INSTITUTION:
John Theurer Cancer Center at
Hackensack University Medical Center
92 Second Street
Hackensack, NJ 07601
Principal Investigators:
Noa Biran, MD
551-996-8704
Sub Investigators:
David Siegel, MD, PhD
David H. Vesole, MD, PhD
Joshua R. Richter, MD
Susan M. Kumka, APN
Amy Pierre, APN
Rena Feinman, PhD
Robert Korngold, PhD
Michele Donato, MD
Scott Rowley, MD
Alan Skarbnik, MD
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Pembrolizumab (MK-3475), Biran N, HUMC
SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Protocol Version Date: 19August2016
_____________________________________
____________________________
Signature of Site Principal Investigator
Date (dd/mmm/yyyy)
___________________________________________________________________________
Printed Name of Site Principal Investigator
Institution Name: ____________________________________________________________
By my signature, I agree to personally supervise the conduct of this study at my study site
and to ensure its conduct is in compliance with the protocol, informed consent, Institutional
Review Board (IRB)/ Ethics Committee (EC) procedures, instructions from the Sponsor, the
Declaration of Helsinki, ICH Good Clinical Practices Guidelines, and local regulations
governing the conduct of clinical studies.
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Pembrolizumab (MK-3475), Biran N, HUMC
CONTENTS
TRIAL SUMMARY
7
1.0
TRIAL DESIGN
7
1.1
Trial Design
7
2.0
OBJECTIVES & HYPOTHESES
11
2.1
Primary Objective(s) & Hypothesis
11
2.2
Secondary Objective(s) & Hypothesis(es)
11
2.3
Exploratory Objective
11
3.0
BACKGROUND & RATIONALE
12
3.1
Background
12
3.1.1
Pharmaceutical and Therapeutic Background
12
3.1.2
Preclinical and Clinical Trial Data
13
3.2
Rationale
14
3.2.1
Rationale for the Trial and Selected Subject Population
14
3.2.2
Rationale for Dose Selection/Regimen/Modification
17
3.2.3
Rationale for Endpoints
18
4.0
METHODOLOGY
21
4.1
Entry Criteria
21
4.1.1
Diagnosis/Condition for Entry into the Trial
21
4.1.2
Subject Inclusion Criteria
21
4.1.3
Subject Exclusion Criteria
23
4.2
Trial Treatments
25
4.2.1
Dose Selection/Modification
26
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Pembrolizumab (MK-3475), Biran N, HUMC
4.2.2
Timing of Dose Administration
31
4.2.3
Trial Blinding/Masking
31
4.3
Randomization or Treatment Allocation
32
4.4
Stratification
32
4.5
Concomitant Medications/Vaccinations (allowed & prohibited)
32
4.5.1
Acceptable Concomitant Medications
32
4.5.2
Prohibited Concomitant Medications
32
4.6
Rescue Medications & Supportive Care
33
4.6.1
Supportive Care Guidelines
33
4.7
Diet/Activity/Other Considerations
36
4.7.1
Diet
36
4.7.2
Contraception
37
4.7.3
Use in Pregnancy
39
4.7.4
Use in Nursing Women
39
4.8
Subject Withdrawal/Discontinuation Criteria
39
4.9
Subject Replacement Strategy
Error! Bookmark not defined.
4.10
Clinical Criteria for Early Trial Termination
40
5.0
TRIAL FLOW CHART
41
5.1
Study Flow Chart
41
6.0
TRIAL PROCEDURES
45
6.1
Trial Procedures
45
6.1.1
Administrative Procedures
45
6.1.2
Clinical Procedures/Assessments
47
6.1.3
Laboratory Procedures/Assessments
51
6.1.4
Other Procedures
53
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Pembrolizumab (MK-3475), Biran N, HUMC
6.2
Assessing and Recording Adverse Events
54
6.2.1
Definition of an Overdose for This Protocol and Reporting of Overdose to
the Sponsor and to Merck
55
6.2.2
Reporting of Pregnancy and Lactation to the Sponsor and to Merck
55
6.2.3
Immediate Reporting of Adverse Events to the Sponsor
56
6.2.4
Evaluating Adverse Events
58
6.2.5
Sponsor Responsibility for Reporting Adverse Events
61
7.0
STATISTICAL ANALYSIS PLAN
61
7.1
Statistical Analysis Plan Summary
61
7.1.1
Efficacy Analysis
61
7.1.2
Safety Analysis
62
7.1.3
Power and Sample Size
62
7.1.4
Responsibility for Analyses
63
7.1.5
Hypotheses/Estimation
63
7.1.6
Analysis Endpoints
63
7.1.7
Analysis Populations
64
7.1.8
Statistical Methods
65
7.1.9
Multiplicity
67
7.1.10 Sample Size and Power Calculations
67
7.1.11 Subgroup Analyses and Effect of Baseline Factors
67
7.1.12 Interim Analysis
67
7.1.13 Compliance (Medication Adherence)
67
8.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL
SUPPLIES
68
8.1
Investigational Product
68
8.2
Packaging and Labeling Information
68
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Pembrolizumab (MK-3475), Biran N, HUMC
8.3
Clinical Supplies Disclosure
68
8.4
Storage and Handling Requirements
68
8.5
Returns and Reconciliation
69
9.0
ADMINISTRATIVE AND REGULATORY DETAILS
69
9.1
Confidentiality
69
9.2
Compliance with Financial Disclosure Requirements
69
9.3
Compliance with Law, Audit and Debarment
70
9.4
Compliance with Trial Registration and Results Posting Requirements 71
9.5
Quality Management System
71
9.6
Data Management
72
9.7
Data and Safety Monitoring Committee (DSMC)
73
10.0
References
76
11.0
APPENDICES
80
11.1
Common Terminology Criteria for Adverse Events V4.0 (CTCAE)
80
11.2
MM Diagnostic Criteria
81
11.3
International Staging System
82
11.4
ECOG Performance Status
83
11.5
Multiple Myeloma Disease Response Criteria
84
11.6
Events of Clinical Interest Reference Table
85
85
11.7
List of Abbreviations
86
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Pembrolizumab (MK-3475), Biran N, HUMC
TRIAL SUMMARY
Abbreviated Title
Pembrolizumab + lenalidomide post autologous stem cell transplant in
high-risk MM
Trial Phase
II
Clinical Indication
Multiple Myeloma
Trial Type
Single arm Phase II efficacy/safety study
Type of control
No treatment control (historical control)
Route of administration
IV
Trial Blinding
Unblinded open label
Treatment Groups
Fixed dose pembrolizumab 200 mg every 3 weeks and lenalidomide 25 mg
po daily x 14 days and dexamethasone 40 mg once weekly for a 21-day
cycle x 2 cycles followed by fixed dose pembrolizumab 200 mg every 3
weeks and lenalidomide 25 mg po daily x 14 days for a 21-day cycle x 2
cycles for a total of 4 cycles
Number of trial subjects
Approximately 43 subjects will be enrolled
Estimated enrollment period
October 1, 2015 – October 1, 2016
Estimated duration of trial
The trial will require approximately 24 months from the time the first
subject signs the informed consent until the last subject’s last visit.
Duration of Participation
Each subject will participate in the trial from the time the subject signs the
Informed Consent Form (ICF) through the final protocol-specified contact.
After a screening phase of 28 days, eligible subjects will receive assigned
treatment appropriate for the trial stage in which they are enrolled as
described below. The assigned treatment will continue for 4 cycles, until
documented confirmed disease progression, unacceptable adverse event(s),
documented
confirmed
disease
progression,
intercurrent illness that
prevents further administration of treatment, investigator’s decision to
withdraw the subject, 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 90 days for adverse event monitoring (serious adverse events
will be collected until disease progression on an every 3 month basis +/- 3
months).
Subjects
who
discontinue for reasons other than disease
progression will have posttreatment follow-up of disease status until disease
progression, initiating a non-study cancer treatment, withdrawing consent,
or becoming lost to follow-up. All subjects will be followed by telephone or
direct contact for overall survival until death, withdrawal of consent, or the
end of the study
1.0 TRIAL DESIGN
1.1
Trial Design
This is an open-label, Phase II, single center trial of pembrolizumab (MK-3475),
lenalidomide and dexamethasone in subjects with high risk Multiple Myeloma (hrMM) post
high-dose chemotherapy with autologous stem cell transplantation (ASCT).
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Pembrolizumab (MK-3475), Biran N, HUMC
Patients with high-risk MM defined as those with one of the following abnormalities who
have undergone induction therapy followed by single or tandem melphalan -based ASCT will
be considered eligible.
1.
International Staging System (ISS) stage 3 (See Appendix 3 for ISS Staging)
and/or
2. Deletion 13q by cytogenetics and/or
3. 1q amplification, 1p deletion, p53 deletions (17p deletions), t(4;14), t(14;16),
t(14;20), hypodiploidy by FISH and/or
4. High-risk gene expression profile (GEP) scores
Post engraftment, between days +60 and day +180 post ASCT patients will undergo
restaging evaluation to include a screening BM aspirate and biopsy. Patients will then be
initiated on pembrolizumab, lenalidomide and dexamethasone for 2 cycles followed by
pembrolizumab and lenalidomide alone for 2 cycles for a total period of 4 months.
Adverse events will be monitored at every visit and graded in severity according to the
guidelines outlined in the NCI Common Terminology Criteria for Adverse Events (CTCAE)
version 4.03. (See Appendix 1).
Treatment with pembrolizumab, lenalidomide and dexamethasone for the first 2 cycles then
pembrolizumab and lenalidomide will continue for cycle 3 and 4 for a total of four cycles or
until unacceptable adverse event(s), documented confirmed disease progression, intercurrent
illness that prevents further administration of treatment, investigator’s decision to withdraw
the subject, subject withdraws consent, pregnancy of the subject, noncompliance with trial
treatment or procedure requirements, or administrative reasons. After the completion of
cycle 4, each subject will be followed for 30 days for adverse event monitoring (serious
adverse events will be collected for 90 days after the end of treatment). Subjects who
discontinue treatment for reasons other than disease progression will have post-treatment
follow-up for disease status until disease progression, initiating a non-study cancer
treatment, withdrawing consent, or becoming lost to follow-up. All subjects will be followed
by telephone contact for overall survival until death, withdrawal of consent or the end of the
trial, whichever comes first.
The primary objectives of this trial are to establish the progression free survival (PFS) of
ASCT followed by consolidative therapy with pembrolizumab plus lenalidomide and
dexamethasone and to evaluate the safety of pembrolizumab plus lenalidomide and
dexamethasone following ASCT. The immunological analysis of cells and cytokines pre and
post-therapy will be determined from patient bone marrow aspirate and peripheral blood
samples as exploratory objectives. The overall composition of the gut microbiome will also
be determined in patient stool samples.
Patients will be followed by response, EFS/PFS/OS and safety endpoints on an every 3 week
basis. Bone marrow aspirate specimens will be obtained at screening and at completing of the
8


Pembrolizumab (MK-3475), Biran N, HUMC
study and peripheral blood specimens will be obtained on a monthly basis to evaluate in
correlative studies.
This trial will be conducted in conformance with Good Clinical Practices.
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 5.0.
An interim efficacy analysis will be performed after 15 patients are accrued. The study will
stop and treatment will be rejected if there are more than 8 patients (≥9 patients) who
progress at 12 months. If 8 or more of the first 15 patients have not progressed at 12 months,
a further 26 patients will be recruited into the second stage. If the overall PFS is 70% or
above at 12 months, pembrolizumab, lenalidomide and dexamethasone will be considered to
have shown worthwhile efficacy.
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Pembrolizumab (MK-3475), Biran N, HUMC
Trial Diagram
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Pembrolizumab (MK-3475), Biran N, HUMC
2.0 OBJECTIVES & HYPOTHESES
2.1
Primary
Objective(s)
&
Hypothesis
(1) Objective: To establish the progression free survival (PFS) of high risk MM patients
receiving pembrolizumab (MK-3475), lenalidomide and dexamethasone consolidation
post autologous stem cell transplant (ASCT).
Hypothesis:
The 12-month PFS of high risk MM patients receiving pembrolizumab
(MK-3475), lenalidomide and dexamethasone consolidation post ASCT will be 70% or
above. There will be an increase in the number of long-term remitters.
2.2
Secondary
Objective(s)
&
Hypothesis(es)
(1) Objective:
To determine the safety and tolerability of pembrolizumab (MK-3475),
lenalidomide and dexamethasone following ASCT in subjects with high risk MM.
Hypothesis:
Intravenous administration of pembrolizumab (MK-3475), lenalidomide
and dexamethasone to subjects with high risk MM as consolidation therapy post ASCT is
sufficiently well tolerated.
(2) Objective: To evaluate stringent complete response, complete response, and very good
partial response rate (sCR + CR + VGPR rate) in subjects with high risk MM post-ASCT.
(3) Objective: To evaluate Overall Response Rate (ORR) in subjects with high risk MM
post-ASCT.
(4) Objective: To evaluate Time to Progression (TTP) in subjects with high risk MM
post-ASCT.
(5) Objective: To evaluate Duration of Response (DOR) in subjects with high risk MM
post-ASCT.
(6) Objective: To evaluate Overall Survival (OS) in subjects with high risk MM post-ASCT.
2.3
Exploratory
Objective
(1)
Objective: To compare in bone marrow aspirates the extent of pre-pembrolizumab
(MK-3475), lenalidomide and dexamethasone PD-L1 expression and change from
baseline PD-L1 expression in responders versus non-responders in subjects with high
risk MM post-ASCT.
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Pembrolizumab (MK-3475), Biran N, HUMC
Hypothesis: Subjects with deeper and longer duration of response to pembrolizumab,
lenalidomide and dexamethasone will have a greater change from baseline PD-L1
expression compared to subjects without response or with shorter duration of response.
(2)
Objective: To assess immune phenotype and T cell repertoire in bone marrow aspirates
and peripheral blood samples and plasma cytokines before and after treatment in
responders versus non-responders in subjects with high-risk MM post-ASCT. Assays
for these studies include flow cytometry, TCR Immunoseq for Vbeta CDR3 highest
frequency specificities, real-time PCR analysis and multiplex cytokine ELISA.
Hypothesis: Subjects with deeper and longer duration of response to pembrolizumab
and lenalidomide will have an increase from baseline of inflammatory cytokines
(TNF-alpha, IL-2, IL-4, IL-6, IL-10) and activated T cells (CD8+) compared to subjects
without response or with shorter duration of response. In particular, the presence of
CD8+ T-cells and the ratio of CD8+ effector T-cells/FoxP3+ regulatory T-cells will
correlate with improved prognosis.
(3)
Objective: To identify specific intestinal microbial strains associated with improved
outcome in autologous stem cell transplantation patients treated with PEM+LEN+DEX
compared to PEM+LEN. The overall microbial composition in stool samples of
patients will be at screening or cycle 1, day 1, cycle 2 day 1, cycle 3 day 1, cycle 4 day
1, and at the completion of cycle 4 and every 12 weeks for the duration of follow up.
Additional sample will be collected at confirmation of response.
A 16S ribosomal
RNA (rRNA) miSeq Illumina platform will be used for overall microbial composition
and quantitative real-time PCR analysis will validate the specific microbial strains
identified by miSeq.
Hypothesis: Subjects with deeper and longer duration of response to pembrolizumab
and lenalidomide will have diverse gut microbiome compared to subjects without
response or with shorter duration of response. This hypothesis is based on several
studies demonstrating that the diversity of intestinal microbiota at the time of
engraftment improves clinical outcome post-ASCT[1] and specific bacterial species
boost immune responsiveness to chemotherapy[2, 3] and checkpoint inhibitors[4, 5]
3.0 BACKGROUND & RATIONALE
3.1
Background
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background
information on Pembrolizumab.
3.1.1
Pharmaceutical and Therapeutic Background
The importance of intact immune surveillance in controlling outgrowth of neoplastic
transformation has been known for decades [6]. Accumulating evidence shows a correlation
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Pembrolizumab (MK-3475), Biran N, HUMC
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in
various malignancies [7-11].
In particular, the presence of CD8+ T-cells and the ratio of
CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved
prognosis and long-term survival in many solid tumors.
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 Ig
superfamily member related to CD28 and CTLA-4 which has been shown to negatively
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2)
[12, 13]. The structure of murine PD-1 has been resolved[14]. PD-1 and family members
are type I transmembrane glycoproteins containing an Ig Variable-type (V-type) domain
responsible for ligand binding and a cytoplasmic tail which 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 (ITIM) and an immunoreceptor
tyrosine-based switch motif (ITSM). Following T-cell stimulation, PD-1 recruits the tyrosine
phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the
dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 which are
involved in the CD3 T-cell signaling cascade[12, 15-17]. 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[18, 19]. PD-1 was shown to be
expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T
regs and Natural Killer cells[20, 21].
Expression has also been shown during thymic
development on CD4-CD8- (double negative) T-cells as well as subsets of macrophages and
dendritic cells[22]. The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or
can be induced in a variety of cell types, including non-hematopoietic tissues as well as in
various tumors[18, 23-25]. Both ligands are type I transmembrane receptors containing both
IgV- and IgC-like domains in the extracellular region and contain short cytoplasmic regions
with no known signaling motifs.
Binding of either PD-1 ligand to PD-1 inhibits T-cell
activation triggered through the T-cell receptor. PD-L1 is expressed at low levels on various
non-hematopoietic tissues, most notably on vascular endothelium, whereas PD-L2 protein is
only detectably expressed on antigen-presenting cells found in lymphoid tissue or chronic
inflammatory environments.
PD-L2 is thought to control immune T-cell activation in
lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function in peripheral
tissues[18]. Although healthy organs express little (if any) PD-L1, a variety of cancers were
demonstrated to express abundant levels of this T-cell inhibitor. PD-1 has been suggested to
regulate tumor-specific T-cell expansion in subjects with melanoma (MEL)[26].
This
suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and
should be considered as an attractive target for therapeutic intervention.
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of
the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its
ligands, PD-L1 and PD-L2. KeytrudaTM (pembrolizumab) has recently been approved in the
United Stated for the treatment of patients with unresectable or metastatic melanoma and
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Pembrolizumab (MK-3475), Biran N, HUMC
disease progression following ipilumumab and, if BRAF V600 mutation positive, a BRAF
inhibitor.
3.1.2
Preclinical and Clinical Trial Data
Refer to the Investigator’s Brochure for Preclinical and Clinical data.
3.2
Rationale
3.2.1
Rationale for the Trial and Selected Subject Population
3.2.1.1
Rationale for evaluating anti-PD-1 Therapy in Patients with Multiple Myeloma
Multiple Myeloma (MM), accounting for 10% of all hematological malignancies, is a
malignancy that results in the accumulation of clonal plasma cells in the bone marrow
leading to bone destruction and marrow failure.
It has an incidence of 20,000 cases per
year in the United States with a median age of onset of 69 years[27-30]. The diagnosis of
MM is made when there are more than 10% plasma cells in the bone marrow, presence of
monoclonal proteins in serum, and/or in urine with one or more of end organ effects such as
hypercalcemia, renal failure, anemia, or bone destruction (CRAB)[31, 32]. Patients with
MM respond to systemic immunomodulator therapy such as thalidomide, lenalidomide, and
pomalidomide. Although improvements in overall survival have been achieved with newer
therapies such as proteasome inhibitors and immunomodulatory drugs (IMiDs), myeloma
remains, in general, an incurable disease. Relapsed/refractory MM patients have an overall
survival of 9 months, but only 3 months if they receive no therapy following relapse, thus
reflecting the poor outcome among these patients[33-35].
PD-L1 is expressed on most MM plasma cells[36], and PD-L1 overexpression enhanced
MM invasiveness and rendered tumor cells less susceptible to cytotoxic T lymphocytes
(CTLs). This effect was alleviated by anti–PD-L1 antibody treatment, demonstrating the
importance of the PD-1/PD-L1 pathway in disease progression[37]. In addition, a recent
report demonstrated increased levels of PD-L1 on MM cells together with enhanced PD-1
expression on T cells with an “exhausted” phenotype. The immunosuppressive effects of
myeloma are overcome by PD-L1 blockade[38]. A Phase 1 clinical trial conducted in
advanced hematologic malignancies using CT-011, showed clinical responses in 6 of 17
patients including stable disease in multiple myeloma patients [39].
3.2.1.2
Rationale for Evaluating anti-PD-1 Therapy in Patients with High-Risk
Multiple Myeloma Post High-Dose Chemotherapy followed by Peripheral
Blood Autologous Stem Cell Transplant
Overall survival in MM ranges from several months to greater than 15 years.
With
modern therapy, survival in MM has increased from a median overall survival (OS) of 3–5
years to a 5-year survival rate of greater than 70% in transplant-eligible patients[40]. The
improvement in survival, however, is not universal, and approximately 25% of patients
have a median survival of 2 years or less[41]. The definition of high-risk MM has been in
considerable flux. Some of the largest studies have used International Staging System
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Pembrolizumab (MK-3475), Biran N, HUMC
(ISS) and the presence of chromosome 13q abnormalities by cytogenetics as the primary
definition[42].
The revised-ISS (R-ISS) combines ISS 3, high-risk cytogenetics, and
elevated LDH as markers for inferior survival[43].
More recently, p53 deletions have
been associated with PFS of 11.8 months[44]. Patients with high-risk gene expression
profiling (GEP)-70 scores (and patients with chromosome 1q amplifications and 1p
deletions by fluorescent in situ hybridization (FISH) show similar patterns[45]. Internal
data from the Hackensack University Medical Center Multiple Myeloma division show
that high-risk MM patients defined as those carrying 1q amplifications, 1p deletions, 13q
deletions by cytogenetics, p53 deletions, high-risk GEP 70 scores, t(4;14), t(14;16) and
t(14;20), hypodiploidy have a median event free survival (EFS) of 14 months post ASCT.
The MRC IX trial showed that patients with high-risk MM by FISH have a 50% 12-month
PFS from transplant[46].
While tandem ASCT remains a standard of care, the abovementioned high-risk patients
will ultimately relapse within one to two years of first transplant and there are virtually no
long-term remitters.
In contrast, patients with smoldering (asymptomatic) MM that carry
the same high-risk features are not significantly more likely to progress to active disease
than are patients without high-risk markers[47]. One of the prevailing theories as to why
smoldering MM patients, even those with high-risk disease, can remain stable for
extended periods of time is that the host immune system can maintain homeostasis. For
patients who are long term-remitters post transplant, it is likely that it is the reacquisition
of this immune-competent phenotype, rather than a greater debulking of disease, that is
responsible for long-term disease control.
In fact, it may not be necessary to attain
stringent levels of debulking in order to achieve long-term remission, as patients with
easily measurable disease can achieve long periods of stable control without anti-myeloma
therapies.
PDL-1 is routinely expressed on plasma cells of patients with MM[36]. While MM is a
highly immunogenic tumor which can activate strong T-cell mediated immunity, MM is
able to induce anergy, presumably via the PD-1/PDL-1 interaction. Re-establishing an
effective immune response through blockade of PD-1 on responding activated T-cells has
been shown to be possible, as discussed above. Our hypothesis is that in the
post-transplant setting, where the host immune system is in significant flux, the
PD-1/PDL-1 blockade will promote a recapturing of the smoldering MM phenotype. If
we can establish that such a phenomenon is relevant for patients with high-risk MM then
we can extend this intervention to the wider population of patients with standard-risk MM
as well.
3.2.1.3 Rationale for IMiDs as a Combination Agent:
IMiDs (Thalidomide, Lenalidomide, and Pomalidomide) are a class of immunomodulatory
agents, which are a mainstay in myeloma therapy, and could be rationally combined with
anti-PD-1 therapy. IMiDs derive their designation as “Immunomodulators” designed as
therapeutic
immune
stimulators
derived
from
the
parent
compound
thalidomide.
Lenalidomide, and now pomalidomide, are approved therapies for multiple myeloma. The
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Pembrolizumab (MK-3475), Biran N, HUMC
immunostimulatory properties of IMiDs, in contrast to other active myeloma classes such as
proteasome inhibitors, could synergize with anti-PD-1 therapies. Published literature
suggests that IMiDs have T-cell co-stimulatory and positive effects on antigen presenting
cells (APCs). T-cell co-stimulation has been demonstrated by increased IFN-g and IL-2
production, which result in clonal T-cell expansion and increased natural killer (NK) cell
activity [28]. There is also evidence of increased IL-12 production in the setting of T-cell
costimulation, which activates APCs[48].
3.2.1.4 Rationale for Lenalidomide and Low-dose Dexamethasone
Lenalidomide is a good choice among the three available IMiDs due to its better safety
profile compared to thalidomide and broader use in earlier lines of therapy compared to the
newer pomalidomide. Clinical studies have shown that lenalidomide has single-agent
activity against relapsed/refractory MM, and synergistic effects when combined with
dexamethasone [49-51]. Two recent pivotal Phase III studies (MM-009 and MM-010) have
robustly demonstrated the clinical benefit of lenalidomide plus high-dose dexamethasone,
over dexamethasone alone in subjects with relapsed/ refractory MM[51, 52]. A combined
analysis of the data from the two pivotal Phase III studies demonstrated that lenalidomide
plus high-dose dexamethasone achieved an OR in the region of 60%, including 15% of
patients achieving CR, a median OS of 35 months, and a median TTP of 11 months [36]. In
clinical trials, among the most common grade 3–4 adverse events according to the National
Cancer Institute Common Toxicity Criteria associated with the use of lenalidomide plus
dexamethasone in subjects with MM have been cytopenias, fatigue, muscle cramps, rash,
infection, insomnia, and venous thromboembolism (VTE)[49, 51, 53, 54]. Such events are
largely manageable through subject evaluation and monitoring, dose adjustment, or
prophylactic intervention.
Lenalidomide was initially indicated in MM, in combination with dexamethasone, in
patients who have received at least one prior therapy. The dose of dexamethasone approved
by the FDA, in combination with lenalidomide in myeloma, is 40 mg q.d. p.o. on Days 1-4,
9-12, and 17-20 in the first 4 cycles and on Days 1-4 in Cycle 5 and above in each 28-day
treatment cycle, which was defined as high dose dexamethasone. The Phase III registration
studies of lenalidomide were done in combination with high dose dexamethasone versus
high dose dexamethasone alone.
However, a more recent Phase III randomized study (known as E4A03) sponsored by the US
National Cancer Institute (NCI), and conducted by a network of researchers led by the
Eastern Cooperative Oncology Group (ECOG) compared combination treatment of
lenalidomide
and
either
high-
or
low-dose
dexamethasone
in
445
patients
with
myeloma[55]. The dose of dexamethasone considered "low-dose" in this trial was 40 mg on
Days 1, 8, 15, and 22 (i.e. once weekly) in each 28-day cycle. Researchers found that
patients in the study who received low-dose dexamethasone and lenalidomide had a
one-year survival of 96 percent compared to 86 percent for patients treated with the standard
or high -dose of dexamethasone and lenalidomide[56]. In addition, there were fewer side
effects associated with the low-dose dexamethasone and lenalidomide. Based on this study,
there is evidence that lowering the dexamethasone dose may reduce side effects and improve
survival. The National Comprehensive Cancer Network (NCCN) MM guidelines also list
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Pembrolizumab (MK-3475), Biran N, HUMC
the
lenalidomide,
low
dose-dexamethasone
combination
as
an
initial
therapy
for
non-transplant candidates. There is an ongoing Phase I trial to establish the safety and the
RP2D of pembrolizumab (MK-3475) in combination with lenalidomide and low-dose
dexamethasone in subjects with relapsed/refractory MM who have failed at least two lines of
prior therapy, including a proteasome inhibitor (e.g. bortezomib or carfilzomib) and an IMiD
(thalidomide, pomalidomide, lenalidomide).
Biologically,
this Phase 2 pilot study allows the combination of pembrolizumab,
lenalidomide and dexamethasone to provide maximal cytoreduction post-ASCT for the first
two cycles of therapy.
And subsequently, the discontinuation of dexamethasone for the
following 2 cycles will allow for maximization of potential long-term immunological
benefits seen with pembrolizumab combined with lenalidomide alone.
3.2.2
Rationale for Dose Selection/Regimen/Modification
3.2.2.1 Rationale for Fixed Dose Pembrolizumab
In KEYNOTE-001, two randomized cohort evaluations of melanoma subjects receiving
pembrolizumab (MK-3475) at a dose of 2 mg/kg versus 10 mg/kg Q3W have been
completed, and one randomized cohort evaluating of 10 mg/kg Q3W versus 10 mg/kg Q2W
has also been completed. The clinical efficacy and safety data demonstrate a lack of clinically
important differences in efficacy response or safety profile at these doses. For example, in
Cohort B2, advanced melanoma subjects who had received prior ipilimumab therapy were
randomized to receive MK-3475 at 2 mg/kg versus 10 mg/kg Q3W. The overall response rate
(ORR) was 26% (21/81) in the 2mg/kg group and 26% (25/79) in the 10 mg/kg group (full
analysis set (FAS)). The proportion of subjects with drug-related adverse events (AEs), grade
3-5 drug-related AEs, serious drug-related AEs, death or discontinuation due to an AE was
comparable between groups or lower in the 10 mg/kg group. In Cohort B3, advanced
melanoma subjects (irrespective of prior ipilimumab therapy) were randomized to receive
MK-3475 at 10 mg/kg Q2W versus 10 mg/kg Q3W. Preliminary results demonstrate that the
ORR was 32.8% (38/116) in the 10mg/kg Q2W group and 27.8% (30/108) in the 10 mg/kg
Q3W group (FAS Population by irRC; data through 28-Feb-2014). The proportion of
subjects with drug-related AEs, grade 3-5 drug-related AEs, serious drug-related AEs, death
or discontinuation due to an AE was comparable between groups.
Available pharmacokinetic results in subjects with melanoma, NSCLC, and other solid tumor
types support a lack of meaningful difference in pharmacokinetic exposures obtained at a
given dose among tumor types. Moreover, population PK analysis has been performed and
has confirmed the expectation that intrinsic factors do not affect exposure to pembrolizumab
(MK-3475) to a clinically meaningful extent. Importantly, the analysis revealed no
significant impact of tumor burden on exposure. Taken together, this data support the use of
lower doses (with similar exposure to 2 mg/kg Q3W) in all solid tumor indications. Selection
of 200 mg as the appropriate dose for a switch to fixed dosing is based on simulation results
indicating that 200 mg will provide exposures that are reasonably consistent with those
obtained with 2 mg/kg dose and importantly will maintain individual patient exposures
within the exposure range established in melanoma as associated with maximal clinical
response. A population PK model which characterized the influence of body weight and
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Pembrolizumab (MK-3475), Biran N, HUMC
other patient covariates on exposure has been developed using available data from 476
subjects from KEYNOTE 001. The distribution of exposures from the 200 mg fixed dose are
predicted to considerably overlap those obtained with the 2 mg/kg dose, with some tendency
for individual values to range slightly higher with the 200 mg fixed dose. The slight increase
in PK variability predicted for the fixed dose relative to weight-based dosing is not expected
to be clinically important given that the range of individual exposures is well contained
within the range of exposures shown in the melanoma studies of 2 and 10 mg/kg to provide
similar efficacy and safety. The population PK evaluation revealed that there was no
significant impact of tumor burden on exposure. In addition, exposure was similar between
the NSCLC and melanoma indications. Therefore, there are no anticipated changes in
exposure between different indication settings.
3.2.3
Rationale for Endpoints
3.2.3.1
Efficacy Endpoints
The primary efficacy objective of this trial is to determine Progression Free Survival (PFS)
from the date of ASCT, with day 0 defined as date of stem cell infusion (if tandem transplant
the 2nd of 2 transplants will be used) until the date of progression, defined as the date at
which the patient starts the next line of therapy or the date of death. The Overall Survival
(OS) will also be calculated from the date of ASCT as previously defined until the date of
death.
The secondary efficacy objective of this trial is to evaluate the anti-tumor activity of
pembrolizumab (MK-3475), lenalidomide and dexamethasone in subjects with high-risk MM
post-ASCT. This will be complete response (CR) + stringent complete response (sCR) + very
good partial response (VGPR) rate and objective response rate (ORR) as assessed by the
investigator per International Myeloma Working Group (IMWG) uniform response criteria
for MM[57].
Immunotherapeutic
agents
such
as
pembrolizumab
(MK-3475),
lenalidomide
and
dexamethasone may produce anti-tumor 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
comprehensive response assessment of immunotherapeutic agents such as pembrolizumab
(MK-3475), lenalidomide and dexamethasone. Disease response assessment will be
performed every 21-day treatment cycles. PD must be confirmed prior to discontinuation
from study.
3.2.3.2
Safety Endpoints
The primary safety objective of this trial is to characterize the safety and tolerability of
pembrolizumab (MK-3475), lenalidomide and dexamethasone in subjects with high-risk
MM post-ASCT. The primary safety analysis will be based on subjects who experienced
toxicities as defined by CTCAE criteria version 4.03. Safety will be assessed by quantifying
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Pembrolizumab (MK-3475), Biran N, HUMC
the toxicities and grades experienced by subjects who have received pembrolizumab
(MK-3475), lenalidomide and dexamethasone, including serious adverse events (SAEs).
Safety will be assessed by reported adverse experiences using CTCAE, Version 4.03. 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.
3.2.3.3
Biomarker Research
Additional research may evaluate factors important for predicting responsiveness or
resistance to pembrolizumab (MK-3475), lenalidomide and dexamethasone therapy and
other immunologic targets; or evaluate assay stability using clinical samples.
Assays may include but are not be limited
to: Flow Cytometric Phenotype Analysis:
Emerging data suggest that blockade of the PD-1/PDL-1 pathway results in enhanced T cell
mediated immune response. To test the hypothesis that T cell activation mediated by
pembrolizumab (MK-3475), lenalidomide and dexamethasone or pembrolizumab and
lenalidomide treatment correlates with clinical response, T cell subsets in peripheral blood,
e.g. PD-1+ T cells, effector, memory and regulatory T cells, will be assessed pre- and
post-dose and in both responders and non-responders.
T Cells:
CD3; CD4; CD8; CD4+CD25+PD1+; CTLA-4
Follicular Helper T: CD3+,CD4+,CXCR5+,PD1+
CD4 and CD8 T naïve (RO-; CCR7+)
Central Memory: (TCM;RO+,CCR7-)
Effector Memory (TEM, RO+,CCR7-)
Terminally differentiated effector memory (TEMRA; RO-,CCR7-)
T regulatory cells (Treg): CD4+,CD25hi, CD127low, CD39+, CD152hi, RO- (resting);
CD4+,CD25hi, CD127low, CD39+, CD152hi, RO+ (activated)
Dendritic Cells:
Lin-, CD11c+, CD1a+, CD80 (B7-1)low, CD86 (B7-2)low, MHC Class IIlow (DC resting);
CD11c+, CD1a+, CD123-, CD80hi, CD86hi, HLADRhi (DC1 activated); HLADRhi, CD11c-,
CD123+ (DC2)
Macrophages:
HLADR+, CD14+, CD86+, CXCL9+, CD127 (M1); HLADR+, CD14+, CD206+, CD163+
(M2)
Myeloid derived suppressor cells:
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Pembrolizumab (MK-3475), Biran N, HUMC
HLADR-/low, CD11b+, CD14+,CD33+hi,CD34+, CD66b- (M-MDSC); HLADR-, CD11b+,
CD14-,CD33+low,CD34+, CD66b+ (G-MDSC)
B Cells:
CD19+, B7-1low, B7-2low, MHC Class IIlow (resting); CD19+, B7-1hi, B7-2hi, MHC Class IIhi
(activated)
NK cells:
CD16+,CD3-,CD56+
NKT Cells:
CD16+,CD3+,CD56+
Real Time PCR Analysis
Real-time PCR analysis will be performed to determine the expression of T-cell and
subsets;T-bet(Th1); STAT3, RORgamma t (TH17); STAT6 (Th2); FoxP3 (Treg) as well as
checkpoint inhibitor induced markers such as granzyme A (GZMA) and perforin (PRF1)
T Cell Repertoire Analysis
To assess blood immune phenotype and TCR sequencing prior to and serially after Pem and
Len , TCR Immunoseq for Vbeta CDR3 highest frequency specificities will be done.
Tumor Site Immune Phenotype and PD-L1/L2 Analysis
To assess tumor site immune phenotype and PD L1/2 expression in bone marrow aspirates
available prior to and after last cycle of Pem +Len.
Gut Microbiome Analysis
Given that reduced diversity of intestinal microbiota leads to poor outcome post- allogeneic
hematopoietic stem cell transplantation and specific intestinal bacterial species have been
shown to boost responses to chemotherapy and checkpoint inhibitors, stool samples will be
analyzed for the overall composition of the patient’s gut microbiome prior and serially after
PEM+ LEN treatments. A 16S ribosomal RNA (rRNA) miSeq Illumina platform will be used
for overall microbial composition and quantitative real-time PCR analysis will validate the
specific microbial strains identified by miSeq.
Multiparametric (Two-Color) IHC
Spatial association of PD-1+ tumor infiltrating lymphocytes (TILs) and PD-L1+ cells (tumor
and myeloid cells) suggests “induction” of PD-L1. Interferon-gamma production by
antigen-specific
PD-1+ CD8+ T cells is hypothesized to drive local intratumoral
upregulation of PD-L1 on adjacent tumor and myeloid cells, leading to a “stalled CTL”
response, which may be predictive of response to pembrolizumab (MK-3475), lenalidomide,
dexamethasone or pembrolizumab, and lenalidomide therapy. By assessing both of the
20


Pembrolizumab (MK-3475), Biran N, HUMC
required elements, i.e. PD-L1 positive cells and PD-1+ T cells, a two-color IHC assay may
be a better predictor of response than PD-L1 positivity alone.
Transcriptional Analyses
mRNA expression profiling in archival material will be completed to assess gene expression
and to attempt to define a gene set critical for clinical response to pembrolizumab
(MK-3475), lenalidomide and dexamethasone or pembrolizumab and lenalidomide. The
hypothesis to be tested is that treatment responders will exhibit a “stalled Cytotoxic T
Lymphocyte (CTL)” response within the tumor reflected in the physical proximity between
PD-1 and PD-L1 expression and the presence of an aborted (e.g. 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 (e.g., IL-10).
Gene Sequencing
New data are emerging that suggest we can define certain tumor types as being
‘hypermutated’. There is a potential that this hypermutated state may correlate with
response to pembrolizumab (MK-3475), lenalidomide, dexamethasone or pembrolizumab,
lenalidomide therapy, and/or that the converse, ‘hypomutated’ state may correlate with
non-response.
4.0 METHODOLOGY
4.1
Entry Criteria
4.1.1
Diagnosis/Condition for Entry into the Trial
Male/Female subjects with multiple myeloma (MM) of at least 18 years will be enrolled into
this trial.
4.1.2
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. Be willing and able to provide written informed consent/assent for the trial.
2. Be ≥18 years of age on day of signing informed consent.
3. Has a confirmed diagnosis of MM based on standard criteria. (See Appendix 2 for
MM Diagnostic Criteria.)
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Pembrolizumab (MK-3475), Biran N, HUMC
4. Is between 60 and 180 days from peripheral blood autologous stem cell transplant.
5. At diagnosis, had MM with measurable disease, defined as:
●
A monoclonal immunoglobulin spike on serum electrophoresis of at least 0.5
g/dL and/or
●
Urine monoclonal levels of at least 200 mg/24 hours
●
For subjects without measurable serum and urine M-protein levels, an
abnormal free light chain (FLC) ratio (normal value 0.26 – 1.65) with
involved FLC ≥10 mg/dL
●
Radiographic evidence of disease for those without measurable M-spike or
free light chains.
6.
Has high-risk MM, which must be present at the time of diagnosis, and defined by:
a.
International Staging System (ISS) stage 3 (See Appendix 3 for ISS Staging),
and/or
b.
Deletion 13q by cytogenetics, and/or
c.
1q amplification, 1p deletion, p53 deletions (17p deletions), t(4;14), t(14;16),
t(14;20), hypodiploidy, and/or
d. High-risk gene expression profile (GEP) scores
7. Be able to provide a newly obtained bone marrow aspirate/biopsy material for
biomarker analysis and disease assessment.
8. Have a performance status of ≤2 on the ECOG Performance Scale (See Appendix 4).
9. Demonstrate adequate organ function as defined in Table 1, all screening labs should
be performed within 28 days of treatment initiation.
Table 1 Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1,000 /mcL
Platelets
≥75,000 / mcL
Hemoglobin
≥8g/dL or ≥5.6 mmol/L without transfusion or EPO dependency
(within 7 days of assessment)
Renal
Serum creatinine OR
Measured or calculateda creatinine
clearance
(GFR can also be used in place of
creatinine or CrCl)
≤1.5 X upper limit of normal (ULN) OR
≥60 mL/min for subject with creatinine levels > 1.5 X
institutional ULN
Hepatic
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Pembrolizumab (MK-3475), Biran N, HUMC
Serum total bilirubin
≤1.5 X ULN OR
Direct bilirubin ≤ULN for subjects with total bilirubin levels >
1.5 ULN
AST (SGOT) and ALT (SGPT)
≤2.5 X ULN OR
≤5 X ULN for subjects with liver metastases
Coagulation
International Normalized Ratio (INR) or
Prothrombin Time (PT)
Activated Partial Thromboplastin Time
(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
≤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
aCreatinine clearance should be calculated per institutional standard.
10. All subjects must agree to follow the regional requirements for lenalidomide
counseling, pregnancy testing, and birth control; and be willing and able to comply
with the regional requirements (for example, periodic pregnancy tests, safety labs,
etc.).
11. Female subjects of childbearing potential should have a negative urine or serum
pregnancy test within 10-14 days prior to and again within 24 hours prior to
receiving
the
first
dose
of
pembrolizumab
(MK-3475),
lenalidomide
and
dexamethasone or pembrolizumab (MK-3475) and lenalidomide. If the urine test is
positive or cannot be confirmed as negative, a serum pregnancy test will be required.
Female subjects of childbearing potential should agree to ongoing pregnancy testing.
12. Female subjects of childbearing potential must be willing to use 2 methods of birth
control or be surgically sterile, or abstain from heterosexual activity for the course of
the study through 120 days after the last dose of study medication (Reference Section
4.7.2). Subjects of childbearing potential are those who have not been surgically
sterilized or have not been free from menses for > 2 years.
13. Male subjects must agree to use a latex condom during sexual contact with females
of childbearing potential even if they have had a successful vasectomy starting with
the first dose of study therapy through 120 days after the last dose of study therapy.
14. Subject is able to swallow capsules and is able to take or tolerate oral medications on
a continuous basis.
15. Male subjects should agree to use an adequate method of contraception starting with
the first dose of study therapy through 120 days after the last dose of study therapy.
4.1.3
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Is currently participating and receiving study therapy or has participated in a study of
an investigational agent and received study therapy or used an investigational device
within 4 weeks of the first dose of treatment.
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Pembrolizumab (MK-3475), Biran N, HUMC
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the first dose of trial
treatment. The use of physiologic doses of corticosteroids may be used at the
investigator’s discretion.
3. Has received an allogeneic stem cell transplant.
4. Has received any myeloma-directed therapy after ASCT.
5. Has a known history of active TB (Bacillus Tuberculosis)
6. Hypersensitivity to pembrolizumab or any of its excipients.
7. Progressive disease from autologous transplantation at the time of screening. See
Appendix 11.5 for criteria
8. Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis.
Subjects with previously treated brain metastases may participate
provided they are stable (without evidence of progression by imaging for at least four
weeks prior to the first dose of trial treatment and any neurologic symptoms have
returned to baseline), have no evidence of new or enlarging brain metastases, and are
not using steroids for at least 7 days prior to trial treatment. This exception does not
include carcinomatous meningitis which is excluded regardless of clinical stability.
9. Has active autoimmune disease that has required systemic treatment in the past 2
years
(i.e.
with
use
of
disease
modifying
agents,
corticosteroids
or
immunosuppressive
drugs).
Replacement
therapy
(eg.,
thyroxine,
insulin,
or
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency,
etc.) is not considered a form of systemic treatment.
10. Has a history of (non-infectious) pneumonitis that required steroids or current
pneumonitis.
11. Has an active infection requiring intravenous systemic therapy.
12. Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject’s participation
for the full duration of the trial, or is not in the best interest of the subject to
participate, in the opinion of the treating investigator.
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.
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Pembrolizumab (MK-3475), Biran N, HUMC
15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
17. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
[qualitative] is detected).
18. Has received a live vaccine within 30 days of planned start of study therapy.
Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines
and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live
attenuated vaccines, and are not allowed.
4.2
Trial
Treatments
Trial treatment should be administered starting with Day 1 of the first 28-day cycle after all
procedures/assessments have been completed as detailed on the Trial Flow Chart (Section
5.0). Trial treatment may be administered up to 3 days before or after the scheduled day of
administration due to administrative reasons. The treatment(s) to be used in this trial are
outlined below in Table 2.
Table 2 Trial Treatments
Dose
Pembrolizumab
(MK-3475)
Lenalidomide
Dexamethasone
200 mg
25 mg
40 mg*
Pembrolizumab (MK-3475) will be administered every 3 weeks (on Day 1 of each 21-day cycle.
Lenalidomide will be dosed on Days 1-14 of each 21-day cycle.
Dexamethasone will be dosed on Days 1,8, and 15 of each 21-day cycle for the first 2 cycles only.
* A dexamethasone dose of 20 mg on Days 1,8, and 15 of each 21-day cycle is recommend for subjects aged >75.
Pembrolizumab (MK-3475)
Pembrolizumab (MK-3475) will be administered as a 30 minute IV infusion every three
weeks (on Day 1) of a 21-day cycle (treatment dose may be reduced due to toxicity as
described in Section 4.2.1.2). 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 (i.e., infusion time is 30
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Pembrolizumab (MK-3475), Biran N, HUMC
minutes: -5 min/+10 min). The starting dose of pembrolizumab (MK-3475) is 200 mg, fixed
dose.
Lenalidomide
The recommended starting dose of lenalidomide is 25 mg once daily on Days 1 -14 of
repeated 21-day cycles. If 25 mg dose of lenalidomide is not tolerated due to toxicity, the
dose could be decreased to 15 mg. Lenalidomide should be taken orally at about the same
time each day, either with or without food. Lenalidomide capsules should be swallowed
whole with water. The capsules should not be opened, broken, or chewed. Refer to local
product label for more details.
Dexamethasone
The recommended dose of dexamethasone is 40 mg once weekly on Days 1, 8, and 15of
each 21-day cycle. A dexamethasone dose of 20 mg once weekly on Days 1, 8, and 15, in
subjects aged >75 years is recommended. Refer to local product label for more details.
Patients to receive dexamethasone in the first 2 cycles only.
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.
4.2.1
Dose Selection/Modification
4.2.1.1
Dose Selection
The dose amount required to prepare the pembrolizumab (MK-3475) infusion solution will
be a fixed dose of 200 mg IV.
4.2.1.2
Dose Modification
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may
represent an immunologic etiology. These adverse events may occur shortly after the first
dose or several months after the last dose of treatment. Pembrolizumab must be withheld for
drug-related toxicities and severe or life-threatening AEs as per Table 3 below. See Section
4.6.1 and Events of Clinical Interest Guidance Document for supportive care guidelines,
including use of corticosteroids.
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Table 3a:
Dose Modification Guidelines for Pembrolizumab Drug-Related Adverse Events
Toxicity
Hold
Treatment
For Grade
Timing for Restarting Treatment
Discontinue Subject
Diarrhea/Colitis
2-3
Toxicity resolves to Grade 0-1.
Toxicity does not resolve within 12 weeks of last dose or inability
to reduce corticosteroid to 10 mg or less of prednisone or
equivalent per day within 12 weeks.
4
Permanently discontinue
Permanently discontinue
AST, ALT, or
Increased
Bilirubin
2
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks of last dose.
3-4
Permanently discontinue
(see exception below)1
Permanently discontinue
Type 1 diabetes
mellitus (if new
onset) or
Hyperglycemia
T1DM or
3-4
Hold pembrolizumab for new onset Type
1
diabetes
mellitus
or
Grade
3-4
hyperglycemia associated with evidence
of beta cell failure.
Resume pembrolizumab when patients are clinically and
metabolically stable.
Hypophysitis
2-3
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks of last dose or inability
to reduce corticosteroid to 10 mg or less of prednisone or
equivalent per day within 12 weeks.
4
Permanently discontinue
Permanently discontinue
Hyperthyroidism
3
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks of last dose or inability
to reduce corticosteroid to 10 mg or less of prednisone or
equivalent per day within 12 weeks.
4
Permanently discontinue
Permanently discontinue
Hypothyroidism
2-4
Therapy with pembrolizumab can be
continued while treatment for the thyroid
disorder is instituted
Therapy with pembrolizumab can be continued while treatment for
the thyroid disorder is instituted.
Infusion Reaction
3-4
Permanently discontinue
Permanently discontinue
Renal Failure or
Nephritis
2
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks of last dose or inability
to reduce corticosteroid to 10 mg or less of prednisone or
equivalent per day within 12 weeks.
3-4
Permanently discontinue
Permanently discontinue
All Other
Drug-Related
Toxicity2
3or Severe
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks of last dose or inability
to reduce corticosteroid to 10 mg or less of prednisone or
equivalent per day within 12 weeks.
4
Permanently discontinue
Permanently discontinue
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event.
1For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative to baseline
and lasts for at least 1 week then patients should be discontinued.
2 Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion. Permanently discontinue study drug for
persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose.
27


Pembrolizumab (MK-3475), Biran N, HUMC
Table 3b:
Dose-Modification Guidelines for Hematological Toxicity
Toxicity
Grade
Hold
Treatment
(Y/N)
Timing for
restarting
treatment
Dose/Schedule
for restarting
treatment 1
Discontinue
Subject
(after
consultation
with
Sponsor)
Hematological Toxicity
1, 2, 3
No
N/A
N/A
N/A
4
Yes
Toxicity
resolves to
Grade 0-1 or
baseline
May decrease
dose to next dose
level below
Toxicity does
not resolve
within 4 weeks
of last infusion
Permanent
discontinuation
should be
considered for
any severe or
life-threatening
event
Dosing interruptions are permitted in the case of medical / surgical events or logistical
reasons not related to study therapy (e.g., elective surgery, unrelated medical events, patient
vacation, and/or holidays). Subjects should be placed back on study therapy within 3 weeks
of the scheduled interruption, unless otherwise discussed with the Sponsor. The reason for
interruption should be documented in the patient's study record.
4.2.1.3 Dose Modification Guidelines for Lenalidomide
Dose modification guidelines are based on the recommendation provided by the Myeloma
expert panel review[58] of the efficacy and toxicity of lenalidomide plus dexamethasone,
and the guidance provided in the product label for lenalidomide. Any toxicity associated
with lenalidomide that prompts a dose reduction of lenalidomide is outlined in the Sections
below.
Lenalidomide is administered once daily from Day 1 through Day 14 in each 21 day cycle.
If a subject receiving 5 mg of lenalidomide experiences an AE related to lenalidomide and
is in need of dose modification, the subject should discontinue lenalidomide and continue
only pembrolizumab (MK-3475) and dexamethasone, as 5 mg is the lowest dose used in
28


Pembrolizumab (MK-3475), Biran N, HUMC
this trial. A maximum of three dose reductions of lenalidomide will be allowed in the order
indicated in Table 6, where applicable. The duration of administration will remain the
same.
A
subject
cannot
be
restarted
on
lenalidomide
unless
non-hematologic
lenalidomide-related toxicities have returned to at least Grade 1 toxicity or baseline.
4.2.1.3.1 Dose Adjustments for Hematologic Toxicities during Multiple Myeloma
Treatment
Dose modification guidelines, as summarized below in Table 4 and Table 5, are
recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3
or 4 toxicities judged to be related to lenalidomide. Please refer to local product label for
additional guidelines.
Table 4 Platelet Counts: Thrombocytopenia in MM
When Platelets
Recommended Course
Fall
to <30,000/mcL
Return
to
≥30,000/mcL
Interrupt lenalidomide treatment,
follow
CBC weekly
Restart lenalidomide at 15 mg daily
For
each
subsequent
drop
<30,000/mcL Return to ≥30,000/mcL
Interrupt lenalidomide treatment
Resume lenalidomide at 5 mg less than the
previous dose. Do not dose below 5 mg
daily.
Table 5 Absolute Neutrophil Counts (ANC): Neutropenia in MM
When Neutrophils
Recommended Course1
Fall to <1,000/mcL
Return to ≥1,000/mcL and neutropenia is the
only toxicity
Interrupt lenalidomide treatment, add G-CSF,
follow CBC weekly
Resume lenalidomide at 25 mg daily
Return to ≥1,000/mcL and if other toxicity
Resume lenalidomide at 15 mg daily
29


Pembrolizumab (MK-3475), Biran N, HUMC
For each subsequent drop <1,000/mcL
Return to ≥1,000/mcL
Interrupt lenalidomide treatment
Resume lenalidomide at 5 mg less than the
previous dose. Do not dose below 5 mg
daily.
1 If the subject is receiving Len 10 mg, the subject may resume Len at 5 mg.
4.2.1.3.2 Other Grade 3/4 Toxicities in MM
For other Grade 3/4 toxicities, hold treatment and restart at the physician’s discretion at
next lower dose level when toxicity has resolved to ≤Grade 2 as outlined below in Table 6.
Table 6 Lenalidomide Dose Reductions for Subjects with Other Grade 3/4 Toxicities
Modification
Dose 1, 2
Starting Dose
Lenalidomide 25 mg every day for 14 days, every 21 days
Dose Reduction 1
Lenalidomide 15 mg every day for 14 days, every 21 days
Dose Reduction 2
Lenalidomide 10 mg every day for 14 days, every 21 days
Dose Reduction 3
Lenalidomide 5 mg every day for 14 days, every 21 days
1 Do not dose below 5 mg daily
2 If the subject is receiving Len 10 mg, the subject may resume Len at 5 mg.
4.2.1.3.3 Recommended Dose Adjustments for Subjects with Impaired Renal Function
Renal function may be impaired in subjects with MM by immunoglobulin light chains,
amyloidosis. MM subjects with normal renal function may develop renal dysfunction or
renal impairment during treatment with lenalidomide and dexamethasone. If renal toxicity
occurs during study treatment, drug should not be restarted unless the toxicity resolved to
≤Grade 1.
4.2.1.4 Dose Modification Guidelines for Dexamethasone
30


Pembrolizumab (MK-3475), Biran N, HUMC
Dexamethasone will be given at 40 mg q.d. p.o. on Days 1, 8, and 15 (i.e. once weekly) in
each 21-day cycle. If a subject experiences adverse events, up to two dose reductions of
dexamethasone will be allowed. The duration of administration will remain the same;
however, the daily dose will be modified.
For grade 3 or 4 toxicities, the dose will be
modified from a starting dose of 40 mg to 20 mg, and a second dose reduction can be to 10
mg. For grade 3 or 4 toxicities in patients >75, in the starting dose of 20 mg can be dose
reduced to 10 mg and then a second dose reduction can be to 4 mg. Additional supportive
care guidelines specific to dexamethasone are indicated in Table 7.
A subject cannot be restarted on dexamethasone unless non-hematologic dexamethasone
related toxicities have returned to at least Grade 1 toxicity or baseline.
4.2.1.4.1 Supportive Care Guidelines Specific to Dexamethasone
Table 7 Supportive Care Guidelines Specific to Dexamethasone
Body System
Symptom
Recommended Action
Gastrointestinal
Dyspepsia,
gastric
or
duodenal
ulcer, gastritis Grade 1–2 (requiring
medical management)
Treat with H2 blockers, sucralfate, or omeprazole. If
symptoms persist despite above measures, decrease
dexamethasone dose by one dose level.
Gastrointestinal
>
Grade
3
(requiring
hospitalization or surgery)
Hold dexamethasone until symptoms adequately
controlled. Restart and decrease one dose level of
current dose along with concurrent therapy with H2
blockers, sucralfate, or omeprazole. If symptoms
persist
despite above
measures,
discontinue
dexamethasone and do not resume.
Gastrointestinal
Acute pancreatitis
Discontinue dexamethasone and do not resume.
Cardiovascular
Edema
>Grade 3
(limiting function and
unresponsive to therapy or anasarca)
Diuretics as needed, and decrease dexamethasone
dose by one dose level; if edema persists despite
above measures, decrease dose another dose level.
Discontinue dexamethasone and do not resume if
symptoms persist despite second reduction.
Neurology
Confusion
or
Mood
alteration
> Grade 2 (interfering with function
+/- interfering with activities of daily
living)
Hold
dexamethasone
until
symptoms resolve.
Restart with one dose level reduction. If symptoms
persist despite above measures, discontinue
dexamethasone do not resume.
Musculoskeletal Muscle
weakness
>
Grade
2
(symptomatic and interfering with
function +/- interfering with
activities of daily living)
Decrease dexamethasone dose by one dose level. If
weakness persists despite above measures, decrease
dose by one dose level. Discontinue dexamethasone
and do not resume if symptoms persist.
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Pembrolizumab (MK-3475), Biran N, HUMC
Metabolic
Hyperglycemia > Grade 3 or higher
Treatment with insulin or oral hypoglycemics as
needed. If uncontrolled despite above measures,
decrease dose by one dose level until levels are
satisfactory.
4.2.2
Timing of Dose Administration
Trial
treatment
should
be
administered
on
Day
1
of
each
cycle
after
all
procedures/assessments have been completed as detailed on the Trial Flow Chart (Section
5.0). Trial treatment may be administered up to 3 days before or after the scheduled Day 1 of
each cycle due to administrative reasons.
All trial treatments will be administered on an outpatient basis.
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.
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 (i.e., infusion time is 30 minutes: -5 min/+10 min).
4.2.3
Trial Blinding/Masking
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the
treatment administered.
4.3
Randomization
or
Treatment
Allocation
No randomization or treatment allocation will be used in this trial as it is a single arm,
open-label trial.
4.4
Stratification
No stratification based on age, sex or other characteristic will be used in this trial.
4.5
Concomitant
Medications/Va
ccinations
(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 one of these or other medications
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or
32


Pembrolizumab (MK-3475), Biran N, HUMC
vaccination may be required. The final decision on any supportive therapy or vaccination
rests with the investigator and/or the subject's primary physician.
4.5.1
Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a subject’s welfare may be
administered at the discretion of the investigator in keeping with the community standards of
medical care. All concomitant medication will be recorded on the case report form (CRF)
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications
and fluids.
If changes occur during the trial period, documentation of drug dosage,
frequency, route, and date may also be included on the CRF.
All concomitant medications received within 28 days before the first dose of trial treatment
and 30 days after the last dose of trial treatment should be recorded.
Concomitant
medications administered after 30 days after the last dose of trial treatment should be
recorded for SAEs.
4.5.2
Prohibited Concomitant Medications
Subjects are prohibited from receiving the following therapies during the Screening and
Treatment Phase (including retreatment for post-complete response relapse) of this trial:
●
Antineoplastic systemic chemotherapy or biological therapy
●
Immunotherapy not specified in this protocol
●
Chemotherapy not specified in this protocol
●
Investigational agents other than pembrolizumab
●
Radiation therapy
o
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may
be allowed at the investigator’s discretion.
●
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, varicella/zoster, yellow fever, rabies, BCG, and
typhoid vaccine.
●
Systemic glucocorticoids for any purpose other than to modulate symptoms from an
event of clinical interest of suspected immunologic etiology. The use of physiologic
doses of corticosteroids may be approved after consultation with the Sponsor.
Subjects who, in the assessment by the investigator, require the use of any of the
aforementioned treatments for clinical management should be removed from the trial.
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.
33


Pembrolizumab (MK-3475), Biran N, HUMC
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
4.6
Rescue
Medications
&
Supportive
Care
4.6.1
Supportive Care Guidelines
Subjects should receive appropriate supportive care measures as deemed necessary by the
treating investigator.
Suggested supportive care measures for the management of adverse
events with potential immunologic etiology are outlined below and in greater detail in the
ECI guidance document. Where appropriate, these guidelines include the use of oral or
intravenous treatment with corticosteroids as well as additional anti-inflammatory agents if
symptoms do not improve with administration 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 the event is determined not to be related, the investigator is
instructed to follow the ECI reporting guidance but does not need to follow the treatment
guidance (as outlined in the ECI guidance document). Refer to Section 4.2.1 for dose
modification.
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or
skin photography as part of evaluation of the event. Suggested conditional procedures, as
appropriate, can be found in the ECI guidance document.
●
Pneumonitis:
o
For Grade 2 events, treat with systemic corticosteroids. When symptoms
improve to Grade 1 or less, steroid taper should be started and continued over
no less than 4 weeks.
o
For Grade 3-4 events, immediately treat with intravenous steroids.
Administer additional anti-inflammatory measures, as needed.
o
Add prophylactic antibiotics for opportunistic infections in the case of
prolonged steroid administration.
●
Diarrhea/Colitis:
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of
bowel perforation (such as peritoneal signs and ileus).
34


Pembrolizumab (MK-3475), Biran N, HUMC
o
All subjects who experience 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. For Grade 2 or higher
diarrhea, consider GI consultation and endoscopy to confirm or rule out
colitis.
o
For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral
corticosteroids.
o
For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with
intravenous steroids followed by high dose oral steroids.
o
When symptoms improve to Grade 1 or less, steroid taper should be started
and continued over no less than 4 weeks.
●
Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or
≥Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic
acidosis (DKA)
o
For T1DM or Grade 3-4 Hyperglycemia
▪
Insulin replacement therapy is recommended for Type I diabetes
mellitus and for Grade 3-4 hyperglycemia associated with metabolic
acidosis or ketonuria.
▪
Evaluate patients with serum glucose and a metabolic panel, urine
ketones, glycosylated hemoglobin, and C-peptide.
●
Hypophysitis:
o
For Grade 2 events, treat with corticosteroids. When symptoms improve to
Grade 1 or less, steroid taper should be started and continued over no less than
4 weeks. Replacement of appropriate hormones may be required as the steroid
dose is tapered.
o
For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed
by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid
taper should be started and continued over no less than 4 weeks. Replacement
of appropriate hormones may be required as the steroid dose is tapered.
●
Hyperthyroidism or Hypothyroidism:
Thyroid disorders can occur at any time during treatment. Monitor patients for
changes in thyroid function (at the start of treatment, periodically during treatment,
and as indicated based on clinical evaluation) and for clinical signs and symptoms of
thyroid disorders.
o
Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism):
35


Pembrolizumab (MK-3475), Biran N, HUMC
▪
In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are
suggested as initial therapy.
▪
In
hypothyroidism,
thyroid
hormone
replacement therapy, with
levothyroxine or liothyroinine, is indicated per standard of care.
o
Grade 3-4 hyperthyroidism
▪
Treat with an initial dose of IV corticosteroid followed by oral
corticosteroids. When symptoms improve to Grade 1 or less, steroid
taper should be started and continued over no less than 4 weeks.
Replacement of appropriate hormones may be required as the steroid
dose is tapered.
●
Hepatic:
o
For Grade 2 events, monitor liver function tests more frequently until
returned to baseline values (consider weekly).
▪
Treat with IV or oral corticosteroids
o
For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48
hours.
o
When symptoms improve to Grade 1 or less, a steroid taper should be started
and continued over no less than 4 weeks.
●
Renal Failure or Nephritis:
o
For Grade 2 events, treat with corticosteroids.
o
For Grade 3-4 events, treat with systemic corticosteroids.
o
When symptoms improve to Grade 1 or less, steroid taper should be started and
continued over no less than 4 weeks.
Management of Infusion Reactions: Signs and symptoms usually develop during or
shortly after drug infusion and generally resolve completely within 24 hours of
completion of infusion.
Table 8 below shows treatment guidelines for subjects who experience an infusion
reaction associated with administration of pembrolizumab (MK-3475).
Table 8 Infusion Reaction Treatment Guidelines
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Pembrolizumab (MK-3475), Biran N, HUMC
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 infusion interruption but
responds promptly to symptomatic
treatment (e.g., antihistamines,
NSAIDS, narcotics, IV fluids);
prophylactic medications indicated for
< =24 hrs
Stop Infusion and monitor symptoms.
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 one hour of stopping
drug infusion, the infusion may be restarted at
50% of the original infusion rate (e.g., 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
treatment administration.
Subject may be premedicated 1.5h
(± 30 minutes) prior to infusion of
pembrolizumab (MK-3475) with:
Diphenhydramine 50 mg po (or
equivalent dose of antihistamine).
Acetaminophen 500-1000 mg po
(or equivalent dose of antipyretic).
Grades 3 or 4
Grade 3:
Prolonged (i.e., not rapidly responsive
to symptomatic medication and/or
brief interruption of infusion);
recurrence of symptoms following
initial improvement; hospitalization
indicated for other clinical sequelae
(e.g., 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:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Epinephrine
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.
Subject is permanently discontinued from
further trial treatment administration.
No subsequent dosing
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug
administration.
4.7
Diet/Activity/Ot
her
Considerations
4.7.1
Diet
Subjects should maintain a normal diet unless modifications are required to manage an AE
such as diarrhea, nausea or vomiting.
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Pembrolizumab (MK-3475), Biran N, HUMC
4.7.2
Contraception
Pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is not known if
pembrolizumab has transient adverse effects on the composition of sperm. Non-pregnant,
non-breast-feeding women may be enrolled if they are willing to use 2 methods of birth
control or are considered highly unlikely to conceive. Highly unlikely to conceive is defined
as 1) surgically sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has
not had menses for greater than 1 year will be considered postmenopausal), or 3) not
heterosexually active for the duration of the study. The two birth control methods can be
either two barrier methods or a barrier method plus a hormonal method to prevent pregnancy.
Subjects should start using birth control from study Visit 1 throughout the study period up to
120 days after the last dose of study therapy.
The following are considered adequate barrier methods of contraception: diaphragm, condom
(by the partner), copper intrauterine device, sponge, or spermicide. Appropriate hormonal
contraceptives will include any registered and marketed contraceptive agent that contains an
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or
intramuscular agents).
Subjects should be informed that taking the study medication may involve unknown risks to
the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in
the study they must adhere to the contraception requirement (described above) for the
duration of the study and during the follow-up period defined in section 6.2.2-Reporting of
Pregnancy and Lactation to the Sponsor and to Merck. If there is any question that a subject
will not reliably comply with the requirements for contraception, that subject should not be
entered into the study.
† Lenalidomide (REVLIMID®) is only available through a restricted distribution program
called the REVLIMID REMSTM program (formally known as the “RevAssist®
program”).
Required components of the REVLIMID REMSTM program include the following:
Prescribers must be certified with the REVLIMID REMSTM program by enrolling
and complying with the REMS requirements. Study sites in the United States
register with Celgene’s Revlimid REMS® Program prior to prescribing the
Celgene Product in accordance with the Revlimid REMS® guidelines and for
investigators at Study sites outside of the United States register with the appropriate
Celgene risk minimization program in that country prior to prescribing the Celgene
Product
Study investigators must follow Global Pregnancy Prevention Plan as presented by
Revlimid REMS
Subjects must sign a “Patient-Prescriber agreement form” and comply with the
REMS requirements in the United States or the appropriate Celgene risk
minimization program for countries outside of the United States. In particular,
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Pembrolizumab (MK-3475), Biran N, HUMC
female subjects of reproductive potential who are not pregnant must comply with
the pregnancy testing and contraception requirements and males must comply with
contraception requirements. Refer to local product label.
Pharmacies must be certified with the REVLIMID REMSTM program, must only
dispense to subjects who are authorized to receive lenalidomide (REVLIMID®)
and comply with REMS requirements. At the termination or conclusion of the
study sites shall direct all patients to return to Celgene any unused quantities of the
Celgene Product in accordance with the Celgene REMS® Program.
Further information about the REVLIMID REMSTM program is available at
celgeneriskmanagement.com or by telephone at 1-888-423-5436.
Females of Reproductive Potential:
Females of reproductive potential must avoid pregnancy for at least 4 weeks before
beginning lenalidomide (REVLIMD®) therapy, during therapy, during dose
interruptions and for at least 4 weeks after completing therapy.
Females must commit either to abstain continuously from heterosexual intercourse
or to use two methods of reliable birth control, beginning 4 weeks prior to initiating
treatment
with
lenalidomide
(REVLIMID®),
during
therapy,
during
dose
interruptions
and
continuing
for
4
weeks
following
discontinuation
of
REVLIMID® therapy.
Two negative pregnancy tests must be obtained prior to initiating therapy. The first
test should be performed within 10-14 days and the second test within 24 hours
prior to prescribing lenalidomide (REVLIMID) therapy and then weekly during the
first month, then monthly thereafter in women with regular menstrual cycles or
every 2 weeks in women with irregular menstrual cycles. Refer to local product
label for additional details.
Pregnancy testing and counseling should be performed if a subject misses her period
or
if
there
is
any
abnormality
in her menstrual bleeding. Lenalidomide
(REVLIMID®) treatment must be discontinued during this evaluation.
Males of Reproductive Potential:
Lenalidomide (REVLIMID®) is present in the semen of subjects receiving the drug.
Therefore, males must always use a latex or synthetic condom during any sexual
contact
with
females
of
reproductive
potential
while
taking lenalidomide
(REVLIMID)
and
for
up
to
28
days
after
discontinuing
lenalidomide
(REVLIMID®), even if they have undergone a successful vasectomy. Male
subjects taking lenalidomide (REVLIMID®) must not donate sperm. Refer to local
product label for additional details.
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Pembrolizumab (MK-3475), Biran N, HUMC
4.7.3
Use in Pregnancy
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the
subject will immediately be removed from the study. 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 and to Merck
without delay and within 24 hours to the Sponsor and within 2 working days to Merck if the
outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other
disabling or life-threatening complication to the mother or newborn).
The study investigator will make every effort to obtain permission to follow the outcome of
the pregnancy and report the condition of the fetus or newborn to the Sponsor.
If a male
subject impregnates his female partner the study personnel at the site must be informed
immediately and the pregnancy reported to the Sponsor and to Merck and followed as
described above and in Section 6.2.2.
*Lenalidomide (REVLIMID®) can cause fetal harm when administered to a
pregnant female. If lenalidomide is used during pregnancy or if the subject
becomes pregnant while taking lenalidomide, the subject should be apprised of
the potential hazard to the fetus. Refer to local product label for further
details.
4.7.4
Use in Nursing Women
It is unknown whether pembrolizumab (MK-3475), or lenalidomide is excreted in human
milk. Since many drugs are excreted in human milk, and because of the potential for
serious adverse reactions in the nursing infant, subjects who are breast-feeding are not
eligible for enrollment. Because of the potential for serious adverse reactions in nursing
infants,
breast
feeding
must
be
discontinued
for
the
duration
of
therapy with
pembrolizumab (MK-3475), or lenalidomide, if applicable. A decision should be made
whether to discontinue nursing or to discontinue the drug, taking into account the
importance of drug to the mother. Please refer to lenalidomide local product labels for
further information.
4.8
Subject
Withdrawal/Dis
continuation
Criteria
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the
discretion of the investigator should any untoward effect occur. In addition, a subject may be
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the
40


Pembrolizumab (MK-3475), Biran N, HUMC
trial plan is violated, or for administrative and/or other safety reasons.
Specific details
regarding discontinuation or withdrawal are provided in Section 6.1.4 – Other Procedures.
A subject must be discontinued from the trial for any of the following reasons:
●
The subject or legal representative (such as a parent or legal guardian) withdraws
consent.
●
Confirmed disease progression, including biochemical disease progression, and
radiographic disease progression
●
Unacceptable adverse experiences as described in Section 4.2.1.
●
Intercurrent illness that prevents further administration of treatment
●
Investigator’s decision to withdraw the subject
●
The subject has a confirmed positive serum pregnancy test
●
Noncompliance with trial treatment or procedure requirements
●
The subject is lost to follow-up
●
Administrative reasons
The End of Treatment and Follow-up visit procedures are listed in Section 5 (Protocol Flow
Chart).
After the end of treatment, each subject will be followed for 30 days for adverse
event monitoring (serious adverse events will be collected for 90 days after the end of
treatment as described). Subjects who discontinue for reasons other than progressive disease
will have post-treatment follow-up for disease status until disease progression, initiating a
non-study cancer treatment, withdrawing consent or becoming lost to follow-up.
After
documented disease progression each subject will be followed by telephone for overall
survival until death, withdrawal of consent, or the end of the study, whichever occurs first.
4.9
Clinical
Criteria
for
Early
Trial
Termination
Early trial termination will be the result of the criteria specified below:
1. Quality or quantity of data recording is inaccurate or incomplete
2. Poor adherence to protocol and regulatory requirements
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential
health hazard to subjects
41


Pembrolizumab (MK-3475), Biran N, HUMC
4. Plans to modify or discontinue the development of the study drug
In the event of Merck decision to no longer supply study drug, ample notification will be
provided so that appropriate adjustments to subject treatment can be made.
42


5.0 TRIAL FLOW CHART
5.1
Study Flow Chart
Trial Period:
Treatment Cycles1, 4
End of
Treatment
Post-treatment2
Cycle = 21 Days
Treatment Cycle/Title:
Screening
(Visit 1)
Cycle 1
Cycle 2
Cycle 3 and 4
At the completion
of cycle 4
Post-
Treatment
Safety
Follow-up
Follow-
up Visits3
Survival
Follow-up7
Cycle Day
1
8
15
1
15
1
15
At the completion
of cycle 4
30 days
post completion
of cycle 4
Every 12
weeks post
completion
Every 12
weeks
Scheduling Window (Days)4:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
± 7
Administrative Procedures
Informed Consent
X
43


Inclusion/Exclusion Criteria
X
Demographics and Medical History
X
Prior Multiple Myeloma treatment history
X
International Staging System Criteria
X
Prior and Concomitant Medication Review5
9
X
X
X
X
X
X
X
X
X
X
Trial Treatment Administration
See Section 4.2
Post-study anticancer therapy status
X
X
Survival Status 7
X
Clinical Procedures/Assessments
Review Adverse Events 8,9
X
X
X
X
X
X
X
X
X
X
X
Full Physical Examination
X
X
X
X
X
X
Directed Physical Examination 10
X
X
X
X
Vital Signs and Weight 11
X
X
X
X
X
X
X
X
X
X
X
Trial Period:
Treatment Cycles1, 4
End of
Treatment
Post-treatment2
Cycle = 21 Days
44


Treatment Cycle/Title:
Screening
(Visit 1)
Cycle 1
Cycle 2
Cycle 3 and 4
At the completion of
cycle 4
Post-
Treatment
Safety
Follow-up
Follow-
up Visits3
Survival
Follow-up7
Cycle Day
1
8
15
1
15
1
15
At the completion
of cycle 4
30 days
post completion
of cycle 4
Every 12
weeks post
completion
Every 12
weeks
12-Lead Electrocardiogram
X
ECOG Performance Status
X
X
X
X
X
X
X
X
X
Skeletal survey 12
X
MRI/CT/PET 12
X
International Uniform Response Criteria13
X
X
X
X
X13
X13
Pregnancy Test – urine or serum Beta-HCG 14
X
X
X
X
X
X
X
X
CBC with differential 15
X
X
X
X
X
X
X
X
X
X 16
Comprehensive blood chemistry panel 15
X
X
X
X
X
X
X
X
X
X 16
LDH 15
X
X
X
X
Coagulation
X
45


Urinalysis
X
TSH, T3 and free T4 15
X
X
X
Quantitative serum immunogloublins 13
X
X
X
X
X
X
Serum
protein
electrophoresis
and
serum
immunofixation 13
X
X
X
X
X
X
Serum free light chain analysis 13
X
X
X
X
X
X
24 hour urine protein electrophoresis and urine
immunofixation 13
X
X
X
X
X
X
M-protein quantitation (urine and/or serum) 13
X
X
X
X
X
X
Beta-2 microglobulin 13
X
X
X
X
X
X
Bone marrow aspiration and biopsy 17,19
X
X
Trial Period:
Treatment Cycles1, 4
End of
Treatment
Post-treatment2
Cycle = 21 Days
Treatment Cycle/Title:
Screening
(Visit 1)
Cycle 1
Cycle 2
Cycle 3 and 4
At the completion
of cycle 4
Post-
Treatment
Safety
Follow-up
Follow-
up Visits3
Survival
Follow-up7
46


Cycle Day
1
8
15
1
15
1
15
At the completion
of cycle 4
30 days
post
completion of
cycle 4
of
Cycle 4
Every 12
weeks post
completion
post
Discon
Every 12
weeks
Bone marrow morphology, IHC, cytogenetics by
standard karyotyping, FISH panel, and minimal
residual disease (MRD) analysis 17, 19
X17,
19
X17
X17
X
Correlative Studies – bone marrow and peripheral
blood collection, stool samples 6
X6
X6
X
X
X
1.
In general, assessments/procedures are to be performed on Day 1 and prior to the first dose of treatment for each cycle unless otherwise specified. Treatment cycles are 21
days. Unless otherwise noted, procedures should be on Day 1 of each Cycle.
2.
Procedures outlined for visit, 30-day Safety-Follow-up and Survival Follow-up should be performed for subjects who complete the study or progress.
3.
Subjects who discontinue trial treatment for a reason other than disease progression will move into the Follow-Up Phase and should be assessed every 12 weeks (84 ± 7
days) to monitor disease status. Every effort should be made to collect information regarding disease status
4.
In general, the window for each visit is ± 3 days unless otherwise noted.
5.
Record all medications taken from 28 days prior to cycle 1 day 1 to the 30 day post completion of cycle 4 visit.
6.
For correlative studies, collection will be at screening or cycle 1 day 1, then every day 1 of each cycle, and at completion of cycle 4 and to confirm response.
47


7.
After documented disease progression or the start of new antineoplastic therapy, each subject will be followed by
telephone for overall survival until death, withdrawal consent or the end of the trial, whichever occurs first.
8.
AEs and laboratory safety measurements will be graded per NCI CTCAE version 4.03. All AEs, whether gradable
by CTCAE or not, will also be evaluated for seriousness. AEs will be evaluated every two weeks, on Days 1 and
15 of each 21-day cycle.
9.
Record all AEs occurring within 30 days after the last dose of study drug. Report all SAEs (related and unrelated
to trial treatment) and ECIs occurring up until 90 days after the last dose of trial treatment or the start of new
anti-cancer treatment, whichever comes first. Afterwards, report only SAEs and ECIs that are related to trial
treatment.
10. Directed PE performed to collect any new/clinically significant abnormalities (i.e. ECI/AE).
11. Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure. Height will be measured at
screening only.
12. Skeletal survey should include a chest (PA or AP; lateral), skull (lateral), upper extremities (shoulder to elbow),
lower extremities (hip to knee; AP), pelvis (AP), cervical/thoracic/lumbar spine (AP and lateral). For suspected
progression to bone disease bidimensional measurement of the target lytic lesions must be performed.
MRI/CT/PET (MRI for subjects with bone disease and CT/PET for plasmacytomas) is required when clinically
indicated for subjects with bony disease and should just include the bony lesions. Subjects with measurable
plasmacytomas at baseline should have imaging performed every 12 weeks.
13. Disease response assessment is based upon the multiple myeloma response criteria (See Appendix 5 ). Myeloma
lab assessments should be performed every 3 weeks, that is, on Day 1 of every 21-day treatment cycle. Disease
assessments should occur at Day 1 of each 21-day treatment cycle (+/- 7 days) throughout the course of the trial.
14. For women of reproductive potential, a urine pregnancy test should be performed. If urine pregnancy results
cannot be confirmed as negative, a serum pregnancy test performed by the local trial site laboratory will be
required. Pregnancy tests (serum and/or urine tests) should be performed monthly (on Day 1 of each Cycle) for
women with regular menstrual cycles, or every two weeks in women with irregular menstrual cycles. Pregnancy
tests (urine and/or serum tests) may be performed more frequently if required by local guidelines. Pregnancy
testing and counseling should be performed if a subject misses her period or if there is any abnormality in her
menstrual bleeding. Lenalidomide (REVLIMID) treatment must be discontinued during this evaluation.
Pharmacies must be certified with the REVLIMID REMSTM program, and must only dispense to subjects who
are authorized to receive REVLIMID® and comply with REMS requirements. Refer to Local Product Label.
15. After cycle 1, lab samples can be collected up to 72 hours prior to the scheduled time point. Repeat lab samples on
Days 1 each cycle.
16. Labs do not need to be repeated after the end of treatment if labs returned to baseline.
17. Bone marrow morphology, IHC, Cytogenetics by standard karyotyping, and FISH panel should be performed with
bone marrow aspirate/biopsy, at screening/cycle 1 day 1, at completion of cycle 4, and to confirm complete
response.
18. In subjects who discontinue study therapy without confirmed disease progression, a response assessment should be
performed at the time of treatment discontinuation, then a repeat assessment at treatment discontinuation is not
mandatory.
19. FISH panel should include del 1p, del 13, del 17p13, t(4;14), t(11;14), t(14;16), and 1q21 amplification.
48


6.0 TRIAL PROCEDURES
6.1
Trial
Procedures
The Trial Flow Chart - Section 5.0 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 Sponsor and/or
Merck 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.
6.1.1
Administrative Procedures
6.1.1.1
Informed Consent
The Investigator must obtain documented consent from each potential subject prior to
participating in a clinical trial.
6.1.1.1.1 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 IRBs 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 requirements, applicable laws and regulations and
Sponsor requirements.
49


6.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee
to ensure that the subject qualifies for the trial.
6.1.1.3
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 study will be recorded separately and not listed as
medical history.
6.1.1.4
Prior and Concomitant Medications Review
6.1.1.4.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any
protocol-specified washout requirement, and record prior medication taken by the subject
within 28 days before starting the trial. Treatment for the disease for which the subject has
enrolled in this study will be recorded separately and not listed as a prior medication.
6.1.1.4.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject
during the trial. All medications related to reportable SAEs and ECIs should be recorded.
6.1.1.5
Disease Details and Treatments
6.1.1.5.1 Disease Details
The investigator or qualified designee will obtain prior and current details regarding disease
status.
6.1.1.5.2 Prior Treatment Details
The investigator or qualified designee will review all prior cancer treatments including
systemic treatments, radiation and surgeries.
6.1.1.5.3 Subsequent Anti-Cancer Therapy Status
The investigator or qualified designee will review all new anti-neoplastic therapy initiated
after the last dose of trial treatment. If a subject initiates a new anti-cancer therapy within 30
days after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before
50


the first dose of the new therapy. Once new anti-cancer therapy has been initiated the subject
will move into survival follow-up.
6.1.1.6
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify
the subject for all procedures that occur prior. 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.
6.1.1.7
Assignment of Randomization Number
This trial is an open-label single arm, phase II clinical trial and therefore does not require
randomization.
6.1.1.8
Trial Compliance (Medication/Diet/Activity/Other)
Interruptions from the protocol specified treatment plan for 4 weeks require consultation
between the investigator and the Sponsor and written documentation of the collaborative
decision on subject management.
Administration of trial treatment will be witnessed by the investigator and/or trial staff. The
total volume of pembrolizumab (MK-3475) infused will be compared to the total volume
prepared
to
determine
compliance
with
each
dose
of pembrolizumab (MK-3475)
administered.
Medication Compliance
The instructions for preparing and administering pembrolizumab (MK-3475), will be
provided / referenced in the Pharmacy Manual.
6.1.2
Clinical Procedures/Assessments
6.1.2.1
Adverse Event (AE) Monitoring
The investigator or qualified designee will assess each subject to evaluate for potential new
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically
indicated. Adverse experiences will be graded and recorded throughout the study and during
the follow-up period according to NCI CTCAE Version 4.03 (see Appendix 1). Toxicities
will be characterized in terms regarding seriousness, causality, toxicity grading, and action
taken with regard to trial treatment.
51


For subjects receiving treatment with pembrolizumab all AEs of unknown etiology
associated with pembrolizumab exposure should be evaluated to determine if it is possibly an
event of clinical interest (ECI) of a potentially immunologic etiology.
Please refer to section 6.2 for detailed information regarding the assessment and recording of
AEs.
6.1.2.2
Full Physical Exam
The investigator or qualified designee will perform a complete physical exam during the
screening period.
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. After the first dose of trial treatment new
clinically significant abnormal findings should be recorded as AEs.
6.1.2.3
Directed Physical Exam
For cycle days that do not require a full physical exam per the Trial Flow Chart, the
investigator or qualified designee will perform a directed physical exam as clinically
indicated prior to trial treatment administration. New clinically significant abnormal findings
should be recorded as AEs.
6.1.2.4
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 5.0). Vital signs should include temperature, pulse, respiratory
rate, weight and blood pressure. Height will be measured at screening only.
6.1.2.5
Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator or qualified designee will assess ECOG status at screening, prior to the
administration of each dose of trial treatment and discontinuation of trial treatment as
specified in the Trial Flow Chart.
6.1.2.6
Electrocardiogram (ECG)
A standard 12-lead ECG will be performed using local standard procedures at Screening.
Clinically significant abnormal findings should be recorded as medical history.
6.1.2.7
Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator or qualified designee will assess ECOG status at screening, prior to the
administration of each dose of trial treatment and discontinuation of trial treatment as
specified in the Trial Flow Chart.
52


6.1.2.7.1 Myeloma Disease Measurements
Primary Myeloma Panel
The Primary Myeloma Panel that the Investigator followed for subject’s disease status
should be specified on trial eCRF. Along with other Myeloma Markers, the clinical site
should consistently record and follow the Primary Myeloma Panel throughout the trial.
Monoclonal Protein Considerations
Laboratory tests for measurement of Serum M-protein level are quantitated using
densitometry on SPEP except in cases where the SPEP is felt to be unreliable such as in
patients with IgA monoclonal proteins migrating in the beta region. If SPEP is not available
or felt to be unreliable (e.g., in some cases of IgA myeloma) for routine M -protein
quantitation during therapy, then quantitative immunoglobulin levels on nephelometry or
turbidometry can be accepted. However, this must be explicitly reported, and only
nephelometry can be used for that patient to assess response and SPEP and nephelometric
values cannot be used interchangeably.
Urine M-protein measurement is estimated using 24-h UPEP only. Random or 24 h urine
tests measuring kappa and lambda light chain levels are not reliable and are not
recommended.
See Appendix 5 for Myeloma Response Criteria.
6.1.2.7.2 Criteria for Assessment of Disease
Multiple Myeloma: International uniform response criteria for multiple myeloma[57].
The International Working Group criteria will be applied by the site as the primary measure
for assessment of disease response and as a basis for all protocol guidelines related to disease
status (e.g., discontinuation of trial treatment).
6.1.2.8
Disease Assessment of Immunotherapeutic Agent
Immunotherapeutic agents such as pembrolizumab (MK-3475) 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 (MK-3475). Therefore in the setting
where a subject’s assessment shows PD, study drug should not be discontinued unless
53


progression is confirmed at least 3 weeks later, provided that the subject’s clinical condition
is stable.
6.1.2.9
Timing of Disease Assessments
Uniform disease response assessment will be performed every 21-day treatment cycle.
6.1.2.10 Initial Disease Assessment
Initial disease assessments must be performed within 28 days prior to the first dose of trial
treatment (See 5.0 – Trial Flow Charts).
Bone marrow aspirates/biopsies performed as part of standard of care prior to signing
informed consent may be used for screening if performed within 28 days of Day 1.
Myeloma laboratory disease assessments should be performed within 28 days prior to the
first dose of trial treatment (See 5.0 – Trial Flow Charts).
6.1.2.11 Disease Assessment during Trial
Disease assessments should be performed per the frequency defined in Section 5.0 – Trial
Flow Charts. There is a ±3 day window for assessments performed after Day 1. Disease
assessments should not be delayed for delays in cycle starts.
Disease assessments should continue to be performed until documented disease progression,
the start of new anti-cancer treatment, withdrawal of consent, death, or the end of the study,
whichever occurs first. Disease assessments should be performed to confirm stringent CR or
as clinically indicated.. Subjects who have unconfirmed disease progression may continue
on treatment until progression is confirmed at the next scheduled assessment.
6.1.2.12 Confirmation Assessments
A subject with progression of disease may continue trial treatment until confirmation of
progression of disease is documented per the respective response evaluation criteria at least
21 days later. 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
●
Absence of rapid progression of disease.
●
Absence of progressive tumor at critical anatomical sites (e.g. cord compression)
requiring urgent alternative medical intervention.
54


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 at least 21 days later. When feasible, subjects should not be discontinued until
repeat disease response assessment is performed at least 21 days later.
6.1.2.13 Biopsy Collection and Correlative Studies Aspirate and Blood Collection
All subjects enrolled into this study must be able to provide an archived bone marrow biopsy
sample for biomarker analysis and is willing to provide a newly obtained bone marrow
aspirate/biopsy sample to be submitted for characterization. Bone marrow assessments will
include a biopsy for morphologic and immunohistochemistry assessment, and aspirate for
FISH
panel, metaphase cytogenetics, and minimal residual disease assessment by
ClonoSIGHT.
Bone marrow biopsies, aspirates and whole blood for correlative biomarker studies should
be collected per Table 9A and 9B below:
Table 9A: Bone Marrow Biopsy Collection
Bone marrow
biopsies will be
collected as per
Table 5 below:
Table 5A Bone
Marrow Biopsy
AssessmentsIndicati
on
Timing of Biopsy
Bone marrow aspirate
and biopsy
Cycle 1 Day 1, to confirm Complete Remission and at End-of Study. (See
Section 5.0 for Trial Flow Chart and Procedures Manual for further
details).
Table 9B Blood Collection for Correlative Biomarker Studies
Peripheral Blood
and Stool
Collection
Timing of Correlative Blood Collection
Screening or Cycle 1 Day 1, Cycle 2 day 1, Cycle 3 Day 1, Cycle 4 Day 1, and at
the completion of cycle 4
every 12 weeks
55


eve
For subjects with Progressive Disease, a bone marrow aspirate and
Peripheral blood and stool
including confirmation of response. A window of +/- 7 days will be allowed for
specimen collection
An additional sample should be performed as part of confirmation of response
Our patient A Jon Prusmack is on Sanofi TED14154 study and needs
post infusion PK samples done Wednesday 2/3, Thursday 2/4 and
Friday 2/5.  As per the protocol, these samples do not have a window
for collection and need to be obtained at exactly 8:30AM.
We would appreciate it if our patient could have these research PK
samples collected in the third floor infusion suite in an effort to
ensure the samples are collected at 8:30AM. If the samples are not
collected at exactly 8:30AM we will be deviating from the protocol
and must submit deviations to the IRB.
We will have the chart with the order and the tubes in the clinic at
8:00AM every day and the patient will be instructed to come in at
8:15AM for the 8:30AM collection.
Please let us know if this is feasible on your end.
I appreciate your help.
56


(See Section 5.0 for Trial Flow Chart and Procedures Manual for further details).
6.1.3
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 Procedures
Manual.
Table 10 Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Serum β-human chorionic
gonadotropin (β-hCG)
Hemoglobin
Alkaline phosphatase
Glucose
PT (INR)
Platelet count
Alanine aminotransferase (ALT)
Protein
aPTT
WBC
(total
and
differential)
Aspartate
aminotransferase
(AST)
Specific gravity
Total
Thriodothyronine
(T3)†
Red
Blood
Cell
Count
Bicarbonate
Microscopic
exam,
if
abnormal
results
are
noted
Free tyroxine (T4)
Absolute
Neutrophil Count
Calcium
Urine pregnancy test*
Thyroid
stimulating
hormone (TSH)
Chloride
Creatinine
GFR
Uric Acid
Calcium
Glucose
LDH
57


Phosphorus
Potassium
Sodium
Magnesium
Total Bilirubin
Direct Bilirubin, if total bilirubin
is elevated above the upper limit
of normal
Total protein
Blood Urea Nitrogen
⃰Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a
serum pregnancy test will be required.
† Free T3 may be performed in place of Total T3 per local standards
Laboratory tests for Screening or entry into the Second Course Phase should be performed
within 10 days prior to the first dose of treatment. After Cycle 1, pre-dose laboratory
procedures can be conducted up to 72 hours prior to dosing. Results must be reviewed by
the investigator or qualified designee and found to be acceptable prior to each dose of trial
treatment.
6.1.3.1
Pharmacokinetic/Pharmacodynamic Evaluations
There will be no pharmacokinetetic or pharmacodynamics sampling for this protocol.
6.1.4
Other Procedures
6.1.4.1
Withdrawal/Discontinuation
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 the protocol. Visit Requirements
Visit requirements are outlined in Section 5.0 - Trial Flow Chart.
58


6.1.4.2
Screening
6.1.4.2.1 Screening Period
Approximately 28 days prior to enrollment, potential subjects will be evaluated to
determine that they fulfill the entry requirements as set forth in Section 4.1. Visit
requirements are outlined in Section 5.0 – Trial Flow Chart.
Written consent for the main study 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:
●
Female subject of childbearing potential should have a negative serum or urine
pregnancy test within 72 hours prior to receiving retreatment with study medication.
Subjects may be rescreened 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.
6.1.4.3
Treatment Period
6.1.4.4
Post-Treatment Visits
6.1.4.4.1 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 anti-cancer 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 anti-neoplastic therapy, whichever occurs first. SAEs that
occur within 90 days of the end of treatment or before initiation of a new anti-cancer
treatment should also be followed and recorded.
6.1.4.5
Follow-up Visits
Subjects who discontinue trial treatment for a reason other than disease progression will
move into the Follow-Up Phase and should be assessed every 12 weeks (84 ± 7 days) to
monitor disease status. Every effort should be made to collect information regarding disease
status until the start of new anti-neoplastic therapy, disease progression, death, end of the
study. Information regarding post-study anti-neoplastic treatment will be collected if new
treatment is initiated.
59


6.1.4.5.1 Survival Follow-up
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy,
the subject moves into the survival follow-up phase and should be contacted by telephone
every 12 weeks to assess for survival status until death, withdrawal of consent, or the end of
the study, whichever occurs first.
6.2
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
unfavorable 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 Merck’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.
Merck 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 Merck for human use.
Adverse events may occur during the course of the use of Merck product in clinical trials or
within the follow-up period specified by the protocol, or prescribed in clinical practice, from
overdose (whether accidental or intentional), from abuse and from withdrawal.
Adverse events may also occur in screened subjects during any pre-allocation baseline period
as a result of a protocol-specified intervention, including washout or discontinuation of usual
therapy, diet, placebo treatment or a procedure.
Progression of the cancer under study is not considered an adverse event unless it is
considered to be drug related by the investigator.
All adverse events will be recorded from the time the consent form is signed through 30 days
following cessation of treatment and at each examination on the Adverse Event case report
60


forms/worksheets. The reporting timeframe for adverse events meeting any serious criteria is
described in section 6.2.3.1.
6.2.1
Definition of an Overdose for This Protocol and Reporting of Overdose to the
Sponsor and to Merck
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000
mg or greater (≥5 times the indicated dose).
No specific information is available on the
treatment of overdose of pembrolizumab. Appropriate supportive treatment should be
provided if clinically indicated. In the event of overdose, 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 a Merck product,
the adverse event(s) is reported as a serious adverse event, even if no other seriousness
criteria are met.
If a dose of Merck’s product 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 within 24 hours
to the Sponsor and within 2 working days hours to Merck Global Safety. (Attn: Worldwide
Product Safety; FAX 215 993-1220)
6.2.2
Reporting of Pregnancy and Lactation to the Sponsor and to Merck
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 or within 120 days of completing the trial completing the trial, or
30 days following cessation of treatment if the subject initiates new anticancer therapy,
whichever is earlier. All subjects and female partners of male subjects who become pregnant
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 and within 2 working days to
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220)
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6.2.3
Immediate Reporting of Adverse Events to the Sponsor
6.2.3.1
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of
Merck’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 a new cancer (that is not a condition of the study);
●
Is associated with an overdose;
●
Is another important medical event
Refer to Table 7 for additional details regarding each of the above criteria.
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 that occurs to any subject from
the time the consent is signed through 90 days following cessation of treatment, or the
initiation of new anti-cancer therapy, whichever is earlier, whether or not related to Merck
product, must be reported within 24 hours to the Sponsor and within 2 working days to
Merck Global Safety.
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety and will be
handled in the same manner as SAEs.
Additionally, any serious adverse event, considered by an investigator who is a qualified
physician to be related to Merck product that is brought to the attention of the investigator at
any time outside of the time period specified in the previous paragraph also must be reported
immediately to the Sponsor and to Merck.
SAE reports and any other relevant safety information are to be reported to
Georgetown DSMB, Hackensack eIRB, Merck Global Safety (FAX: 215-993-1220).
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA,
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local
regulators. Investigators will cross reference this submission according to local regulations to
the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.
Additionally investigators will submit a copy of these reports to Merck & Co., Inc. (Attn:
Worldwide Product Safety; FAX 215 993-1220) at the time of submission to FDA.
All subjects with serious adverse events must be followed up for outcome.
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6.2.3.2
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest
(ECI) and must be recorded as such on the Adverse Event case report forms/worksheets and
reported within 24 hours to the Sponsor and within 2 working days to Merck Global Safety.
(Attn: Worldwide Product Safety; FAX 215 993-1220)Events of clinical interest for this trial
include:
1. an overdose of Merck product, as defined in Section 6.2.1 - 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). See Appendix 6 for ECI Reference Guidance.
1. Additional adverse events:
A separate guidance document has been provided entitled “Event of Clinical Interest
Guidance
Document”
(previously
entitled,
“Event
of
Clinical
Interest
and
Immune-Related Adverse Event Guidance Document”).
ECIs (both non-serious and serious adverse events) identified in this guidance document
from the date of first dose through 90 days following cessation of treatment, or 30 days
after the initiation of a new anticancer therapy, whichever is earlier, need to be reported
within 24 hours to the Sponsor and within 2 working days to Merck Global Safety. (Attn:
Worldwide Product Safety; FAX 215 993-1220), regardless of attribution to study
treatment, consistent with standard SAE reporting guidelines.
Subjects should be assessed for possible ECIs prior to each dose. Lab results should be
evaluated and subjects should be asked for signs and symptoms suggestive of an
immune-related event.
Subjects who develop an ECI thought to be immune-related
should have additional testing to rule out other etiologic causes.
If lab results or
symptoms indicate a possible immune-related ECI, then additional testing should be
performed to rule out other etiologic causes.
If no other cause is found, then it is
assumed to be immune-related.
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6.2.4
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 4.03. 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.
64


Table 11 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 Merck 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 [including hospitalization for an elective procedure] for a preexisting
condition which has not worsened does not constitute a serious adverse event.); 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) or
Is an overdose (whether accidental or intentional). Any adverse event associated with an overdose is considered a serious adverse event. 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 Merck product to be discontinued?
Relationship to
test drug
Did the Merck product cause the adverse event? The determination of the likelihood that the Merck 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 Merck product and the AE; the greater the correlation with the components and
their respective elements (in number and/or intensity), the more likely the Merck product caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to the Merck product such as: reliable history, acceptable compliance assessment (pill
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
65


Time Course
Did the AE follow in a reasonable temporal sequence from administration of the Merck 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 Merck
product
(continued)
Dechallenge
Was the Merck 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 Merck product; or (3) the trial is a single-dose drug trial); or (4) Merck product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Merck 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) Merck 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 MERCK PRODUCT, OR IF REEXPOSURE TO THE MERCK PRODUCT POSES ADDITIONAL POTENTIAL
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. CLINICAL
MONITOR 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 Merck product or drug class pharmacology
or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including
consideration of the above elements.
Record one of the following
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Merck product relationship).
Yes, there is a reasonable
possibility of Merck product
relationship.
There is evidence of exposure to the Merck product. The temporal sequence of the AE onset relative to the administration of the Merck product
is reasonable. The AE is more likely explained by the Merck product than by another cause.
No, there is not a reasonable
possibility Merck product
relationship
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to administration of the Merck product is not
reasonable OR there is another obvious cause of the AE. (Also entered for a subject with overdose without an associated AE.)
66


6.2.5
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.
7.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the
study has begun, changes are made to primary and/or key secondary hypotheses, or the
statistical methods related to those hypotheses, then the protocol will be amended (consistent
with ICH Guideline E-9). Post hoc exploratory analyses will be clearly identified in the CSR.
No separate Statistical Analysis Plan (SAP) will be issued for this study.
7.1
Statistical
Analysis
Plan
Summary
This section contains a brief summary of the statistical analyses for this trial. Full detail is in
the Statistical Analysis Plan (SAP) (Section 7.1.8).
7.1.1
Efficacy Analysis
The primary and key secondary endpoints, primary analysis population, and statistical methods
that will be employed for the efficacy analysis are presented in Table 11 below.
The CR+sCR+VGPR response rate and objective response rate (ORR) per IMWG criteria
based on investigator assessment will be conducted in the Full Analysis Set (FAS) population.
No multiplicity adjustment is planned.
Table 12: Summary of Analysis Strategy for Key Efficacy Endpoints
Endpoint/Variable
(Description, Time
point)
Statistical Method
Analysis Population
Missing Data
Approach
PFS
Kaplan Meier
FAS
Subjects with
missing data are
considered
non-progressors
CR + sCR + VGPR
response rate per
IMWG criteria
based on
Exact test of
binomial parameter
FAS
Subjects with
missing data are
considered
non-responders
67


investigator
assessment
ORR per IMWG
criteria based on
investigator
assessment
Exact test of
binomial parameter
FAS
Subjects with
missing data are
considered
non-responders
7.1.2
Safety Analysis
The All-Subjects-as-Treated (ASaT) population will be employed for safety analyses. The
ASaT population consists of all subjects who received at least one dose of trial treatment.
Subjects who entered the study and did not take any of the study drug(s) and had this
confirmed, will not be evaluated for safety.
Descriptive tables that summarize the number and percentage of subjects that experience
adverse events as categorized in the NCI CTCAE Version 4 will be generated by dose level.
Stopping rules:   
·
Death greater than 10% of patients in any part independent of their relationship to
study treatment.
·
Grade 4 non-hematologic toxicity in greater than 10% of patients in any part
independent of their relationship to study treatment.
The severity of the toxicities will be graded according to the NCI CTCAE v4.0 whenever
possible. An interim safety analysis will be performed in between stages 1 and 2 of
recruitment (See Section 7.1.3) at the same time as the planned efficacy analysis per the
Simon-two-staged design.
7.1.3
Power and Sample Size
Using a Simon’s two-stage design, this study has 80% power at a one-sided significance level
of 0.05 to discount an ‘ineffective’ progression-free survival (PFS) rate of 50% (po) in favor of
a PFS rate of at least 70% (p1).
A total of 15 patients will be accrued in stage one and, if successful, a further 28 patients will
be accrued in stage two, bringing the total number of patients required to 43 evaluable patients.
There will be a planned stopping rule in recruitment between stages 1 and 2.
The study will stop and treatment will be rejected if there are 8 or fewer patients are
progression free at 12 months. If 9 or more of the first 15 patients have not progressed at 12
months, a further 28 patients will be recruited into the second stage, bringing the final size to
43. At the end of stage two, if 26 or fewer of the 43 patients are progression free then no
further investigation of the 4-cycle PEM+LEN+DEX therapy is warranted. If 27 or more of the
43 patients are progression-free, then the hypothesis PFS is 59% will be rejected. The optimal
design has an expected sample size of 23.5 and probability of early termination of 0.696. If the
68


overall PFS is 70% or above at 12 months, pembrolizumab will be considered to have shown
worthwhile efficacy.
7.1.4
Responsibility for Analyses
The statistical analysis of the data obtained from this study will be the responsibility of the
Clinical Biostatistician of Hackensack University Medical Center.
The study will be done as an open-label study. The official database will be finalized after
medical/scientific review has been performed, protocol violations have been identified, and
data have been declared final and complete.
7.1.5
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.0.
7.1.6
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated by dosing schedules, dose levels, and
disease-specific cohorts are listed below.
7.1.6.1
Efficacy Endpoints
Key efficacy endpoints for the trial include the following as assessed by IMWG:
●
PFS: defined as the time from Day 0 of ASCT to progressive disease (PD) or death,
whichever occurs earlier, per IMWG criteria by investigator assessment. Subjects
without documented PD/death will be censored at the last disease assessment date.
●
Complete response, stringent complete response, and very good partial response rate
(CR + sCR + VGPR) rate using IMWG criteria. Response rates will be determined
with the following baselines 1) Prior to ASCT
2) Cycle 1 day 1 of study drug or
screening visit, whichever is higher.
●
ORR: Defined as the proportion of subjects who have achieved sCR, CR, VGPR or PR
according to the IMWG criteria by investigator assessment. Subjects with missing
outcome on objective response will be considered non-responders. Response rates will
be determined with the following baselines 1) Prior to ASCT 2) Cycle 1 day 1 of study
drug or screening visit, whichever is higher.
●
DOR: defined as the time interval between the date of first response (sCR, CR, VGPR,
PR) and the date of first documented disease progression.
●
TTP: defined as the time from 1) Day 0 ASCT and 2) Date of enrollment to
progressive disease (PD) per IMWG criteria by investigator assessment. Subjects
without documented PD or death will be censored at the last disease assessment date,
and subjects who died without documented PD will be censored at the time of death.
69


●
OS: defined as the time from Day 0 ASCT to death from any cause.
In addition, overall survival (OS) and change from baseline in bone marrow/aspirate
PD-L1 expression, T-cell subsets, and cytokine analysis will be evaluated.
7.1.6.2
Safety Endpoints
The primary safety endpoints include the AEs graded using CTCAE (Version 4.03) criteria.
Safety will be assessed by quantifying the toxicities and grades experienced by subjects who
have received pembrolizumab (MK-3475), including serious AEs and events of clinical
interest (ECIs). Immune-related AEs (irAEs), as defined in Section 6.2.3.2 will be collected.
Other safety endpoints include laboratory safety assessments, vital signs and physical
examinations. Safety measurements are described in Section 6.
7.1.7
Analysis Populations
7.1.7.1
Efficacy Analysis Populations
The Full Analysis Set (FAS) population will serve as the primary population for the analysis
of response rate data in this study. The FAS population consists of all subjects who:
receive at least one dose of study treatment
have a post baseline disease assessment OR discontinue the trial due to progressive
disease/drug-related AE
The Intent-to-Treat (ITT) population will serve as the primary population for the analyses of
PFS, TTP and OS in this study. The ITT population consists of all enrolled subjects.
The analysis of response duration is based on all responders.
Details on the approach to handling missing data are provided in Section 7.1.8 Statistical
Methods.
7.1.7.2
Safety Analysis Populations
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in
this trial. The ASaT population consists of all subjects who received at least one dose of trial
treatment. At least one laboratory or vital sign measurement obtained subsequent to at least
one 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.
Details on the approach to handling missing data for safety analyses are provided in Section
7.1.8.1 Statistical Methods.
70


For safety analysis related to AE rate, the AE evaluable population will be used. The AE
evaluable population consists of all AE evaluable subjects. In order to be considered
evaluable, the subject must complete the first cycle of therapy or discontinue from the trial
due to a drug-related adverse event. Subjects who discontinue prematurely due to a
non-drug-related cause are not included in the AE evaluable population.
7.1.8
Statistical Methods
7.1.8.1
Statistical Methods for Efficacy Analysis
Kaplan-Meier estimates and corresponding 95% confidence intervals of time to event
endpoints, including PFS, OS, TTP and DOR, will be provided.
For key efficacy endpoints including CR + sCR + VGPR rate + ORR, the point estimate, 90%
confidence interval and p-value for testing response rate is greater than the historical control
for each arm will be provided using exact binomial distribution.
Table 13 Summarizes key efficacy analyses.
Table 13 Analysis Strategies for Key Efficacy Variables
Endpoint/Variable
(Description, Time Point)
Primary vs.
Supportive
Approach
Analysis
Population
Statistical Method
Missing Data Approach
Primary
PFS
P
ITT
Summary statistics
using Kaplan-
Meier method
Censored
at
last
disease
assessment
date
Secondary
ORR per IMWG criteria based
on investigator assessment
P
S
FAS
ITT
Exact
test
of binomial
parameter
Subjects
with
missing
data
are
considered
as
non-responders
CR+sCR+VGPR
response
rate per IMWG criteria based
on investigator assessment
P
S
FAS
ITT
Exact
test
of binomial
parameter
Subjects
with
missing
data
are
considered
as
non-responders
OS
P
ITT
Summary statistics
using Kaplan-
Meier method
Censored at the last date
known to be alive
TTP
P
ITT
Summary statistics
using Kaplan-
Meier method
Censored at the last non-
PD assessment date
DOR
P
All responders
Summary statistics
using Kaplan-
Meier method
Non-responders
are
excluded
in
analysis
71


P=Primary approach; S=Secondary approach; FAS=Full Analysis Set; ITT=Intention to treat.
7.1.8.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including
adverse experiences (AEs), ECOG, laboratory tests, vital signs, and ECG measurements.
Summary statistics (median and range) for time to onset of first drug-related toxicity in each
dose level will be provided. Adverse experiences will be summarized as counts, frequencies
and grade by NCI CTCAE version 4.03. Laboratory values will be graded by NCI CTCAE
version 4.03. The percentage of subjects with laboratory abnormalities by grades will be
tabulated. The change of grades during the study will be summarized by a lab shift table. In
this analysis, the percentage of subjects who improve or worsen from baseline for each
laboratory test will be summarized. A clinically meaningful worsening in CTCAE grade was
defined as a shift from less than Grade 3 at baseline to Grade 3 or above, or a shift from
Grade 0 to Grade 2. Summary statistics for baseline, on-treatment, and change from baseline
values of continuous measures such as changes from baseline in ECOG, laboratory, vital
signs, and ECG parameters will be provided by dose-level in table format. Immune-related
AEs (irAEs) that are designated as events of special interest will be summarized separately
from other AEs.
7.1.8.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses
Demographic and Baseline Characteristics
Each relevant characteristic will be assessed by the use of tables/graphs. No statistical
hypothesis tests will be performed on these characteristics. The number and percentage of
subjects screened, the primary reasons for screening failure, and the primary reason for
discontinuation will be displayed.
Demographic variables (such as age) and baseline
characteristics will be summarized by treatment either by descriptive statistics or categorical
tables.
The reason for exclusion from the Full Analysis Set (if any) will be summarized.
Exploratory Analyses
Change from baseline in bone marrow aspirate/biopsy PD-L1 expression will be summarized
by dosing schedules using descriptive statistics.
Comparison of change from baseline in bone marrow aspirate/biopsy PD-L1 expression
between responders with longer duration of response and non-responders or responders with a
short duration of response will be performed using mixed regression analysis. Longitudinal
analysis of bone marrow aspirate/biopsy PD-L1 expression over time will be examined using
mixed model repeated measure design with levels observed serially over time and response
type (long responders vs short responders/non-response) as a fixed variable.
72


Longitudinal analysis will be performed on blood samples collected at time points 1) screening
visit 2) Day 1 of Cycle 1, 3 ) Day 1 of Cycle 2, 3) Day 1 of Cycle 3, 4) Day 1 of Cycle 4,
5) Post completion of Cycle 4. Discrete variables such as cell counts of the absolute number
of inflammatory cytokines (TNF-alpha, IL-2, IL-4, IL-6, IL-10) and activated T cells (CD8+)
will be examined for changes over time using Poisson Regression Analysis based on
generalized estimating equations (GEE) method obtained by utilizing PROC GENMOD SAS
9.4 with Poisson distribution, log link function and independent covariance structure. The
repeated
counts
will
be
compared
between
long
responders
vs
short
responders/non-responders.
Longitudinal analysis of specific intestinal microbial strains identified form blood and stool
samples collected at time points 1) screening visit 2) Day 1 of Cycle 1, 3 ) Day 1 of Cycle 2,
3) Day 1 of Cycle 3, 4) Day 1 of Cycle 4, 5) Post completion of Cycle 4, will be performed
using GEE method described above with type of responder as grouping variable.
7.1.9
Multiplicity
There is no multiplicity adjustment planned for this study.
7.1.10 Sample Size and Power Calculations
Using a Simon’s two-stage design, this study has 80% power at a one-sided significance level
of 0.05 to discount an ‘ineffective’ progression-free survival (PFS) rate of 50% (po) in favor of
a PFS rate of at least 70% (p1).
A total of 15 patients will be accrued in stage one and, if successful, a further 28 patients will
be accrued in stage two, bringing the total number of patients required to 43 evaluable patients.
There will be a planned stopping rule in recruitment between stages 1 and 2.
7.1.11 Subgroup Analyses and Effect of Baseline Factors
There is no formal subgroup analysis for this study.
7.1.12 Interim Analysis
The study will stop and treatment will be rejected if there are 8 or fewer patients are
progression free at 12 months. If 9 or more of the first 15 patients have not progressed at 12
months, a further 28 patients will be recruited into the second stage.
The optimal design has
an expected sample size of 23.5 and probability of early termination of 0.696. If the overall
PFS is 70% or above at 12 months, pembrolizumab, lenalidomide and dexamethasone will be
considered to have shown worthwhile efficacy. A safety analysis will also be conducted at this
time and the study will be terminated if the safety stopping rules are met (See section 7.1.2).
7.1.13 Compliance (Medication Adherence)
Drug accountability data for trial treatment will be collected during the study. Compliance
with pembrolizumab (MK-3475), lenalidomide and dexamethasone treatment administration
will be measured by subjects: 1) receiving unscheduled study agent infusions/injections; or 2)
73


missing an infusion/injection. Numbers and percentages of subjects and infusion/injection
visits with any deviation in these measures will be reported for the ITT population.
Compliance will be defined as the percentage of the “Number of Days on Therapy” over the
“Number of Days Should be on Therapy”. A day within the study will be considered an
“On-Therapy” day if the subject takes study drug on a scheduled day for treatment
administration without dose variation or with dose variation, including dose reduction and
dose interruption, for reasons other than non-compliance. For each subject, the “Number of
Days Should be on Therapy” is the total number of scheduled days for treatment
administration from entry to the study to the date of discontinuation.
For each subject, percent compliance will then be calculated using the following formula:
Number of Days on Therapy
Percent Compliance
=
x 100.
Number of Days Should be on Therapy
Summary statistics will be provided on percent compliance by treatment group for the ASaT
population.
8.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES
8.1
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.
Table 14 Product Descriptions
Product Name & Potency
Dosage Form
Pembrolizumab 50 mg
Lyophilized Powder for Injection
Pembrolizumab 100 mg/ 4mL
Solution for Injection
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8.2
Packaging
and
Labeling
Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory
requirements.
8.3
Clinical Supplies
Disclosure
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or
designee are not blinded to treatment. Drug identity (name, strength) is included in the label
text; random code/disclosure envelopes or lists are not provided.
8.4
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.
8.5
Returns
and
Reconciliation
The investigator is responsible for keeping accurate records of the clinical supplies received
from Merck or designee, the amount dispensed to and returned by the subjects and the amount
remaining at the conclusion of the trial. Upon completion or termination of the study, all
unused and/or partially used investigational product will be destroyed at the site per
institutional policy. It is the Investigator’s responsibility to arrange for disposal of all empty
containers, provided that procedures for proper disposal have been established according to
applicable federal, state, local and institutional guidelines and procedures, and provided that
appropriate records of disposal are kept.
9.0
ADMINISTRATIVE AND REGULATORY DETAILS
9.1
Confidentiality
9.1.1 Confidentiality of Data
All information regarding this trial 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,
75


except to the extent that it is included in a publication as provided in the Publications section
of this protocol.
9.1.2 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.
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.
9.2
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/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
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.
.
9.3
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.
76


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.
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 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 discarding
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.
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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.
9.4
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. Information posted
will allow subjects to identify potentially appropriate trials for their disease conditions and
pursue participation by calling a central contact number for further information on appropriate
trial locations and trial site contact information.
9.5
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.
9.6
Data
Management
Data Collection Instruments
The Investigator will prepare and maintain adequate and accurate source documents designed
to record all observations and other pertinent data for each subject treated with the study drug. 
Study personnel at each site will enter data from source documents corresponding to a
subject’s visit into the protocol-specific paper Case Report Forms (CRFs) when the
information corresponding to that visit is available.  Subjects will not be identified by name in
the study database or on any study documents to be collected by the Sponsor (or designee), but
will be identified by a subject ID number and initials.
78


If a correction is made on a CRF, the study staff member will line through the incorrect data,
write in the correct data and initial and date the change.
The Investigator is responsible for all information collected on subjects enrolled in this study. 
All data collected during the course of this study must be reviewed and verified for
completeness and accuracy by the Investigator. 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 by the Sponsor.
Data Management Procedures
The data will be entered into a validated database.  The Data Management group will be
responsible for data processing, in accordance with procedural documentation.  Database lock
will occur once quality assurance procedures have been completed.
All procedures for the handling and analysis of data will be conducted using good computing
practices meeting FDA guidelines for the handling and analysis of data for clinical trials.
Data Quality Control and Reporting
After data have been entered into the study database, a system of computerized data validation
checks will be implemented and applied to the database on a regular basis. Query reports
(Data Clarification Requests) pertaining to data omissions and discrepancies will be forwarded
to the Investigators and study monitors for resolution.  The study database will be updated in
accordance with the resolved queries.  All changes to the study database will be documented.
Archival of Data
The database is safeguarded against unauthorized access by established security procedures;
appropriate backup copies of the database and related software files will be maintained. 
At critical junctures of the protocol (e.g., production of interim reports and final reports), data
for analysis is locked and cleaned per established procedures.
Availability and Retention of Investigational Records
The Investigator must make study data accessible to the monitor, other authorized
representatives of the Sponsor (or designee), IRB/IEC, and Regulatory Agency (e.g., FDA)
inspectors upon request.  A file for each subject must be maintained that includes the signed
Informed Consent, HIPAA Authorization and Assent Form and copies of all source
documentation related to that subject.  The Investigator must ensure the reliability and
availability of source documents from which the information on the CRF was derived.
All study documents (patient files, signed informed consent forms, copies of CRFs, Study File
Notebook, etc.) must be kept secured for a period of two years following marketing of the
investigational product or for two years after centers have been notified that the IND has been
discontinued.  There may be other circumstances for which the Sponsor is required to maintain
study records and, therefore, the Sponsor should be contacted prior to removing study records
for any reason.
79


Monitoring
Monitoring visits will be conducted by representatives of the Sponsor according to the U.S.
CFR Title 21 Parts 50, 56, and 312 and ICH Guidelines for GCP (E6).    By signing this
protocol, the Investigator grants permission to the Sponsor (or designee), and appropriate
regulatory authorities to conduct on-site monitoring and/or auditing of all appropriate study
documentation.
Subject Confidentiality
In order to maintain subject confidentiality, only a subject number and subject initials will
identify all study subjects on CRFs and other documentation submitted to the Sponsor. 
Additional subject confidentiality issues (if applicable) are covered in the Clinical Study
Agreement.
9.7
Data and Safety
Monitoring
Committee
(DSMC)
The Georgetown Lombardi Comprehensive Cancer Center will be responsible for the data and
safety monitoring of this multi-site trial. As this study is an investigator initiated Phase II
study utilizing an FDA approved drug for which the PI does not hold the IND it is considered
a moderate risk study which requires real-time monitoring by the PI and study team and
semi-annual reviews by the LCCC Data and Safety Monitoring Committee (DSMC).
The Principal Investigator and the Co-Investigators will review the data including safety
monitoring at their weekly institution based disease group meetings and on monthly disease
group teleconferences.
All Severe Adverse Events (SAEs) are required to be reported to the IRB. Based on SAEs, the
IRB retains the authority to suspend further accrual pending more detailed reporting and/or
modifications to further reduce risk and maximize the safety of participating patients.
Progress on the trial and the toxicities experienced will be reviewed by the LCCC Data and
Safety Monitoring Committee every 6 months from the time the first patient is enrolled on the
study. Results of the DSMC meetings will be forwarded to the IRB with recommendations
regarding need for study closure.
DSMC recommendations should be based not only on results for the trial being monitored as
well as on data available to the DSMC from other studies. It is the responsibility of the PI to
ensure that the DSMC is kept apprised of non-confidential results from related studies that
become available. It is the responsibility of the DSMC to determine the extent to which this
information is relevant to its decisions related to the specific trial being monitored.
A written copy of the DSMC recommendations will be given to the trial PI and the IRB. If the
DSMC recommends a study change for patient safety or efficacy reasons the trial PI must act
to implement the change as expeditiously as possible. In the unlikely event that the trial PI
does not concur with the DSMC recommendations, then the LCCC Associate Director of
Clinical Research must be informed of the reason for the disagreement. The trial PI, DSMC
80


Chair, and the LCCC AD for Clinical Research will be responsible for reaching a mutually
acceptable decision about the study and providing details of that decision to the IRB.
Confidentiality must be preserved during these discussions. However, in some cases, relevant
data may be shared with other selected trial investigators and staff to seek advice to assist in
reaching a mutually acceptable decision.
If a recommendation is made to change a trial for reasons other than patient safety or efficacy
the DSMC will provide an adequate rationale for its decision. If the DSMC recommends that
the trial be closed for any reason, the recommendation will be reviewed by the Associate
Director for Clinical Research at G-LCCC. Authority to close a trial for safety reasons lies
with the IRB, with the above described input from DSMC and the AD for Clinical Research.
10.7 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.
Authors of the primary results manuscript will be provided the complete results from the
Clinical Study Report, subject to the confidentiality agreement. When a manuscript is
submitted to a biomedical journal, the Sponsor's policy is to also include the protocol and
statistical analysis plan to facilitate the peer and editorial review of the manuscript. If the
manuscript is subsequently accepted for publication, the Sponsor will allow the journal, if it
so desires, to post on its website the key sections of the protocol that are relevant to evaluating
the trial, specifically those sections describing the trial objectives and hypotheses, the subject
inclusion and exclusion criteria, the trial design and procedures, the efficacy and safety
measures, the statistical analysis plan, and any amendments relating to those sections. The
Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an
investigator and his/her colleagues may publish their data independently. In most cases,
publication of individual trial site data does not add value to complete multicenter results, due
to statistical concerns. In rare cases, publication of single trial site data prior to the main paper
may be of value. Limitations of single trial site observations in a multicenter trial should
always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, or
acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising it
critically for important intellectual content; and 3) final approval of the version to be
published. Authors must meet conditions 1, 2 and 3. Significant contributions to trial
execution may also be taken into account to determine authorship, provided that 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
81


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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Weber, D.M., et al., Lenalidomide plus dexamethasone for relapsed multiple myeloma
in North America. N Engl J Med, 2007. 357(21): p. 2133-42.
52.
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Rajkumar,
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86


11.0 APPENDICES
11.1 Common
Terminology
Criteria
for
Adverse
Events
V4.03 (CTCAE)
The descriptions and grading scales found in the revised NCI Common Terminology Criteria
for Adverse Events (CTCAE) version 4.03 will be utilized for adverse event reporting.
(http://ctep.cancer.gov/reporting/ctc.html)
87


11.2 MM
Diagnostic
Criteria
Durie, Seminars in Oncology, Vol 13, No 3 (September), 1986: pp300-309:
88


11.3 International
Staging System
Greipp PR et al, Journal of Clinical Oncology 2005, May 20:23 (15): 3412-20.
Stage
Criteria
Median survival (mos)
I
Serum Beta-2 microglobulin
<3.5 mg/dL
AND
Albumin >3.5 mg/L
62
II
Neither I or III
45
III
Serum Beta-2 microglobulin
>5.5 mg/L
29
89


11.4 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.
90


11.5 Multiple Myeloma Disease Response Criteria
Durie et al. International uniform response criteria for multiple myeloma. Leukemia. 2006;
20:1467-1473.
Criteria for multiple myeloma disease assessment:
91


11.6 Events of Clinical
Interest
Reference Table
92


93


11.7 List
of
Abbreviations
Abbreviation/Term
Definition
AE
Adverse event
ADA
Anti-Drug Antibodies
ADCC
Antibody-Dependent Cell-Mediated Cytotoxicity
ALT
Alanine aminotransferase
AML
Acute Myelogenous Leukemia
ANC
Absolute neutrophil count
APC
Antigen Presenting Cells
aPTT
Activated partial thromboplastin time
AUC
Area Under Curve
AST
Aspartate aminotransferase
ᵝ-HCG
Beta human chorionic gonadotropin
CBC
Complete blood count
CDC
Complement-Dependent Cytotoxicity
CNS
Central nervous system
CR
Complete response
CrCl
Calculated creatinine clearance
CRF
Case report form
CSR
Clinical study report
CT
Computed tomography
CTCAE
Common Toxicity Criteria for Adverse Events
CTL
Cytotoxic T Lymphocytes
CTLA-4
Cytotoxic T-lymphocyte-associated antigen-4
Dex
Dexamethasone
DL
Dose Level
94


DLT
Dose Limiting Toxicity
DNA
Deoxyribonucleic acid
DOR
Duration of Response
ECI
Events of clinical interest
ECI-ie
Events of clinical interest with a potential immunologic etiology
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EMA
European Medicines Agency
ERC
Ethics review committee
FAS
Full analysis set
FBR
Future Biomedical Research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FDAMA
Food and Drug Administration Modernization Act
FLC
Free Light Chain
GCP
Good Clinical Practice
GFR
Glomerular filtration rate
Hb
Hemoglobin
95


Abbreviation/Term
Definition
HBV
Hepatitis B
HCV
Hepatitis C
HIV
Human immunodeficiency virus
IB
Investigator’s brochure
ICF
Informed consent form
ICH
International Conference on Harmonization
IHC
Immunohistochemistry
IMiD
Immunomodulatory
IMWG
International Myeloma Working Group
INR
International normalized ratio
irAEs
Immune-related adverse events
IRB
Institutional Review Board
ISS
International Staging System
ITIM
Immunoreceptor tyrosine-based switch motif
ITSM
Immunoreceptor Tyrosine-based Switch Motif
IV
Intravenous
Kg
kilogram
LDH
lactate dehydrogenase
Len
Lenalidomide
LMWH
Low molecular weight heparin
mAb
Monoclonal antibody
MAD
Maximum administered dose
mcL
Millimeters
MEL
Melanoma
96


MG
Milligram
Mg/kg
Milligram per kilogram
ML
milliliter
MM
Multiple Myeloma
MRI
Magnetic resonance imaging
MSD
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
MTD
Maximum tolerated dose
NA or N/A
Not Applicable
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NK
Natural Killer
NSAID
Non-steroidal anti-inflammatory drug
ORR
Overall response rate
OS
Overall survival
OTC
Over-the-counter
PD
Progressive disease
PET
Positron emission tomography
PFS
Progression free survival
PGt
Pharmacogenetic
Abbreviation/Term
Definition
PK-PD
Pharmacokinetic-Pharmacodynamic
PO
Oral administration
PR
Partial response
PT
Prothrombin time
RNA
Ribonucleic acid
RP2D
Recommended Phase 2 Dose
97


RR
Response rate
Q3W
Every 3 weeks
SAE
Serious adverse events
SAP
Statistical Analysis Plan
sCR
Stringent Complete Response
SFU
Survival follow-up
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SoC
Standard of Care
SJS
Stevens-Johnson Syndrome
SOP
Standard Operating Procedures
SPEP
serum protein electrophoresis
TEN
Toxic Epidermal Necrolysis
TIL
Tumor-infiltrating lymphocytes
TPI
Toxicity Probability Interval
TSH
Thyroid stimulating hormone
TTP
Time To Progression
ULN
Upper limit of normal
UPEP
urinary protein electrophoresis
VTE
Venous Thromboembolism
WHO
World Health Organization
98